Sreenivas Reddy Bathula*, Sharada P.S., B.E. Rangaswamy Department of Biotechnology, Bapuji Institute of Engineering & Technology, Davangere, Karnataka, India

Abstract

The causative role of human papillomavirus (HPV) in all cancers of the uterine cervix has

been firmly recognized biologically and epidemiologically. Most cancers of the vagina and

anus are likewise caused by HPV, as are a fraction of cancers of the vulva, penis, and

oropharynx. HPV-16 and -18 account for about 70% of cancers of the cervix, vagina, and

anus and for about 30–40% of cancers of the vulva, penis, and oropharynx. Other cancers

causally linked to HPV are non-melanoma skin cancer and cancer of the conjunctiva.

Although HPV is a necessary cause of cervical cancer, it is not enough cause. Thus, other

cofactors are necessary for development from cervical HPV infection to cancer. Long-term

use of hormonal contraceptives, high parity, tobacco smoking, and co-infection with HIV

have been identified as established cofactors; co-infection with Chlamydia trachomatis (CT)

and herpes simplex virus type-2 (HSV-2), immunosuppression, and certain dietary

deficiencies are other probable cofactors. Genetic and immunological host factors and viral

factors other than type, such as variants of type, viral load and viral integration, are likely to

be important but have not been clearly identified [1].

Keywords: Uterine cervix, oropharynx, conjunctiva, Chlamydia trachomatis, non-melanoma

skin cancer

*Author for Correspondence: Email ID: [email protected]

INTRODUCTION

Cervical cancer is the second most

common cancer in women worldwide, and

knowledge regarding its cause and

pathogenesis is expanding rapidly. The

common cause is persistent infection with

one of about 15 genotypes of carcinogenic

human papillomavirus (HPV).

There are four major steps in cervical

cancer development: infection of

metaplastic epithelium at the cervical

transformation zone, viral persistence,

progression of persistently infected

epithelium to cervical precancer, and

invasion through the basement membrane

of the epithelium. Infection is extremely

common in young women in their first

decade of sexual activity. Persistent

infections and precancer are recognized,

typically within 5–10 years, from less than

10% of new infections. Invasive cancer

arises over many years, even decades, in a

minority of women with precancer, with a

peak or plateau in risk at about 35–

55 years of age. Each genotype of HPV

acts as an autonomous infection, with

differing carcinogenic risks linked to

evolutionary species. Our understanding

has led to improved prevention and

clinical management strategies, including

improved screening tests and vaccines.

The new HPV-oriented model of cervical

carcinogenesis should gradually replace

older morphological models based only on

cytology and histology. If applied wisely,

HPV-related technology can minimise the

incidence of cervical cancer, and the

morbidity and mortality it causes, even in

low-resource settings [1]

mailto:[email protected]

HPV Caused Cervical Cancer Bathula et al.

__________________________________________________________________________________________

THEORY

Cancer

Cancer is a disease in which the body cells

become abnormal and divide without

control. Cancer cells invade nearby tissues

and they may spread through the blood

stream and lymphatic system to other parts

of the body.

Definition of HPV

Human papillomavirus (HPV) is a virus

that can be passed from person to person

through skin-to-skin contact.

More than 100 types of HPV have been

found. More are harmless, but about 30 of

these types infect the genital areas and you

get them through sexual contact with an

infected partner. Usually the body fights

off HPV before it can cause health

problems, if it is not cleared then they may

lead to either low-risk or high risk factors.

Low-risk HPV types (6, 11, 42, 43, and

44) can cause genital warts in both men

and women. These are soft growth on the

skin and mucus membranes of genitals.

They may also be found on the penis,

vulva, urethra, vagina, cervix, and around

and in the anus. Warts are not life

threatening, but can be emotionally hard

for a person to deal with [2]

High-risk HPV types (16, 18, 31, 33, 39,

45, 51, 52, 56, 58, 59, 66, 68, and 73) can

lead to cancers of cervix, vulva, vagina

and anus in women. In men it leads to

cancers of anus and penis.

