Cancer is not one disease, but a collection of related diseases that can

occur almost anywhere in the body.

At its most basic, cancer is a disease of the genes in the cells of our
body.
Genes control the way our cells work.
But, changes to these genes can cause cells to malfunction, causing
them to grow and divide when they should not—or preventing them
from dying when they should. These abnormal cells can become
cancer.
 Overview of changes
in cells that cause cancer
The cancer-forming process, called oncogenesis or
tumorigenesis, is an interplay between genetics and the
environment. Most cancers arise after genes are altered by cancer-
causing chemicals, known as carcinogens, or by errors in their
copying and repair.
More typically, a series of mutations
in multiple genes creates a
progressively more rapidly
proliferating cell type that escapes
normal growth restraints, creating
an opportunity for additional
mutations.
The cells also acquire other properties that give them an advantage,
such as the ability to escape from normal epithelia and to stimulate
the growth of vasculature to obtain oxygen. Eventually the clone of
cells grows into a tumor (neoplasm).
In some cases, cells from the
primary tumor migrate to new
sites, where they form secondary
tumors, a process termed
metastasis.
Most cancer deaths are due to
invasive, fast-growing
metastasized tumors.
Clinically, cancers are often classified by their embryonic tissue of origin. Malignant
tumors are classified as carcinomas if they derive from epithelia such as endoderm
(gut epithelium) or ectoderm (skin and neural epithelia) and sarcomas if they derive
from mesoderm (muscle, blood and connective tissue precursors).
Carcinomas are by far the most common type of malignant tumor.
Cancer that do not fit in either of these two broad categories include
the various leukemias and lymphomas, derived from white
blood cells and their precursors (hemopoietic cells), as well
as cancers derived from cells of the nervous system.
Each broad category has many subdivisions according to;
the spesific cell type,
location in the body and
the microscopic appearance of the tumor
Adenocarcinoma cancer that
forms in the glandular tissue,
which lines certain internal organs
and makes and releases
substances in the body, such as
mucus, digestive juices, and other
fluids.
Most cancers of the breast, lung, esophagus, stomach, colon, rectum, pancreas, prostate, and
uterus are adenocarcinomas.
There is a related set of names for benign tumors: an adenoma.
As long as the neoplastic cells do not become invasive, tumor is said
to be benign, and removing or destroying the mass locally usually
achieves a complete cure.
A tumor is considered a cancer only if it is malignant.
The genetic makeup of most cancer cells is dramatically altered

Tumors harbor all types of genetic alterations—

point mutations,
small and large amplifications and deletions,
translocations and
aberrant numbers of chromosomes—a condition known as aneuploidy.
Also, mutations, deletions, and changes in copy number of
mitochondrial DNA (mtDNA), are observed throughout cancers.
Cancer-critical genes can be classified into two groups, according to
whether their gain of function or their loss of function
contributes to cancer development.
Gain of function mutations that convert proto-oncogenes to
oncogenes stimulate cells to increase their numbers when they
should not;
loss of function mutations of tumor suppressor genes
abolish the inhibitory controls that normally help to hold cell
numbers in check.
Mutations in three broad classes of genes have been implicated in the onset of
cancer.
Proto-oncogenes normally promote cell growth; mutations change them into
oncogenes whose products are excessively active in growth promotion.
Oncogenic mutations usually result in either increased gene expression and
production of a hyperactive gene product.
Tumor-suppressor genes
normally restrain growth, so
mutations that inactivate them allow
inappropriate cell division.
A third class of genes often linked to
cancer, called genome
maintenance genes, are involved
in maintaining the genome’s
integrity.
Many of the genes in these three classes encode proteins that help
regulate cell proliferation (i.e., entry into and progression
through the cell cycle) or cell death by apoptosis; others encode
proteins that participate in repairing damaged DNA.
Even if the genetic damage occurs in
only one somatic cell, division of this
cell will transmit the damage to its
daughter cells, giving rise to a clone
of altered cells.
Rarely, however, does mutation in a
single gene lead to the onset of
cancer.
 Tumor growth requires formation of new blood vessels

