Immune system and cancer

 215

THE CLINICAL CONTEXT

The annual incidence of cancer in the United States is estimated at 439.2 per 100,000 per-

sons, with an annual rate of deaths due to can- cer of 163.5 per 100,000 persons. As a cause of death in the United States, cancer ranks second, just behind heart disease. 1 Data from 2013 to 2015 indicate that about 38% of men and women in the United States will be diagnosed with cancer sometime in their lifetime. 2 Worldwide estimates of cancer cases are 18.1 million new cancer cases and 9.6 million cancer deaths annually. 3

Over the past 25 years, death rates have dropped in the United States for cancers of the lung and bronchus, prostate, colon and rectum, and stomach, while liver cancer death rates have increased. At least 42% of cancer cases in the United States may be preventable with lifestyle changes such as smoking cessation, weight loss, physical activity, alcohol use reduction or avoid- ance, improved nutrition, use of sunblock, and avoidance of tanning devices. Vaccination or anti- biotic use can reduce incidence of cancer-causing infections such as those due to hepatitis B and C viruses, human papillomavirus, and Helicobacter pylori . Clinicians should educate their patients about these cancer-reduction strategies as well as promoting evidence-based screening tests to reduce cancer morbidity and mortality. 4

OVERVIEW OF CANCER PATHOPHYSIOLOGY

In the United States, cancer remains a leading cause of death, with nearly one in four deaths resulting from this disease. 5 Unique to cancer cells is the acquisition of

traits that impart a proliferative capacity that bypasses many of the inherent safety features designed to pre- vent abnormal growth. This uninhibited cell division, even in a single tissue or organ, harbors the potential to cause demise of the entire body. In line with this, the ability of cancer cells to spread to additional organs and form new tumors remains the most clinically rele- vant aspect of the disease. As discussed in this chapter, a diverse array of molecular alterations leads to key changes in cellular function, survival, and proliferation.

Although cancer remains heterogeneous in its development, experimental molecular evidence, ani- mal model characterization, and analysis from clini- cal studies have elucidated key features common to cancer cells. Most cases of cancer arise sporadically from the accumulation of changes in DNA that may be infl uenced by environmental interactions. This feature is highlighted by the fact that overall cancer incidence increases with age. Characterization of heritable forms of cancer in individuals with a strong family history has further increased our understanding of the genetic basis of cancer. Importantly, our knowledge in this area has been supplemented by genomic-based approaches that continue to delineate the complex and interrelated changes underlying cancer initiation and progression. Taken together, these studies have propelled the devel- opment of novel therapies aimed at disrupting the sig- naling mechanisms responsible for promoting various aspects of cancer cell function.

As uncontrolled cellular growth is the central fl aw in a cancer cell, we begin this chapter with a brief over- view of the cell cycle to highlight important aspects of growth initiation and control. We then expand our discussion to encompass tumor terminology and phe- notypic changes that drive the aggressive qualities of a cancer cell and distinguish it from its normal coun- terparts. Finally, we examine specifi c examples of mutations that initiate and promote the progression of cancer from a clinical perspective, and discuss geno- typing in cancer diagnosis and treatment.

NEOPLASIA Kolbrun (Kolla) Kristjansdottir , Thomas M. Bodenstine , and Sandhya Noronha

7

Copyright Springer Publishing Company. All Rights Reserved. From: Advanced Physiology and Pathophysiology DOI: 10.1891/9780826177087.0007

216 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

THE CELL CYCLE

The steps of cell division, collectively referred to as the cell cycle, encompass a complex system of interacting molecules. In multicellular organisms, coordinated cell division gives rise to tissues and organs during embryo- genesis that are subsequently maintained by a balance between cell growth and cell death. Rates of cell divi- sion vary widely among mammalian cells. For example, mature cardiac cells and neurons exhibit low rates of division, whereas cells lining the gastrointestinal tract and blood cell precursors of the bone marrow divide rapidly. The steps of the cell cycle must proceed in a careful, regulated manner to ensure proper production of new cells. Consequently, the cell cycle exhibits dis- tinct phases, each with its own molecular signatures and specific functions to accomplish the generation of viable new cells. To achieve this feat, cells not only manage their internal machinery, but integrate cues from the extracellular environment, including the influ- ence of growth factors, availability of nutrients, and physical interactions with neighboring cells. During this process, tight regulation of cellular proliferation must exist to avoid pathological consequence. As dis- cussed later in this chapter, an inability to control cell division remains the fundamental defect in cancer.

Although researchers have learned much about the regulation of cell division from experimental models such as the fruit fly, nematode, and amphibian, our discussion focuses on the division of human somatic cells, which account for the majority of cells present within the body. (Stem and reproductive cells exhibit specialized forms

Cell prepares for division

G1

S

M

G2

G1

S

M

DNA replicated

Cell grows, RNA/ protein synthesis, organelle duplication begins

Repair DNA errors, continued growth Interphase: S G2G1

G2

Cell divides

Cytokinesis, cellular contents divided

Mitosis, DNA separated, two nuclei form

Mitotic phase: M

(a)

(b)

FIGURE 7.1 Two major phases of the cell cycle. (a) During interphase, the cell prepares for division. In G

1 , the cell grows, organelles begin duplication, and RNA and protein synthesis are

increased to complete replication of DNA in S phase. Integrity of DNA is assessed and repaired if necessary during G

2 . (b) The mitotic phase (M phase) details the process by which replicated DNA

is separated, forming two nuclei. During cytokinesis, the contents of the cell are separated as two new cells form.

of division.) In its simplest categorization, the cell cycle is divided into two broad stages (Figure 7.1). Interphase describes the period in which the cell grows, replicates its DNA, and activates factors necessary for cell divi- sion. M phase, or the mitotic phase, entails separation of chromosomes and cytoplasm. Thus, cells prepare for division in interphase and carry out this division in M phase. Although the molecular complexities of the cell cycle and its regulation are extensive, brief descriptions of its basic components are provided here.

INTERPHASE Cells spend the majority of their time in interphase. It is during this period that they evaluate whether conditions are appropriate for cell division, irreversibly commit to the process, and complete the necessary preparations required for successful duplication. Interphase is char- acterized by three subphases referred to as G

1 (first gap

phase), S (synthesis), and G 2 (second gap phase), as

illustrated in Figure 7.1a. G

1 is the most variable portion of interphase in regard

to duration, and the amount of time cells spend in this period depends on cell type. Cells with high rates of divi- sion spend less time in G

1 than cells with less frequent

division. Throughout G 1 , high RNA and protein synthesis

rates support cell growth. Organelles such as mitochon- dria and lysosomes begin their own process of biogen- esis in preparation for providing each new cell with the necessary repertoire of organelles that will support cell function. It is also during this time that cells make a commitment to completing the remaining steps of cell division.

Chapter 7 • Neoplasia 217

S phase is so named because the primary function involves DNA synthesis within the nucleus. During this phase, DNA from all 46 chromosomes is replicated, with each new copy remaining linked to the original by cohesive proteins. These connected chromosomes are referred to as sister chromatids . Production of histone proteins increases during S phase, and DNA becomes tightly coiled around these proteins. This creates a DNA–histone complex known as chromatin , which helps organize, condense, and package DNA in later stages of the cell cycle.

Following DNA duplication, the cell enters G 2 , in

which integrity of the DNA is checked for errors and corrected if necessary by DNA repair pathways. This ensures that new cells inherit DNA that is free from mistakes that would compromise its ability to carry out the vital tasks of the cell, tissue, or organ. Following completion of G

2 , the cell has reached a critical size,

doubled its internal contents, replicated and checked its DNA, and is now ready to divide.

M PHASE (MITOTIC PHASE) Upon completing interphase, the cell must separate its DNA and cellular contents to properly form two new cells in the intricate process known as M phase (Figure 7.2).

This phase can be described in two stages: (a) Mitosis, with its own set of subphases, encompasses the process of breaking down the nuclear membrane and dividing the now duplicated chromosomes, while (b) cytokinesis entails equal splitting of the cell membrane and all of the components contained within it ( Figure 7.1b ).

Mitosis involves fi ve distinct subphases: prophase, prometaphase, metaphase, anaphase, and telophase. These processes are shown in Figure 7.2a and described in Box 7.1 . Interpreting the steps of mito- sis allows us to understand the process by which cells perform the critical task of dividing their genomic content.

Cytokinesis completes the fi nal phase of the cell cycle by separating the cellular contents and fi nal- izing the formation of the new cells, each with their own nuclei. By this time, a ring composed of actin and myosin has formed and been positioned toward the center of the cell. Known as the cleavage furrow, the ring begins to separate the cytoplasm as it contracts, ultimately sealing off the plasma membrane on each side ( Figure 7.2b ). At the end of cytokinesis, the cell cycle is now complete, resulting in the production of two daughter cells, each with its own set of DNA and cytoplasm to support function and survival.

1. Prophase 3. Metaphase 4. Anaphase 5. Telophase 2. Prometaphase

M it

o si

s C

yt o

ki ne

si s

“Cleavage furrow” Ring contracts

Centromere regions

Attachment of kinetochores to centromeres

Microtubules attach to kinetochores

Sister chromatids separate Microtubules shorten

(a)

(b)

FIGURE 7.2 Details of M phase. (a) The process of mitosis involves condensation of DNA into chromosomes during prophase while centromeres move toward opposite ends of the nucleus. Kinetochore complexes attach to centromere regions of chromosomes in prophase, while the nuclear membrane begins to break down, allowing binding of microtubules to kinetochores. Chromosomes are lined up during metaphase and separated by shortening microtubules in anaphase. Nuclear membranes form around newly separated chromosomes, which begin to decondense during telophase. (b) During cytokinesis, an actin and myosin ring aligned at the center of the dividing cell begins to contract. This serves to separate the cellular components and seal off the membranes of each new cell.