HPV is a very common virus. It is more

common in young men and women in their

late teens and early 20s. Some researches

suggest that at least three out four people

who have sex will get a genital HPV

infection at some time in their lives.

IS HPV MORE COMMON IN

WOMEN OR MEN?

HPV is just as common in men and

women. But HPV is less likely to cause

serious health problems in men. Most men

with HPV never get symptoms or health

problems from it. There is no approved

test for HPV in men. HPV and genital

warts are just as common in native women

as in women of other ethnicities.

Cervical cancer is less common in native

women than in African-American and

Hispanic women. But cervical cancer is

more common in native women than in

white women.

In United States, about 12,000 women get

cervical or other genital cancers from HPV

every year.

And about 7,000 men get head, neck and

anal cancers from HPV every year. HPV

and genital warts are just as common in

native women as in women of other

ethnicities.

TRANSMISSION

HPV is primarily spread through vaginal,

anal, or oral sex, but sexual intercourse is

not required for infection to occur. HPV is

spread by skin-to-skin contact. Sexual

contact with an infected partner is the most

common way the virus is spread. Like

many other sexually transmitted diseases,

there often are no signs and symptoms of

genital HPV infection.

YOU CANNOT GET HPV FROM

o Toilet seats; o Kissing, hugging, or holding hands; o Being unclean; o Sharing food or utensils, Family

history.

WHAT DISEASES DOES HPV

INFECTION CAUSES?

o Approximately 12 types of HPV cause genital warts. These growths may

appear on the outside or inside of the

vagina or on the penis and can spread

to nearby skin. Genital warts also can

grow around the anus, on the vulva, or

on the cervix.

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o Approximately 15 types of HPV are linked to cancer of the anus, cervix,

vulva, vaginal and penis they also can

cause cancer of the head and neck.

These types are known as “high-risk

types” [3]

Cervical cancer begins in the women’s

cervix. It is the narrow organ at the bottom

of the uterus that connects to the vagina.

And in the same way it can grow on other

body organs.

HOW DOES HPV CAUSES CANCER

OF CARVIX?

The cervix is covered by a thin layer of

tissue made up of cells. If HPV is present,

it may enter these cells. Infected cells may

become abnormal or damaged and begin to

grow differently. The changes in these

cells may progress to what is known as

precancer. Changes in the thin tissue

covering the cervix are called dysplasia or

cervical intraepithelial neoplasia (CIN). In

most women, the immune system destroys

the virus before it causes cancer. But in

some women, HPV is not destroyed by the

immune system and does not go away. In

these cases, HPV can lead to cancer or,

more commonly, precancer [4]

Types of Cervical Cancer

There are mainly two types of cervical

cancer. They are distinguished by the

appearance of cells under a microscope:

a. Squamous cell carcinoma, b. Adenocarcinoma.

Squamous Cell Carcinoma Begin in the thin flat cells that line the

bottom of the cervix. This type of cervical

cancer accounts for 80 to 90 percent of

cervical cancer.

Adenocarcinoma Develop in the glandular cells that line the

upper portion of the cervix. These cancers

make up 10 to 20 percent of cervical

cancer.

Sometimes both types of cells are involved

in cervical cancer, other types of cancer

can develop in the cervix, but these are

rare. Like metastatic cervical cancer, they

spread to other parts of body.

Symptoms When present, common symptoms of

cervical cancer:

Normally appear in the form of a

cauliflower like growths, may also be flat

they can be found on the inside and the

outside of the vagina. These growths may

take weeks or even an year to show after

having sex with an infected partner [5]

Vaginal Bleeding This includes bleeding between periods,

after sexual intercourse or postmenopausal

bleeding.

Unusual Vaginal Discharge A watery, pink or swelling discharge is

common.

Pelvic Pain Pain during intercourse or at other times

may be a sign of abnormal changes to the

cervix or less serious condition.

