==== Cancer Biology ===

Cancer: A Genetic Disease 

Mutations in genes that control cell growth and division are responsible for cancer.

Carcinogens ➔ DNA mutations (A carcinogen is defined as an agent that increases the incidence
of neoplasms)

 Cancers arise when critical genes are mutated, causing unregulated proliferation of cells.
 These rapidly dividing cells pile up on top of each other to form a tumor.
 When cells detach from the tumor and invade surrounding tissues, the tumor is malignant
and may form secondary tumors at other locations in a process called metastasis.
 A tumor whose cells do not invade surrounding tissues is benign.
 Tumor – is a condition where there is abnormal cellular growth thus forming a lesion or in
most cases, a lump in some part of your body.
 Benign tumor – grows in confined area
 Malignant tumor – capable of invading surrounding tissues
 Cancer – degenerative disease with a cellular condition where there is uncontrolled growing
mass of cells capable of invading neighboring tissues and spreading via body fluids to other
parts of the body.
 Types of cancer based on the site of origin:

a) Carcinomas – epithelial cells; cover external & internal body surfaces (90%)
b) Sarcomas – supporting tissue; bone, cartilage, fat, connective tissue, pancreas,
Liver.
c) Lymphoma & leukemias – blood & lymphatic tissue (leukemia reserved for
cancers that reside in bloodstream not as solid tissue)

Normal cells vs. Cancer cells 

Normal cells Cancer cells

Anchorage dependent Anchorage independent
Density-dependent inhibition Can grow on top of one another
Limited number of cell divisions Immortal
Telomere shortening Telomere maintenance
Proliferation dependent upon extracellular signals Constant signal to divide independent
Checkpoints activated at appropriate times Loss of checkpoint
Apoptosis functional Apoptosis inhibited

Basic Properties of a Cancer Cell 

– In culture, normal cells can be transformed by chemicals or viruses.

– Different types of cancer cells share a number of similarities such as :
• Aberrant chromosome numbers (aneuploidy)
• High metabolic requirements
• Unregulated growth
• Synthesis of unusual cell surface proteins

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Manoj Kumar Singh PhD, Associate Professor, Dept. of Biotechnology, Adamas University
Stages in the Process of Invasion and Metastasis


• Loss of contact inhibition may lead to tumor

growth
• Loss of cell-cell adhesion may lead to spread
of the cancer cells to other organ via blood
circulation.

Evidence of a Genetic Basis for Cancer 

Cause of cancer is always associated with the gene

such as:
 The cancerous state is clonally inherited.
 Some types of viruses can induce the
formation of tumors in experimental
animals.
 Cancer can be induced by mutagens.
 Certain types of white blood cell cancers are associated with particular chromosomal
abnormalities

Oncogenes and Tumor Suppressor Genes 

 Oncogene:
Proto-oncogenes are genes that normally help cells grow. When a proto-oncogene mutates
(changes) or there are too many copies of it, it becomes abnormal that can become
permanently turned on or activated when it is not supposed to be. When this happens, the cell
grows out of control, which can lead to cancer. This abnormal gene is called an oncogene.
(e.g. Myc gene, Ras gene)
**Mutant alleles (oncogenes) tend to be dominant: one copy of the mutant allele is sufficient
to induce excessive cell proliferation.
 Tumor suppressor genes
Tumor suppressor genes are normal genes that slow down cell division, repair DNA damage,
or signal cells when to die (a process known as apoptosis or programmed cell death). When
tumor suppressor genes don't work properly, cells can grow out of control, which can lead to
cancer.(e.g. BRCA2 gene, TP53 gene, RB1 gene)
**Mutant alleles are recessive (both alleles must be mutated to produce excessive
cell proliferation).
Tumor-Inducing Retroviruses and Viral Oncogenes 
When viruses cause an infection, they spread their DNA by integrating with the host DNA and
potentially causing them to turn into cancer.
 Retroviruses have an RNA genome.
 The Rous sarcoma virus, the first tumor-inducing virus, contains four genes
– gag encodes the capsid protein of the virus
– pol encodes the reverse transcriptase
– env encodes a viral envelope protein
– v-src encodes a protein kinase that inserts into the plasma membranes of infected
cells. The v-src gene is an oncogene that is responsible for the virus’s ability to
induce abnormal cell growth.
Proteins Encoded by Viral Oncogenes mimic the host proteins with an altered function such as:
 Growth factors similar to those encoded by cellular genes
 Proteins similar to growth-factor and hormone receptors
 Tyrosine kinases that do not span the plasma membrane
 Transcription factors homologous to cellular proteins
…………………………………………………………………………………………………………………………………………………………….
Manoj Kumar Singh PhD, Associate Professor, Dept. of Biotechnology, Adamas University
 retrovirus inserts its RNA
into the cell; the viral
RNA undergoes reverse
transcription and inserts
into the host chromosome
next to a proto-oncogene

In repeated rounds of
viral infection and
reproduction, the proto-
oncogene becomes
rearranged or mutated or
both,…

...producing an oncogene
that is inserted back into
the host chromosome.

