Cancer cells acquire several hallmarks that allow malignant growth and spread. These include self-sufficiency in growth signals, evading growth suppression, resisting cell death, unlimited replication potential, inducing angiogenesis, invading locally and spreading to distant sites, reprogramming metabolism, and avoiding immune destruction. Specifically, cancer cells overexpress growth factors and receptors, mutate tumor suppressors and cell death pathways, activate telomerase to achieve immortality, secrete angiogenic factors, degrade the extracellular matrix, and suppress their own immunogenicity. These hallmark capabilities collectively enable cancer to develop and progress.

1. HALLMARKS OF CANCER

2. 1. Self-sufficiency in growth signals
2. Insensitivity to growth inhibitory signals
3. Evasion of cell death
4. Limitless replicative potential
5. Development of sustained angiogenesis
6. Ability to invade and metastasize
7. Reprogramming of energy metabolism
8. Evasion of the immune system

3. 1.Self-Sufficiency in Growth Signals
 Many cancer cells acquire growth self-
sufficiency by acquiring the ability to synthesize
the same growth factors to which they are
responsive,
 Growth factor genes are overexpressed to
stimulate large secretion of GFs which stimulate
cell proliferation.
e.g., many glioblastomas secrete PDGF and express
the PDGF receptor, and many sarcomas make both
TGF-α and its receptor interaction with stroma.
 Overexpression of growth factor receptors can render
cancer cells hyperresponsive to levels of the growth
factor that would not normally trigger proliferation or
mutation of growth factor receptors e.g. epidermal
growth factor (EGF)receptor family in squamous cell
carcinomas of the lung. ERBB1, the EGF receptor, is
overexpressed in 80% of squamous cell carcinomas of
the lung, 50% or more of glioblastomas, and 80% to
100% of epithelial tumors of the head and neck

4.  Mutant receptor proteins deliver continuous mitogenic signals to cells, even in the absence of the
growth factor in the environment.
 Mutations in genes that encode various components of the signaling pathways downstream of growth
factor receptors.
e.g.- RAS Protein. RAS is the most commonly mutated proto-oncogene in human tumours. It’s a G protein
that relays a growth signal from a growth factor receptor to a cascade of protein kinases. Many RAS
oncogenes have a point mutation that leads to hyperactive version of RAS protein that can issue signals on
its own resulting in excessive cell division.
- ABL proto-oncogene tyrosine kinase activity that is dampened by internal negative regulatory
domains.

5. 2.Insensitivity to Growth Inhibitory Signals
 The mutation of normal growth suppressor anti-oncogenes results in removal of the brakes for
growth; thus the inhibitory effect to cell growth is removed and the abnormal growth continues
unchecked.
 oncogenes encode proteins that promote cell growth, the products of tumor suppressor genes
apply brakes to cell proliferation.
 Disruption of such genes renders cells refractory to growth inhibition and mimics the growth-
promoting effects of oncogenes

6. 3.Evasion of Cell Death
 Apoptosis in normal cell is guided by cell death receptor, CD95, and other genes regulating apoptosis
and cancer pro-apoptotic factors (BAD, BAX, BID and p53) and apoptosis-inhibitors (BCL2, BCL-X).
 In cancer cells, the function of apoptosis is interfered due to mutations in the above genes which
regulate apoptosis in the normal cell.
 Example; BCL2 gene mutation removes the apoptosis-inhibitory control on cancer cells, thus more
live cells undergoing mitosis contributing to tumour growth. e.g. in B-cell lymphoma. It is also seen in
many other human cancers such as that of breast, thyroid and prostate.
 MYC oncogene and p53 tumour suppressor gene are also connected to apoptosis. While MYC allows
cell growth BCL2 inhibits cell death; thus MYC and BCL2 together allow cell proliferation. Normally,
p53 activates proapoptotic gene BAX but mutated p53 (i.e. absence of p53) reduces apoptotic activity
and thus allows cell proliferation.
 CD95 receptors are depleted in hepatocellular carcinoma and hence the tumour cells escape
apoptosis

