HALLMARK OF CANCER

Following are the major genetic properties or hallmark of

cancer.
1. Excessive and autonomous growth: growth promoting
oncogenes.
Mutated form of normal proto-oncogenes in cancer is called
oncogenes. Such genes lack normal growth promoting
signals and act by over-expression to promote autonomous
and excessive cellular proliferation.
Activation occurs by mechanism like point mutations or
deletion, chromosomal translocations or gene amplification.
2. Refractoriness to growth inhibition: growth suppressing
anti-oncogenes.
Mutation of normal growth suppressor anti-oncogenes or
TSG results in removal of the brakes for growth, thus
inhibitory effect to cell growth is removed and abnormal
growth continues unchecked.
3. Escaping cell death by apoptosis: genes regulating apoptosis
and cancer.
The function of apoptosis is interfered due to mutation in
the genes regulating apoptosis in cancer.
4. Avoiding cellular aging: Telomeres and telomerase in cancer
 After each mitosis, progressive shortening of telomeres
occurs which are the terminal tips of chromosome.
Telomerase is the RNA enzyme that helps in repair of
such damage to DNA and maintains normal length of
telomeres in successive cell division.
5. Continued perfusion of cancer: cancer angiogenesis.
Cancer cells can survive only if the cancer cells are
adequately nourished and perfumed. Neovascularisation
in the cancers supplies oxygen, nutrients and also
elaborate few growth factors. Stimulus for angiogenesis is
by release of various factors such as vascular endothelial
growth factors (VEGF) and basic fibroblasts growth
factors.(bFGF).
6. Invasion and distant metastasis: cancer dissemination
One of the most important features of cancer is invasion
and metastasis.
7. DNA damage and repair system: mutator genes and cancer
Normal cells suffer from minor damage to the DNA are
detected and repaired before mitosis. So the the integrity
of genome is maintained. TP53 gene is responsible for
this detection and repair. When this is defective, the
defective DNA passed to next progeny.
8. Cancer progression and heterogeneity: clonal
aggressiveness.
Another feature of cancer is its aggressive growth with
time. This is called tumor progression. Cancer cell
acquire more and more heterogeneity which means
though cancer cells monoclonal in origin, they acquire
more and more mutations which in turn produce multiple
mutated sub populations of more aggressive clones of
cancer.
 Steps of Successful Metastasis
1. Aggressive clonal proliferation and angiogenesis
2. Tumor cell loosening (lose or inactivation of adhesion
molecules—Detachment of tumor cells)
3. Tumor cell — ECM interaction (tumor cells to ECM
proteins [laminin and fibronectin]
4. Degradation of ECM (by over expression of proteases and
matrix degrading enzymes, metaloproteinases—
[collagenase and gelatinase] while reduction in
metaloproteinases inhibitors. Enzymes bring about
dissolution of ECM → 1st basement membrane of tumor
cells → make way to interstitial matrix →basement
membrane of vessel wall)
5. Entry of tumor cells into capillary lumen
6. Thrombus formation: give nourishment to tumor cells.
7. Extravasation of tumor cells
8. Survival and growth of metastatic deposits: extravasated
tumor cells on lodgment in the right environment grow
further with the influence of growth factors. Metastatic
deposits grow further if host immune system fails to
eliminate it. This may metastasis to the same or to the other
sites by forming emboli.
 ETIOPATHOGENESIS OF CANCER
Pathogenesis of cancer undergoes in the following 4 mechanism
1. – Molecular pathogenesis of cancer (genes and cancer)
2. – Chemical carcinogens and chemical carcinogenesis
3. – Physical carcinogens and radiation carcinogenesis
4. – Biologic carcinogens and viral oncogenesis.
1. Molecular pathogenesis of cancer
• Also known as genetic mechanisms of cancer. The
transformation of normal cells to cancer cell is complex. It may
be either based on
a. Monoclonality of tumors
– Tumors are formed from single clone of cells by genetic
transformation or mutation.
– Ex: multiple myeloma— a malignant disorder of plasma.
b. Genetic theory of cancer:
Cell growth is under genetic control. In cancer there is either
abnormality in the genes of the cells or there are normal genes
with abnormal expressions. The abnormality in the genetic
composition may be from inherited or induced mutation. The
mutated cells transmit their characters to the next progeny of
cells and results in cancer.
c. Genetic regulators of normal and abnormal mitosis:
In normal cell growth regulatory genes controls mitosis as well
as cell aging, terminating in cell death by apoptosis. Various
gene regulate the normal mechanism of growth in human body
like
– Proto-oncogenes:growth-promoting genes
–Anti-oncogenes: growth-inhibiting or growth suppressor genes.
– Apoptosis regulatory genes control the programmed cell death.
– DNA repair genes which regulate the repair of DNA damage
that has occurred during mitosis.
