Etiology Of Cancer

It is easy to kill cancer

cells, but the challenge is
keeping the patient alive at
the same time…..!
Manish Jain
Objectives
1. Carcinogens
2. Mechanism of carcinogenesis
3. Classification
 Key words:
• Carcinogenesis: Pathogenesis of
cancer/tumorigenesis
• Carcinogen - agent causing cancer.
Chemicals
Viruses
Radiation
• Mutagen - agent causing mutation.
• Proto-Oncogenes – genes causing cancer
Cancer
• Cancer is one of the most common diseases in the
developed world:
• 1 in 4 deaths are due to cancer
• 1 in 17 deaths are due to lung cancer
• Lung cancer is the most common cancer in men
• Breast cancer is the most common cancer in
women
• There are over 100 different forms of cancer
• Breast cancer, lung cancer, colon cancer, skin cancer, ...
 Carcinogenesis
 Carcinogenesis refers to the process by which a normal
cell is transformed into a cancer cell.

 The process is characterized by changes at the cellular,

genetic, and epigenetic levels and abnormal cell division.

 Carcinogenesis may take as long as 15-25 years in

humans.

 Several animal models have shown the involvement of

three stages, initiation, promotion and transformation.
 Carcinogen
A chemical which can initiate this process is called a
carcinogen.

Genes/Proteins

DNA Cell Cycle

Chemical Repair Control Disease
Cell Death/
Differentiation

-In general, carcinogens are mutagens, and they have the

potential to interact with DNA.
-Patients with DNA repair defects have increased
incidence of cancer.
 Co-carcinogen
– Co-carcinogen: Chemicals which are non-
carcinogenic or only weakly carcinogenic can
greatly enhance the effectiveness of
carcinogenic chemicals.

– Such "helpers" are called cocarcinogens.

– They may act by altering uptake or metabolism

of carcinogens by cells.
Etiology of Cancer
• The process of transformation from
a normal cell to a cancerous one
• A cancer, is thought to develop from a
cell in which the normal mechanisms
for control of growth and proliferation
are altered.

• Carcinogenesis is a multistage
process that is genetically regulated

Cancers are
caused by a series
of mutations
•Carcinogenesis is characterized :
• At cellular level
• Uncontrolled proliferation- Excessive cellular
proliferation
• De-differentiation and loss/gain of function
• Local Invasiveness- Tissue infiltration
• Metastasis- move to other tissues

• At molecular level
• Disorder of growth regulatory genes
 Uncontrolled proliferation
• Cancer cells proliferate faster than normal cells?
• Epithelium of the GI tract undergo continuous
rapid division.

• Cancer cells have escaped from the mechanisms that

normally regulate cell division and cell death.
 Uncontrolled proliferation
What are the changes that lead to the uncontrolled
proliferation of tumor cells?

Inactivation of tumor suppressor genes or

transformation of proto-oncogenes into oncogenes.

• Growth factors, their receptors and signaling

pathways
• Cell cycle transducers, for example cyclins, cyclin-
dependent kinases (cdks) or the cdk inhibitors
• Apoptotic machinery that normally disposes of
abnormal cells
• Telomerase expression
 DE-DIFFERENTIATION AND
LOSS/GAIN OF FUNCTION
Differentiation- The multiplication of normal
cells to mature non-dividing daughter cells

De-differentiation- Dividing again

One of the main characteristics of cancer cells is
that they de-differentiate to varying degrees.
 INVASIVENESS
• Normal cells, are not generally found outside their
‘designated’ tissue of origin, because of various
tissue-specific survival factors that prevent
apoptosis

• Any cells that escape accidentally lose these

survival signals and die.

• A cancer of the rectal mucosa, invades other

surrounding tissues. Cancer cells secrete enzymes
(e.g. MMPs;) that break down the extracellular
matrix, enabling them to move around.
 METASTASIS

• Metastases are secondary tumors formed by

cells that have been released from the initial or
primary tumor and which have reached other
sites through blood vessels or lymphatics.

