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1. By: M idekso Sento Jimma University October ,2020 Seminar presentation on Molecular basis of Neoplasia

2. Outline Objective Introduction to N eoplasia Molecular basis of Neoplasia Reference 10/27/2020 2

3. Objective At the end of this presentation the participants will able to answer What is neoplasia What are the molecular basis of neoplasia 10/27/2020 3

4. Introduction Cancer is characterized by abnormal and uncontrolled growth Cancer arises from a loss of normal growth control In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer, this balance is disrupted and can result from Uncontrolled cell growth Loss of a cell's ability to undergo apoptosis 10/27/2020 4

5. Cont.. Neoplasia M eans “new growth.” Neoplastic cells are said to be transformed because they continue to replicate, apparently oblivious to the regulatory influences that control normal cells. Neoplasms therefore enjoy a degree of autonomy and tend to increase in size regardless of their local environment. Neoplasms derived from hormone responsive tissues often also require endocrine support. 10/27/2020 5

6. Molecular Basis of Neoplasia (carcinogenesis) Fortunately, in most if not all instances, no single mutation is sufficient to transform a normal cell into a cancer cell. Carcinogenesis Is a multistep process Resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype and all of its associated hallmarks 10/27/2020 6

7. Cont… Four classes of normal regulatory genes are the principal targets of genetic damage Growth-promoting proto-oncogenes Growth-inhibiting tumor suppressor genes Genes that regulate apoptosis Genes involved in DNA repair . 10/27/2020 7

8. Cont… It appears that all cancers display eight fundamental changes in cell physiology, which are considered the hallmarks of cancer. Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Altered cellular metabolism Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Invasion and metastasis Evasion of immune surveillance These hallmarks may be accelerated by cancer promoting inflammation and by genomic instability . 10/27/2020 8

9. Self-sufficiency in growth signals Tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation. The self-sufficiency in growth that characterizes cancer cells generally stems from gain-of-function mutations that convert proto-oncogenes to oncogenes. Oncogenes encode proteins called oncoproteins that promote cell growth , even in the absence of normal growth-promoting signals . Cancers may secrete their own growth factors or induce stromal cells to produce growth factors in the tumor microenvironment 10/27/2020 9

10. Cont… In a normal cell, Proto-oncogenes have multiple roles, participating in cellular functions related to growth and proliferation. Self sufficiency for growth to a cancerous cell is provided by oncogenes, which are the mutant proto-oncogenes. Mutations convert inducible proto-oncogenes into constitutively active oncogenes , which is responsible for progressive cell divisions 10/27/2020 10

11. Cont… Most soluble growth factors are made by one cell type and act on a neighboring cell to stimulate proliferation. Some cancer cells acquire growth self-sufficiency by acquiring the ability to synthesize the same growth factors to which they are responsive Another mechanism by which cancer cells acquire growth self-sufficiency is by interaction with stroma . 10/27/2020 11

12. Cont… Proto-oncogenes:  Normal cellular genes whose products promote cell proliferation Physiologic regulators of cell proliferation and differentiation Oncogenes:  Mutant or overexpressed versions of proto oncogenes that   function autonomously without a requirement for normal growth-promoting signals Oncogenes are characterized by the ability to promote cell growth in the absence of normal mitogenic stimulus Oncoproteins promote uncontrolled cell proliferation because they have Stimulus-independent expression of growth factor and its receptor .  10/27/2020 12

13. Cont… Oncogene products, called oncoproteins , resemble the normal products of protooncogenes with the exception that oncoproteins are devoid of important regulatory elements. Cells expressing oncoproteins are thus freed from the normal checkpoints and controls that limit growth, and as a result proliferate excessively . 10/27/2020 13

14. Cont… 10/27/2020 14

15. Cont… Growth Factors and Growth Factor Receptors Normally cell require stimulation by GFs to undergo proliferation Mostly these GFs are secreted by one cell type and act on a neighboring cell to stimulate proliferation. Cancer cells acquire the ability to synthesize their own GFs . Several oncogenes that encode growth factor receptors have been found Cancers may secrete their own growth factors or induce stromal cells to produce growth factors in the tumor microenvironment . 10/27/2020 15