Tumors must recruit new blood vessels in order to grow to a large size.
Most tumors induce the formation of new blood vessels that invade the
tumor and nourish it, a process called angiogenesis.
Many tumors produce growth factors that stimulate angiogenesis; other
tumors somehow induce surrounding normal cells to synthesize and
secrete such factors.
Basic Fibroblast Growth Factor (b-FGF),
Transforming Growth Factor α (TGF-α) and
Vascular Endothelial Growth Factor (VEGF),
which are secreted by many tumors,
all have angiogenic properties.
 Carcinogens induce cancer by damaging DNA

The ability of chemical carcinogens to induce cancer results from the

DNA damage they cause as well as the errors introduced into DNA
during the cells’ efforts to repair that damage. Thus carcinogens are
also mutagens.
Cancer incidence should increase with
age because it can take decades for the
required multiple mutations to occur.
However, the incidence of most types
of cancer would be independent of age
if only one mutation were required to
convert a normal cell into a malignant
one.
 Cancer development can be studied in cultured
cells and in animal models

Most cultured cells have a finite lifespan. After about 50 divisions, human cells
cease to divide and eventually die due to erosion of their telomeres. Some cells,
however, escape this fate and become immortal; that is, they gain the ability to
divide indefinitely.
Telomeres cap the ends of linear chromosomes. In humans, they are made
up of hundreds to thousands of TTAGGG motif DNA repeats that bend over to
form a specialised loop structure.
The full length of the telomeres cannot be fully replicated and so telomeres
become shorter with each cell division.
When telomeres become critically short, the cell stops dividing or dies.
Telomeres have hence been described as a 'biological clock' that determines
how long a cell can carry on contributing to cell population growth.
Cancer cells activate telomere length maintenance mechanisms that enable
them to achieve immortality and support ongoing tumour growth.
When telomeres become critically short, they can no longer form a protective
structure that protects the chromosome ends. These short telomeres are
recognised by the cell's DNA repair machinery as a DNA break and further cell
division is blocked.
 Cancer can result from the expression of mutant forms of seven
types of protein
(I) extracellular signaling molecules,
(II) signal receptors,
(III) signal-transducing proteins,
(IV) transcription factors and
(V) cell cycle control proteins
which function to restrain cell proliferation,
(VI) DNA-repair proteins
(VII) apoptotic proteins are encoded by tumor-suppressor genes.
 Gain-of-function mutations convert
proto-oncogenes into oncogenes
For example, the RAS gene is a proto-oncogene that encodes an
intracellular signal-transducing protein that promotes cell division; the
mutant rasD gene derived from RAS is an oncogene whose protein
product provides an excessive or uncontrolled proliferation-promoting
signal.
Other proto-oncogenes encode growth-promoting signaling molecules
and their receptors, anti-apoptotic (cell-survival) proteins and
transcription factors.
At least four mechanisms can produce oncogenes from the corresponding
proto-oncogenes:
1. A point mutation (i.e., a change in a single base pair) in a proto-
oncogene that results in a hyperactive or constitutively active protein
product.
2. A chromosomal translocation that fuses two genes to-gather to
produce a hybrid gene encoding a chimeric protein whose activity, unlike
that of the parent proteins.
3. A chromosomal translocation that brings a growth regulatory
gene under the control of alternative enhancers that cause
inappropriate expression of the gene.
4. Amplification (i.e., abnormal DNA replication) of a DNA
segment including a proto-oncogene so that numerous copies exist,
leading to overproduction of the encoded protein.
 Loss-of-function mutations in
tumor- suppressor genes are oncogenic

Tumor-suppressor genes generally encode proteins that in one way

or another inhibit cell proliferation. Loss-of-function mutations in
one or more of these proliferation inhibitory proteins contribute to
the development of many cancers.
Prominent among the classes of proteins encoded by tumor-
suppressor genes are these five:
1. Intracellular proteins that regulate or inhibit entry into the cell
cycle (e.g., p16 and Rb)
2. Receptors or signal transducers for secreted hormones or
developmental signals that inhibit cell proliferation (e.g., TGF-β)
3. Checkpoint pathway proteins that arrest the cell cycle if DNA is
damaged (e.g., p53)
4. Proteins that promote apoptosis
5. Enzymes that participate in DNA repair
Generally, one copy of a tumor-suppressor gene suffices to control
cell proliferation, so both alleles of a tumor-suppressor gene must be
lost or inactivated in order to promote tumor development. Thus
tumorigenesis-promoting loss-of-function mutations in tumor-
suppressor genes are recessive.
Epigenetic changes can also contribute to tumorigenesis