• Metastases are the principal cause of

mortality and morbidity and constitute a
major problem for cancer therapy
Characteristics of Cancer
 The principal targets of gene damage
There are three broad categories of genes that are affected.
1. Oncogenes- An oncogene is a gene that has the potential to
cause cancer. In tumor cells, these genes are often mutated,
or expressed at high levels and promote the malignant
phenotype of cancer cells. The normal version of an
oncogene is called proto-oncogene.
2. Tumor suppressor genes are genes that inhibit cell division,
survival, or other properties of cancer cells. Tumor
suppressor genes are often disabled by cancer-promoting
genetic changes.
3. Genes that regulate programmed cell death or apoptosis

In addition, a disability in DNA repair genes can predispose to

widespread mutations
• Growth factors bind to specific receptors on the plasma
membrane to trigger cell division

Growth factor

Plasma membrane

Relay
Receptor proteins G1 checkpoint
protein
Signal
transduction Cell cycle
pathway control
system

Figure 8.8B
 Cancer suppressor genes
• Cancer may also arise by inactivation of genes that
normally suppress cell proliferation (cancer suppressor
genes). e.g. P53
• Mutations of P53 are seen in a wide variety of tumors:
• carcinomas of the breast, colon, and lung.
• Mutant P53 fails to arrest cell proliferation, hence cells
with DNA damage continue to divide and accumulate
mutations lead to neoplastic transformation
 Genes that regulate apoptosis:
• Accumulation of neoplastic cells may result also from
mutations in genes that regulate apoptosis
(programmed cell death).

• This results from the ability of normal cells to repair

DNA-damage and thus prevent mutation in genes that
regulate cell growth and apoptosis.
 Different Steps of Carcinogenesis
Initiation: Mutation in one or more cellular
genes controlling key regulatory pathways of
the cell (irreversible)—must be a heritable
DNA alteration.
Promotion: Selective growth enhancement
induced in the initiated cell and its progeny by
the continuous exposure to a promoting
agent.
Progression: results from continuing
evolution of unstable chromosomes; further
mutations from genetic instability during
promotion—results in further degrees of
independence, invasiveness, metastasis, etc.
Initiation
Initiation - Initiation is the induction of a mutation
in a critical gene involved in the control of cell
proliferation

Initiation:
(1) Is essentially irreversible
(2) Occurs rapidly after carcinogen exposure
(3) Requires one or more rounds of cell division for the
“fixation” of the process
(4) The high efficiency of DNA repair of the tissue can
alter the process of initiation.
(5) Alone does not result in tumor formation
(6) May involve conversion of proto-oncogene to
oncogene
 Targets of Initiation
Chemical carcinogens initiate cells via:
1. Mutational activation of oncogenic (proliferative) pathways
(e.g. growth factor receptors and downstream signaling
proteins, proteins involved in cell cycle checkpoints.

2. Mutational inactivation of apoptotic (cell death) pathways

(e.g. growth inhibitory receptors, proteins involved in
apoptosis, tumor suppressors).

3. Mutational inactivation of DNA repair mechanisms.

4. Mutational inactivation of antioxidant response (e.g. SOD).

Oncogenic (proliferative) pathways
 Tumor suppressors
ATM, is a

2-Tumor suppressor genes, p53, serine/threonine protein

kinase that is recruited

are inherent genes that play a role in and activated by DNA

double-strand breaks.

cell division and DNA repair and

are critical for detecting
inappropriate growth signals in
cells. If these genes, become unable
to function, genetic mutations in
other genes can proceed unchecked,
leading to neoplastic transformation.

• Inactive or altered apoptotic genes

allows cells with abnormal DNA to
survive and divide.
 Role of p53
• The p53 protein is a transcription factor that
enhances the rate of transcription of 6-7 known
genes
• Normally, in a cell, the p53 protein is kept at a low
concentration due to its proteasomal degradation by
the E3 ligase, MDM2
• In response to
diverse stress
stimuli, like DNA
damage or
nutrient
deprivation, the
levels of p53
protein rise
substantially
 Role of p53
These stress stimuli either inhibit MDM2, or induce
some modifications in the p53 protein itself (e.g.,
acetylation, phosphorylation).

Upon activation,
induces the
transcription of its
target genes
P53 induced genes: role in cell cycle
arrest and apoptosis
Promotion
Promotion is the process whereby an initiated tissue or
organ develop focal proliferations and it requires the
presence of continuous stimulation.

A promotor: is a substance which doesn't damage DNA

but enhance growth of tumor induced by genotoxic
carcinogens e.g.: skin cancer in mice can be induced
by application of benzopyrene ( initiator) followed by
phorbol ester from cotton oil ( promoter).

