Hallmark of cancer

1. HALLMARKS OF CANCER

2.  Self sufficiency in growth signals
 Insensitivity to growth inhibitory signals
 Altered cellular metabolism
 Evasion of apoptosis
 Limitless replicative potential
 Sustained angiogenesis
 Ability to invade and metastasize
 Ability to evade host immune response

3. Warburg effect
 Distinct form of cellular metabolism
 High levels of glucose uptake and increased conversion of glucose to lactose
via glycolytic pathway
 PET scan-FDG
 Why rely on glycolysis instead of oxidative phosphorylation?

4.  Function of mitochondria
 Metabolic reprogramming
 PI3K/AKT-upregulates activities of glucose transporters,glycolytic enzymes
 Shunting of mitochondrial intermediates –protein,lipid synthesis
 Receptor tyrosine kinase:
Rapidly growing cells-Express M2 Pyruvate kinase
Tyrosine kinase phosphorylate-Buildup of glycolytic intermediates
 Myc:
Drive changes in gene expression favouring cell growth
 AUTOPHAGY

6. EVASION OF APOPTOSIS
 Due to mutations in genes regulating apoptosis
 INTRINSIC(MITOCHONDRIAL):
StressPermeabilization of outer membranestimulated by
apoptotic proteins BAK,BAXInhibited by anti apoptotic proteins BCL2,BCL-
XL,MCL-1BH3 PROTEINS neutralise antiapoptotic
BAD,BID,PUMAPorescytochrome c leaksBinds with APAF 1Caspase
9Executioner caspases
 EXTRINSIC-CD95/Fas binds to CD95L/Fas LCaspase 8

8. Pathways by which tumor cells evade
apoptosis
 Loss of p53-Prevents upregulation of PUMA(Pro apoptotic BH3 protein)
 Overexpression of anti apoptotic members of BCL 2 family-Follicular
lymphomas (>85%) have BCL2 Overexpressed due to (14,18) translocation

9. Limitless replicative potential
 Evasion of senescence
 Evasion of mitotic crisis
 Self renewal

10. Evasion of senescence
 Divide 60-70 times
 Senescent state associated with upregulation of
p53,INK4aHypophosphorylated Rbcell cycle arrest
 Rb dependent G1/S checkpoint disrupted

11. Evasion of mitotic crisis
 Cells resistant to senescence have increased replicativr capacitymitotic
crisis
 Attributed to progressive shortening of telomeres at chromosomal ends
 When telomeric DNA is eroded,exposed chromosomal ends sensed as double
stranded breaks
 If functional p53Apoptosis
 If dysfunctionalNon homologous end joining pathwayDicentric
chromosomesNew double stranded breaksTelomerase expressioncancer

13. Self renewal
 At least some cells in all cancers must be stem cell–like, these cells are
sometimes referred to as cancer stem cells.
 These may arise through transformation of a normal stem cell or through
acquired genetic lesions that impart a stem-like state on a more mature cell.
 Cancer cells acquire lesions that inactivate senescence signals and reactivate
telomerase, which act together to convey limitless replicative potential.

14. THANK YOU