Signs of Advanced Stages of Cervical

Cancer o Cervical cancer may spread within

the pelvis, to the lymph nodes or

else, where in the body signs of

advanced cervical cancer includes:

o Weight loss, o Back pain, o Leg pain or swelling, o Involuntary, ongoing release of

urine or feces,

o Bone-fracture, o Fatigue[6].

Screening Tests for Cervical Cancer

It usually takes years for cervical cancer to

develop. During this time, HPV infection

can cause cells on or around the cervix to

become abnormal which may lead to

cancer.

HPV Caused Cervical Cancer Bathula et al.

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The two cervical cancer screening methods

are:

a. Pap test, b. HPV test.

Pap Test (Sometimes called cervical

cytology screening)

o The Pap test is one of the most reliable and effective cancer

screening methods available for

women. It checks for changes on

your cervix so that problems can be

found and removed before they

turn into cancer.

o Here in the Pap test, the health care provider will use a swab to collect

cells from your cervix and check

under a microscope for any

problems.

o Women should start getting Pap tests three years after the first sex,

or by age of 21, whichever comes

first.

o Women should get Pap test at least once every three years.

HPV Test

o HPV test may also be used with the Pap test in certain cases. The HPV

test looks for HPV, the virus that

can cause cell changes in the

cervix.

o The HPV test can identify 13–14 of the high-risk types of HPV

[7] .

HPV Vaccine against Cervical Cancers

and Genital Warts

The vaccine has been widely tested in girls

and women. It is safe and has no side

effects. The most common side effect is

soreness in the arm.

There are two types of HPV vaccines

namely:

a. Cervarix, b. Gardasil.

Cervarix

o It is a 3-dose series. o Only to females.

o Female: 11 or 12 years of age. This age group has the best response to

the vaccine, and the vaccine must

be given before sexual activity

begins. HPV vaccine can be started

at 9 years. It is also recommended

for females aged 13 through

26 years who have not been

vaccinated.

o Prevents most cases of cervical and anal cancer in females if the

vaccine is given before a person is

exposed to HPV.

Gardasile

o A series of 3-dose series given for both males and females.

o Female and male: 11 or 12 years of age. This age group has the best

response to vaccine, and the

vaccine must be given before

sexual activity beings. HPV

vaccine started at 9 years. It is

recommended for females aged 13

through 26 years who have not

been vaccinated or did not finish

the 3-shot series.

o It is also recommended for males aged 13 through 21 years who have

not been vaccinated or did not

finish the 3-shot series. It may be

given to males aged 22 through

26 years and should be given to

high-risk males aged 9 through

26 years [8]

BIOLOGICAL MECHANISMS OF

HPV CARCINOGENESIS

In previous decades, our understanding of

cancer pathways was rudimentary and

often incorrect. In the face of such

uncertainty, arguments based on

assumptions of molecular biology were not

particularly convincing. However, with the

large body of work now available it is

possible to develop a reasonable

understanding of the ways in which cancer

may develop and ways in which HPV

infection can drive the process. Thus, we

can say with some confidence that it is

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plausible for HPV to cause cervical cancer

and, furthermore, we can describe with

reasonable clarity the general steps by

which HPV may do so. Of course there is

a lot of detail still to be revealed, but we

are well on our way to a factual basis for

understanding carcinogenesis rather than

the guesswork and rudimentary models of

just two decades ago.

What follows is a description of selected

information that may illuminate salient

aspects of the natural history of HPV and

reasons why a mostly benign infectious

process sometimes results in malignancy.

It must be understood by readers that the

pathways are based on extensive

experimentation in biopsied human tissues,

in tissue culture, and other kinds of

molecular biology systems. However,

many details of pathway modifications and

aberrant pathway effects are speculative;

they have not been shown to occur inside

the relevant precancerous and cancerous

tissues of living hosts. However, despite

the many holes and inconsistencies, the

models are still quite compelling and

cohesive in facts. In future, we expect to

see these molecular models being tested in

human subjects.

