Introduction to Cancer Stem cells and cancer cells major pathways that lead to formation of tumors. Tumor Supressors Colon cancer to prove Knudson hypothesis. The modern treatments available to treat cancer.

1. THE GENETIC BASIS OF
CANCER
CELL BIOLOGY AND BIOCHEMISTRY
DIGITAL ASSIGNMENT-2
BHAVISHYA NELAKUDITI
17BCB0121

2. Oncogenes
Cancer is a disease in which abnormal cells divide uncontrollably
and destroy body tissue.
Genes that promote autonomous cell growth in cancer cells are
called oncogenes, and their normal cellular counterparts are
called proto-oncogenes. Proto-oncogenes are physiologic
regulators of cell proliferation and differentiation while oncogenes
are characterised by the ability to promote cell growth in the
absence of normal mitogenic signals.
The RAS oncogene is the most frequently mutated oncogene in
human cancer. It encodes a GTP-binding protein Ras that functions
as an on-off ‘switch’ for a number of key signaling pathways
controlling cellular proliferation. In a normal cell, Ras is transiently
activated and recruits Raf, to activate the MAP-kinase pathway to
transmit growth-promoting signals to the nucleus. The mutant Ras
protein is permanently activated leading to continuous stimulation
of cells without any external trigger.
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3. Tumor
Tumor suppressor genes are protective genes. Normally, they limit cell
growth by monitoring how quickly cells divide into new cells, repairing
mismatched DNA, and controlling when a cell dies. When a tumor
suppressor gene is mutated, cells grow uncontrollably and may
eventually form a mass called a tumor. BRCA1, BRCA2, and p53 are
examples of tumor suppressor genes.
Types of tumors:
1. Cancerous tumours
grows into nearby tissues
has cells that can break away and travel through the blood or lymphatic
system and spread to lymph nodes and distant parts of the body
2. Non-cancerous tumours
stay in one place and don’t spread to other parts of the body
don’t usually come back after they are removed
tend to have a regular and smooth shape and have a covering called a
capsule
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4. Oncogenesis
Oncogenesis, is the formation of a cancer, whereby
normal cells are transformed into cancer cells. The process
is characterized by changes at the cellular, genetic,
and epigenetic levels and abnormal cell division. Cell
division is a physiological process that occurs in almost
all tissues and under a variety of circumstances. Normally
the balance between proliferation and programmed cell
death, in the form of apoptosis, is maintained to ensure
the integrity of tissues and organs.
mutations in DNA and epimutations that lead to cancer
disrupt these orderly processes by disrupting the
programming regulating the processes, upsetting the
normal balance between proliferation and cell death.
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5. Causes of Cancer
Mutations
Cancer development is based on the accumulation of somatic mutations over lifetime. Germ line mutations are typically
not involved, but in very rare cases of inherited cancer predisposition, they are contributing to disease progression.
Typically the basal mutation rate is low in humans, but it may be enhanced through one of the three following groups of
environmental carcinogens: chemical mutagens, radiation and tumor viruses. Exposure to mutagens or radiation greatly
increases the mutation rate and thus the probability of developing cancer.
Chemical mutagens comprise a quite disparate group of chemicals that modify DNA through a range of mechanisms,
such as alkylation or deamination of DNA bases, or through intercalation between base pairs and formation of DNA
adducts (e.g. aromatic hydrocarbons). Oxidative damage may also affect DNA integrity.
X-rays and radioactive radiation tend to induce DNA double-strand breaks, whereas UV radiation results in the
formation of pyrimidine dimers, by cross-linking of adjacent pyrimidine bases.
Viral causes of cancer
Certain viruses, derived from quite different taxonomic groups (Table 3), are able to induce cancer development. We
distinguish the highly oncogenic viruses, which contain viral oncogenes in their genomes that are in most cases derived
from cellular proto-oncogenes, whereas slowly transforming viruses do not contain such genes.
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6. Cell signalling in carcinogenesis
Growth factors (GFs) play an important physiological role
in the normal process of growth control aimed at
maintaining tissue homeostasis. They transmit growth
signals from one cell to another. These signals are sensed
on the cell surface by specific growth factor receptors
(GFRs). GFRs transfer the growth signal via signaling
pathways to activate target molecules that promote
proliferation.
