Hallmarks of cancer

Hallmarks of cancer.

1. HALLMARKS OF CANCER By Dr. N. Sreekanth DNB-RT, BIACH&RI

2. What is Normal? Dependence on growth factors –Cell and tissue specific signals –Loss of these signals leads to apoptosis Anchorage dependent proliferation –Requires interaction of transmembrane proteins ( integrins ) with components of the ECM Contact inhibition –Contact with other cells inhibits proliferation and movement Limited proliferative capacity –Normal somatic cells have a limited number of divisions before entering senescence

3. New capabilities or Loosing control ? The hallmarks of cancer are the distinctive and complementary capabilities that enable tumor growth and metastatic dissemination.

4. Oncogene and Tumor Suppressor Genes Oncogene : Mutated forms of normal cellular genes generally involved in promoting cell proliferation. These mutations result in dominant gain of function . Tumor suppressor: Genes whose normal function in regulating proliferation is to stop it. Mutation results in recessive loss of function.

5. Hallmarks of Cancer Sustaining proliferative signaling, Evading growth suppressors Resisting cell death Enabling replicative Immortality Inducing angiogenesis Activating invasion and metastasis Deregulating cellular energetics Evading immune destruction

6. Douglas hanahan Robert weinberg

7. Sustaining Proliferative Signaling

8. (1) P roduce their own growth factors  autocrine stimulation. ( 2) P roduce paracrine signals  produce growth factors to support the cancer cells. ( 3) G rowth factor receptor levels elevated  H yper responsive cancer cells . (4) I ndependent from growth factors  A ctivation of downstream signaling pathways or the disruption of negative-feedback mechanisms. anti-EGFR therapy ( Cetixumab )

9. Clinical implication of KRAS mutation Patients with mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy ( Cetixumab ). Patients with metastatic CRC who are being considered for anti-EGFR antibody therapy should be tested for the presence of a KRAS mutation prior to therapy.

10. Evading Growth Suppressors

11. The most prominent brakes: Retinoblastoma protein ( pRb ) ( G atekeeper) D irect regulator of the cell division cycle. RB transduces growth-inhibitory signals and decides whether or not a cell should proceed through its growth-and-division cycle. D efects in the RB pathway function  persistent cell proliferation .

12. p53 pathways : Guardian of the genome TP53 receives inputs from stress and abnormality sensors that function within the cell’s intracellular operating systems. TP53 can halt further cell-cycle progression trigger apoptosis

13. Merlin (cytoplasmic NF2 gene product) Contact inhibition by coupling cell-surface adhesion molecules (e.g., E-cadherin) to transmembrane receptor tyrosine kinases (e.g., the EGF receptor ).

14. Resisting Cell D eath

15. The most prominent of these programs : 1) Apoptosis  maintain tissue homoeostasis. 2) Necrosis  various conditions like oxygen and energy deprivation. 3) Autophagy  generates the metabolites and nutrients that cells are unable to acquire from their surroundings .

16. Apoptosis Death receptors transmit signals leading to apoptosis FAS ligand and FAS receptor TNF- α and TNF- α R1 Decoy receptors that don’t signal can promote survival Intracellular proteins that monitor DNA damage p53 Pro-survival factors Bcl-2 family of proteins

17. The loss of TP53 tumor suppressor function. Increasing the expression of anti-apoptotic regulators Bcl-2 family. Down regulating proapoptotic Bcl-2– related factors ( Bax , Bim , Puma).

18. Enabling Replicative Immortality

19. Cells have a finite lifespan and limited ability to replicate Due to chromosome shortening Ends of chromosomes are called telomeres ( hexamer repeats -TTAGGG) Hayflick limit : approximately 50-80 doublings Cells reach replicative senescence Enzyme TOLEMERASE  maintain chromosome length (adds telomeres to the ends of telomeric DNA)

20. Cancer cells must have unlimited replicative potential. All cancer cells maintain their telomeres. 90% of them do so by increasing the production of telomerase enzyme. A cquire the unlimited replicative potential—termed cellular immortality

21. Inducing A ngiogenesis

22. All tumors require a blood supply to grow to a significant size. Hypoxia will induce apoptosis by activation of p53. The formation and maintenance of new blood vessels (angiogenesis) plays a critical role in tumour growth & metastasis. New blood vessels supply the cancer cells with oxygen and nutrients, allowing the tumour to grow. Angiogenesis is mediated principally through vascular endothelial growth factor (VEGF )

23. Tumor-associated angiogenic factors may be produced by the tumor or by inflammatory cells P53 inhibit angiogenesis by stimulation of anti-angiogenesis molecules VEGF is under the control of RAS oncogene.

24. Activating Invasion and Metastasis

25. A ctivation of Epithelial M esenchymal T ransition (EMT): Normally during embryonic morphogenesis Epithelial cells acquire Mesenchymal traits Loss of adherent junctions Change in cellular morphology Expression of proteases Increased motility

26. Tumor cells binds to leukocytes, which protect them from host defense mechanisms Tumor cells adhere to vascular endothelium & pass through Basement membrane Site of extravasations & Mets depends on: Blood & Lymphatic supply Organ tropism/adhesion Functional loss of E-cadherin, which serves as a widely acting suppressor of invasion

27. Deregulating Cellular Energetics

28. Rapidly growing cancer cells need fuel for cell growth cellular building blocks to generate new cancer cells

29. Warburg Effect or aerobic glycolysis Cancer cells reprogram their glucose metabolism, by limiting their energy production largely to glycolysis Consume more than 20 times as much glucose compared to normal cells, but secrete lactic acid instead of breaking it down completely into carbon dioxide. Divert glycolytic intermediates to other biosynthetic pathways to make macromolecules which are used as building blocks for the production of proteins, lipids and DNA required by the rapidly dividing cells .

30. Evading Immune Destruction

31. Cells and tissues are under constant surveillance by the immune system T he immune system detects and tries to kill cancer cells. Cancer cells paralyze infiltrating CTLs and NK cells by secreting TGF-β or other immunosuppressive factors. express immunosuppressive cell-surface ligands, such as PD-L1, that prevent activation of the cytotoxic mechanisms of the CTLs .

32. New anti-cancer treatments have attempted to stop these immune checkpoint signals. Ipilimumab ( Yervoy )- Melanoma Nivolumab ( Opdivo )- NSCLC Pembrolizumab ( Keytruda )- Melanoma .

33. Enabling Characteristics: Genome Instability and Mutation Tumor-Promoting Inflammation

34. Genome Instability and Mutation Acquisition of the hallmarks in part depends on genomic alterations Two of the most famous proteins in cancer, BRCA1 and BRCA2, play a central role in DNA repair. Result in mutations that convey on cancer cells hallmark capabilities This may be acquired through Clonal selection DNA methylation Histone modifications Alterations in DNA maintenance machinery

35. Tumor-Promoting Inflammation Tumors are “wounds that don’t heal” Immune cells that normally participate in wound healing help cancer cells acquire hallmark capabilities & become more aggressive Major risk factors for cancer Chronic infections, obesity, smoking, alcohol consumption, environmental pollutants and high fat diets Linked to cancer through inflammation .

36. Inflammation contribute to multiple hallmarks by supplying bioactive molecules to the tumor microenvironment, including growth factors and survival factors .

37. TUMOR MICROENVIRONMENT

38. Whole Picture

39. THERAPEUTIC TARGETING OF THE HALLMARKS OF CANCER

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