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Molecular basis of Cancer contd.pptx

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Hallmarks of cancer
Hallmarks of cancer
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Molecular basis of Cancer contd.pptx

  1. 1. Molecular basis of Cancer Prepared by Dr. Ashish Adhikari 1st year resident, NAIHS Moderator: Maj. Dr. Suman Gurung
  2. 2. Cellular and molecular hallmarks of cancer a) Self-sufficiency in growth signals. b) Insensitivity to growth inhibitory signals c) Altered cellular metabolism. d) Evasion of apoptosis. e) Limitless replicative potential (Immortality) f) Sustained angiogenesis. g) Ability to invade and metastasize. h) Ability to evade the host immune response.
  3. 3. c) Altered cellular metabolism: The Warburg effect • Two main pathways for ATP generation. a) Aerobic glycolysis: - Generates 2 molecules of ATP/ Glucose molecule.(Inefficient) - Generates metabolic intermediates needed for synthesizing DNA, RNA, Protein, lipids required for cell division. b) Oxidative phosphorylation: - Efficient, Generates 36 ATP/Glucose molecule.
  4. 4. Contd…. • Normal cells: Go predominantly for oxidative phosphorylation.(Efficient) • Rapidly dividing normal cells/ Cancer cells: Go for Aerobic glycolysis.(Inefficient) • Why??? - Aerobic glycolysis provides metabolic intermediates(DNA, RNA, Protein, Lipid) required by rapidly dividing normal cells(embryonal cells) or cancer cells.
  5. 5. Contd… - Oxidative phosphorylation on other hand don’t provide metabolic intermediates/ carbon moieties required for cell growth. - Thus, in presence of ample amount of oxygen, cancer cells demonstrate distinctive form of cellular metabolism characterized by high levels of glucose uptake and increased conversion of glucose to lactose via glycolytic pathway. - This phenomenon is known as “ Warburg effect”.
  6. 6. Clinical implications • As cancer cells are hungry for glucose (Useful to visualize tumor via PET scan): 18-Fluoro-deoxy-glucose (Non-metabolizable derivative of glucose) injected. • Preferentially taken up by tumor cells (As well as normal actively dividing tissues such as Bone marrow).
  7. 7. • Normally Tissue Growth required ( Increased Aerobic fermentation) When growth is achieved In Normal cells Cancer cells Aerobic fermentation stops Aerobic fermentation continues because of unopposed action of oncogenes and loss of function of tumor suppressor genes.
  8. 8. Quiescent cell • Quiescent cells rely mainly in Kreb’s cycle for ATP production. • If starved, Autophagy(self eating) is induced.
  9. 9. Growing cell (Normal / Tumor cells) • Three pathways: - PI3K-AKT pathway. - Receptor Tyrosine kinase - MYC
  10. 10. a) PI3K-AKT pathway: - Upregulates activity of glucose transporters and glycolytic enzymes. Increased glycolysis. - Promotes shunting of mitochondrial intermediates to pathways leading to lipid biosynthesis. - Stimulates factors required for protein synthesis.
  11. 11. b) Receptor tyrosine kinase - Inhibits enzyme pyruvate kinase which catalyses last step of glycolysis. - Build up glycolytic intermediates. - Used for DNA, RNA, Protein and Lipid synthesis.
  12. 12. c) MYC - Activates multiple glycolytic enzymes and glutaminase ( Increased glutamine utilization by mitochondria) - Biosynthesis of cellular components.
  13. 13. Onco-metabolism • Surprising group of genetic alteration discovered through tumor genome sequencing studies. • Consists of mutation in enzymes that participate in Kreb’s cycle. • Of these, mutation in Isocitrate dehydrogenase (IDH) is of most interest. • Revealed a new mechanism of oncogenesis.
  14. 14. • IDH acquires mutation via amino acid substitution. • Mutated IDH loses its function. • Instead catalyzes formation of 2HG(2- Hydroxy glutarate) • Inhibits several enzymes including TET family. • Loss of TET2 activity leads to abnormal patterns of DNA methylation.
  15. 15. Contd… • Oncogenic IDH mutations occur in a diverse collection of cancers including Cholangiocarcinomas, gliomas, acute myeloid leukemias and sarcomas.
  16. 16. d) Evasion of cell death • Tumor cells in order to survive contain mutations in genes that result in resistance to apoptotic cell death. • Most disabled / dysregulated in cancer cells. (Intrinsic / Mitochondrial pathway) • WHY?? - Cancer cells are subject to intrinsic stresses(DNA damage, Hypoxia, metabolic alterations, Increased misfolded protein, chemoradiotherapy)that initiates Apoptosis via Intrinsic pathway.
