Cancer

Vipin Shankar
Cancer; the current
scenario
 Causes about one fifth of deaths in the
world.
 Between 100 and 350 of every 100,000
deaths is caused by cancer.
 Cancer occurs due to failure of the
mechanisms that control the growth
and proliferation of cells.
Cancer: facts
 During normal development and
throughout adult life, intricate genetic
control systems regulate the balance
between cell birth and death in
response to growth signals, growth-
inhibiting signals, and death signals.
 Cell birth and death rates determine
adult body size, and the rate of growth
in reaching that size.
Cancer: Incidence
 The incidence of cancer
increases exponentially
with age in a human
population from the age
of ~40 to -80
 This suggests that
cancer is the result of
the occurrence of a
series of independent
events.
 From the trend of the
curve we can estimate
that a range of 4-10
stochastic events are
required to generate a
cancer.
Types of cancer
 Cancer can result from abnormal
proliferation of any of the different kinds of
cells in the body, so there are more than 100
distinct types of cancer.
 Tumor : any abnormal proliferation of cells, which
may be either benign or malignant.
 Benign tumor : remains confined to original
location, neither invading surrounding cells nor
spreading to distant bodies.
 Malignant tumor : capable of both invading
surrounding tissue and spreading throughout the
body via the circulatory or lymphatic system
(metastasis).
Types of cancer…
 Both benign and malignant tumors are
classified according to the type of cell
from which they arise.
 Carcinoma : malignancies of the epithelial
cells.
 Sarcoma : solid tumors of the connective
tissue such as muscle, bone and cartilage.
 Leukemia and Lymphoma : arise from
blood forming cells and from cells of the
immune system.
Cancer development
 The development of cancer can be
studied under
 Tumor initiation : results from a genetic
alteration leading to abnormal
proliferation of a single cell.
 Tumor progression : continues as
additional mutations occur within the cells
of the tumor population.
Cancer development…
 The basic model for the occurrence of cancer
is that cancer is a multistage process in
which initiation of a tumor requires several
steps, which may then be followed by further
changes to strengthen the tumorigenic state.
 Tumor progression is then driven by selection
among the tumor cells for those that can
grow more aggressively.
 The two major types of change in the genome
are the accumulation of somatic mutations
and the development of genetic instability.
Cancer development…
 Most cancer cells have an increased number
of mutations compared to normal cells.
 As the cancer progresses, the number of
mutations increases.
 The occurrence of different mutations creates
an opportunity to select among the
population for cells with particular
properties.
 In the case of cancer, a mutation that
increases the growth potential of a cell will
give it a selective advantage.
Cancer development…
 At each stage during the progression of a cancer,
the cell population is selected for those cells that
can grow more aggressively (this meaning initially
that they can grow more rapidly and later that they
can migrate to start colonies in new locations).
 Our current view of cancer is that it is driven by
twin features: an increased rate of mutation is
responsible for generating cells with altered growth
properties; and the population of cells is then
selected for those with an increased rate of
proliferation.
 A cancer progresses by multiple cycles of mutation
and selection.
Cancer development…
 By comparing cancer cells with normal cells,
we can identify genes that have been changed
by mutation.
 Those that have direct effects on the
generation of a cancer can be divided into
 Oncogenes (where a mutation has activated a gene
whose function contributes to the tumorigenic
state)
 Tumor suppressors (where a mutation has
inactivated a gene whose function antagonizes the
tumorigenic state).
Causes of cancer
 Substances that cause cancer are
called carcinogens.
 Since the development of malignancy is
a complex multistep process, many
factors may affect the likelihood that a
cancer may develop.
 Mutagens.
 Tumor promoters.
Properties of cancer cells
 Lacks density-dependent inhibition.
 Reduced requirement of growth factors.
 Continuous auto stimulation of cell division – autocrine
growth stimulation.
 Less adhesive.
 Rounder than normal cells.
 Lacks contact inhibition.
 Secrete proteases that digest ECM, allowing the cells to
invade adjacent normal tissue.
 Secrete growth factors that promote the formation of
new blood vessels (angiogenesis).
 Fail to differentiate normally.
 Fail to undergo apoptosis.
Tumor viruses
 Members of several families of animal
viruses are capable of directly causing
cancer.
 Hepatitis B & C viruses (liver cancer).
 Papillomavirus (cervical cancer).
 Epstein-Barr virus (Burkitt’s lymphoma &
nasopharyngeal carcinoma).
