Molecular biology of cancer I

Key aspects and basic mechanisms; Tumor viruses

 Many genes control the complex and critical balance between
cell growth and the factors preventing unchecked growth.

these genes are involved in:

GENETIC
REGULATI
cell cycle regulation

ON OF cellular adhesion

THE CELL contact inhibition

CYCLE
DNA repair and maintenance

and programmed cell death (known as apoptosis).

• The eukaryotic cell cycle has four phases Three of these, G1, S, and G2,
comprise interphase—the period between two successive mitoses.
• Cells are provoked into cell division by the initiating actions of growth
factors and hormones that permit transitions through the cell cycle.
• Different cyclins are present within the cell at different stages of the cell
cycle.
• For example, at the all-important transition from G1 to S, cyclin D is
expressed following growth factor stimulation.
• cyclin kinase inhibitors – CKIs - inhibit the action of cyclin-CDK
complexes, tend to slow cell cycle progression
• It can be appreciated now that tumors arise from alterations in the cell cycle resulting from abnormal
proteins that dramatically alter the balance between cell growth and cell death.
• genes associated with cancer are important in normal cell growth, proliferation, differentiation, death, and
maintenance of the genome
• initial mutation leading to cancer either can occur spontaneously (de novo) in certain sporadic patients or
can be inherited.
 Proto-oncogenes - are normal cellular
proteins that work to regulate normal
growth and development.

If mutated or misexpressed, the proto-

ONCOGENS oncogenes become oncogenes and lead to
aberrant cell cycle control.

The aberrant expression of oncogenes

results in entry of the cell into the cell cycle
with abnormal cell growth, suggesting a
gain of function.
 Tumor-suppressor genes are cellular proteins,
which when their activity is reduced, result in
uncontrolled cell growth.

Tumor- Cell surface molecules

suppressor
There are numerous cell surface molecules that
genes antagonize normal cell growth and
development.

Transforming growth factor-b (TGF-b) receptor

mediates its inhibitory effects by stimulating
the production of CDK inhibitors.
Molecules that regulate signal transduction
• These molecules possess an antagonistic role to the actions of
intracellular proto-oncogenes.
• Neurofibromatosis-1 (NF-1) gene product and GTPase-activating
protein (GAP) activate the GTPase function of ras, converting GTP to
GDP and suppressing the growth-promoting function of ras.
• Von Recklinghausen disease, which is also known as
neurofibromatosis-1, results from mutations of NF-1.
• This autosomal recessive disorder results in the development of cafe-
au-lait spots as well as multiple tumors of the peripheral nerve sheath
(schwannomas) and tumors of cranial nerve 7 (acoustic neuromas).
Retinoblastoma
• rare form of cancer that rapidly develops from the immature cells of
a retina, the light-detecting tissue of the eye.
• It is the most common primary malignant intraocular cancer in
children, and it is almost exclusively found in young children
• Alterations in RB1 or MYCN can give rise to retinoblastoma
• RB1 - negative regulator effect on the cell cycle principally arises from
binding and inactivation of the transcription factor E2F, thus
repressing the transcription of genes which are required for
the Sphase.
• A cell cycle critical substrate of the G1/S Cdks is Rb protein (retinoblastoma sensitivity
protein), named after its deficiency in the cancer retinoblastoma.
• Rb protein is unphosphorylared in the G1 and G0 phases, and unphosphorylated Rb
binds and sequesters the transcription factor E2F
• On phosphorylation by the G1 and G1/S-Cdks, Rb changes conformation and releases
E2F.
• The E2F binds to regulatory elements in target genes to increase transcriprion of the
gene products required for S phase such as DNA polymerase, dihydrofolate reductase,
thymidine kinase, and the G1/S phase cyclin proteins.
• The G/S cyclin proteins increase the activity of G1/S Cdks.
