CANCER

PATHOPHYSIOLOGY
Radhika D Prabhu
0UTLINE- Pathophysiology
Genetics-
Cancer genes

Environmental
 Carcinogenesis:
Chemical
Physical
Viral
 What is Cancer?
• Neoplasia means ‘new growth’
• Neoplasm means ‘tumour/ cancer’
• A neoplasm is : Abnormal mass of tissue which grows in an
uncoordinated manner even after cessation of the stimuli which
evoked the change.
• Cancer results from a series of molecular events that fundamentally
alter the normal properties of cells.
• As long as these cells remain in their original location, they are
considered benign and if they become invasive, they are considered
malignant.
PREVALENCE
World Health
Organisation's
Globocan 2012
All tumors, benign and malignant, have two basic
components
 clonal neoplastic cells that constitute their
parenchyma
 reactive stroma made up of connective tissue,
blood vessels, and variable numbers of
macrophages and lymphocytes
When normal cells become old/damaged, they An important hallmark of many cancers is
go through apoptosis (programmed cell death) resistance to apoptosis, which contributes to
the ability of the cells to divide uncontrollably

• Tumors are clonal (one parent)

• But have different mutations  different shapes &
features.
Normal cell • Each new mutation adds a new feature.
division
Apoptosis
Cancer cell Cell damage –
division no repair

First Second Third Fourth or

mutation mutation mutation later Uncontrolled
mutation growth
How apoptosis happens…….
Genetics of Cancer
Four kinds of normal genes:

• Genes that promote growth (proto-oncogenes)

• Genes that inhibit growth (tumor-suppressor genes)
• Genes that regulate apoptosis (apoptotic genes)
• Genes involved in DNA repair (DNA repair genes)
ONCOGENES
 What are the genes responsible for cancer
cell growth?

Proto-oncogenes + Cell growth

Normal and
Tumor suppressor genes
- proliferation

Cancer Mutated or “activated” ++

oncogenes Malignant
transformation
Loss or mutation of
Tumor suppressor genes
“Cancer genes” contribute:

1. Autonomous growth
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Defects in DNA repair
5. Limitless replication
6. Sustained angiogenesis
7. Invasion and metastasis
• Heredity - 5%
AUTONOMOUS GROWTH

In cancer cells…
• Growth factors may be made by cell itself!
• Receptors may be over expressed or always on
• Signal-transducing proteins may always be on
• Nuclear transcription factors may always be expressed
• Cyclins may be overactive

Cell divides on its own!!!

INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS

Tumor-suppressor genes/ anti-oncogenes : normal

genes whose products act as “brakes” on the cell
cycle.
Mutation cause loss of these brakes!
EVASION OF APOPTOSIS
 DEFECTS IN DNA REPAIR

• Normal cells have ability to

repair DNA damage
• Thus, prevent mutations in
genes
• But if mutations are not
repaired, results in cancer.
LIMITLESS REPLICATION

Normal human cells:

Telomeres keep getting shorter…leading to
cell cycle arrest
In cancer cells:
Length
of telomeres – regulated by enzyme
TELOMERASE
Stem cells and cancer cells use telomerase
to maintain telomere length and keep
replicating!
SUSTAINED ANGIOGENESIS

• Tumor cells need blood too!

• Can’t grow >1-2 mm without new
vessels
• Tumor cells eventually stimulate
angiogenesis
• Tumor vessels are abnormal
 INVASION AND METASTASIS

• Abnormal cells proliferate and spread

(metastasize) to other parts of the body

• Invasion - direct migration and

penetration into neighboring tissues

• Metastasis - cancer cells penetrate into

lymphatic system and blood vessels
CARCINOGENESIS
• Carcinogens: Substances known to cause cancer or produce
an increase in incidence of cancer.
o PHYSICAL CARCINOGENESIS

o CHEMICAL CARCINOGENESIS

o MICROBIAL CARCINOGENESIS
Physical Carcinogenesis-Radiation
Properties of radiation carcinogens:
Result in mutations following a long period of latency after the initial
exposure (10-20 yrs)
May enhance the effect of other carcinogens
2 types:
• Ionizing radiation
• Ultraviolet rays
 Ionizing radiation
• Ex- X-rays, alpha, beta & gamma rays, radioactive isotopes
• Mechanism of action:
1. Directly alter cellular DNA
2. Dislodge ions from water & other molecules  free radicals  damage
• Causes chromosome breakage, translocations
• Occasionally, point mutations

genetic damage and carcinogenesis.

