The Tumor Microenvironment: A Scientific Brief
Introduction
The tumor microenvironment consists of the tumor cells and its surrounding environment
of blood and lymph vessels, fibroblasts, endothelial cells, immune cells, cytokines, extracellular
vesicles, and extracellular matrix.1 Both the relationship of the tumor and its surrounding
environment play an important role between interactions and influencing each other positively
and negatively. Paget’s seed and soil hypothesis suggests how tumorigenesis can spread to other
organs. His theory suggest that the spread of cancer cells is not random, but that the cancer cells
will leave from the original tumor and plant seeds in other organs that allow for new tumors to
form.1,3 For the successful formation of tumorigenesis, it will go through three stages: initiation,
progression, and metastasis.1 Paget’s hypothesis was prominent finding in understanding
metastasis in neighboring organs.
Tumor Initiation and Progression
For the formation of a tumor, it will first undergo initiation in which the cellular genes
will undergo mutations. This will cause the cells to proliferate, along with inflammation and
active wounding.1 In research conducted in mice, it was learned that the overexpression of the
ECM remodeling enzyme, MMP-3, lead to upregulation of the enzyme expression that caused a
small study of the mice to develop carcinomas. Because of the overexpression of the ECM
remodeling enzyme, this formed the tumorigenesis initiation for it to ultimately become a tumor.1
In the progression stage of tumorigenesis, the tumor cells are rapidly proliferating and reaching
towards malignancy and metastasis. These cells that undergo progression can be due to poor diet,
exposure to carcinogens, or genetic makeup that can lead to activation or inactivation of tumor
suppression.2 Protooncogenes can be activated by two mechanisms involving the ras gene family
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The Tumor Microenvironment: A Scientific Brief
and members of the myc, raf, HER2, and june multigene families. The first mechanism has point
mutations that are found in specific regions of the gene.5 The second mechanism involves the
genes being overexpressed and amplification of the chromosomal segments.5
Metastasis
Metastasis is the final stage of tumorigenesis to be successful. The cancer cells from the
first organ that developed a tumor will spread to other parts of the body. There are various
hypotheses that exist to explain the underpinnings of how metastasis occurs.4 These theories
include epithelial mesenchymal transition, an accumulation of mutations in stem cells, a
macrophage facilitation process and origin involving neoplastic cells.9An important hypothesis is
metastatic cancer cells seen in normal macrophages. Malignant tumors contain macrophages
which may act as cellular chaperones that facilitate tumor development, progression, and the
eventual seeding of metastasis.3,4 In a human study conducted, evidence was shown that
metastatic tumors contained neoplastic cells with the macrophage properties.3 Since there are
many theories to suggest the origin of metastasis, scientists may be able to understand the
mechanisms to inhibit metastasis and potential cancer therapies.
Conclusion
There is so much that we have been able to learn about the tumor microenvironment from
many years of research that scientists have conducted. It has been established with evidence to
back up the development of tumors occur from initiation, progression, and metastasis. Learning
from the clinical studies may provide insight that the microenvironment can contribute to
chemotherapy treatments or potential development of cancer therapies at the cellular level.
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The Tumor Microenvironment: A Scientific Brief
References
1. Mendelsohn J, Gray JW, Thompson CB, Israel MA. Infectious Agents and Cancer. In: Howley
PM, ed. The Molecular Basis of Cancer. 4th ed. Philadelphia, PA: Elsevier/Saunders;
2015:103-130.
2. Bissell MJ, Hines WC. Why don’t we get more cancer? A proposed role of the
microenvironment in restraining cancer progression. Nat Med. 2011 Mar;17(3):320-9
3. Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Critical reviews in
oncogenesis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597235/. Published 2013.
4. Wei R, Liu S, Zhang S, Min L, Zhu S. Cellular and extracellular components in tumor
microenvironment and their application in early diagnosis of cancers. Analytical cellular
pathology (Amsterdam). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199555/.
Published January 8, 2020.
5. Weston A, Harris CC. Multistage carcinogenesis - holland-frei cancer medicine - NCBI
bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK13982/. Published 2003.
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