This pathway is often derailed in cancer and allows
wayward cells to generate their own internal signals
that stimulate proliferation and become independent
of their environments. Cancer cells are able to induce
their own growth stimulatory signals when mutations
in the GFR gene occur, which facilitates activation in
the absence of GFs or when overproduction of GFs
results in an autocrine signalling loop.
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7. Stem cells and Cancer
Stem cells
Stem cells are undifferentiated biological cells that
can differentiate into specialized cells and
can divide (through mitosis) to produce more stem
cells. They are found in multicellular organisms.
In mammals, there are two broad types of stem
cells: embryonic stem cells, which are isolated from
the inner cell mass of blastocysts, and adult stem
cells, which are found in various tissues.
In adult organisms, stem cells and progenitor cells act
as a repair system for the body, replenishing adult
tissues.
Normal stem cells in adult somatic tissues and cancer
stem cells share the common features of self-renewal
and slow cycling.
cancer stem cells resulting from mutations in
stem/progenitor cells most likely undergo
uncontrolled proliferation.
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8. Major Pathways
MAPK/ERK pathway: A pathway that couples intracellular
responses to the binding of growth -
factors to cell surface receptors. This pathway is very complex
and includes many protein components.In many cell types,
activation of this pathway promotes cell division, and many
forms of cancer are associated with aberrations in it.
IP3/DAG pathway: DAG remains bound to the membrane, and
IP3 is released as a soluble structure into the cytosol. IP3 then
diffuses through the cytosol to bind to IP3 receptors,
particular calcium channels in the endoplasmic
reticulum (ER). These channels are specific to calcium and allow
the passage of only calcium to move through. This causes the
cytosolic concentration of Calcium to increase, causing a
cascade of intracellular changes and activity. Calcium and DAG
together works to activate PKC, which goes on to phosphorylate
other molecules, leading to altered cellular activity. End-effects
include, manic depression, tumor promotion, etc
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9. Activation of Oncogenes
The activation of oncogenes involves genetic changes to cellular protooncogenes. The
consequence of these genetic alterations is to confer a growth advantage to the cell.
Three genetic mechanisms activate oncogenes in human neoplasms:
(1) mutation
Mutations activate protooncogenes through structural alterations in their encoded
proteins. These alterations, which usually involve critical protein regulatory regions,
often lead to the uncontrolled, continuous activity of the mutated protein.
(2) gene amplification
Gene amplification refers to the expansion in copy number of a gene within the
genome of a cell. Gene amplification was first discovered as a mechanism by which
some tumor cell lines can acquire resistance to growth-inhibiting drugs.
(3) chromosome rearrangements.
Recurring chromosomal rearrangements are often detected in hematologic
malignancies as well as in some solid tumors. These rearrangements consist mainly of
chromosomal translocations and, less frequently, chromosomal inversions.
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10. Viral Oncogenes
DNA and RNA viruses differ in some important characteristics:
(a) DNA viruses. The DNA tumour viruses may also grow in culture
on a variety of cells, which can be classified into following two
types : (i) 'permissive cells', which can be productively infected
and
(ii) 'non-permissive cells', which are not productively infected, but
merely get transformed.Most oncogenes in these viruses are
expressed by alternative splicing. Unlike RNA viruses, oncogenes in
these DNA viruses do not have cellular counterparts.
(b) RNA viruses. RNA tumour viruses may be transformation
competent (able to transform the infected cells) or transformation-
incompetent (able to replicate, but not transform the infected
cells). They may replicate via DNA intermediate or an RNA
intermediate and can transfer genetic information horizontally or
vertically.
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11. Tumor Suppressors
Genes that normally block cell cycle progression are known as tumor
suppressors. Tumor suppressors prevent the formation of cancerous
tumors when they are working correctly, and tumors may form when
they mutate so they no longer work.