  17. 17. • Mechanism by which apoptosis is avoided by cancer: - Loss of p53 response. - Overexpression of anti-apoptotic members of BCL-2 family. (BCL-2, BCL-XL, MCL-1) [ Also associated with drug resistance] Eg: Follicular lymphoma t (14;18) Increased BCL-2 which protects transformed lymphocytes from apoptosis. Tumor grows by evading apoptosis.(Not by increased growth) Therefore, Follicular lymphoma is slow growing (Indolent tumor) - Might upregulate members of inhibitor of apoptosis family (IAP).
  18. 18. e) Limitless replicative potential: - The stem cell like property of tumor cells. - How? • Evasion of senescene. • Evasion of mitotic crisis. • Capacity for self renewal.
  19. 19. • Evasion of Senescence Normally human cells Divide 60-70 times Permanent cell cycle arrest (Senescence) Due to increased p53 and INK4A/ p16 which maintains Rb gene (Hypophosporylated – Active state) which enforces G1/S checkpoint to cell cycle arrest.
  20. 20. Contd… • This G1/ S check point is disrupted in virtually every cancer. (Mutation/ Epigenetic changes)
  21. 21. • Evasion of mitotic crisis - Telomeres: Present at the chromosomal ends. Normally prevents senescence(ageing). - Normally length of this telomeres maintained by enzyme telomerase. - Very low level of this enzyme is present in most somatic cells.
  22. 22. Contd… • Normal cells(Somatic) undergoes senescence after 50-60 divisions. • If they escape senescense by chance, then they undergo mitotic crisis ultimately leading to death.
  23. 23. • Capacity of self renewal: • Tissue stem cells and germ cells - Has telomerase activity. - Resistant to mitotic crisis. - Resistant to genetic and epigenetic changes that trigger senescence. - Capacity of self renewal: Each time a stem cell divides at least one of the two daughter cells remain stem cells.
  24. 24. Contd… • Types of self renewal: - Symmetric: Both daughter cells remain stem cells. Eg: During embryogenesis/ Stress. - Asymmetric: Only one daughter cell remain stem cell. Non stem cell undergoes differentiation pathway with highly proliferative cells. But eventually differentiate and stop dividing because of (Apoptosis and senescence)
  25. 25. Contd… • Cancer cells too must contain cells that self renew. (Known as cancer stem cells)
  26. 26. f) Angiogenesis • Solid tumors with all genetic aberrations required for malignant transformation can’t enlarge beyond 1-2mm in diameter unless it has capacity to induce angiogenesis. • Growing tumor also needs O2 and nutrients for growth and need to remove waste products. • Growing tumor cells induce new blood vessels formation. Relaese of growth factors (IGFs and PDGF) which stimulate growth of adjacent cells. • Vessels are leaky and dilated and have a haphazard pattern of connection.
  27. 27. Contd… • Angiogenesis is controlled by a balance between angiogenesis promoters and inhibitors. • In angiogenic tumors, this balance is skewed in favour of Promotors. • Angiogenic switch : Tumor cells, Inflammatory cells, Stromal cells, ECM release factors which is responsible for switch. • Promotors: VEGF, bFGF, TNFα, Platelets activating factors, Angiogenin, IL-8. • Inhibitors: Thrombospondin-1, Angiostatin/Endostatin.
  28. 28. Factors responsible: Regulation of balance between pro and anti- angiogenic factors: a) Hypoxia: Most important driving force for angiogenesis. - Stabilises HIF-1α transcription factor. - Stimulates transcription of VEGF and bFGF leading to angiogenesis.
  29. 29. Contd… b) Mutation in tumor suppressor genes and oncogenes: • Normally, p53 + Antiangiogenic factor (Thrombospondin-1) - Proangiogenic factor (VEGF) • Loss of p53 activity favor angiogenesis. • Gain of function mutation of RAS/ MYC upregulate the production of VEGF.
  30. 30. Contd… c) Proteases from tumor cells /stromal cells : Many proteases release bFGF from ECM favouring angiogenesis.
  31. 31. g) Invasion and metastasis: • Hallmark of malignancy. • Associated with cancer mortality and morbidity. • Metastasis: - Tumor cells must undergo series of steps. - Avoid immune defense. - Adapt to new microenvironment.
  32. 32. Contd…. • Metastatic cascade has 2 phases: i) Invasion of ECM. ii) Vascular dissemination, Tissue homing; Colonization.
  33. 33. i) Invasion of ECM: Steps: - “Lossening up” of tumor cell- tumor cell interactions. - Degradation of ECM. - Attachment to “remodeled” ECM components. - Migration and invasion of tumor cells.