16. Cont… Cell Cycle Regulators ( Cyclins and CDK) The ultimate outcome of all growth-promoting stimuli is the entry of inactive cells into the cell cycle. Progression of cells through the cell cycle is directed by CDKs Cancers may grow autonomously if the genes that drive the cell cycle become dysregulated by mutations or amplification There are two main cell cycle checkpoints , G1/S transition G2/M transition Regulated by a balance of growth promoting and growth-suppressing factors . 10/27/2020 16

17. Insensitivity to growth-inhibitory signals The products of most tumor suppressor genes apply brakes to cell proliferation , abnormalities in these genes lead to failure of growth inhibition Tumors may not respond to molecules that are inhibitory to the proliferation of normal cells Where as oncogenes encode proteins that promote cell growth , the products of tumor suppressor genes apply brakes to cell proliferation . 10/27/2020 17

18. Cont… Disruption of such genes renders cells refractory to growth inhibition and mimics the growth-promoting effects of oncogenes Tumor suppressor proteins form a network of checkpoints that prevent uncontrolled growth. Loss of normal cell cycle control is central to malignant transformation and key regulators of the cell cycle is dysregulated in the vast majority of human cancers 10/27/2020 18

19. Cont… Tumor suppressor genes normal function is to inhibit cell proliferation but absence/inactivation of inhibitor leads to cancer RB and p53, are part of a regulatory network that recognizes genotoxic stress from any source and responds by shutting down proliferation . RB Governor of Proliferation Regulating the G1-S checkpoint of the cell cycle Directly or indirectly inactivated in most human cancers 10/27/2020 19

20. Cont… p53 gene Located on chromosome 17p13.1, and it is the most common frequently mutated gene in human cancers. Acts as a molecular policeman that prevents the propagation of genetically damaged cells. Inhibits neoplastic transformation by three interlocking mechanisms: Activation of temporary cell cycle arrest (quiescence ) Induction of permanent cell cycle arrest (senescence) Triggering of programmed cell death (apoptosis ). 10/27/2020 20

21. Cont… P53 Is virtually undetectable in normal cells. In stressed cells, p53 is released from the inhibitory effects via two major mechanisms: DNA damage Hypoxia both of them are key initiators of p53 activation With loss of normal p53 function, DNA damage goes unrepaired, mutations become fixed in dividing cells, and the cell turns onto a one-way street leading to malignant transformation 10/27/2020 21

22. Altered cellular metabolism Conversion of glucose to lactose (fermentation) via the glycolytic pathway Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components, whereas mitochondrial oxidative phosphorylation does not. Warburg  metabolism is a form  of pro-growth  metabolism favoring  glycolysis over oxidative phosphorylation 10/27/2020 22

23. Cont… 10/27/2020 23 Growing cell has a strict biosynthetic requirement; it must duplicate all of its cellular components (nucleic acids ,proteins , lipid) and organelles before it can divide and produce two daughter cells. While oxidative phosphorylation yields abundant ATP, it fails to produce any carbon moieties that can be used to build the cellular components needed for growth (proteins, lipids, and nucleic acids).

24. Evasion of apoptosis Accumulation of neoplastic cells may result not only from activation of growth-promoting oncogenes or inactivation of growth suppressing genes , but also from mutations in the genes that regulate apoptosis. Tumors may be resistant to apoptosis , as a consequence of inactivation of p53 or activation of anti-apoptotic genes . Apoptosis represents a barrier that must be overcome for cancer to occur. In the adult, cell death by apoptosis is a physiologic response to several pathologic conditions that might contribute to malignancy if the cells remained viable . 10/27/2020 24

25. Cont… Genes that regulate apoptosis Genes that prevent or induce programmed cell death are also important variables in the cancer equation. Genes that regulate apoptosis may be dominant as are protooncogenes or may behave as cancer suppressor genes. 10/27/2020 25

26. Cont… 10/27/2020 26 Two pathways that lead to apoptosis: Extrinsic pathway Intrinsic pathway also known as the mitochondrial pathway , initiated by loss of growth factors, hypoxia and DNA damage . The most common abnormalities involve loss of p53 function,