Essentially all HPV types produce warty

lesions but only high risk types promote

the development of cervical cancer to any

appreciable extent. Such differences

between HPV types may seem surprising,

given the high DNA and structural

similarities. However, a large functional

divergence caused by small genetic

changes is the norm in many biological

systems. Variations in carcinogenic

potential among HPVs are principally

governed by the E6 and E7 proteins;

specifically by the capacities of these

proteins to interact with and alter or

destroy key cell cycle regulatory

molecules.

The progress and outcome of an HPV

infection depends on HPV type,

anatomical location, and the nature and

timing of local cellular and tissue

influences. Virions access basal and

parabasal cells in areas of erosion and viral

DNA enters the cell nuclei. Establishment

is tied to the tissue proliferative activity of

epithelial cells and, in the case of

extensive tissue repair; the viral infection

can become widely disseminated.

Persistence in keratinocytes is variable and

related to viral type. Finally, integration of

viral DNA may occur, resulting in lifetime

persistence of certain viral genes in the

cell. In the cervix, detectable infection by

low risk HPV types is of relatively short

duration, whereas infection by most high

risk types lasts longer. On occasions, such

infections may become persistent and last

for years or even decades; it is in these

cases that the risk of cancer is increased.

The establishment of HPV infection can be

modulated by a competent and primed

immune system. In vitro experiments have

revealed an inverse association between

the degree of cervical neoplasia and

interleukin 2 production by peripheral

blood mononuclear cells in response to

HPV-16 E6 and E7 peptides. Women with

CIN 3 or cancer appear to have a

decreased ability to mount a T helper cell

type 1 (Th1) mediated immune response to

HPV E6/E7, compared with women with

CIN 1 or HPV infected women without

lesions. It is possible that a Th1 mediated

cellular immune response could play a role

in host immunological control of HPV

infection and that lack of such an

appropriate response may predispose to the

progression of cervical disease.

If HPV enters immature metaplastic basal

stem cells that are actively dividing the

infection can become widely dispersed and

persistent. In contrast, if infection occurs

only in the parabasal transit amplifying

cells the infection may become transient or

HPV Caused Cervical Cancer Bathula et al.

__________________________________________________________________________________________

quasi-persistent. The size, histological

grade, and duration of lesions can depend

on the number and types of cells that

become infected by HPV. In either

transient or persistent infection there may

be periodic viral genome amplification,

depending on the activity of the infected

daughter cells, which can lead to variable

detection of the lesion by HPV DNA or

Pap tests.

There is an important difference in host–

virus interactions of carcinogenic HPV

types and low risk HPV types; the former

have activities that more strongly interfere

with a set of host cell cycle control

mechanisms. It is therefore useful to

consider the effects of carcinogenic HPV

types. HPV initially replicates to reach

about 25–50 genomes/cell. The process by

which this occurs is tied to the activities of

four multifunctional viral proteins E1, E2,

E6, and E7. One key activity of E7 is to

overcome the pRB tumour suppressor

block. Binding of E7 to pRB and its

related members result in the liberation of

E2F transcription factors, which play key

roles in promoting host cell and viral DNA

synthesis. E7 also binds and activates

cyclin complexes, such as p33–cyclin

dependent kinase 2, which control

progression through the cell cycle. E6

protein can overcome the p53 protective

control pathways, which are important in

preventing the genetic damage that may

lead to cancer.

HPV genomes attach to host chromatin via

the E2 protein and replicate at a steady

state, once for each cell division. It has

been speculated that a benefit of this

tethered theta mode of replication is that

the loss of HPV DNA from cells by non-

disjunction is minimised and the presence

of low amounts of HPV DNA in cells is

less likely to be detected by intracellular

interference mechanisms that could trigger

apoptosis. As cells differentiate and move

to the surface there is a normal

differentiation and maturation process that

leads to pyknotic condensed cells that

slough from the tissue. However, in virally

infected tissues there is activation of

unscheduled DNA replication in some

spinous cells, accompanied by a switch in

viral DNA replication to the rolling circle

mode, which leads to the production of

viral progeny. This reactivation of DNA

synthesis can be detected by the presence

of punctate proliferating cell nuclear

antigen tissue staining (a protein with a

key role in DNA replication) and the

presence of HPV virions in a subset of

upper layer cells.