218 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

EXIT AND REENTRY OF THE CELL CYCLE While replicating cells continue to move through addi- tional rounds of the cell cycle, a cell may leave this pro- gression and enter a state known as G

0 . In G

0 , cells remain

both viable and functional, but do not actively prolifer- ate. A cell may permanently leave the cycle and enter G

0

once it has matured and performs a specific function. This is true for cells such as cardiac myocytes and neu- rons. These cells are said to be terminally differentiated, indicating that they carry out their function but no longer divide. This is a primary reason that ischemic damage of heart and brain often results in long-term and potentially permanent consequences. In addition to differentiation, most cells have a finite number of division cycles that they can complete as the ends of their chromosomes (telomeres) become progressively shorter with each divi- sion, a process known as replicative senescence. Once a critical length is reached, DNA cannot be appropriately

replicated and the cells enter a permanent state of G 0 .

Collectively, terminally differentiated and senescent cells are thus thought to be in a state of irreversible G

0 .

Compared to heart and brain, liver cells maintain a much higher capability of compensatory growth, and portions of liver can regrow following injury. These liver cells have the capacity to exit G

0 and reenter the

cell cycle. Cells possessing this ability are said to be quiescent, in that they can enter G

0 but later resume the

cell cycle if necessary by returning to G 1 . In an addi-

tional example, memory T cells of the immune system follow patterns of quiescence. During exposure to a pathogen, activated T cells increase in number as part of the immune response. Following resolution of the infection, a portion of these cells remains in the body in a quiescent state of G0

. Should the body again encoun- ter the same pathogen, these cells will rapidly reenter the cell cycle and proliferate.

BOX 7.1 Subphases of Mitosis

PROPHASE

• During the initial step of mitosis, prophase, the chromatin condenses into chromosomes, a process that involves regulated compaction of DNA while the nuclear membrane remains intact.

• A protein complex known as the kinetochore assembles on each sister chromatid at specialized regions known as centromeres. These structures will be important for separation of the sister chromatids by microtubules, dynamic protein structures that constitute part of the cytoskeleton.

• In each cell, microtubules are organized in a structure known as the centrosome. Centrosomes duplicate during cell division and move toward opposing sides of the nucleus during prophase, awaiting dissolution of the nucleus.

PROMETAPHASE

• In prometaphase, the nuclear membrane breaks down and exposes the sister chromatids to the microtubules of the centrosome.

• Microtubules from opposite centrosomes bind to the bound kinetochore protein complexes of each sister chromatid, forming a tight connection and creating tension on the proteins holding them together.

METAPHASE

• During metaphase, the microtubules align sister chromatids toward the center of the cell. This creates an appearance sometimes referred to as the metaphase plate or equatorial plane due to the alignment of the sister chromatids along the center. The next phase of mitosis will not occur until all kinetochores are attached to microtubules and properly aligned.

ANAPHASE

• With sister chromatids aligned at the center of the cell and microtubules attached to kinetochores, the proteins linking the chromatids are released and bound microtubules begin to shorten during anaphase. As this occurs, the chromatids are effectively separated and pulled to opposite ends of the cell by the shortening microtubules.

TELOPHASE

• Following this separation, in telophase, kineto- chores and their attached microtubules disas- semble while two nuclear membranes begin to form around the now separated and decondensing chromosomes. At this stage, the replicated DNA has been split and moved to opposite ends, but the cell must still effectively divide the cytoplasm.

Chapter 7 • Neoplasia 219

CONTROL OF THE CELL CYCLE While the cell cycle itself has been well characterized experimentally and its phases documented in detail through microscopy, the underpinnings of these func- tional events lie at the molecular level in an enor- mously complex network of signaling interactions. Any discussion of these mechanisms must include a basic understanding of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs). Although these molecules are not the only contributors to control of the cell cycle, our understanding of the regulation of cell division stems largely from what has been discov- ered about them.

CDKs are a family of kinase proteins that, when active, phosphorylate a specifi c set of protein sub- strates. These phosphorylation events set in motion various stages and transition points in the cell cycle by activating or inhibiting a multitude of proteins at key times. The activity of CDKs is regulated by their own phosphorylation signatures, and as the name implies, depends on the binding of proteins known as cyclins, which increase CDK function. As such, active CDKs exist as a heterodimer with cyclins and have both a cyclin-binding domain and a kinase domain that increases in activity following cyclin binding. Various CDKs have roles in the cell cycle (e.g., CDK1, CDK2, CDK4, CDK6), and different combinations of CDKs and their cyclins are important for regulation (e.g., cyclin D/ CDK4, cyclin E/CDK2, cyclin B/CDK1). A key feature of these interactions is that while cellular levels of CDKs remain relatively constant, the levels of cyclins rise and fall as the cell cycle progresses ( Figure 7.3 ). Thus, cell cycle regulation is controlled in part by fl uctuations in the amount and type of cyclins present. This allows

the process to occur in a sequential order, and activity of some CDK/cyclin complexes will upregulate levels of the cyclin required for the next phase. For exam- ple, cyclin D/CDK6, which guides the cell through G

1 ,

upregulates the levels of cyclin E, which is important for the transition from G

1 to S phase through its associ-

ation with CDK2. Of equal importance to cell cycle progression is

the ability to halt the cycle when necessary. If a cell experiences alterations to its DNA through damage or mutations, the cell must be prevented from proceeding through cellular division so as not to produce daughter cells with the same genetic alterations. Additionally, cells must ensure that the necessary nutrients and building blocks are present before proceeding through the steps of division. One regulatory protein of cell division, the retinoblastoma protein (pRb), inhibits the cell cycle from progressing through G

1 by binding and

inhibiting the activity of necessary transcription fac- tors. As levels of cyclin D rise in response to growth factor—and nutrient-induced signaling—the cyclin D–activated CDKs phosphorylate pRb, leading to a change in its structure. This structural shift causes the release of the bound transcription factors and allows the cell to continue through G

1 .

CKIs represent additional modes of cell cycle con- trol and include the in hibitors of k inase 4 (INK4) family (p15, p16, p18, p19) and C DK- i nteracting p rotein/ k inase i nhibitory p rotein (CIP/KIP) inhibitors (p21, p27, p57). These molecules have potent inhibitory activities on numerous cyclin/CDK complexes and interactions. Of these inhibitors, p21 is of particular note in that it is capable of disrupting numerous cyclin/CDK combina- tions and, as a result, possesses the ability to halt the cell cycle at multiple stages. 6 , 7

G1 Phase G2 PhaseS Phase

C on

ce nt

ra tio

n

Mitosis

Cyclin E Cyclin A Cyclin B

Cyclin D

FIGURE 7.3 Levels of cyclins vary through the cell cycle. While cellular levels of cyclin-dependent kinases stay relatively constant throughout the cell cycle, levels of their activating proteins, the cyclins, fl uctuate with the cell cycle phases. Along with additional activating mechanisms, these fl uctuations determine the timing of transitions between phases, controlling the rate of cell division.

220 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

Equally important as the inhibitors are the molecules that control inhibitor expression and activity. The TP53 gene encodes the protein p53, which is critical to halt- ing the cell cycle when DNA is damaged or the cell has suffered injury—two scenarios in which progression through the cell cycle would be detrimental. Several proteins and complexes survey the genome for damage and, when present, initiate signaling pathways that lead to activation of p53. The p53 protein enters the nucleus and functions as a transcription factor, inducing the expression of numerous genes capable of halting the cell cycle, activating DNA repair pathways, or inducing cell death if defects cannot be reversed. In the case of its inhibitory cell cycle effects, p53 mediates this in part, by increasing the expression of p21. The link between p53 and the suppression of neoplastic growth was fi rst proposed following experiments utilizing colorectal carcinoma cells in which loss of p53 function was con- sistently observed. 8 This fi nding was later supported by additional evidence in other types of cancer, solidifying the idea that loss of the p53 brakes of the cell opened the door to unregulated cell proliferation. 9 , 10

CHECKPOINTS Multiple checkpoints are present within the cell cycle machinery to ensure the cell undergoes division appro- priately. Progression through a G

1 checkpoint, also

known as the restriction point, ensures the presence of necessary growth conditions and commits the cell to the remainder of the division process. Up to this point, the cell is infl uenced by the presence of external growth factors, which increase the activation of signaling path- ways that promote cell division by increasing cyclin D, as previously discussed. Thus, this checkpoint ensures that nutrients and growth factors are present and the extracellular environment is favorable for cell division. Once the cell has reached necessary levels of this acti- vation, it moves through this checkpoint and proceeds through the remainder of the cell cycle without the need for extracellular factors. Additional checkpoints exist within the cell; for example, a DNA damage checkpoint ensures that DNA has been correctly replicated and is free of alterations prior to mitosis, while an M-phase checkpoint assesses that all kinetochores are bound to microtubules before chromosome separation begins. Failure to pass any of these checkpoints results in ces- sation of the cell cycle until the issues are corrected. Each of these checkpoints is regulated by an elaborate system of coordinated molecular interactions.

Collectively, cell division is characterized by numer- ous phases and an abundance of coordinated intracel- lular activity. This setup ensures that these complex functions occur in a regulated manner. Nonetheless, con- trol mechanisms are often circumvented in cancer cells, leading to unregulated growth that threatens the body.

Thought Questions

1. What is the fundamental feature of all cancer cells?

2. How does regulation of the cell cycle relate to cancer development?

PROPERTIES OF NEOPLASMS

TUMOR TERMINOLOGY A tumor is defi ned as “[a]n abnormal mass of tissue that results when cells divide more than they should or do not die when they should.” 11 Similarly, a neo- plasm refers to a new and uncontrolled proliferation of cells that can be benign (noncancerous) or malig- nant (cancerous). It is important to note that not all malignant cellular proliferations form a tumor. Hematological malignancies are the most common examples of those that do not form discrete tumors. For example, acute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoblasts in the bone marrow and the peripheral blood without overt for- mation of a tumor. Histopathological examination of a tissue biopsy sample, or observation of a blood smear, together with knowledge of the salient clinical features (derived from the history, physical examina- tion, and imaging results), helps to make a diagnosis of a malignancy.