In cancer cell these are replaced by
• Activation of growth-promoting oncogenes
• Inactivation of cancer-suppressor genes
• Abnormal apoptosis regulatory genes
• Failure of DNA repair genes
d. Multistep process of cancer growth and progression
Carcinogenesis is a gradual multistep process involving many
generations of cells. Various causes may act on the cells one
after another— multi- hit process.
Tumor progression and generation of heterogeneity. New
subclones arise from the descendants of the original transformed
cell by multiple mutations. With progression the tumor mass
becomes enriched for variants that are more adept at evading
host defenses and are likely to be more aggressive
Chemical carcinogens and chemical carcinogenesis
• Chemical carcinogens can be classified into
 DIRECT-ACTING CARCINOGENS:
They do not require metabolic activation
– Alkylating agents: various anti-cancer drugs (e.g.
cyclophosphamide, chlorambucil, busulfan, melphalan,
nitrosourea etc), β-propiolactone and epoxides.
– Acylating agents: acetyl imidazole and dimethyl carbamyl
chloride
 INDIRECT ACTING CARCINOGENS /PROCARCINOGENS
They undergo prior metabolic activation before becoming potent
carcinogens.
–Polycyclic aromatic hydrocarbons:
Anthracenes, Benzapyrene, Methylcholanthrene
– Aromatic amines and azo-dyes:
β-naphthylamine, Benzidine
– Naturally-occurring products:
Aflatoxin Bl, Actinomycin D,Mitomycin C, Safrole, Betel
nut
– Miscellaneous:
Nitrosamines and nitrosamides, Vinyl chloride monomer,
Asbestos, Saccharin and cyclomates,
 Two-step/ multistep process of chemical carcinigenesis are,
– Initiation : causes permanent DNA damage (Mutation)
– Promotion(Proliferation)
INITIATORS
• Direct acting compounds: Direct acting carcinogens are bind
covalently to cellular macromolecules.
• Indirect acting carcinogen (Procarcinogens): Require
metabolic conversion to form ultimate active carcinogen.
PROMOTERS
• Can cause cellular proliferation & induce tumors in initiated
cells, e.g estrogen but they are non tumorigenic by themselves.
• Proliferation of a mutated cell may lead to accumulation of
additional mutations.
 PHYSICAL CARCINOGENESIS
• Radiation
– ultraviolet light and ionising radiation like X-rays, α-, β- and
γ-rays, radioactive isotopes, protons and neutron
 Ionizing radiation: X-rays, gamma rays, and particulate
radiation are all carcinogenic. Ionizing radiation is
electromagnetic or particulate radiation strong enough to
cause ionization of atoms and damage DNA and other
macromolecules inside cells. There are two types of
radiation-induced DNA damage:
 Direct DNA damage: ionizing radiation penetrates cell
membrane and cytoplasm, breaking bonds in DNA and protein.
Single or double strand breaks, deamination, or apurination can
all occur with radiation exposure. In addition, radiation can
break off the amino acid side chains of proteins to cause reduced
function or changes in the tertiary protein structure.
 Indirect DNA damage: ionizing radiation can induce
formation of reactive oxygen species like hydroxyl (OH·) and
peroxy (HO2·) radicals from water. These free radicals can react
with DNA bases to cause mutations or break hydrogen bonds in
macromolecules.
 Bystander effects: besides causing mutations or
macromolecule destruction, ionizing radiation can also induce
changes in signalling pathways, causing cytokine and growth
factor release. These “bystander effects” may be responsible for
causing cell proliferation in irradiated cells, allowing promotion
to occur.
 Adaptive response: cells can adaptive to chronic radiation
exposure if they are primed by a low-dose radiation exposure.
DNA repair and cell cycle regulation pathways are upregulated
to prepare for impending radiation damage. This effect lasts
weeks to months.
 Ultraviolet radiation: causes pyrimidine dimers in DNA,
which gives rise to mutations.
UV radiation can affect the function of proteins and lipids
as well, leading to changes in cell signalling. Like ionizing
radiation, UV radiation cause cell proliferation and
carcinogenesis.
• Non-radiation
– Continuous mechanical injury to the tissues
– implants of inert materials such as plastic, glass etc
 BIOLOGIC CARCINOGENESIS
• Various studies have proved the direct role of MCO’s in
causing cancer.
• Parasites: Schistosoma haematobium - squamous cell
carcinoma of the urinary bladder,
– Clonorchis sinensis, the liver fluke - cholangiocarcinoma.
• Fungus: Aspergillus flavus (in certain grains) - hepatocellular
carcinoma.
• Bacteria: Helicobacter pylori - chronic gastritis and peptic
ulcer; its prolonged infection may lead to gastric lymphoma and
gastric carcinoma,
• Viral: most important organism
–OncogenicRNAViruses:humanT-cellleukemiavirus-1(HTLV-1),
only retrovirus that has been demonstrated to cause cancer in
humans
–OncogenicDNAViruses:-humanpapillomavirus(HPV),Epstein-
Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) also
called human herpesvirus 8), and hepatitis B virus (HBV).
Etiopathogenesis of cancer: Flow chart
Grading and staging of cancer
TNM staging