The word “epigenetic” literally means “in addition to changes in genetic

sequence.” The term has evolved to include any process that alters gene
activity without changing the DNA sequence.
Many types of epigenetic processes have been identified—they include
methylation, acetylation, phosphorylation, ubiquitylation and
sumolyation.
Epigenetic processes are natural and essential to many organism
functions, but if they occur improperly, there can be major adverse
health and behavioral effects.
It is now clear that epigenetic silencing of tumor suppressor genes,
which may be considered functionally equivalent to mutations and
deletions, plays a major role in the development of cancer. Changes in
DNA methylation, as well as changes in the activity of histone-
modifying enzymes or chromatin-remodeling complexes are now
recognized as major drivers of tumorigenesis.
 Micro-RNAs can promote and inhibit tumorigenesis

In the last decade, a new class of oncogenic factors has emerged.

Noncoding RNAs (RNAs that do not encode proteins), especially
micro-RNAs (miRNAs), play a critical role in tumorigenesis.
 BCR ABL Translocation

In the 1960s, researchers first realized that some cancers harbor

characteristic chromosome alterations. Chronic myelogenous leukemia
(CML) was found to be associated with the Philadelphia chromosome,
which is generated by a translocation between chromosomes 22 and 9.
At the breakpoint of this translocation, a new fusion protein, the BCR-ABL
fusion, is generated, creating a protein kinase that phosphorylates proteins
that the wild-type ABL kinase normally does not phosphorylate. Thereby
activating many intracellular signal-transducing proteins.
Misregulation of Cell Growth and Death
Pathways in Cancer
Oncogenic receptors can promote
proliferation in the absence of
external growth factors
 Many oncogenes encode constitutively active
signal-transducing proteins

A large number of oncogenes are derived from proto-oncogenes whose

encoded proteins are components or regulators of signal transduction
pathways- most prominent among them the Ras pathway.
Every component of this RTK/Ras/MAP kinase signaling cascade has been
identified as an oncogene or tumor-suppressor gene.
For example, constitutively active forms of RAF have been identified in
approximately 50 percent of melanomas.
In addition to RTK/RAS/MAP kinase signaling pathway constituents,
cytoplasmic protein kinases are frequently mutated in cancer.
 Inappropriate production of nuclear
transcription factors can induce transformation

Since the most direct effect on gene expression is exerted by transcription

factors, it is not surprising that many oncogenes encode transcription factors.
Two examples, the JUN and FOS function as oncoproteins by
activating the transcription of key genes that encode growth-
promoting proteins or by inhibiting the transcription of growth-
repressing genes.
 Aberrations in signaling pathways that control
development are associated with many cancers

During normal development, secreted signals such as Hedgehog (Hh), Wnt

and TGF-β are used to direct cells to particular developmental fates.

For example, APC gene, mutated on the path to colon cancer, is a part of the
Wnt signaling pathway.
Associated with Hedgehog Signaling
The Hedgehog (Hh) signaling pathway, which is used repeatedly during
development to control cell fates, is a good example of a signaling
pathway implicated in cancer induction.
In the skin and cerebellum, one of the human Hh proteins stimulates cell
division by binding to and inactivating a membrane protein called
Patched1 (PTC1). Loss-of-function mutations in PTC1 permit cell
proliferation in the absence of an Hh signal; thus PTC1 is a tumor-
suppressor gene.
Associated with TGF-β
Transforming growth factor β (TGF-β), despite its name, inhibits
proliferation of many cell types.
In normal cells, binding of TGF-β to its receptor activates cytosolic Smad
transcription factors. After translocating to the nucleus, Smads can
promote expression of the gene encoding p15, an inhibitor of cyclin-
dependent kinase 4 (CDK4), which causes cells to arrest in G1.
Loss-of-function mutations in either
TGF-β receptors thus promote cell
proliferation and probably contribute
to the invasiveness and metastasis of
tumor cells.
 Genes that regulate apoptosis can function as
proto-oncogenes or tumor-suppressor genes