7. 4. Limitless Replicative Potential
 Cancer cells in most malignancies have markedly upregulated telomerase
enzyme, and hence telomere length is maintained. Thus, cancer cells avoid
aging, mitosis does not slow down or cease, thereby immortalizing the
cancer cells. In immortalized cancer cells, telomerase is usually reactivated
and telomere length is stabilized, allowing the cells to proliferate
indefinitely.
 In normal cells, which lack expression of telomerase, the shortened
telomeres generated by cell division eventually activate cell cycle
checkpoints, leading to senescence and placing a limit on the number of
divisions a cell may undergo.
 In cells that have disabled checkpoints, DNA repair pathways are
inappropriately activated by shortened telomeres, leading to massive
chromosomal instability and mitotic crisis.
 Tumor cells reactivate telomerase, thus staving off mitotic catastrophe and
achieving immortality.

8. 5. Development of Sustained Angiogenesis.
 Cancer cells (and large benign tumors) can stimulate neoangiogenesis, during which new vessels sprout from
previously existing capillaries, or, in some cases, vasculogenesis, in which endothelial cells are recruited from
the bone marrow.
 Neovascularisation -supplies needed nutrients and oxygen, and newly formed endothelial cells stimulate the
growth of adjacent tumor cells by secreting growth factors such as insulin-like growth factors, PDGF, and
granulocyte macrophage colony-stimulating factor.
 Promoters of tumour angiogenesis –VEGF (released from genes in the parenchymal tumour cells) and basic
fibroblast growth factor (bFGF).
 Anti-angiogenesis factors inhibiting angiogenesis include thrombospondin-1 (also produced by tumour cells
themselves), angiostatin, endostatin and vasculostatin. Mutated form of p53 gene in both alleles in various
cancers results in removal of anti-angiogenic role of thrombospondin-1, thus favouring continued angiogenesis.

9. 6.Ability to Invade and Metastasize
 Invasion–metastasis cascade, which include: local invasion,
intravasation into blood and lymph vessels, transit through
the vasculature, extravasation from the vessels, formation
of micrometastases, and growth of micrometastases into
macroscopic tumors.
1.Invasion of extracellular matrix
 ECM is made of collagens, glycoproteins, and involves the basement membrane and the
interstitial connecting tissue.
 Tumour cell must first penetrate the bm and then the interstitial ct in the following sequence

10.  Detachment of tumour cells from each other
-Cells are adhered to each other by adhesion molecules like E-cadherins. These are down regulated
and the cells become loose.
 Attachment to matrix components
-Tumour cells bind to laminin and fibronectin through receptors.
 Degradation of ECM
-Tumour cells secrete proteolytic enzymes that degrade the matrix and create passage ways.
 Migration of tumour cells.
2) Vascular dissemination and homing
 Tumour cells form emboli in circulation by aggregation and by adhering to lymphoid cells and
platelets
 This tumour emboli adhere to the endothelium, then extravasates and forms a metastatic
deposit.

13. 7. Reprogramming Energy Metabolism
 Cancer cells shift their glucose metabolism away from the oxygen-hungry but efficient
mitochondria to glycolysis. This phenomenon is called the Warburg effect and also known as
aerobic glycolysis.
 e.g. Burkitt lymphoma.
 Oncogenes and tumour suppressors that favour cell growth, such as TP53, PTEN, and Akt (an
intermediary in RAS signalling) stimulate glucose uptake by affecting glucose transporter
proteins and favour aerobic glycolysis.
 Tumor cells that adapt this altered metabolism are able to divide more rapidly and outpace
competing tumor cells that do not.

14. 8. Evasion of the Immune System
 Selective outgrowth of antigen-negative variants.
 Loss or reduced expression of MHC molecules.
 Immunosuppression.
 Antigen masking
 Downregulation of co-stimulatory molecules.
 Rapid growth
 Induction of suppressor cells

15. REFERENCES
 Robins Basic Pathology 9th edition
 Harsh Mohan Textbook of Pathology 6th edition
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