HPV E7 proteins of both low and high risk

types have an ability to promote

unscheduled DNA replication in spinous

cells. It is believed that the extent to which

E7 stimulates cells, and the tissue location

at which such stimulation occurs, is

important to malignant progression.

Spinous cells respond to E7 by the

production of a cyclin kinase inhibitor,

p21cip1, translated from sequestered

RNA. In basal and parabasal cells existing

mRNA for p21cip1 is not available and the

protein is typically produced from new

transcripts stimulated by p53; however, if

p53 is inactivated by E6 the p21cip1

cannot be made. Spinous cells thus have a

control advantage lacking in basal cells.

Interestingly, high amounts of E7 can bind

and block the activity of p21cip1. The

relative amounts of E7 and p21cip1 are

believed to determine whether cells re-

enter S phase and replicate viral DNA or

whether cells block viral production. The

inspection of tissues reveals a mutually

exclusive set of spinous cells with high

amounts of either E7 or p21cip1. Cells in

which E7 overcomes the p21cip1 block

can become koilocytes and produce viral

particles. This balance can explain the

patchy expression of the HPV effect in

infected tissues. A key function of the E6

oncoprotein is the destruction of p53, a

protein that is activated upon

phosphorylation via DNA damage sensing

proteins. Activated p53 stops the cell cycle

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in the G phase as a result of direct

stimulation of p21cip1 by this molecule.

Alternatively, in the case of major DNA

damage or high amounts of viral

replication, p53 may activate an apoptotic

pathway. E7 also interferes with

alternative non-p53 dependent apoptotic

pathways. Thus, in the case of E6

mediated destruction of p53, cells are

unable to prevent the accumulation of

genetic mutations. Cells have other

defensive homeostasis mechanisms, but E6

and E7 have counter functions that can lift

the blocks and direct cells to enter S phase.

Therefore, it appears that the development

of malignancy is a consequence of an

aberrant host-virus interaction. A

potentially important event in this process

is the aberrant regulation of E6/E7

expression. In low grade CIN lesions,

E6/E7 expression is mainly found in

differentiating spinous cells that have

withdrawn from the cell cycle. In high

grade CIN lesions and cervical

carcinomas, strong E6/E7 expression is

seen in the proliferating cell

compartments.

HPV DNA is frequently incorporated into

the host genomes in cancers in such a way

that the E2 repressor protein is inactive

and allows overexpression of E6 and E7.

In cases where HPV integration is not

detected, other mutations can be shown in

the E2 protein or in repressor functions,

such as YYI sites, which appear to allow

continuous expression of the E6 and E7

oncoproteins. Yet another way in which

E6 and E7 could be overexpressed in

proliferating cells is by the generation of

chimaeric HPV mRNAs encoding the E6

and E7 proteins that have host sequences

at their 3' termini. Such RNAs are

frequently more stable and allow more

protein to be synthesized.

In persistent HPV lesions, viral genomes

in the basal cells continue to stimulate the

cells to ignore the DNA damage that may

be accumulating. Cell stimulation by E6

and E7 of high risk carcinogenic HPV

types produces clones with an extended

life span that have passed a point called

mortality 1 or M1, although the cells are

still not immortal. An important step in

immortalisation is related to telomeres.

Normally, telomeres shorten every cell

generation and once they reach a critical

length the cells die. Telomere length is

maintained by telomerase, which in

combination with a capping function, can

stabilize and even lengthen telomeres,

allowing cells to continue dividing. E6 can

activate telomerase and additional cell

mutation(s) can then stabilize the

telomeres and allow cells to pass a second

stage called mortality 2 or M2. It is not

known many additional independent

mutations are needed to transform

immortalised cells fully to malignancy.