Chronic lymphoblastic leukemia (CLL) cells have chromosomal

translocations that activate a gene called BCL2, which is critical
blocker of apoptosis. The resultant inappropriate over-production of
BCL2 protein prevents normal apoptosis and allows survival of these
tumor cells.
Associated with AKT pathway

Genes whose protein products stimulate apoptosis behave as tumor

suppressors such as PTEN gene. The phosphatase encoded by this
gene, a secondary messenger, functions in activation of AKT.
Cells lacking PTEN phosphatase have elevated levels of PIP3 and active
AKT, which promotes cell survival, growth and proliferation and
prevents apoptosis by several pathways.
Thus PTEN acts as a pro-apoptotic tumor suppressor by decreasing the
anti-apoptotic and proliferation-promoting effects of AKT.
Via p53

The most common pro-apoptotic tumor-suppressor gene implicated in

human cancers is p53. Among the genes activated by p53 are several
encoding pro-apoptotic proteins such as BAX. When cells suffer
extensive DNA damage or numerous other stresses such as hypoxia, the
p53-induced expression of pro-apoptotic proteins leads to their quick
demise.
Via p53

While apoptosis may seem like a drastic response to DNA damage, it

prevents proliferation of cells that are likely to accumulate multiple
mutations.
When p53 function is lost, apoptosis can not be induced and the
accumulation of mutations required for cancer to develop and progress
becomes more likely.
The activity of p53 is normally kept low by a protein called MDM2.
When MDM2 is bound to p53, it inhibits the transcription-activating
ability of p53 and at the same time, because it has E3 ubiquitin
ligase activity, catalyzes the ubiquitinylation of p53, thus targeting
it for proteasomal degradation.
Phosphorylation of p53 by ATM or ATR displaces bound MDM2
from p53, thereby stabilizing it. Because the MDM2 gene is itself
transcriptionally activated by p53, MDM2 functions in an
autoregulatory feedback loop with p53, perhaps normally preventing
excess p53 function.
The MDM2 gene is amplified in many sarcomas and other human
tumors that contain a normal p53 gene.
A key regulator of MDM2 is the p14ARF protein, binds to MDM2
and sequesters it in the nucleolus, away from p53.
Thus p14ARF is an important inhibitor of tumorigenesis, since it
induces p53 activation.
 Deregulation of the Cell Cycle and
Genome Maintenance Pathways in Cancer
 Mutations that promote unregulated passage
from G to S phase are oncogenic

The pathway that controls entry into the cell cycle is estimated to be
misregulated in approximately 80 percent of human cancers.
Molecules at the center of this pathway are cyclin D- CDK4/6
complexes and the transcription inhibitor RB.
Elevated levels of cyclin D1, one of the three cyclin Ds, are found in
many human cancers.
Loss of RB gene function is also found in more common cancers.

In particular, loss-of-function mutations that prevent p16 from inhibiting

cyclin D–CDK4/6 kinase activity are also common in several human
cancers.
p16 gene or genes encoding other functionally related proteins, is
inactivated by hypermethylation of its promoter region, which
prevents its transcription.
 Loss of DNA-repair systems can lead to cancer

Damage to DNA-repair systems leads to an increased rate of genetic

alterations. Many mutations that accumulate in cells with defects in DNA
repair mechanisms promote cancer.
Therefore, people who inherit mutations in genes that encode a crucial
mismatch-repair or excision-repair protein have an enormously
increased probability of developing certain cancers.
For instance, HNPCC (hereditary nonpolyposis colorectal cancer) genes
encode components of the mismatch-repair system and mutations in
these genes are found in 20 percent of sporadic colon cancers.
WHATEVER YOU ARE, BE A GOOD ONE