• Generation of phosphorylated Rb by the G 1/S-Cdks and release of the E2F transcription
factor is a key requirement for entry into S phase from G1•
• Unphosphoiylated Rb is the active form of Rb, as it acts to sequester and inhibit E2F.
• The phosphmylated form of Rb that no longer acts to sequester E2F is the inactive form
of Rb.
• The p53 gene has an important gate-keeper role in cellular proliferation.
• The p53 gene is induced when DNA is damaged by irradiation, ultraviolet
(UV) light, or chemical mutagenesis.
• The p53 gene then exerts its growth-inhibitory function in one of two ways
to ensure adequate repair of the damaged DNA before proceeding through
the cell cycle.
• The p53 gene induces the transcription of the CDK inhibitor p21, which
inhibits the CDK and cyclin-mediated phosphorylation of Rb required for the
cell to transition to the S phase.
• If DNA damage inflicted on the cell cannot be successfully repaired, p53
mediates the transcription of genes implicated in the process of
programmed cell death, or apoptosis.
• Mutations in the tumor-suppressor gene, p53, are the most common
molecular alterations in cancer, with more than 50% of human tumors
harboring mutations in p53.
• Germline mutations in p53 result in Li-Fraumeni syndrome.
• Patients in families with a history of Li-Fraumeni syndrome inherit one
mutant copy of p53 in their cells, thereby requiring only one sporadic
mutation in their other allele to develop cancer.
• These patients develop sarcomas, breast cancers, tumors of the
central nervous system, and leukemias at an increased frequency and
decreased age compared with normal individuals.
 Viral
carcinogenesis
• Viruses, both DNA and RNA, have evolved numerous strategies for
promoting the aberrant growth of their host cell types
 Human papillomaviruses
(HPVs)
• have evolved over millions of years to propagate themselves in a range
of different animal species including humans.
• Viruses that have co-evolved slowly in this way typically cause chronic
inapparent infections, with virion production in the absence of apparent
disease.
• This is the case for many Beta and Gamma HPV types.
• The Alpha papillomavirus types have however evolved immunoevasion
strategies that allow them to cause persistent visible papillomas.
• Human papillomavirus infection is an infection by human
papillomavirus (HPV). 
• Most HPV infections cause no symptoms and resolve spontaneously.
• In some people, an HPV infection persists and results
in warts or precancerous lesions.  
• The precancerous lesions increase the risk of cancer of
the cervix, vulva, vagina, penis, anus, mouth, or throat. 
• Nearly all cervical cancer is due to HPV with two types, HPV16 and
HPV18, accounting for 70% of cases.
• HPV6 and HPV11 are common causes of genital warts and laryngeal
papillomatosis.
• An HPV infection is caused by human papillomavirus, a DNA virus from
the papillomavirus family, of which over 170 types are known.
• More than 40 types are transmitted through sexual contact and infect
the anus and genitals.
• Risk factors for persistent HPV infections include early age of first 
sexual intercourse, multiple partners, smoking, and 
poor immune function
•  It does not spread via common items like toilet seats.
• People can become infected with more than one type of HPV. 
• HPV affects only humans
• These viruses activate the cell cycle as the infected epithelial cell
differentiates in order to create a replication competent environment that
allows viral genome amplification and packaging into infectious particles.
• This is mediated by the viral E6, E7, and E5 proteins.
• High-risk E6 and E7 proteins differ from their low-risk counterparts
however in being able to drive cell cycle entry in the upper epithelial
layers and also to stimulate cell proliferation in the basal and parabasal
layers.
• Deregulated expression of these cell cycle regulators underlies neoplasia
and the eventual progression to cancer in individuals who cannot resolve
high-risk HPV infection.
• HPV is believed to cause cancer both by integrating into DNA and in non-
integrated episomes. 

