Molecular Biology of Cancer

Dr. Maya Datt Joshi

 MOLECULAR BIOLOGY OF
CANCER
Normal cells have a defined lifespan – they
grow, divide, and die in an orderly fashion. A
critical balance is maintained between cell
growth, proliferation, differentiation, and
apoptosis.
In the presence of agents that promote tumor
formation, such as an inherited genetic defect,
a chemical carcinogen, viral infection, or
irradiation, this critical balance is disrupted.
When cells in a part of the body begin to grow
out of control, cancer develops.
 MOLECULAR BIOLOGY OF
CANCER
Cancer is unchecked cell growth. Mutations in
genes can cause cancer by accelerating cell
division rates or inhibiting normal controls on the
system, such as cell cycle arrest or programmed
cell death. As a mass of cancerous cells grows, it
can develop into a tumor.
Cancer is a term for diseases in which abnormal
cells divide without control and can invade nearby
tissues. Cancer cells can also spread to other parts
of the body through the blood and lymph systems.
Therefore many types of cancer are present.
 MOLECULAR BIOLOGY OF
CANCER
Cancer is a multistep disease. The emergence of a
tumor cell requires the accumulation of many –
estimated to be between four and eight – genetic
changes over the course of years.
Gene mutations that increase the risk for
developing cancer can be inherited or
acquired.
Acquired genetic changes result from spontaneous
or environmentally inflicted errors during DNA
replication.
 MAJOR CHANGES THAT
OCCUR WHEN A CELL
BECOMES CANCEROUS

1. Immortalization: The cancer cell

acquires the ability to grow and divide
indefinitely.
2. Transformation: The cancer cell fails
to observe the normal determinants of
growth; i.e. growth occurs independently
of cell growth factors. Transformed cells
may form a sold tumor. In order for the
tumor to grow it must develop its own
blood supply through the process of
MAJOR CHANGES THAT OCCUR WHEN
A CELL BECOMES CANCEROUS