A benign tumor is typically slow growing and on macroscopic examination appears to be well circum- scribed. On microscopic examination, the tumor cells do not infi ltrate into the adjacent tissue. The term dys- plasia is used to describe a change or an alteration in a cell. Dysplastic cells, when viewed on a stained tissue section, show variation in the size and shape of their nuclei (nuclear pleomorphism), and the nuclei may appear darkly stained (hyperchromatic). An increased number of mitoses may be seen in tissue sections along with mitotic fi gures that are atypical. For example, infection of human ectocervical epithelial cells with the human papillomavirus (HPV) can result in dysplasia. Dysplasia may be low grade or high grade. In low-grade dysplasia, the cells in the lower third of the ectocervical epithelium are altered, and in high-grade dysplasia, the altered cells extend into the middle and upper thirds of the cervical epithelium ( Figure 7.4) .

The term carcinoma in situ has been used to describe aggregates of abnormal cells that have not extended beyond the basement membrane. For exam- ple, ductal carcinoma in situ of the breast refers to a condition in which neoplastic cells fi ll some of the

Chapter 7 • Neoplasia 221

ducts in breast tissue. The neoplastic cells are con- tained within the ducts and do not breach the basement membrane, which is a specialized matrix to which the cells are attached. An invasive cancer occurs when the neoplastic cells break through this basement mem- brane and extend into the underlying stroma.

A malignant tumor is composed of cells that are able to infi ltrate into the adjacent stroma or connective tis- sue. Macroscopic examination of the tumor reveals the tumor margins to be poorly circumscribed. Microscopic examination reveals infi ltration of the tumor cells into the surrounding connective tissue, which may allow the malignant cells to extend into lymphatics or blood vessels and to disseminate to distant organs where the tumor cells can form new tumors—a process known as metastasis . Malignant tumors (cancers) are named based on the tissue from which they develop. A carci- noma, for instance, is a malignant tumor derived from cells of epithelial origin; examples are squamous cell carcinoma, adenocarcinoma, and small cell carcinoma.

• A squamous cell carcinoma is a malignant tumor arising from squamous epithelial cells. For example, a squamous cell carcinoma of the skin is derived from squamous cells in the epidermis of the skin.

• Adenocarcinomas are malignant tumors arising from glandular epithelial cells. For example, an ade- nocarcinoma of the lung is derived from glandular epithelial cells lining the tracheobronchial tree in the lungs.

• A small cell carcinoma arises from neuroendo- crine cells that occur normally in various tissues in the body. For example, a small cell carcinoma of the lung arises from neuroendocrine cells in lung tissue.

Sarcomas are malignant tumors arising from mes- enchymal tissue (e.g., blood vessels, cartilage, bone,

muscle) and are rare in comparison to carcinomas. The prefi x of a sarcoma designates its origin; for example, an osteosarcoma arises from bone tissue, whereas a liposarcoma indicates a sarcoma arising from adipose tissue. Additional examples are chondrosarcoma (car- tilage), leiomyosarcoma (smooth muscle), rhabdomyo- sarcoma (skeletal muscle), and angiosarcoma (blood vessels).

In hematopoietic neoplasms, there is an abnor- mal proliferation of cells in the bone marrow, periph- eral blood, or other hematopoietic tissues such as the lymph nodes, spleen, or liver. A lymphoma refers to a malignant tumor that results from a monoclonal pro- liferation of lymphoid cells such as B lymphocytes or T lymphocytes. Leukemia occurs secondary to a monoclonal proliferation of early hematopoietic cells (blast cells) in the bone marrow, accompanied by an arrest in the normal maturation of the cells.

Other malignant tumors likely to be encountered in clinical practice include melanoma, brain tumors, and teratoma. Melanoma arises from melanocytes such as those seen within the skin. Tumors of the brain may arise from a multitude of cells in the ner- vous system, including neurons, glial cells, choroid plexus, and meninges. Brain tumors commonly seen in clinical practice include glial tumors, meningioma, and secondary tumors that have metastasized to the brain from other sites in the body. A teratoma is a tumor that arises from germ cells and is composed of tissues derived from one or more of the embryo- logical germ cell layers. For example, a mature cystic teratoma, also known as a dermoid cyst, may occur in organs such as the testes or ovaries, and may be com- posed of an aggregate of mature tissues representing various organs in the body; for example, skin and hair (ectoderm), lungs and intestines (endoderm), and bone and cartilage (mesoderm).

(a) (b)

FIGURE 7.4 Micrographs of normal cervical epithelium (a) and level II cervical intraepithelial neoplasia (b). Abnormal cells (b) have larger and darker nuclei and are found in the lower third of the epithelial layer but do not breach the basal lamina.

222 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

Thought Questions

3. What features help to diff erentiate a benign tumor from a malignant tumor?

4. What tissues give rise to a carcinoma, a sarcoma, and a lymphoma?

CHARACTERISTICS OF A CANCER CELL The development of a malignant neoplasm, or cancer, is a stepwise process that includes a series of genetic changes in a normally functioning cell that gradually transform the cell into a cancer cell. These genetic changes result in the inability of the body to restrain cell division and can lead to the spread of the cancer cells around the body. Collectively, the characteristics that a cell acquires when it becomes cancerous are referred to as the hallmarks of cancer . 12 , 13 Some of these char- acteristics include uncontrolled proliferative signal- ing, evading growth suppressors, genomic instability, enabling cell immortality, resisting cell death, hijacking or generating blood supply sources for nourishment, and acquiring invasive and metastatic abilities.

Proto-Oncogenes, Oncogenes, and Tumor Suppressor Genes As a general principle, the genetic changes that promote the stepwise progression from normal cell function to malignancy alter the amount, activity, or regulation of two types of genes.

First, some genes possess the ability to promote cellular proliferation and survival, but are subject to careful regulation to limit these functions to appro- priate circumstances. Genes with these characteris- tics are known as proto-oncogenes, and the majority of these proto-oncogenes are involved in regulation of the cell cycle and responses to growth factor acti- vation. Proto-oncogene mutations may lead to loss of proper regulation and result in disease due to overac- tivity of their inherent properties. This conversion from proto-oncogene to oncogene leads to sustained activ- ity of their encoded proteins, resulting in unchecked growth that may progress to neoplasia. Such mutations are referred to as gain-of-function mutations because the resulting protein has an increase in activity.

Second, many protective genes encode proteins that inhibit uncontrolled cell division and conduct surveil- lance of DNA. Signals of DNA damage or deranged cell function result in DNA repair (if possible) or initiation of apoptosis if the cell is beyond repair. These genes can collectively be referred to as tumor suppressor genes . As described next, the loss of normal function of a single tumor suppressor gene allele is not suffi cient to induce loss of normal protein function; both copies of

the gene must be mutated in order for decreased tumor suppressor activity and promotion of cancer. These mutations are referred to as loss-of-function mutations because absence of the normal protein function is inte- gral to cancer promotion ( Figure 7.5 ).

Uncontrolled Proliferative Signaling An oncogene may be formed as a result of mutations within the proto-oncogene or as a consequence of larger alterations such as chromosomal translocations that disrupt normal controls on oncogene expression. One of the most commonly observed oncogenes is mutated Ras , found in about 20% of all human cancers. Ras is an important intracellular signaling protein that, when properly stimulated, transmits signals that activate cell growth for a brief time before being turned off. Mutated Ras results in continuous stimulation that fuels tumor growth. Another proto-oncogene codes for the mem- brane epidermal growth factor receptor (EGFR) a mem- ber of the ErbB family of growth-promoting tyrosine kinases. Increased levels of EGFR or mutated forms of EGFR are frequently present in cancers, resulting in unregulated cell division due to the continual activation of its signaling properties. Inhibitors that bind to EGFR and decrease cellular growth are used in the treatment of some breast, pancreatic, and colon cancers.

Evading Growth Suppressors Cells have many mechanisms to regulate cell prolifera- tion in response to activation of oncogenes or cell stress, including halting cell division, inducing DNA repair, and initiating cell death. The tumor suppressor genes controlling these processes include many cell cycle inhibitors and regulators. When a tumor suppressor is inactivated or turned off , the likelihood of cancer devel- opment is increased. As such, the actions of a normally functioning tumor suppressor will inhibit proliferation, but upon loss of its function unregulated growth can occur. Over half of all human cancers have mutations in the TP53 tumor suppressor gene, illustrating its vital importance in maintaining genome integrity and elimi- nating irreversibly altered cells. When the p53 protein is not functional, DNA damage goes unrepaired and muta- tions accumulate in cells, leading to acquisition of other cancer cell characteristics. RB1 represents an additional tumor suppressor gene and its product, pRb, has the capacity to stop the cell cycle in G

1 . The consequence of

losing this function is underscored by the common fi nd- ings of RB1 mutations in retinoblastoma, osteosarcoma, and carcinomas of breast, lung, and colon.

Genomic Instability Defects in DNA repair pathways are not directly onco- genic; however, because the DNA cannot be effectively repaired, DNA mutations accumulate. The genome becomes unstable, signifi cantly increasing the risk of mutations occurring in processes that regulate cell

Chapter 7 • Neoplasia 223

growth, such as tumor suppressors, proto-oncogenes, and cell death pathways. For example, patients with the disease xeroderma pigmentosum have germ- line mutations in nucleotide excision repair pathways, decreasing their ability to correct DNA damage caused by ultraviolet (UV) light. As a result, these patients are extremely susceptible to UV-induced burns and skin damage. Without protection from sun or other UV sources, about half of these patients will develop their fi rst skin cancer by age 10 years. 14

Enabling Replicative Immortality The human body must maintain equilibrium between the replacement of old cells and generation of new ones. The cell cycle continuously produces new cells, but each cell has a limited number of cell divisions before it undergoes a process called cellular aging, or senescence . Senescent cells function but are no longer able to enter the cell cycle and divide. A hallmark of cancer cells is the ability to bypass senescence and continue cell divi- sion. This occurs, in part, because of increased levels of telomerase , an enzyme that maintains chromosome length, making cancer cells in essence immortal. This property is supported by the fact that many cancer cell lines derived from cancer patients can survive indefi - nitely in the laboratory if maintained under appropriate growth conditions. Telomerase inhibitors are promising

anticancer agents because telomerase is expressed in the majority of cancer cells and is not present, or is pres- ent in very low amounts, in normal cells.