 Some viral oncogenes produce more

protein than their cellular counterpart.
 Other viral oncogenes express their proteins
at inappropriate times.
 Other viral oncogenes express mutant
forms of the cellular proteins.

The c-ras Gene

 The c-H-ras oncogene was identified by the transfection test (homologue to the Harvey strain
of the rat sarcoma virus)
 The mutant c-H-ras protein has a mutation that impairs its ability to hydrolyze GTP. This
keeps the mutant protein in an active signaling mode and causes it to stimulate cell division.
 Mutant versions of c-ras have been found in many types of tumors.

…………………………………………………………………………………………………………………………………………………………….
Manoj Kumar Singh PhD, Associate Professor, Dept. of Biotechnology, Adamas University
 Changes in Chromosome Number and Structure Are Often Associated with Cancer

Philadelphia chromosome
 The Philadelphia chromosome is the result of
a reciprocal translocation between
chromosomes 9 and 22 with breakpoints in
the c-abl gene on chromosome 9 and the c-bcr
gene on chromosome 22.
 The fusion gene created by this rearrangement
encodes a tyrosine kinase which is much
more active than the protein produced by the
normal c-ABL gene and therefore promotes
cancer in white blood cells.
 This translocation produces a shortened
chromosome 22, called the Philadelphia
chromosome because it was first discovered in
Philadelphia. (leukemia)
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Manoj Kumar Singh PhD, Associate Professor, Dept. of Biotechnology, Adamas University
 Burkitt’s Lymphoma
 Many people with Burkitt lymphoma
possess a reciprocal translocation
between chromosome 8 and
chromosome 2, 14, or 22.
 This translocation relocates a gene
called c-MYC from the tip of
chromosome 8 to a position in
chromosome 2, 14, or 22 that is next to
a gene that encodes an
immunoglobulin protein.
 At this new location, c-MYC, a cancer-
causing gene, comes under the control
of regulatory sequences that normally
activate the production of
immunoglobulins, and c-MYC is
expressed in B cells. The c-MYC
protein stimulates the division of the B
cells and leads to Burkitt lymphoma.

Knudson’s Two-Hit Hypothesis

 When tumor suppressor genes are mutated, a predisposition to develop cancer often follows a
dominant pattern of inheritance.
 The mutation is usually a loss-of-function mutation in the tumor suppressor gene.
 Cancer develops only if a second mutation in somatic cells knocks out the function of the
wild-type allele.

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Manoj Kumar Singh PhD, Associate Professor, Dept. of Biotechnology, Adamas University
Cellular Roles of Tumor Suppressor Genes

 The proteins encoded by tumor suppressor genes are involved in

 cell division,
 cell differentiation,
 programmed cell death,
 DNA repair.

pRB and its role in Cell Cycle regulation

 The retinoblastoma protein (pRB) is a tumor-suppressor protein (105KDa) that controls the
G1/S cell-cycle checkpoint.
 The loss or mutation of the RB1 (retinoblastoma 1) tumorsuppressor gene contributes to the
development of many cancers, including those of the breast, bone, lung, and bladder.
 The pRB protein is found in the nuclei of all cell types at all stages of the cell cycle. However,
its activity varies throughout the cell cycle, depending on its phosphorylation state.

(Fig. )During G0 and early G1, pRB interacts with and inactivates transcription factor E2F. As the
cell moves from G1 to S phase, a CDK4/cyclinD1 complex forms and adds phosphate groups to pRB.
As pRB becomes phosphorylated, E2F is released and becomes transcriptionally active, allowing the
cell to pass through S phase. Phosphorylation of pRB is transitory; as CDK/cyclin complexes are
degraded and the cell moves through the cell cycle to early G1, pRB phosphorylation declines,
allowing pRB to reassociate with E2F.

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Manoj Kumar Singh PhD, Associate Professor, Dept. of Biotechnology, Adamas University
p53 and its Role in Regulation of Cell Cycle and Apoptosis

 The p53 tumor suppressor protein is encoded by the TP53 gene (53 KDa).
 Inherited mutations in TP53 are associated with Li-Fraumeni syndrome.
 Somatic mutations that inactivate both copies of TP53 are associated with the majority of
cancers.

Fig. Most mutations in that inactivate p53 are in the DNA-binding domain (DBD) and impair
its ability to bind enhancer sequences in its target genes. Mutations in this domain are “lost-
of-function.”
OD: homo-oligomerazation domain. Mutations in this domain are “dominant negative.”
TAD: transcriptional activation domain
The Cellular Function of p53
 Expression of p53 is very low in normal cells.
 Expression of p53 increases in response to DNA damage due to a decrease in degradation.
 p53 can inhibit cell division or induce apoptosis.

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Manoj Kumar Singh PhD, Associate Professor, Dept. of Biotechnology, Adamas University