Promotion
(1) Reversible
(2) Acts only after exposure to an initiating agent
(3) Requires repeated exposure of a promoter
(4) Is not carcinogenic in itself
 Promoters

1. Reactive Oxygen Species (ROS)

2. Phorbol esters
3. Polycyclic aromatic compounds (e.g. Dioxin)
4. Peroxisome Proliferators (oxidized fats)
5. Endocrine Disruptors (estradiol) - are involved in
breast, ovarian, colon, prostate cancers.
Progression
 Mechanisms of Progression
Progression is an irreversible process and leads to metastasis.

Progression requires:
1. Further mutations from genetic instability (chromosomal
instability) during promotion.
2. Recruitment of inflammatory immune cells to the tumor.
3. The tumor cell acquiring “wound-healing” characteristics
(secretion of chemo-attractants to attract inflammatory immune
cells, angiogenesis factors, proteases, etc).
 Simplified outline of the genesis of cancer.

• Tumor promotors– DDT, Dioxin

• Hormones– Estradiol, DES
• Immunosuppressants– Cyclosporin A
Cause of cancer

• Chemicals
• Diet
• Radiation
• Infection
• Heredity
 Carcinogenic Agents- Chemicals
• Natural or synthetic
• Direct reacting or indirect
• Direct  are highly reactive as they have electron-
deficient atoms. They react with the electron rich atoms
in RNA,DNA and other cellular proteins
• Indirect  need metabolic conversion to be active and
carcinogenic. Indirect chemicals are called “
procarcinogens “ and their active end products are
called “ ultimate carcinogens”
 Carcinogenic Agents- Chemicals
• Examples:
• Polycyclic hydrocarbons:
• Cigarette smoking
• Aromatic amines and azo dyes
• Nitrosamines and nitrosamides are used as
preservatives. They cause gastric cancer

• Mechanism of action :
• Most of them are mutagenic. i.e. cause mutations
• RAS and P53 are common targets
Carcinogenic Agents- Radiation
• Radiations has mutagenic effects, are capable to damage
DNA, chromosomes breakage, translocations, and point
mutations
• Examples
• UV rays - Causes formation of pyrimidine dimers in the
DNA leading to mutations
• X-rays
• Nuclear radiation
• Therapeutic irradiations
• Can cause skin cancers: squamous cell carcinoma
• Bone Marrow: Acute leukemia occurs before other
radiation-induced neoplasia (Seven year latent period in
atomic bomb survivors).
 Carcinogenic Agents- Infections
• Viral and Microbial oncogenesis
• Host cell has endogenous genes that maintain the
normal cell-cycle
• Viral infection mimics or blocks these normal cellular
signals necessary for growth regulation
• DNA viruses- forms stable association with host’s DNA
• Papilloma viruses; Epstein-Barr (EBV); Hepatitis B (HBV)

• RNA viruses-
• Retrovirus; HIV; Human T-Cell Leukemia Virus type 1

• Other-
• Helicobacter Pylori- gastric carcinoma
 Classification of cancers
• Cancers are classified by the type of cell that the tumor cells
resemble and is therefore presumed to be the origin of the
tumor. These types include:

• Carcinoma: Cancers derived from epithelial cells that lines the

inner or outer surfaces of the body.
• Breast, prostate, lung, pancreas and colon.

• Sarcoma: Cancers arising from connective tissue (i.e. bone,

cartilage, fat, nerve),
• Develops from cells originating in mesenchymal cells
outside the bone marrow.
• Osteosarcoma, Chondrosarcoma, Chordoma.
 Classification of cancers
• Lymphoma and leukemia: These two classes arise from
hematopoietic (blood-forming) cells that leave the marrow
and tend to mature in the lymph nodes and blood
respectively
• Diffuse large B-cell lymphoma (DLBCL); T-cell lymphoma.
• Acute myeloid leukemia (AML); Chronic myeloid leukemia (CML)

• Germ cell tumor: Cancers derived from pluripotent cells,

most often presenting in the testicle or the ovary
• Yolk sac tumor; Choriocarcinoma; seminoma

• Blastoma: Cancers derived from immature "precursor"

cells or embryonic tissue.
• Hepatoblastoma; nephroblastoma
 Cancer- Prevention
• Don't use tobacco. Using any type of tobacco puts you on a
collision course with cancer.
• Eat a healthy diet (avoidance of processed and red meat)
• Maintain a healthy weight and be physically active.
• Protect yourself from the sun.
• Get vaccinated.
• Avoid risky behaviors.
• Get regular medical care
THANK YOU!!