Resisting Cell Death Cell death can occur through two primary routes. Necrosis represents an uncontrolled form of cell death that often occurs in response to an acute cellular injury. The plasma membrane is ruptured and intracellular con- tents spill into the surrounding tissues, promoting infl am- mation and tissue damage. Apoptosis is a regulated and programmed form of cell death. Under normal condi- tions, cells that sustain extensive or unrepairable damage to their DNA undergo apoptosis due to intracellular sur- veillance mechanisms. Abnormal or pathogen-infected cells will also be targeted for apoptosis or outright lysis by immune cells. Thus, apoptotic mechanisms serve a protective function in the body and represent a challenge to the development of cancer. Cancer cells, however, have found ways to evade apoptosis by upregulating anti- apoptotic factors such as inhibitors of apoptosis (IAPs) or decreasing production of proapoptotic factors such as Fas. This enables cancer cells to resist induction of apoptosis. Avoiding this built-in mechanism of cell death allows a cell with mutated DNA to continue to grow and divide, gaining mutations that make the cell more tumor- igenic and ultimately malignant.

(a)

(b)

Normal cell

Normal cell

Overactive mutation (gain of function)

Single mutation event creates oncogene

Activating mutation enables oncogene to promote cell transformation

Cells en route to cancerUnderactive mutation (loss of function)

Mutation event inactivates

tumor suppressor

gene No effect of mutation in

one gene copy

Second mutation event

inactivates second gene

Two inactivating mutants functionally eliminate the tumor suppressor gene,

promoting cell transformation

FIGURE 7.5 Two major groups of genetic mutations favor progression of cells to malignancy. (a) A proto-oncogene within a normal cell is mutated, becoming an oncogene. The oncogene product stimulates excessive and unregulated cell division. (b) A tumor suppressor gene is inactivated by a mutation. The remaining normal allele sustains cell protection from proliferation; however, if the second allele develops an inactivating mutation, tumor suppressor function and this pathway of protection from malignancy are lost.

224 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

Promotion of Angiogenesis Blood vessels provide oxygen and nutrients to tissues and are crucial for cell function and survival. Tumors that are not in close proximity to blood vessels are lim- ited in growth to several millimeters diameter before cells in the hypoxic core become quiescent or die. In order for tumors to continue to grow, they must develop an angiogenic ability to generate new blood vessels or expand the existing vascular tree. The resulting vascu- lature feeds growing tumors with the newly developed blood supply, allowing tumors to enlarge and the cancer cells to invade adjacent tissues, promoting metastasis. To accomplish this, many cancer cells have increased local levels of proangiogenic factors such as vascular endothelial growth factor (VEGF). Molecules such as these normally induce blood vessel formation during development or in response to vascular injury but are repurposed by cancer cells to provide themselves with a blood supply. Scientists have developed angiogene- sis inhibitors with the goal of starving the cancer of its needed blood supply. Bevacizumab is an example of a VEGF inhibitor used in the treatment of cancers that have metastasized or recurred, including glioblastoma multiforme, renal cell cancer, and ovarian cancer.

Invasive and Metastatic Ability Cancer cells have the ability to spread from the origi- nal tumor site to distant areas of the body, through the process of metastasis. In order to metastasize, cells must separate from the original tumor; invade the sur- rounding tissues; enter and survive in the circulation, lymphatics, or peritoneal space; and settle in a distant target organ where they adapt, survive, and proliferate. To do this, metastatic cancer cells typically develop alterations in their shape and in their attachment to other cells and to the extracellular matrix. The epi- thelial–mesenchymal transition (EMT) is an import- ant process that allows transformed epithelial cells to invade tissues, resist apoptosis, and spread. Increased expression of EMT transcriptional regulators results in a loss of adherence, an associated conversion from an epithelial to a fibroblastic, or spindle-like morphol- ogy, expression of matrix-degrading enzymes, and increased cell motility. E-cadherin, a key adhesion mol- ecule, is lost in many cancer cells, allowing tumor cells to detach from surrounding cells, and increasing the risk of invasion and metastasis. The cancer hallmarks and examples of proteins and processes altered are summarized in Table 7.1.

RECENTLY IDENTIFIED CANCER CELL CHARACTERISTICS The concept of cancer hallmarks was further elabo- rated in 2011, with the inclusion of evasion of immune destruction and altered metabolism as additional emerging hallmarks.13

Evasion of Immune Destruction Classical immunology proposes that cytotoxic T lym- phocytes, among other effector cells, are capable of killing not only virus-infected self-cells, but also self- cells that have undergone cancer-causing mutations and unregulated proliferation. Interestingly, having cancer promotes a state of increased generalized inflammation, with elevated cytokine levels both within a tumor and systemically that may promote cancer cell proliferation. In addition, lymphocytes are found within tumor tissue, but they are not always cytotoxic lymphocytes. Rather, regulatory T cells (Tregs) may be present in tumors and downregulate the ability of the immune system to clear the tumor cells. Cancer cells may develop characteristics that activate immune sys- tem inhibitory signaling, particularly through the acti- vation of cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which downregulates immune respon- siveness. Similarly, cancer cells produce a ligand that activates programmed cell death 1 (PD-1) receptors found on T cells, B cells, and natural killer cells, and suppresses immune activity, hindering clearance of the cancer cells.15

Immune-based cancer treatments continue to evolve.16 Chimeric antigen receptor–T cell (CAR-T cell) is a method of altering T-cell receptors to attack antigens associated with a tumor. Monoclonal anti- bodies are also successfully used, and several types have been developed that specifically target proteins unique to a given cancer type. Monoclonal antibodies can opsonize tumor cells, marking them for phago- cytic destruction. At the same time, destruction of the cells increases the reactions of antigen-presenting cells that can drive T-helper– and cytotoxic T-lymphocyte– mediated tumor destruction. Finally, some tumors have

TABLE 7.1 Cancer Characteristics and Exemplar Causative Factors

Cancer Cell Characteristics or Hallmarks

Associated Protein or Key Process

Uncontrolled proliferative signaling

Ras, EGFR

Evading growth suppressors p53, pRb

Genomic instability DNA repair

Enabling replicative immortality Telomerase

Restricting cell death Apoptosis

Promotion of angiogenesis VEGF

Invasive and metastatic ability EMT, E-cadherin

EGFR, epidermal growth factor receptor; EMT, epithelial– mesenchymal transition; VEGF, vascular endothelial growth factor.

Chapter 7 • Neoplasia 225

signals that inhibit lymphocyte proliferation by acti- vating checkpoints that block their entry into the cell cycle needed for clonal proliferation. Checkpoint inhib- itor drugs block those cell membrane signals, allow- ing the lymphocytes to respond with proliferation and immune-mediated eradication of tumor cells.

Cancer Cell Metabolic Alterations As previously noted, a growing tumor will have vary- ing degrees of oxygen supply, depending on prox- imity to existing or newly formed blood vessels. The collection of cells will consist of tumor cells in vary- ing states of genetic alteration, each having somewhat different characteristics and energy requirements, plus

surrounding tissue cells, called the stroma. Cell types making up the tumor include the cancer stem cells that propagate their own growth, immune cells (lym- phocytes, macrophages, dendritic cells) stimulated by infl ammatory signals of the tumor, fi broblasts, and cells undergoing the EMT. The microenvironment of the tumor depends on interactions between these cell types and determines the type of metabolism needed by cells in different stages of tumor progression. One model proposes that hypoxia-stressed cells in the center of a tumor adopt the properties of increased survival, treatment resistance, and immune evasion, ultimately becoming more likely to develop mutations favoring invasion and metastasis 17 ( Figure 7.6 ).

Blood vessels

N or

m ox

ia H

yp ox

ia

Tumor-derived factors • Cytokines/ Chemokines • Metabolites

Stressor tumor conditions • Hypoxia • Acidosis

Invasion and metastasis

Tumor cell adaptations • Aggressive phenotype • Growth advantage • Increased cell survival (autophagy) • Acquisition of EMT and CSC phenotype • Acquired treatment resistance • Immune escape and tolerance • Tumor progression

CTL-sensitive cell

CTL-resistant cancer cell

Cancer stem cell

CTL Macrophage Dendritic cell

Mesenchymal cell (EMT)

FIGURE 7.6 Events in tumor progression. A tumor is made up of CSCs, cancer cells, stroma cells (of the original tissue), lymphocytes, macrophages, dendritic cells, and cells in some phase of the EMT. The tumor region closest to a blood vessel has normal oxygen supply and has cells that may maintain normal sensitivity to killing by CTLs. The tumor region at a distance from the blood vessel has a hypoxic and acidotic environment that induces cell stress. This may promote acquisition of cancer cell immune resistance and development of immune tolerance, as well as favoring mutations that enable invasion and metastasis. CTL, cytotoxic T lymphocyte; CSC, cancer stem cell; EMT, epithelial–mesenchymal transition.

226 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

Early studies of tumor cell metabolism indicated a high rate of glucose uptake due to increased levels of glucose transporter 1 (GLUT1). This alteration is clin- ically useful, as the accelerated glucose uptake forms the basis of PET scanning for fl uorodeoxyglucose uptake to localize tumors and metastases. Rapidly dividing and aggressive tumor cells often rely on gly- colysis for energy production. The glycolytic pathway does not produce as much adenosine triphosphate (ATP) as the usual metabolic pathways of glycolysis, Krebs cycle, and oxidative phosphorylation, but it is rapid and produces lactate, which can be used to syn- thesize new cell components to support further cell division. 18

In summary, accumulation of sporadic mutations can result in the acquisition of cancer cell characteris- tics. A mutated cell acquires more mutations over time, resulting in a heterogeneous tumor composed of cells with a range of cancer cell characteristics. Genomic instability accelerates mutation rates, and some of those mutations further promote the rate of cellu- lar growth and division. A benign neoplasm can, over time, become malignant, highlighting the importance of early identifi cation and treatment. Even established malignant tumors continue to accumulate mutations, adapting to their surroundings and acquiring more can- cer characteristics. Each hallmark of cancer presents a pathway of targeted therapy development to improve clinical outcomes.