One set of mutations allows the cell to

break through the basement membrane by

eliciting a set of novel proteases. Another

mutation(s) allows cells to move in the

dermis. Undoubtedly, metastatic cells have

accumulated many additional mutations

that allow them to create their own

microenvironment for survival in foreign

parts of the body [9]

CONCLUSION Cervical cancer screening has successfully

decreased squamous cell cervical cancer

incidence and mortality. The American

Cancer Society (ACS) Guideline for the

Early Detection of Cervical Cancer was

last reviewed and updated in 2002; for the

first time, those recommendations

incorporated options including liquid-

based cytology and human papillomavirus

(HPV) DNA testing. Since that time, two

vaccines against the most common cancer-

causing HPV types have been developed

and tested in clinical trials [2–7]

. Numerous

studies have been published on the

efficacy of these vaccines, as well as

issues related to policy and

implementation [10]

HPV Caused Cervical Cancer Bathula et al.

__________________________________________________________________________________________

REFERENCE

1. www.medlineplus.com 2. Kohout T, Stewart A. New Report

Examines Laws that Would Mandate

HPV Vaccine for Young Women.

Jacobs Institute for Women's Health,

George Washington University.

Retrieved 2010-02-13.

3. De Vuyst H, Clifford GM, Nascimento MC, et al. Prevalence and

Type Distribution of Human Papilloma

Virus in Carcinoma and Intraepithelial

Neoplasia of the Vulva, Vagina and

Anus: A Meta-Analysis. Int. J. Cancer.

2009; 124(7): 1626–1636p.

doi:10.1002/ijc.24116. PMID

19115209.

4. Cortez Michelle Fay, Pettypiece Shannon. Merck Cancer Shot Cuts

Genital Warts, Lesions in Men.

Bloomberg News. (Bloomberg.com) 13

Nov 2008.

5. FDA Approves Expanded Uses for Gardasil to Include Preventing Certain

Vulvar and Vaginal Cancers. (Press

Release). 2008-09-12. Retrieved 2010-

02-13.

6. Coco. Oral Sex Can Add to HPV Cancer Risk. Time. May 11, 2007.

Retrieved 2010-09-17.

7. FDA Approves Gardasil 9 for Prevention of Certain Cancers Caused

by Five Additional Types of HPV.

(Press Release). 10 Dec 2014.

Retrieved 9 Jan 2015.

8. Medical News Today. http://www.medicalnewstoday.com/cat

egories/cancer-oncology

9. Dunne EF, Unger ER, Sternberg M. Prevalence of HPV Infection among

Females in the United States. JAMA.

Feb 2007; 297(8): 813–19p.

doi:10.1001/jama.297.8.813. PMID

17327523.

10. Cervical Cancer. Medline Plus. Retrieved 15 Nov 2014.

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http://en.wikipedia.org/wiki/Digital_object_identifier

http://dx.doi.org/10.1002%2Fijc.24116

http://en.wikipedia.org/wiki/PubMed_Identifier

http://www.ncbi.nlm.nih.gov/pubmed/19115209

http://www.bloomberg.com/apps/news?pid=20601202&sid=aajzweDaXZh0&refer=healthcare

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116945.htm

http://www.time.com/time/health/article/0,8599,1619814,00.html

http://en.wikipedia.org/wiki/Time_(magazine)

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm426485.htm

http://www.medicalnewstoday.com/articles/64137.php

http://en.wikipedia.org/wiki/Digital_object_identifier

http://dx.doi.org/10.1001%2Fjama.297.8.813

http://en.wikipedia.org/wiki/PubMed_Identifier

http://www.ncbi.nlm.nih.gov/pubmed/17327523

http://www.nlm.nih.gov/medlineplus/ency/article/000893.htm

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