27. Limitless replicative potential Tumor cells have unrestricted proliferative capacity, avoiding cellular senescence and mitotic catastrophe. The Stem Cell Like Properties of Cancer Cells All cancers contain cells that are immortal and have limitless replicative potential Tumor cells reactivate telomerase, thus staving off mitotic catastrophe and achieving immortality .   10/27/2020 27

28. Cont… Three interrelated factors appear critical to the immortality of cancer cells 10/27/2020 28

29. Sustained angiogenesis Tumor cells, like normal cells, are not able to grow without formation of a vascular supply to bring nutrients and oxygen and remove waste products . Solid tumors cannot enlarge beyond 1 to 2 mm in diameter unless they are vascularized. Neovascularization has a dual effect on tumor growth: Perfusion supplies needed nutrients and oxygen Newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors 10/27/2020 29

30. Cont… Tumor angiogenesis is controlled by the balance between angiogenesis promoters and inhibitors factor t hat are produced by tumor and stromal cells respectively . In a ngiogenic tumors this balance is skewed in favor of promoters. Early in their growth, most human tumors do not induce angiogenesis. Mutations involving tumor suppressors and oncogenes in cancers also tilt the balance in favor of angiogenesis and Hypoxia triggers angiogenesis. They remain small or in situ, possibly for years, until the angiogenic switch terminates this stage of vascular quiescence. 10/27/2020 30

31. Cont… The molecular basis of the angiogenic switch involves Increased production of angiogenic factors Loss of angiogenic inhibitors These factors may be produced by the tumor cells themselves or other stromal cells associated with the tumors. In normal cells, p53 can stimulate expression of anti- angiogenic molecules and repress expression of pro- angiogenic molecules . Thus , loss of p53 in tumor cells not only removes the cell cycle checkpoints but also provides a more permissive environment for angiogenesis 10/27/2020 31

32. Cont… 10/27/2020 32 The local balance of angiogenic and anti- angiogenic factors is influenced by several factors: Relative lack of oxygen due to hypoxia, that stimulates the proliferation of endothelial cells and guides the growth of new vessels toward the tumor Mutations involving tumor suppressors and oncogenes in cancers also tilt the balance in favor of angiogenesis

33. Cont… Neovascularization has a dual effect on tumor growth : 10/27/2020 33

34. Invasion and metastasis Are the results of complex interactions involving cancer cells, stromal cells, and the extracellular matrix Major causes of cancer-related morbidity and mortality and depend on processes that are intrinsic to the cell or are initiated by signals from the tissue environment. Carcinoma first must breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane 10/27/2020 34

35. Cont… Dissociation of cells from one another Downregulation of E-cadherin expression reduces the ability of cells to adhere to each other and facilitates their detachment from the primary tumor and their advance into the surrounding tissues. Cell–cell contacts are lost by the inactivation of E-cadherin through a variety of pathways 10/27/2020 35

36. Cont… Metastatic cascade is divided into two phases : 10/27/2020 36

37. Cont… Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several steps“ Loosening of intercellular connections between tumor cells Local degradation of the basement membrane and interstitial connective tissue . Attachment to novel ECM components Migration and invasion of tumor cells is the final step 10/27/2020 37

38. Cont… Vascular Dissemination of Tumor Cells Once in the circulation, tumor cells are vulnerable to destruction by a variety of mechanisms Mechanical shear stress Apoptosis stimulated by loss of adhesion Innate and adaptive immune defenses Heterotypic adhesion between tumor cells and blood cells, particularly platelets . Tumor cells may also bind and activate coagulation factors , resulting in the formation of emboli . 10/27/2020 38

39. Evasion of immune surveillance Tumors may evade immune responses by Losing expression of antigens Major histocompatibility complex (MHC ) molecules Producing immunosuppressive cytokines or ligands such as PD-L1 for inhibitory receptors on T cells . Genomic instability occurs when both copies of the DNA repair gene are lost 10/27/2020 39

40. Reference Robbin basic pathology 10 th edition General pathology lecture note 10/27/2020 40

41. Thank you! 10/27/2020 41