  34. 34. Loosening of intercellular junctions • First step in process of invasion / metastasis. • Downregulation of E-cadherin due to mutation or silencing (Epithelial to mesenchymal transition) EMT. • Metastatic oncogenes encode Transcription factors SNAIL and TWIST control EMT. • EMT characterized by: - Downregulation of Epithelial markers( E-cadherin) - Upregulation of Mesenchymal markers( eg; Vimentin, Smooth muscle actin) - EMT is integral in breast and prostate carcinoma mets.
  35. 35. Degradation of ECM • Second step in invasion. • Accomplished by secretion of proteolytic enzymes: - MMPs (Matrix Metalloproteinases) (2,9) - Cathepsin D - Urokinase plasminogen activator
  36. 36. Attachment to remodelled ECM components • Fibronectin and Laminin receptors called as Integrins. - Bind to basement membrane collagen and laminin. - Helps maintain cell in resting polarized state. • If adhesion between integrins and (collagen/laminin) break, leads to Apoptosis. • In case of tumor cells, Although shows loss of adhesion, doesn’t trigger apoptosis. Escapes cell death. Anoikis (Meaning ‘Without Home”)
  37. 37. Migration and invasion of tumor cells • Locomotion : Final step of invasion • Propelling tumor cells through degradation of Basement membrane and zones of matrix proteolysis. • Cells attach to matrix at their leading edge , detach from matrix at trailing edge, contract the actin cytoskeleton to rachet forward.
  38. 38. Contd… • Such movement is stimulated by multiple factors: - Tumor cell derived cytokines, chemokines and growth factors(IGF)[ Autocrine] - Cleavage product of matrix components (Collagen and Laminin) - Stromal cell derived factor. (Hepatocyte growth factor) [Paracrine]
  39. 39. ii) Vascular dissemination,Tissue homing; Colonization • Once tumor cells are at circulation, vulnerable to destruction. • So, How do tumor cells survive in circulation? - Metastatic tumor cells are much more likely to establish metastasis as tumor aggregates than as single cells.
  40. 40. Contd… • Tumor aggregates: - Platelet activation: Enhance tumor survival - Fibrin deposition due to activation of Factor XII by polyphosphates(anions) on surface of tumor cells: Further stabilise the tumor emboli. - Stem cells giving plasticity to tumor cells: Helps tumor to adapt new microenvironment.
  41. 41. Contd… • Metastatic deposits appear to relate with 3 factors: - Location and vascular drainage of primary tumor: Eg: Colon Ca metastasis to Liver. - Tropism of particular kind of tumor cell for specific tissues: (Organ tropism) Eg: Carcinoma breast/ Prostate metastatis to bone.
  42. 42. h) Evasion of immune surveillance • Four factors supports role of immune cells in destroying tumor cells: - Presence of lymphocytic infiltrates around tumor and reactive changes in lymph node draining sites of cancer. - Increased cancer incidence in immunodeficiency individual. - Demonstration of tumor specific T-cells and Ab in patients. - Response of cancer cells to agents that act by stimulating host T-cell responses. • Therefore, in order to survive, tumor cells must develop certain mechanisms to escape host immune system.
  43. 43. Antitumor effect mechanism: • The principal immune mechanism of tumor eradication is killing of tumor cells by CTLs specific for tumor antigens.
  44. 44. Mechanism of immune evasion by cancers
  45. 45. 1) Selective outgrowth of Antigen negative variants: -During tumor progression, strongly immunogenic antigen-expressing subclones may be eliminated. - Only those tumor cells that have lost their Antigen survive. 2) Loss or reduced expression of MHC molecules - Tumor cells may fail to express normal levels of HLA Class-I molecule. - Therefore, they may escape CD8+ CTLs.
  46. 46. 3) Engagement of pathways that inhibit T-cell activation. - CTLA-4 downregulates B7 in APCs. Leads to decreased Tcell activation. - PD-1 , like CTLA-4 inhbits Tcell production.
  47. 47. Reference • Robbins S, Cotran RS, Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease. 10th ed. South Asia Edition. 2021;p300-12.
  48. 48. Thank you.

Editor's Notes

  • TET2: Controls normal gene expression and often goes awry in cancer.
  • NHEJ: Non homologous end joing.
    Dicentric chromosomes: Joining of naked end of two chromosomes.
  • Basic fibroblast growth factor. (bFGF)
  • Hypoxia inducible factor (HIF)
  • Fibronectin binds to Type IV collagen. Laminin to laminin receptor.
  • Destroyed by: Mechanical shear stress, Apoptosis (Anoikis), Immune system.
  • Malignant tumors express various types of antigens that may be recognized by immune system as foreign antigens.
    MAGE: Melanoma antigen gene
  • Host APCs (Dendritic cells).
  • Only Antigen negative clone remains.
  • PD-I receptor: Programmed death-1