One of the most important tumor suppressors is tumor protein p53,
which plays a key role in the cellular response to DNA damage. p53 acts
primarily at the G checkpoint (controlling the G to S transition), where it
blocks cell cycle progression in response to damaged DNA and other
unfavorable conditions
When a cell’s DNA is damaged, a sensor protein activates p53, which
halts the cell cycle at the G​, end subscript checkpoint by triggering
production of a cell-cycle inhibitor. This pause buys time for DNA repair,
which also depends on p53, whose second job is to activate DNA repair
enzymes. If the damage is fixed, p53 will release the cell, allowing it to
continue through the cell cycle. If the damage is not fixable, p53 will play
its third and final role: triggering apoptosis so that damaged DNA is not
passed on.
In cancer cells, p53 is often missing, nonfunctional, or less active than
normal. For example, many cancerous tumors have a mutant form of p53
that can no longer bind DNA. Since p53 acts by binding to target genes
and activating their transcription, the non-binding mutant protein is
unable to do its job.
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12. BRCA1 Gene
The BRCA1 gene provides instructions for making a protein that acts as a
tumor suppressor. Tumor suppressor proteins help prevent cells from growing
and dividing too rapidly or in an uncontrolled way.
The BRCA1 protein is involved in repairing damaged DNA. In the nucleus of
many types of normal cells, the BRCA1 protein interacts with several other
proteins to mend breaks in DNA. These breaks can be caused by natural and
medical radiation or other environmental exposures, and they also occur
when chromosomes exchange genetic material in preparation for cell division.
By helping to repair DNA, the BRCA1 protein plays a critical role in
maintaining the stability of a cell's genetic information.
Research suggests that the BRCA1 protein also regulates the activity of other
genes and plays an essential role in embryonic development. To carry out
these functions, the BRCA1 protein interacts with many other proteins,
including other tumor suppressors and proteins that regulate cell division.
The inactivation of this gene is the cause of breast cancer.
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13. Knudson hypothesis
Knudson's two-hit hypothesis proposes that as few as two
stochastic events are required for tumor initiation. The first can be
either germline or somatic and the second occurs somatically in
the individual retinoblastoma cells.
A “two hit” model has been proposed to explain the different
clinical features of hereditary and nonhereditary cases of
retinoblastoma. These patients inherit a germline mutation in
the RB1 gene that is present in every cell of the body.
The RB1 Gene
Retinoblastoma occurs as a result of such mutations of
the RB1gene located on chromosome 13q14. This is a tumor
suppressor gene that spans 183-kilo bases of genomic DNA,
consisting of 27 exons and coding for a 110-kd protein p110, with
928 amino acids. Positive and negative regulation of transcription
and thus, cell proliferation are linked to the phosphorylation of
the RB protein.
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14. Colon Cancer
The best characterized example supporting the theory of
multi-step carcinogenesis is colorectal cancer. This is largely
due to the relative accessibility of colon cancer samples and
due to the availability of the distinct histo-morphological
description of early stages of cancer development.
Genetic characterization of a large number of early,
intermediate and late adenomas and frank carcinomas led
to the establishment of a ‘preferred’ sequence of genetic
alterations during the adenoma-adenocarcinoma pathway
of colorectal cancer.
These include the activation of the K-ras oncogene from its
cellular proto-oncogene (pink letters) and the loss for three
tumour suppressor genes (blue letters), where loss of APC
(adenomatous polyposis coli) is an early event, whereas loss
of p53 is normally a late event.
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15. Modern Treatment
The progress in our knowledge about gene mutations frequently occurring in
cancers, combined with the development of modern molecular biology
methods has led to both new diagnostic tools and new treatment modalities
that have shown some success in the management of selected types of
cancers.
The knowledge about cancer–associated genes and their role in cellular growth
signaling pathways has led to the development of a considerable number of
anti-cancer drugs targeting such signaling pathways:
1) monoclonal antibodies that target the extracellular domains of growth
factor receptors and
2) small-molecule inhibitors, targeting either receptor tyrosine kinases or
other components of growth signaling pathways, such as Ras, b-Raf or mTOR .
Two examples of such successful anti-cancer agents are the monoclonal
antibody Herceptin for the treatment of a specific subtype of breast cancer,
and the small-molecule inhibitor Gleevec targeting the fusion protein Bcr-abl, a
mutant tyrosine kinase, involved in the development of chronic myeloic
leukaemia (CML).
A third group of potential drug targets are some anti-apoptotic proteins that
are frequently overexpressed in cancer cells.
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