Thought Questions

5. What is an oncogene?

6. How do cancer cells obtain suffi cient oxygen and nutrients in a large tumor?

7. Why does genomic instability increase cancer risk?

CLINICAL ASPECTS OF NEOPLASIA

PATHOPHYSIOLOGY OF CANCER MANIFESTATIONS AND TREATMENT SEQUELAE Cancer and cancer treatments are associated with a number of pathophysiological alterations at the sys- temic level, in addition to localized manifestations resulting from solid tumors. Chief among these are infl ammation, with elevated cytokine production that may cause fevers and suppress appetite while also promoting clotting. Hypercoagulability also commonly accompanies cancer, particularly in early stages. Some patients originally diagnosed with deep vein thrombosis

and pulmonary embolism are subsequently found to have cancer. In addition, fatigue that is disproportional to effort is common, particularly in more advanced cancer. Poor appetite and wasting can also occur in advanced cancer, as well as resulting from chemother- apy-induced nausea and vomiting. Endocrine-related syndromes can result from tumors that are ectopic sources of hormones and hormone-like substances. An example is parathyroid hormone–related protein, which can cause hypercalcemia and bone loss, and tumor-pro- duced vasopressin, which can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Tumor lysis syndrome is an acute generalized reaction to massive cell death caused by cancer treat- ment. Although tumor lysis syndrome can be a sponta- neous event, it is generally precipitated after initiating a round of treatment that results in robust and rapid killing of malignant cells. The cells then release their contents, causing hyperuricemia, hyperkalemia, hyper- phosphatemia, and hypocalcemia. The ensuing elec- trolyte imbalance can cause instability of excitable tissues, resulting in cardiac arrhythmias and neuro- logical seizures. Acute renal failure is also a potential outcome. Risk stratifi cation to reduce tumor lysis syn- drome is aided by estimating tumor volume, cell lysis potential of the treatment, and patient factors such as fl uid and electrolyte status and renal function. Careful monitoring is required to manage the onset of this com- plication with fl uid supplementation and measures that reduce uric acid, phosphate, and potassium. 19

Other cancer- and therapy-associated complica- tions and symptoms include pain, anemia, neutropenia, thrombocytopenia, nausea and vomiting, stomatitis, fatigue, radiation-induced tissue injury, sleep distur- bance, and dysphoria. Providers in oncology centers continue to refi ne evidence-based strategies to care for patients with cancer with the aim of optimizing qual- ity of life and function. This is a critical step with the striking evolution of novel, highly effective gene- and immune-based therapies that have a high risk of unpre- dictable adverse reactions.

BIOLOGICAL ASPECTS OF GENE MUTATIONS AND CANCER RISK FACTORS Cancers may occur as a result of hereditary or sporadic gene mutations in somatic or germline cells. Germline mutations are mutations that occur in the DNA of germ cells such as ova and spermatozoa. Inheritance of a ger- mline mutation results in every cell in the body having the mutation. Somatic mutations are mutations that occur in the cells spontaneously or as a result of muta- gen exposures. For example, skin cells that have been repeatedly exposed to UV rays may develop a somatic mutation. A somatic mutation is inherited by the prog- eny of the cell with the mutation but does not occur in all cells in the body and cannot be inherited by offspring.

Chapter 7 • Neoplasia 227

Sporadic gene mutations occur more commonly than inherited gene mutations. It has been estimated that only about 5% to 10% of cancers are inherited. 20

Typically, sporadic gene mutations accumulate in the tissues over time prior to the development of a tumor. For example, benign adenomatous polyps of the colon accumulate gene mutations over time before developing into a malignant tumor. Screening pro- cedures such as colonoscopy are extremely import- ant to detect and remove benign polyps of the colon before they become malignant. Some risk factors thought to play a role in the development of cancer include age, race and ethnicity, smoking, alcohol con- sumption, excessive exposure to UV light, exposure to environmental toxins, lack of exercise, and obesity. For example,

• Smoking has been identifi ed as the leading cause of lung cancer and is linked to many other cancers.

• Excessive exposure to UV light has been linked to the development of skin cancer.

• Age is a risk factor for the development of prostate cancer, which typically occurs in older men, and men of African descent appear to have a higher risk of prostate cancer.

• A diet low in fruits and vegetables and rich in red meats is a risk factor for the development of colon cancer.

• Excessive consumption of alcohol is a risk factor for liver and other cancers.

• Exposure to asbestos has been linked to the devel- opment of mesothelioma, a tumor arising from the pleura of the lung.

• Obesity and a lack of physical activity have also been implicated as increasing development of many cancers.

Hereditary gene mutations also play a role in the development of neoplasia, and typically occur in patients at an earlier age than neoplasia due to spo- radic mutations. For example, the inheritance of germline mutations in DNA mismatch repair genes such as hMSH2 , hMLH1 , hMSH6 , and hPMS2 has been implicated in the development of Lynch syn- drome, also known as hereditary nonpolyposis col- orectal cancer (HNPCC). Mismatch repair genes are genes that play a role in ensuring the accurate pair- ing of DNA base pairs. Microsatellites are short DNA sequences that may be altered due to mutations in the mismatch repair genes, which may then result in a genomic instability called microsatellite instability. Patients with mismatch repair gene mutations are at an increased risk for the development of tumors, especially colorectal and endometrial cancers, as well as cancers in organs such as the duodenum, kid- neys, liver, stomach, and ovaries. 21

Mutations in tumor suppressor genes may be inher- ited. Affected individuals are heterozygous, being born with two alleles, of which one has normal func- tion and the other lacks that function. In Li-Fraumeni syndrome, a germline mutation of the tumor suppres- sor gene TP53 is inherited. Patients with Li-Fraumeni syndrome are at an increased risk for the devel- opment of tumors at an early age. Tumors include sarcoma of the bone and soft tissue, breast cancer, brain tumors, and tumors of the adrenal cortex. 22 The breast cancer genes 1 and 2 ( BRCA1 and BRCA2 ) are tumor suppressor genes that are often germline muta- tions, and inheritance of a copy of the mutated gene signifi cantly increases the risk for the development of early breast and ovarian cancer. The inheritance of mutated BRCA1 and BRCA2 has also been associated with the development of cancers in other organs such as the fallopian tube, peritoneum, prostate, and the male breast. 23

Chromosomal alterations due to deletions or trans- locations may also result in oncogene activation and the development of neoplasia. For example, a follicu- lar lymphoma may develop following the overexpres- sion of the oncoprotein (resulting protein produced from an oncogene) BCL-2 in B lymphocytes. In the vast majority of patients, BCL-2 overexpression occurs secondary to a t(14;18) chromosomal translo- cation. The overexpression of BCL-2 prevents normal cell death or apoptosis of B lymphocytes, resulting in the development of a B-cell lymphoma. Acute promy- elocytic leukemia (APL; or acute myeloid leukemia– M3) is a condition in which a t(15;17)(q24.1;q21.2) chromosomal translocation leads to the production of an oncoprotein that prevents the normal matu- ration of promyelocytes to neutrophils in the bone marrow.

The chromosomal translocation t(9;22), a bal- anced translocation between the breakpoint cluster region gene BCR on chromosome 22 and the ABL gene on chromosome 9, results in the generation of the Philadelphia chromosome, fi rst identifi ed at two research laboratories in Philadelphia. The transloca- tion is visible upon karyotyping and labeling, and the chromosomal rearrangement forms an abnormal BCR- ABL fusion gene ( Figure 7.7 ). This abnormal gene pro- duces oncoproteins that have proliferation-promoting tyrosine kinase activity that can no longer be switched off . Uncontrolled proliferation of granulocytic cells ensues and is associated with the development of a chronic myeloid leukemia (CML).

VIRAL CAUSES OF CANCER Adding to the potential mechanisms of cancer ini- tiation, several viruses have been implicated in the development of human cancers. The Epstein–Barr

228 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

virus is a herpesvirus that can infect B lymphocytes. The virus has been associated with a t(8;14) chromo- somal translocation and the development of a B-cell lymphoma called Burkitt lymphoma. The hepatitis B virus is a DNA virus that has been associated with the development of hepatocellular carcinoma. The mechanism by which hepatitis B viruses may induce the development of a tumor is complex but is likely related to changes that occur secondary to the inte- gration of the hepatitis B viral DNA into the genome of patients with chronic hepatitis B. Hepatitis C is caused by an RNA virus that also increases risk of hepatocellular carcinoma. 24

HPV is a small, sexually transmitted DNA virus. There are more than 200 genotypes of HPV. Subtypes 6 and 11 are associated with the development of lesions such as cutaneous and anogenital warts in adults and laryngeal papillomas in children, and HPV subtypes 16 and 18 have been implicated in the devel- opment of head and neck and anogenital cancers. The mechanism by which HPV induces neoplasia has been studied extensively. The virus produces six early (E) proteins and two late (L) proteins. The E6 and E7 proteins are involved in degradation of the pRb tumor suppressor, which allows viral repli- cation in the cell infected with HPV. The E6 protein

Normal chromosome 9

Changed chromosome 9

Normal chromosome 22

Changed chromosome 22

(Philadelphia chromosome)

ABL

BCR

Chromosomes break

BCR-ABL

FIGURE 7.7 A chromosomal translocation activates an oncogene. Chromosomal translocation between chromosomes 9 and 22 produces a mutant Philadelphia chromosome that positions a BCR (breakpoint cluster region) gene next to the ABL proto-oncogene. The protein encoded by the fusion gene BCR-ABL is a continually activated protein tyrosine kinase that stimulates cells to continually divide, bypassing normal controls of the cell cycle. Presence of this gene is common in leukemias, particularly in chronic myelogenous leukemia.

also interacts with the p53 protein, resulting in the degradation of p53 and a decrease in apoptosis or cell death. In addition to p53 and pRb, many other cellular proteins are also targeted, which leads to an uncontrolled proliferation of cells and an increased risk for neoplasia. 25 Vaccines are available against viruses such as hepatitis B and HPV. Immunization with these vaccines is important to decrease the risk of infection with the viruses and, therefore, decrease the risk of developing a cancer. Newer therapies for hepatitis C have played a signifi cant role in clearing the virus from the body and reducing the risk of can- cer development.