• Some of the "early genes" carried by the HPV virus, such as genes E6 and E7,
act as oncogenes that promote tumor growth and malignant transformation.

• Furthermore, HPV can induce a tumorigenic process through integration into a

host genome which is associated with alterations in DNA copy number.
• E6 produces a protein (also called E6) that binds to and inactivates a protein in the host cell
called p53.
• Normally, p53 acts to prevent cell growth, and promotes cell death in the presence of DNA damage.
• p53 also upregulates the p21 protein, which blocks the formation of the cyclin D/Cdk4 complex,
thereby preventing the phosphorylation of RB, and in turn, halting cell cycle progression by
preventing the activation of E2F.
• In short, p53 is a tumor-suppressor protein that arrests the cell cycle and prevents cell growth and
survival when DNA damage occurs.
• Thus, inactivation of p53 by E6 can promote unregulated cell division, cell growth, and cell
survival, characteristics of cancer.
• E6 also has a close relationship with the cellular protein E6-associated protein (E6-AP), which is
involved in the ubiquitin ligase pathway, a system that acts to degrade proteins.
• E6-AP binds ubiquitin to the p53 protein, thereby flagging it for proteosomal degradation.
• Studies have also shown a link between a wide range of HPV types and squamous cell carcinoma
of the skin.
• In such cases, in vitro studies suggest that the E6 protein of the HPV virus may inhibit apoptosis
induced by ultraviolet light
• Most work to date has focused on the study of high-risk HPV types such
as HPV 16 and 18, which has led to an understanding of the molecular
pathways subverted by these viruses.
• Such approaches will lead to the development of better strategies for
disease treatment, including targeted antivirals and
immunotherapeutics.
• Priorities are now focused toward understanding HPV neoplasias at sites
other than the cervix (e.g. tonsils, other transformation zones) and
toward understanding the mechanisms by which low-risk HPV types can
sometimes give rise to papillomatosis and under certain situations even
cancers.
 Kaposi's
sarcoma (KS)
• type of cancer that can form masses in the skin, lymph nodes, or
other organs. 
• The skin lesions are usually purple in color. 
• They can occur singularly, in a limited area, or be widespread. 
• It may worsen either gradually or quickly. 
• Lesions may be flat or raised. 
• Human herpesvirus 8 (HHV8) is found in the lesions of all those who are
affected.
• Risk factors include poor immune function, either as a result of disease or
specific medications, and chronic lymphedema.
• KS lesions are nodules or blotches that may be
red, purple, brown, or black, and are usually 
papular.
• They are typically found on the skin, but
spread elsewhere is common, especially the
mouth, gastrointestinal tract and 
respiratory tract. Growth can range from very
slow to explosively fast, and is associated with
significant mortality and morbidity
 Epstein–Barr virus (EBV)
• also called human herpesvirus 4 (HHV-4), is one of eight known human herpesvirus
types in the herpes family, and is one of the most common viruses in humans.
• It is best known as the cause of infectious mononucleosis ("mono" or "glandular
fever").
• It is also associated with particular forms of cancer, such as Hodgkin's lymphoma, 
Burkitt's lymphoma, gastric cancer, nasopharyngeal carcinoma, and conditions
associated with human immunodeficiency virus, such as hairy leukoplakia and 
central nervous system lymphomas.
• Some evidence indicates infection with EBV is associated with a higher risk of
certain autoimmune diseases, especially dermatomyositis, 
systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and 
multiple sclerosis.
• About 200,000 cancer cases per year are thought to be attributable to EBV.
• Infection with EBV occurs by the oral transfer of saliva and genital secretions.
• Most people become infected with EBV and gain adaptive immunity.
• In the United States, about half of all five-year-old children and about 90% of adults have
evidence of previous infection.
• Infants become susceptible to EBV as soon as maternal antibody protection disappears.
• Many children become infected with EBV, and these infections usually cause no
symptoms or are indistinguishable from the other mild, brief illnesses of childhood.
• In the United States and other developed countries, many people are not infected with
EBV in their childhood years.[
• When infection with EBV occurs during adolescence, it causes infectious mononucleosis
 35 to 50% of the time.
• EBV infects B cells of the immune system and epithelial cells.
• Once EBV's initial lytic infection is brought under control, EBV latency persists in the
individual's B cells for the rest of the individual's life
• Adolescents who contract EBV exhibit few symptoms or may even
appear asymptomatic, but when EBV is contracted as an adult, it may
cause fatigue, fever, inflamed throat, swollen lymph nodes in the
neck, enlarged spleen, swollen liver, or rash.
 Hepatocellular carcinoma (HCC)
• is the most common type of primary liver cancer in adults, and is the most common
cause of death in people with cirrhosis.
• It occurs in the setting of chronic liver inflammation, and is most closely linked to
chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol
 or aflatoxin.
• Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency,
markedly increase the risk of developing HCC.
• As with any cancer, the treatment and prognosis of HCC vary depending on the
specifics of tumor histology, size, how far the cancer has spread, and overall health.
• The vast majority of HCC occurs in Asia and sub-Saharan Africa, in countries where
hepatitis B infection is endemic and many are infected from birth.
• The incidence of HCC in the United States and other developing countries is increasing
due to an increase in hepatitis C virus infections.
• It is more common in males than females for unknown reasons
• Chronic infections of hepatitis B and/or C can aid the development of
hepatocellular carcinoma by repeatedly causing the body's own immune
system to attack the liver cells, some of which are infected by the virus,
others merely bystanders.
• Activated immune-system inflammatory cells release free radicals, such
as reactive oxygen species and nitric oxide reactive species, which in
turn can cause DNA damage and lead to carcinogenic gene mutations.
• Reactive oxygen species also cause epigenetic alterations at the sites of
DNA repair.
• While this constant cycle of damage followed by repair can lead to mistakes during
repair, which in turn lead to carcinogenesis, this hypothesis is more applicable, at
present, to hepatitis C.
• Chronic hepatitis C causes HCC through the stage of cirrhosis.
• In chronic hepatitis B, however, the integration of the viral genome into infected cells
can directly induce a noncirrhotic liver to develop HCC.
• Alternatively, repeated consumption of large amounts of ethanol can have a similar
effect.
• The toxin aflatoxin from certain Aspergillus species of fungi is a carcinogen and aids
carcinogenesis of hepatocellular cancer by building up in the liver.
• The combined high prevalence of rates of aflatoxin and hepatitis B in settings such as 
China and West Africa has led to relatively high rates of hepatocellular carcinoma in
these regions.
• Other viral hepatitides such as hepatitis A have no potential to become a chronic
infection, thus are not related to HCC.
• Since hepatitis B and C are some of the main causes of hepatocellular
carcinoma, prevention of infection is key to then prevent HCC.
• Thus, childhood vaccination against hepatitis B may reduce the risk of
liver cancer in the future.
•  In the case of patients with cirrhosis, alcohol consumption is to be
avoided.
• Also, screening for hemochromatosis may be beneficial for some
patients.
• Whether screening those with chronic liver disease for HCC improves
outcomes is unclear.