Examples:
o Unprotected miners: lung cancer
o Atomic bomb survivors: leukemia, other cancers
o Therapeutic head/neck radiation: thyroid cancer
UV Rays
• UV rays derived from the sun cause an increased incidence of
squamous cell carcinoma, basal cell carcinoma, and possibly
melanoma of the skin.
• The degree of risk depends on the type of UV rays, the intensity of
exposure, and the quantity of the light-absorbing “protective mantle”
of melanin in the skin.
 Chemical Carcinogenesis

• 2 Types:
• Proximate/direct acting: act
locally without metabolic change.
• Indirect acting: carcinogenic only
after being metabolised into
active compounds
• ( procarcinogen ultimate
carcinogen)
Some Chemical Carcinogens
DIRECT-ACTING CARCINOGENS PROCARCINOGENS THAT
REQUIRE METABOLIC
ACTIVATION
1- Alkylating Agents: 1-Polycyclic and Heterocyclic 3- Natural Plant and Microbial
β-Propiolactone, Aromatic Hydrocarbons: Products:
Dimethyl sulfate, Benz[a]anthracene, Aflatoxin B1:
Diepoxybutane, Benzo[a]pyrene, Griseofulvin,
Anticancer drugs Dibenz[a,h]anthracene, Cycasin,
(cyclophosphamide, 3-Methylcholanthrene, Safrole,
chlorambucil, nitrosoureas 7,12-Dimethylbenz[a]anthracene. Betel nuts.
2- Acylating Agents: 2-Aromatic Amines, Amides, 4- Others:
1-Acetyl-imidazole, Azo Dyes: Nitrosamine and amides,
Dimethylcarbamyl chloride 2-Naphthylamine (β- Vinyl chloride, nickel, chromium,
naphthylamine), Insecticides, fungicides,
Benzidine, Polychlorinated biphenyls.
2-Acetylaminofluorene,
Dimethylaminoazobenzene
(butter yellow)
MICROBIAL CARCINOGENESIS
Oncogenic DNA viruses:
1. Human Papilloma Virus
2. Epstein-Barr Virus
3. Hepatitis B Virus

Oncogenic RNA virus:

1. Human T-cell Leukemia virus Type 1

Bacteria:
1. Helicobacter pylori
ONCOGENIC DNA VIRUSES- PATHOGENESIS
• Genomes of oncogenic DNA viruses integrate & form stable
associations with host genome.
The virus is unable to complete its replicative cycle because viral
genes essential for completion of replication are interrupted during
integration of viral DNA.
Thus, the virus can remain in a latent state for years.
HUMAN PAPILLOMA VIRUS
• 70 genetically distinct types identified
• Low risk types- HPV 6, 11 genital warts
• High risk types- 16,18, 31,33,35,51 Ca cervix, severe dysplasia and
CIS
Cervical cancer
Anogenital cancer
Oral cancer
Laryngeal cancer
Infection with high-risk HPV types simulates :

• loss of tumor suppressor genes

• activates cyclins
• inhibits apoptosis
• combats cellular senescence
EPSTEIN-BARR VIRUS

• Burkitt lymphoma
• Post-transplant lymphoproliferative disease
• Primary CNS lymphoma in AIDS patient
• Subsets of Hodgkin lymphoma
• Nasopharyngeal carcinoma
Hepatitis B and Hepatitis C Viruses

70-85% of hepatocellular carcinomas : due to

infection with HBV or HCV
HELICOBACTER PYLORI

• Gastric lymphoma
• Gastric carcinoma
• Mucosal Associated Lymphoid Tumor (MALT)
Oncogenic RNA Virus
• HTLV-1 causes a T-cell leukemia