Thought Questions

8. What is the molecular basis for the development of the Lynch syndrome and the Li-Fraumeni syndrome?

9. What is the Philadelphia chromosome?

10. What viruses are associated with the development of neoplasia?

Chapter 7 • Neoplasia 229

GENOTYPING IN CANCER DIAGNOSIS AND TREATMENT

Approaches to the treatment of cancer depend on the type, location, and progression of the tumor at the time of diagnosis. Included in these options are tradi- tional strategies such as surgery, radiation, and che- motherapy. Surgery is commonly used to excise solid tumors and has the greatest success when tumors have not spread and remain accessible. A subset of cancers responds to radiation treatment, and the tech- nology and accuracy of this approach has dramatically improved over the past several decades.

Given that cancer cells often have fast growth rates, chemotherapy can be used to nonspecifi cally target any rapidly growing cells by damaging DNA or inhibiting its replication. Because chemotherapy is distributed sys- temically, it can be used to treat advanced cancers that have spread from their primary site of origin. However, because normal cells are also affected by the chemother- apeutic agents, side effects of chemotherapy are frequent and often severe. The discovery of common cancer cell characteristics, the mechanism behind cancer develop- ment, and technological advancements have resulted in the identifi cation of numerous targeted cancer drugs that have revolutionized diagnosis and treatment.

Cancers can now be genotyped, identifying cancer-associated genetic abnormalities using a wide variety of techniques, including whole genome sequencing, targeted polymerase chain reaction (PCR), and immunological methods. These genetic abnormal- ities can affect patient outcomes and can be used for diagnosis, prognosis, and, in some cases, to determine therapeutic approach. For example, the detection of the BCR-ABL fusion gene, described earlier, confi rms the diagnosis of CML. Treatment with a specifi c tyro- sine kinase inhibitor such as imatinib will switch off

the growth-promoting activity of the BCR-ABL fusion protein and has resulted in a dramatic improvement in the prognosis for patients with CML. Patients with APL can be diagnosed by the translocation causing the disease, and then treated with all-trans retinoic acid, which induces the promyelocytes to differentiate to neutrophils. The addition of all-trans retinoic acid to the treatment regimen of patients with APL has sig- nifi cantly reduced the mortality and morbidity rates of patients with this disease.

Amplifi cation of the HER2 gene occurs in about 30% of breast cancers and causes the cancer cells to grow and divide rapidly. 26 Patients with breast cancer are routinely tested for HER2 amplifi cation to deter- mine whether they are candidates for treatment with drugs such as trastuzumab or lapatinib that can turn off HER2 activity. Interestingly, diverse cancers can have the same genetic abnormalities. For example, some metastatic stomach or gastroesophageal junction cancers also have an amplifi cation of the HER2 gene and can thus be treated with the same HER2 -targeting drugs as those used in breast cancer. Thus, genetic mutations shared by tumors, irrespective of their tissue of origin, make it possible to treat vastly different can- cers with the same targeted drugs. These newer drug therapies are sometimes combined with radiation ther- apy and chemotherapy.

Thought Questions

11. What is the benefi t of testing for genetic abnormalities in cancers?

12. Why is it sometimes possible to treat diff erent types of cancer with the same targeted drug?

 230

PEDIATRIC CONSIDERATIONS Terri Kyle

BOX 7.2 Signs and Symptoms of Cancer in Children

Continued, unexplained weight loss

Headaches, often with early-morning vomiting

Increased swelling or persistent pain in bones, joints, back, or legs

Lump or mass, especially in the abdomen, neck, chest, pelvis, or armpits

Development of excessive bruising, bleeding, or rash

Constant infections

A whitish color behind the pupil

Nausea that persists or vomiting without nausea

Constant tiredness or noticeable paleness

Eye or vision changes that occur suddenly and persist

Recurrent or persistent fevers of unknown origin

OVERVIEW OF PEDIATRIC CANCER

Cancer in children differs from that in adults in that it is not often of epithelial origin, as it is in adults, and can- not be explained by environmental exposure. The most commonly occurring broad categories of cancer in chil- dren are of hematopoietic origin, followed by nervous system tumors and those of embryonic origin.26 Just as the origin of cancer in children differs from that in adults, the presenting signs and symptoms may differ27,28 (Box 7.2).

LEUKEMIAS

Leukemia is classified as either lymphocytic or myelogenous; each type may occur as either an acute or chronic form of malignancy. The leukemias account for at least a third of all childhood cancer, and ALL accounts for 75% of cases of childhood leukemia.29 Chronic leukemias occur less frequently in children. A primary malignancy of the bone marrow, leukemia, results in the normal bone marrow components being supplanted by abnormal white blood cells. The abnor- mal cells demonstrate a growth advantage over nor- mal cells. Rampant overgrowth of the abnormal cells causes displacement of other blood cells, which can result in pancytopenia leading to anemia and bleed- ing. The exact cause of leukemia remains unknown,

although numerous chromosomal and genetic abnor- malities have been identified in leukemic cells.30

ACUTE LYMPHOBLASTIC LEUKEMIA Risk factors for the development of acute lympho- blastic leukemia (ALL) include numerous genetic conditions, with Down syndrome being the most fre- quent. Ionizing radiation exposure is a known environ- mental risk factor.30 The presentation of ALL is usually nonspecific and may include intermittent low-grade fever, anorexia, malaise, fatigue, and irritability. Lower extremity bone pain may also occur. ALL may metas- tasize to the central nervous system, resulting in signs of increased intracranial pressure such as headache, vomiting, or vision changes. Genetic studies indicate that aneuploidy (having more or less than two copies of each chromosome), particularly trisomy of chromo- somes 4, 10, and 17, predicts likelihood of treatment success. On the other hand, children born with trisomy 21 (Down syndrome) are ten to 20 times more likely to develop ALL.31

ACUTE MYELOGENOUS LEUKEMIA Risk factors for the development of acute myelogenous leukemia (AML) are similar to those for ALL. Signs and symptoms are also similar, although in AML subcutane- ous hemolytic purpuric nodules (often termed blueberry muffin lesions) may occur.30

Source: From Feist P. Signs of childhood cancer. Pediatric Oncology Resource Center. http://www. ped-onc.org/diseases/SOCC. html#anchor75392.

Chapter 7 • Neoplasia 231

BONE TUMORS

In children and adolescents, bone tumors result in localized pain, which may be worse at night or with activity; tender soft tissue mass; and limp or movement limitations. 29 , 32 Osteosarcoma is an aggressive bone tumor affecting the long bones near the metaphyseal plate. It accounts for less than 2% of childhood cancer and is most frequently diagnosed in teenagers. 28 Ewing sarcoma is a small, round cell undifferentiated tumor that is believed to be of neural crest origin. Children with a small nonmetastatic Ewing sarcoma have a good prognosis, but if metastasis is present at diagnosis, the long-term survival rate is much poorer. 32

NERVOUS SYSTEM TUMORS

The second most frequently occurring type of cancer in children and adolescents is malignant brain and spi- nal cord tumors. 27 , 29 Exposure to ionizing radiation or certain inherited disorders may be risk factors for brain tumor development. Presenting symptoms of nervous system tumors are most often consistent with signs and symptoms of increased intracranial pressure resulting simply from tumor presence or blockage of cerebrospi- nal fl ow, or both.

There are more than 100 histological catego- ries of brain tumors. In children, medulloblastoma (primitive neuroectodermal tumor) and pilocytic astrocytoma are the most common, although several other central nervous system tumors may also occur. Medulloblastoma is an embryonic cerebellar tumor, diagnosed most often by the ages of 5 to 7 years, which can spread via cerebrospinal fl uid and can cause fourth ventricle obstruction. Cerebellar dysfunction is often present with this tumor. Astrocytoma also occurs most often in the cerebellar area. Histologically, in the com- pact area of the tumor, Rosenthal fi bers (condensed glial fi lament masses) are present. 33

NEUROBLASTOMA Neuroblastoma occurs only in children, usually younger than 10 years of age, with an average age at diagnosis

of 18 months. The tumor arises from primordial neural crest cells (neuroblasts) of the sympathetic nervous system. The tumors can develop in the adrenal medulla and sympathetic ganglia, and commonly have metas- tasized by the time of diagnosis. Neuroblastoma cells have gene and chromosomal alterations, in most cases involving the MYCN and ALK genes. Approximately half of all children who develop neuroblastoma before age 12 months will experience complete spontaneous regres- sion, whereas children diagnosed later are more likely to require treatment. The most disabling complications of neuroblastoma are spinal cord compression in up to 10% of patients, and a rare condition termed opsoclonus myoclonus syndrome . 34

RETINOBLASTOMA Retinoblastoma is a rare cancer that occurs only in children. It develops either as a hereditary disease, due to an abnormality of the RB1 gene, or sporadically (70% of cases). 29 , 35 Located on chromosome 13q14, the RB1 gene is responsible for encoding pRb, which is a tumor suppressor protein. In the heritable form, the RB1 gene mutation is inherited through germinal cells, with a second mutation occurring in somatic retinal cells. The noninherited type of retinoblastoma occurs as a result of two mutations in the somatic retinal cells. The tumor arises from the inner surface of the retina and then spreads into the retina, resulting in leukocoria—a white appearance to the red refl ex, commonly called cat-eye refl ex—which is most often fi rst identifi ed by the child’s parents. 35

WILMS TUMOR Wilms tumor usually presents in young children as a unilateral, painless abdominal mass that is most often initially observed by parents. 29 , 36 An embryonal malig- nancy of the kidney, it is thought to be due to a genetic predisposition to nephrogenic rests (fragments of embryonic tissue retained in the developed kidney). Rests that persist are thought to develop into Wilms tumor after undergoing further genetic mutation. Genes for Wilms tumor continue to be identifi ed. In addition to abdominal mass presence, some children may exhibit hematuria or hypertension. 36

 232

GERONTOLOGICAL CONSIDERATIONS Rita M. Jakubowski and Janet H. Van Cleave

Between 2015 and 2050, the segment of the U.S. popu- lation aged 65 years and older is projected to undergo rapid growth from nearly 48 million people to 88 million.37 As older adults carry a disproportionate share of the cancer burden in the United States, this increase has implications for cancer care. Adults aged 65 years and older currently make up 15% of the U.S. population, yet account for 53% of cancer diagnoses.37,38 As a result, the incidence of cancer in the United States has been projected to increase by approximately 45% between 2010 and 2030.39

To deliver appropriate care for older adults with can- cer, clinicians must have a fundamental understanding of the association between aging and cancer. This sec- tion describes the physiological processes of aging that may promote cancer development and implications for practice.

