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HALLMARKS OF CANCER.pptx - Eight hallmarks of cancer
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- 2. 8 HALLMARKS • Selfsufficiency in growth signals • Insensitivity to growth inhibitory signals • Altered cellular metabolism • Evasion of apoptosis • Limitless replicative potential( immortality) • Sustained angiogenesis • Ability to invade and metastasize • Ability to evade host immune response
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- 4. EVASION OF APOPTOSIS •Intrinsic pathway more frequently affected • Loss of p53- prevent upregulation of PUMA(p53 induces apoptosis by transcriptional activation of BAX and PUMA) • Overexpression of BCL2- t(14;18)(q32;q21) • Most haematopoietic and solidtumours expresses BCL2 • BCL2 family tumours resistant to chemo and radiotherapy • Extrinsic pathway- decreased levels of CD95 and increased levels of FLIP
- 5. LIMITLESS REPLICATIVE POTENTIAL EVASIONOF SENESCENCE EVASION OF MITOTIC CRISIS SELF RENEWAL
- 6. EVASION OF SENESCENCE •Not known • Upregulation of tumour suppressor genes-p53 and INK4a/p16 RB in hypophosphorylated state cell cycle arrest suppression of p53-RB dependent-G1-S checkpoint is disrupted
- 7. EVASION OF MITOTICCRISIS
- 8. SELF RENEWAL • Tissuestem cell and germ cells – telomerase • Self renewal – stem cell one daughter cell remains as stem cell • Symmetric and asymmetric division
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- 10. ANGIOGENESIS • 1-2 mm •Supply nutrients and oxygen • Newly formed vessels – stimulate the growth of adjacent tumour cells(IGF and PDGF) • Leaky,dilated and have haphazard connection- metastasis • Angiogenic switch- production of angiogenic factors and loss of angiogenic inhibitors • Factors –tumour cells, macrophages, stromal cells • Proteases – tumour cells and stromal cells ( bFGF from ECM)
- 11. ANGIOGENESIS • Angiostatin andendostatin – proteolytic cleavage of plasminogen and collagen respectively • Balance between angiogenic and antgi angiogenic factors influenced by 1) Lack of O2- HIF α activates transcription of proangiogenic cytokines-VEGF/Bfgf stimulate proliferation of endothelial cell- new vessel towards tumour
- 12. ANGIOGENESIS • VEGF- increasedexpression of ligands for NOTCH signaling pathway regular brancing and density of new vessel 2) Mutation involving tumour suppression gene Favours angiogenesis P53- stimulates expression of antiangiogenic – Thrombospondin & represses expression of VEGF
- 13. ANGIOGENESIS 3) Transcription ofVEGF- RAS MAP Kinase pathway gain of function mutation – upregulation of VEGF
- 14. INVASION AND METASTASIS INVASIONOF ECM VASCULAR DISSEMINATION HOMING COLONIZATION
- 15. INVASION OF ECM •LOOSENING OF TUMOUR CELL – CELL INTERACTIONS • DEGRADATION OF ECM • ATTACHMENT TO NOVEL ECM COMPONENTS • MIGRATION AND INVASION OF TUMOUR CELLS
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- 20. INVASION AND METASTASIS ORGANTROPISM • Tumour cell adhesiom molecule- ligand on endothelial cell of target organ • Chemokines • Nonpermissive environment FACTORS GOVERN METASTASIS: • Even escape tissue of origin- inefficient to colonize distant organ • Micro metastasis • Tumour cell secrete cytokines,GF,ECM molecules- act on resident tumour cells – makes metastatic site habitable for cancer cell
- 21. INVASION AND METASTASIS •Carcinoma breast PTHRP osteoblasts RANKL Osteoclasts- degrade bone matrix
- 22. INVASION AND METASTASIS Metastaticoncogenes- SNAIL and TWIST epithelial mesenchymal transition metastasis
- 23. EVASION OF HOSTDEFENSE • Products of mutated genes – altered protein variant • Overexpressed or aberrantly expressed cellular protein • Tumour antigen produced by oncogenic viruses • Oncofetal antigen • Altered cell surface glycolipids and glycoproteins • Cell type specific differentiation antigen
- 24. EVASION OF HOSTDEFENSE Antitumour effects- CTLs, NK cell, Macrophages
- 25. EVASION OF HOSTDEFENSE IMMUNE SURVIELLANCE AND ESCAPE • Selective outgrowth of antigen- negative variants • Loss or expression of MHC molecule • Activation of immunoregulatory pathways- downregulate costimulatory receptor and activate inhibitory receptor CTLA-4 • Increased PD-L1 & PD-L2 • Immunosuppressive factors by cancer cells- TGF β and galeactin • Induction of Tregs
- 26. EVASION OF HOSTDEFENSE
- 27. EVASION OF HOSTDEFENSE
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