 Kaposi’s sarcoma associated herpes virus
( Kaposi’s sarcoma).
Hepatitis B virus
 Has the smallest genome (3kb) of all animal
DNA viruses.
 Specifically infect liver cells of many species.
 Infection results in acute liver damage.
 In 5-10% acute infection is not resolved and
chronic infection of the liver develops.
 Such chronic infection is associated with
more than a hundred fold increases risk of
liver cancer.
 Infection common in Asia & Africa.
Hepatitis B virus…
 Cell transformation is mediated by a
viral gene (X gene) that affects
expression of a variety of cellular genes
that drive abnormal cell proliferation
and survival.
 Development of cancer induced by
continual proliferation of liver cells that
result from chronic tissue damage and
inflammation.
Hepatitis C virus
 RNA virus with a genome of approximately 10
kb
 Can establish chronic liver infections that are
associated with a high risk of cancer.
 Cell proliferation in response to chronic
inflammation is a major contributor to
carcinogenesis.
 It is also possible that some hepatitis C virus
proteins directly stimulate proliferation of
infected liver cells.
SV40 & Polyomavirus
 Not associated with human cancers.
 Critically important as models for
understanding the basis of cellular
transformation.
 Transformation by these viruses has been
found to result from the expression of the
same viral genes that function in early stages
of lytic infection.
 Both SV40 & polyomavirus early proteins
induce transformation by interacting with
host proteins that regulate cell proliferation.
Papillomaviruses
 Small DNA viruses.
 Induce both benign and malignant (Cervical
and anogenital) tumors in humans and
various other animal species.
 Approximately 60 different types which infect
epithelial cells of various tissues have been
identified.
 Cell transformation induced by two early
genes (E6 & E7), interacting with Rb abd
p53.
Adenoviruses
 DNA virus.
 Not associated with natural human
cancers, widely used for studies.
Herpesviruses
 Kaposi’s sarcoma-associated
herpesvirus.
 Epstein-Barr virus (affects
lymphocytes).
Retroviruses
 Human T-cell lymphotropic virus Type I
(HTLV – I) : adult T-cell leukemia.
 HIV: does not cause cancer directly,
but people infected with HIV have a
higher risk of cancer.
 Rous sarcoma virus (RSV).
Genetic abnormalities
triggering carcinogenesis
 Cell proliferation triggered independent
of normal proliferation signals.
 Variety of mechanisms
 Mutations or overproduction of receptors
or transducing proteins.
 Abnormalities of tumor suppressor genes.
Tumor suppressor genes
 Genes that are responsible for
suppressing cell division.
 Abnormalities result in uncontrolled
cell division.
 Result in cancer through failure of the
host to destroy the abnormal cells.
 These are recessive mutations.
Tumor suppressors…
 Hereditary tumors
 Retinoblastoma gene (RB1).
 Wilm’s tumor (WT1).
 Familial polyposis (APC).
 Familial melanoma (CDKN20).
 Familial breast and ovarian cancer
(BRCA1 & BRCA2).
Tumor suppressors…
 p53 Suppressor gene.
 p53 protein suppresses the cell cycle with
multiple complex activities.
 It detects DNA lesions like nucleotide
mismatches, DNA strand breaks etc.
 On detection of DNA lesions, cell cycle is
halted at G1 phase and either repair
mechanisms or apoptosis is triggered.
Oncogenes
 Cancer results from alterations in
critical regulatory genes that control
cell proliferation, differentiation and
survival.
 Studies of tumor virus revealed specific
genes (oncogenes) capable of inducing
cell transformation.
Oncogenes…
 Genes that cause malignant transformation
of normal cells.
 They are constantly associated with
malignancies and may be either of cellular or
retroviral origin.
 More than one oncogene is abnormally active
in cancer.
 Multiple interactions among oncogenes that
are necessary for cell division results in the
activation of many otherwise normal
oncogenes.
Oncogenes…
 Retroviral oncogenes (v-onc).
 Cellular onocogenes.
 Inhibitory genes: produce proteins that
inhibit cell proliferation. Abnormalities lead
to abnormal cell proliferation.
 Proto-oncogenes (c-onc): control proliferation
and differentiation in normal cells. RNA from
transforming retroviruses is homologous with
various proto-oncogenes
 Highly conserved through evolution.
 Codes for proteins that are differentially expressed
during the cell cycle or at specific stages of
development of a tissue.
Thank you
….