PHYSIOLOGICAL PROCESSES OF AGING THAT MAY PROMOTE CANCER DEVELOPMENT

Four processes of aging that may promote cancer devel- opment are (a) a favorable environment for cancer, (b) an accumulation of cellular mutations, (c) a decline in immune function, and (d) alterations in hematopoi- etic stem cells.

FAVORABLE ENVIRONMENT FOR CANCER Research supports the observation that cancer increases with aging,39–41 and in fact, its incidence increases exponentially beginning at approximately the midpoint of the life span.42 The mechanisms under- lying this association have not been fully determined. A number of explanations for increased cancer inci- dence with increased age are summarized in Figure 7.8 and include the following:

• Longer time of exposure to environmental and endogenous sources of DNA mutations, leading to accumulating mutations

• Decline in DNA repair mechanisms • Inevitable telomere shortening that may destabilize

DNA structure • Decreased immune surveillance • Increase in senescent cell number and progression

to the senescence-associated secretory phenotype that promotes chronic inflammation43

ACCUMULATION OF CELLULAR MUTATIONS As outlined earlier in this chapter, cancer originates from the mutation of DNA sequences in cells that reroute pathways regulating tissue homeostasis, cell survival, or cell death.44 These mutations may result in the acti- vation of oncogenes or the loss of tumor-suppressing proteins. Often multiple mutations must occur over many years before the cell actually becomes a cancer stem cell, thus explaining the increased incidence of cancer with aging. As we age, our cells are more likely to accumulate mutations and to develop one that trig- gers the development of cancer.45 When such mutations disrupt genes that regulate cell division and growth, the cells begin to grow uncontrollably. A few cells quickly multiply and then increase rates of cell division, even- tually becoming a tumor. These abnormal cells acquire phenotypes that increase their ability to proliferate, migrate, and colonize at abnormal sites within the body, to survive hostile tissue environments, and to escape immune system surveillance.

DECLINE IN IMMUNE FUNCTION (IMMUNE SENESCENCE) The immune system is a major defense mechanism against the development of cancer, monitoring tissue homeostasis to protect against invading pathogens and eliminate damaged cells.44 It performs these functions by:

• Eliminating or suppressing viral infections to pro- tect the host from virus-induced tumors

• Eliminating pathogens and promptly resolving inflammation to prevent an environment conducive to the development and growth of tumors

• Identifying and eliminating tumor cells by the recog- nition of specific antigens45

The thymus is the major site of T-cell development and maturation. A gradual decline in thymic output of T cells has been proposed as another aspect of the aging process that can aid the development of cancer through a decline in immune function (immunosenescence).46 The decline in functional immunity is not only more permissive to tumor formation but may also promote it by contributing to chronic low-level inflammation. Age-related declines in T-cell numbers and responsive- ness (described in Chapter 6 , The Immune System and Leukocyte Function) contribute to reduced immune surveillance. They help to explain the decreased

Chapter 7 • Neoplasia 233

ability of the elderly to resist infections to which they were not previously exposed, or to respond to the appearance of tumor antigens, as well as to respond adequately to reinfection or to retain memory for anti- gens expressed by relapsing tumors.

ALTERATIONS IN HEMATOPOIETIC STEM CELLS The unique ability of stem cells to proliferate, differen- tiate, and self-renew allows them to play a major role in homeostasis, replacing cells that are weakened or destroyed by aging. 47 This activity occurs through pre- cise coordination of signaling processes throughout the body. Aging brings a cascade of changes in homeo- stasis, including a decline in organ function that affects the hematopoietic system, primarily stem cells. To replace blood cells that are constantly being lost due to splenic destruction or tissue utilization, hemato- poietic stem cells continuously regenerate circulating cells of the blood and immune system throughout life. Hematopoietic reserves, however, are depleted during

aging, and their ability to renew deteriorates. The abil- ity of stem cells to differentiate into different cell types is also altered, with maintenance of myeloid cell pro- duction better than lymphoid cell production.

With aging, there is a decline in stem cell function- ing but not numbers. 48 Because of their long life span and ability to replicate, stem cells are subject to dam- age from both intracellular and extracellular sources. Intracellular sources include the oxidative chemical reactions occurring within the cell. Stem cells undergo repetitive DNA replications during their lifetime, and such repetitive replications can cause random errors. As a result, genetic damage occurs and may accumu- late. Instability of stem cells exists to a greater degree in bone marrow of older adults, which suggests a progressive decrease in DNA repair process. 49 Such a decrease or defect in this process may contribute to the increased incidence of leukemia and myelodysplastic syndrome (MDS) in older individuals.

Cancers of the hematopoietic system (leukemias) are thought to originate within the normal stem cell

Telomere Shortening DNA Repair

Immune Surveillance

Chromosomal Stability Host Resistance

Premalignancy

Time

Age

Malignancy

Microenvironment Imbalance

Apoptosis Resistance

Invasion Metastasis

Angiogenesis Initiation

Free Radicals

Oncogene Activation/Mutation

Tumor-Suppressor Gene Loss

Apoptosis Gene Loss

Carcinogens

Viruses Promotion

FIGURE 7.8 Increased cancer incidence with aging can be related to a number of changes across the life span. There are potentially multiple sporadic DNA-damaging exposures (free radicals, carcinogens, viruses), leading to altered expression of oncogenes, tumor suppressor genes, apoptosis genes; initiation of altered phenotype with increased cell proliferation; accumulation of additional gene alterations; promotion of the transition to malignancy with gradual acquisition of invasive and metastatic capacity; and tumor expansion later supported by angiogenesis—all of which are occurring against the natural backdrop of declining host resistance. When factors favoring malignancy outweigh factors inhibiting malignancy, cancer develops. Source: From Halter JB, et al. Hazzard’s Geriatric Medicine and Gerontology. 7th ed. McGraw- Hill Education. www.accessmedicine.com. All rights reserved.

234 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

through the acquisition of mutations, genetic alter- ations, and chromosomal translocations.50 Over time, these changes transform cells from normal to malig- nant. As previously discussed, the altered cells are able to escape apoptosis and have an endless ability to rep- licate. AML has an increased incidence among older adults and is an example of a cancer that is thought to originate from an accumulation of genetic mutations occurring over the lifetime of an individual.

AGING AND CANCER: PRACTICE IMPLICATIONS

Screening and treatment recommendations for cancer in older adults take into consideration the functional status of the individual, indications of frailty, and per- sonal preference. Frequency of mammography, cervi- cal cancer screening, and colonoscopy may be reduced after the age of 75, depending on an individual’s risk fac- tors and desire for testing. Similarly, frail older adults with reduced functional reserve may be at higher risk for delayed recovery or severe adverse effects after cancer surgeries and conventional chemotherapies. Altered liver and renal drug clearance must be assessed prior to chemotherapy initiation. For these reasons, careful evaluation and consultation with the patient and family are imperative in designing treatment strate- gies for older adults with a new cancer diagnosis.

Remarkable scientific advances over the past 30 years have generated new therapies that are chang- ing the landscape of cancer treatment. First, the grow- ing number of people with AML or MDS, in conjunction with improvements in transplantation science, has increased the use of allogeneic hematopoietic cell trans- plantation as a treatment in older adults. Allogeneic hematopoietic cell transplantation is a process whereby stem cells from either a related or an unrelated donor are infused into a patient with the goal of replacing the patient’s immune and hematopoietic systems. Data from 103 transplant centers between 2000 and 2013 show that the percentage of allogeneic hematopoietic

cell transplantations in adults aged 70 years and older increased from 0.1% of transplants in 2000 to 3.85% in 2013. Nearly 40% of this population was alive 2 years after transplantation.51 These findings suggest that, in the context of a growing older adult population, the use of hematopoietic cell transplantation in older adults will continue to increase. Furthermore, advances in hematopoietic stem cell transplantation have allowed the development of reduced-intensity conditioning as a preparative regimen prior to transplantation for some populations of patients. These regimens use less che- motherapy or radiation therapy, or both, than standard myeloablative conditioning regimens, thereby decreas- ing the potential for organ toxicity. This option has afforded older patients the opportunity for potentially curative therapy.

Second, myriad novel, targeted biological therapies to kill cancer cells are either being used in clinical prac- tice or are under development. One example of a novel targeted therapy is ipilimumab, an immune checkpoint inhibitor, which has demonstrated improvement in survival rates in patients who have undergone surgical resection for stage III melanoma. This therapy blocks CTLA-4 to augment antitumor immune responses.52 However, while proven to be beneficial, such drugs can induce varying degrees of adverse reactions ranging from rashes to pneumonitis.53

One of the major issues in the care of older adults with cancer is the ability of older adults to tolerate these novel therapies. Some evidence supports the con- tention that older adults tolerate these novel therapies as well as their younger counterparts.54 However, older adults are underrepresented in cancer clinical trials; thus, the data on the toxicities of targeted therapies experienced by this special population are limited.55 Because of this limited knowledge regarding the tox- icities of novel therapies in older adults, it is important that practitioners who care for older adults with cancer understand the physiological basis of these novel tar- geted therapies to enable early detection and interven- tion of treatment toxicities.

Chapter 7 • Neoplasia 235

Beth Boyer

Patient Complaint: “ About 2 months ago the skin on my chest felt itchy for several days. It started gradually, but after several days seemed persistent and wouldn’t go away. I performed a self-exam and noticed a new lump in the upper outer corner of my right breast that hadn’t been there before. I’m very concerned because of my family history of breast cancer.”