3. Metastasis: Cancer cells often travel from

the tissue of origin to other parts of the body
where they begin to grow and replace normal
tissue. This process, called metastasis,
occurs as cancer cells gain the ability to
invade the bloodstream or lymph vessels and
other tissues. When cells from a cancer like
colon cancer spread to another organ like the
lung, the cancer is still called colon cancer,
not lung cancer.
 TUMORIGENESIS
The genetic changes associated with tumorigenesis
can be divided into two major categories:
those that result from a gain of function and those
that result from a loss of function. Gain of function
involves inappropriate activation of oncogenes. These
genes are stimulatory for growth and can cause cancer
when hyperactive.
Loss of function involves inactivation of tumor
suppressor genes. These are genes that inhibit cell
growth and which cause cancer when they are not
expressed.
 ACTIVATION OF
ONCOGENES
Oncogenes are defined as genes whose
products have the ability to cause malignant
transformation of eukaryotic cells. They were
originally identified as the “transforming genes”
carried by some DNA and RNA tumor viruses.
The term “proto-oncogene” refers to cellular
genes with the potential to give rise to
oncogenes. For example, oncogenes are the
normal counterparts in the eukaryotic genome
to the oncogenes carried by retroviruses.
ACTIVATION OF
ONCOGENES
ACTIVATION OF
ONCOGENES
 INACTIVATION OF
TUMOR SUPPRESSOR
GENES
The discovery of oncogenes led to the
identification of another class of cellular genes,
the tumor suppressor genes.
Tumor suppressor gene products are required
for normal cell function and, like oncogene
products, play a central role in regulating cell
growth and division.
Cancer arises when there are two independent
mutations that lead to loss of function of both
tumor suppressor alleles at a locus.
 INACTIVATION OF
TUMOR SUPPRESSOR
GENES
Loss can be either sporadic or heritable. If loss of
one allele is inherited through the germline, an
individual is said to have a “genetic predisposition”
to cancer. Sporadic mutation of the second allele in
a somatic cell leads to tumorigenesis.
Loss of function of a tumor suppressor gene can
also occur at a much lower frequency by two
sporadic mutations in the same cell. Two of the
best-characterized tumor suppressor genes encode
the retinoblastoma (pRB) and p53 proteins.
 INACTIVATION OF
TUMOR SUPPRESSOR
GENES
The retinoblastoma protein (pRB) is called the “cell cycle
master switch”. This protein has been implicated in the
regulation of DNA replication, cell differentiation, DNA
repair, cell cycle checkpoints, and apoptosis.
 INACTIVATION OF
TUMOR SUPPRESSOR
GENES
The tumor suppressor protein p53 (named for its molecular
size of 53 kDa) is often referred to as the “guardian of the
genome.”
It regulates multiple components of the DNA damage control
system, and is one of the genes most commonly induced in
response to cellular stress signals.
As a transcription factor, p53 can activate or repress many
target genes. Over 100 genes regulated by p53 have been
identified through microarray analysis.
Bioinformatic studies predict that the number may be much
greater – greater than 4000 human genes contain putative
p53-binding sites in their promoter region.
 INACTIVATION OF
TUMOR SUPPRESSOR
GENES
Role of p53 in cancer Alterations in the p53 gene have
been linked to many cancers including cervix, breast,
bladder, prostate, liver, lung, skin, and colon. Eighty
percent of all human cancers show either deletion of
both alleles on chromosome 17 leading to the absence
of p53 protein (similar to pRB), or a missense point
mutation in one allele.
Mutations in p53 are associated with the hereditary
cancer syndrome, Li–Fraumeni syndrome (named after
its 1969 discoverers), which predisposes patients to
brain tumors, sarcomas, leukemia, and breast cancer.
Because p53 is defective in so many different types of
 DIFFERENT STEPS OF
CARCINOGENESIS
1. Initiation: Mutation in one or more cellular genes
controlling key regulatory pathways of the cell
(irreversible)—must be a heritable DNA alteration.
2. Promotion: selective growth enhancement induced
in the initiated cell and its progeny by the continuous
exposure to a promoting agent.
3. Progression: results from continuing evolution of
unstable chromosomes; further mutations from genetic
instability during promotion—results in further degrees
of independence, invasiveness, metastasis, etc.
METASTASIS
Metastasis of tumor characterized by the following:
1. One of the most important proteins is the cell-cell adhesion
molecules (CAMs), whose main role is to bind cells to
surrounding tissue. Among the CAMs, the most common
protein implicated in metastasis is E-cadherin, found in all
epithelial cells. In normal cells, E-cadherin acts as a bridge
between adjacent cells, enabling cytoplasmic contact and
sharing intracellular signaling factors responsible for inhibiting
invasion and metastatic capability.
Most epithelial cancers show a loss of E- cadherin function
and this elimination plays a significant role in metastatic
capability.
METASTASIS
2. Another class of proteins involved in tissue
invasion are the integrins, a widely distributed family
of transmembrane adhesion receptors, which link
cells to the extracellular matrix. In addition to their
role in angiogenesis, they also play a central role in
cell adhesion and migration, control of cell
differentiation, proliferation and survival.
Changes in integrin expression are also evident in
invasive and metastatic cells. Successful colonization
of new sites (both local and distant) demands
adaptation, which is achieved by changing integrin
subunits displayed by the migrating cells.
METASTASIS
3. Another strategy in successful colonization
is increasing expression of extracellular
proteases (such as MMPs- Matrix
Metaloproteinases) while decreasing levels of
protease inhibitors. Cells in the stroma close
to cancer cells secrete active proteases, which
facilitate invasion by degrading components
of the extracellular matrix. This enables
cancer cells to migrate across blood vessel
boundaries and through normal epithelial cell
 REFERENCES
1. Jawetz, Melnick&Adelberg’s. Medical Microbiology. 25th
edition. 2016
2. Lizabeth A. Allison. Fundementals Molecular Biology. 2007.
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