History of Present Illness/Review of Systems: Your patient is a 55-year-old postmenopausal African American woman who fi rst noticed itching of both breasts that began in the inframammary ridge area but extended to both breasts. The itching was not relieved with use of oral antihistamine and hot and cold packs. She does not have a visible rash or hives, and has noticed no change to the skin. She performed a breast self-examination and noted a lump in the superior right breast. She has not been on any hormone replacement and experienced menopause at age 50.

The review of systems is negative for fever and infections, vision or hearing changes, headaches, and memory loss. The patient reports no abdominal pain and no nausea, vomiting, diarrhea, or constipation. There are no enlarged lymph nodes and no new problems with bleeding or bruising, no back pain or bone pain, and no peripheral neuropathy. She continues to experience mild itching over her right breast without any rash or hives; however, she noted that this is much better than when she fi rst noticed the itching sensation. She reports no itching or skin changes anywhere else. She has no chest pain, palpitations, or dyspnea, and remainder of her review of systems is negative.

Past Medical/Social/Family History: The patient’s past medical history is notable for hypertension and hyperlipidemia. Obstetrical history includes gravida 2, para 2, and pregnancy number 1 at age 29 years; she breastfed both her son and her daughter. Her surgical history includes left knee surgery in 2008 and left axilla lipoma excision in 1992. Social history includes exercise one to two times per week (running) and alcohol intake of one glass of wine daily. She is a former smoker of one pack per month for 10 years; she quit 17 years ago. Oncological family history is negative for ovarian cancer but positive for breast cancer in

her sister at age 44, her maternal aunt at age 61, and her maternal grandmother in her 60s. There is no other contributory family history.

Physical Examination: Findings are as follows: temperature of 98.4°F, blood pressure of 110/76 mm Hg, heart rate of 84 beats/min, respirations of 14 breaths/min. Body mass index (BMI) is 30 kg/m 2 . In general, the patient appears well and in no apparent distress. Her heart rate is regular, lungs are clear, and abdomen is soft. Breast examination is performed with the patient sitting and supine. Examination of the left breast demonstrates no evidence of dominant mass, skin change, nipple discharge, or changes within the nipple–areolar complex on the left side. Examination of the right breast reveals a 2- to 3-cm dominant fi rm mass at the 12 o’clock position, with no overlying skin change, nipple discharge, or change the nipple–areolar complex. There is no supraclavicular or infraclavicular axillary adenopathy on either side.

Laboratory and Diagnostic Findings: Both the CBC with differential and the chemistry panel are normal. Bilateral digital diagnostic mammogram and static ultrasound images are obtained, as follows:

• Mammogram indicates that breast tissue is heterogeneously dense. In the left breast, there are no signifi cant fi ndings or changes. In the right breast at 12 o’clock, there is a suspicious mass, correlating with an area of palpable concern as indicated by a metallic marker. Spot compression views show a few punctate calcifi cations associated with the mass. There are no other suspicious fi ndings in the right breast; specifi cally, there is no mammographic abnormality in an additional area of palpable concern in the inferior right breast as indicated by a metallic marker.

• Static ultrasound images labeled right breast 12:30 , 5 to 6 cm from the nipple, demonstrate a suspicious solid mass with calipers demar- cating measurements of 12 × 18 × 14 mm. This correlates with both the palpable area in the superior breast and mammographic fi nding. There is no sonographic abnormality in the other area of palpable concern in the right breast 4 to 5 o’clock position.

CASE STUDY 7.1: A Patient With Breast Cancer

Beth Boyer

CASE STUDY 7.1:

(continued)

236 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

Ben Cocchiaro

PRINCIPLES OF ASSESSMENT History and Physical Examination • Constitutional symptoms : weight loss, night

sweats, anorexia, fever, and fatigue • Organ-speci� c signs and symptoms :

❍ Lung: chronic cough, hemoptysis, chest pain, dyspnea, hoarseness

❍ Colon: change in bowel habits, hematochezia, change in stool caliber, bowel obstruction

❍ Pancreas: jaundice, abdominal pain, nausea, dark urine, hepatomegaly

❍ Breast: breast mass, nipple discharge (especially unilateral)

❍ Prostate: urinary retention, nodular, lumpy prostate on examination

❍ Skin: lesions with high potential for malignancy often feature asymmetry, uneven borders, multiple colors, diameter greater than ¼″, and change over time

• Vaccination history : The HPV and hepatitis B vaccines prevent cancers of the cervix and liver, respectively

Screening Tests • Age- and risk-appropriate cancer screenings : As

many neoplasms have long asymptomatic periods in which they are more easily treatable, screening programs have been developed for many of the most common cancers. These include cancers of the breast, colon, cervix, and lung. See recommendations from the USPSTF for more information.

Diagnostic Tools • Imaging studies : The diagnostic evaluation of

isolated masses frequently begins with ultrasonography. In contrast, patients with suspected neoplasia of unknown origin often undergo CT scanning of the chest and abdomen. PET imaging is a useful tool for identifying metastases as it highlights areas with high metabolic activity.

• Biopsy : Once a suspicious mass has been identifi ed, tissue must be obtained from the mass and sometimes from nearby lymph nodes in order to guide treatment. Genotyping and special histological stains for tumor cell surface proteins can identify the tissue of origin of a mass as well as guide therapy.

• TNM staging : To help in prognosis and treatment of most cancers, a standardized staging classifi cation has been developed based on characteristics of the primary tumor (T), lymph node (N) biopsies, and the identifi cation of metastases (M).

Laboratory Evaluation • Complete blood count and peripheral smear: useful

in the diagnosis of hematological malignancies • Speci� c tumor markers: Several dozen biomarkers

have been associated with various cancers, but lack of sensitivity and specifi city limits their utility to measuring therapeutic response or recurrence in previously diagnosed patients. PSA is a notable example in that while it is still used for prostate cancer screening, providers are encouraged to

BRIDGE TO CLINICAL PRACTICE

• Pathology ultrasound-guided needle core biopsy: Right breast, 12:30, 5 to 6 cm from nipple: Invasive ductal carcinoma, Nottingham grade 3 of 3; 1 cm in greatest dimension. Lymphovascular invasion is identifi ed.

• Immunohistochemical stains performed at an outside institution demonstrate that the neoplastic cells are immunoreactive for ERs and PRs (75% to 100% strong). The

HER2 (sometimes referred to as HER2/neu) immunohistochemical stain performed at the outside institution is negative (1+).

CASE STUDY 7.1 QUESTIONS • What consequences does this patient’s case

have for the daughter of the patient? Is there a rationale for genetic testing in this case?

• Research tamoxifen and describe the rationale for treating the patient with tamoxifen.

CBC, complete blood count; ERs, estrogen receptors; HER2, human epidermal growth factor receptor 2; PRs, progesterone receptors.

(continued)

Chapter 7 • Neoplasia 237

have in-depth discussions with patients regarding the risks of false-positive test results.

MAJOR THERAPEUTIC MODALITIES AND DRUG CLASSES Surgery: • Surgical removal of affected and adjacent tissue

❍ Surgery may be augmented by immediate analysis (frozen section) of the primary lesion and surrounding tissue to evaluate completion of removal of malignancy.

❍ PET scanning can also identify patterns of lymph node drainage to target lymph nodes to biopsy for signs of metastasis.

• Chemotherapeutic or radioactive (brachyth- erapy) beads are sometimes implanted within cancerous tissue.

Radiotherapy: • Taking advantage of cancer cells’ limited ability

to repair DNA damage compared with healthy cells, ionizing radiation is frequently used in cancer treatment to target tumors.

Chemotherapy drug classes: • Nucleic acid synthesis (DNA or RNA) inhibitors • Protein synthesis inhibitors • Microtubule inhibitors • Enzyme inhibitors (intracellular signaling cascades) • Immune checkpoint inhibitors (promote endoge-

nous immune attack) • Hormone receptor antagonists • Tumor-targeting T lymphocytes (CAR-T cells) .

CAR-T cells, chimeric antigen receptor–T cells; HPV, human papillomavirus; PSA, prostate-specifi c antigen; USPSTF, United States Preventive Services Task Force.

KEY POINTS

• The cell cycle is a series of events in the life of a cell in which cell components are grown and DNA is completely replicated, followed by mitosis: division into two daughter cells, each containing the identical genetic information as the parent cell.

• Cells spend varying amounts of time in G 1 (or

in the dormant state of G 0 ) before cell signals,

particularly levels of cyclin proteins, initiate entry into the cell cycle. After a number of divi- sions, cells may enter replicative senescence after which they will not reenter the cell cycle.

• Control of the cell cycle is dependent on tissue needs, but also on signals internal to the cell indicating that suffi cient supplies are available for DNA duplication and, later, that DNA repli- cation has produced a normal result. Cell cycle checkpoints assure cell readiness and healthy status prior to cycle progression.

• The protein p53 is a critical signal for blocking cell cycle progression when DNA damage has occurred.

• Cancer is a state in which cell proliferation proceeds uninhibited by the usual control mechanisms, producing tumors made up of progressively more abnormal cells.

• Malignant tumors are named by their tissue of origin and share the properties of invasion

(cell growth beyond usual tissue boundaries) and metastasis (ability of tumor cells to break off from the original site and travel through blood or lymph to distant organs).

• Cancer is a genetic disorder in which a single cell with a few gene mutations produces generations of cells that have progressive mutations favoring the development of uncontrolled cell division and, ultimately, invasion and metastasis.

• Proto-oncogenes may be activated into onco- genes (a gain-of-function mutation), stimulat- ing unregulated cell proliferation.

• Tumor suppressor genes may be turned off (loss-of-function mutation), reducing protec- tive reactions such as DNA repair and cell cycle arrest when DNA damage has occurred.

• The hallmarks of cancer include uncontrolled proliferative signaling, evasion of growth suppressors, genomic instability, telomerase activity, apoptosis evasion, angiogenesis pro- motion, epithelial–mesenchymal transition that contributes to invasion and metastasis, evasion of immune destruction, and metabolic alterations that promote cell survival.

• Cancer may be localized to a specifi c organ or may affect bone marrow blood cell precursors, producing leukemias and lymphomas. Whether localized or generalized, cancer can produce systemic changes and symptoms, including infl ammation, hypercoagulability, changes in

238 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

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Chapter 7 • Neoplasia 239

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