Hallmarks of malignancy 5 Development of Sustained Angiogenesis

Hallmarks of malignancy 5. Development of Sustained Angiogenesis: Tumors cannot enlarge beyond 1 -2 mm in diameter unless they are vascularized. Tumor cells require oxygen, nutrients & removal of waste products. l Cancer cells can stimulate neoangiogenesis by: 1 - Sprout of new vessels from pre-existing capillaries 2 - Neo-vasculogenesis: Recruitment of endothelial cells from bone marrow. Tumor vessels are abnormal, leaky & dilated, with haphazard pattern of connection.

l Neovascularization has dual effect on tumor growth: l 1 - Supplies the needed nutrients & oxygen. l 2 - Endothelial cells will secrets growth factors, stimulating further growth of tumor cells. l Angiogenesis is important for: l 1. Continuous growth of tumor. l 2. Access of tumor cells into blood vessels & then metastasized to other site.

l How do growing tumors develop a blood supply? l Angiogenesis is controlled by balance between: • Angiogenesis inducer: Pro-angiogenic factors. Ex. : Vascular endothelial growth factor (VEGF). • Angiogenesis inhibitor: Inhibitory factors. Thrombospondin-1 (TSP-1). l Normal p 53 induces synthesis of TSP-1. • Molecular basis of angiogenesis involves: 1. Increased production of angiogenesis factors 2. Loss of angiogenesis inhibitors.

Hallmarks of malignancy 6. Ability to Invade & Metastasize l Invasion–metastasis cascade: l Steps of tumor spread: 1. Local invasion. 2. Intravasation into blood & lymph vessels. 3. Transition through the vessels. 4. Extravasation from the vessels. 5. Formation of micro-metastasis mass. 6. Growth of micro-metastasis mass into macroscopic tumors.

Metastatic cascade: Two phases: (1) Invasion of ECM. (2) Vascular dissemination & homing of tumor cells. Invasion of ECM): Four steps: l 1. Loosening of tumor cells: v E-cadherins act as intercellular glues attaching & keeping the cells together. v E-cadherin transmit antigrowth signals. l E-cadherin function is lost in almost all epithelial cancers.

l 2. Local degradation of basement membrane & interstitial connective tissue. 1. Tumor cells secrete proteolytic enzymes. 2. Induce stromal cells (fibroblasts & inflam. cells) to elaborate proteases that implicated in tissue degradation & tumor cell invasion. 3. Reduce the levels of proteinase inhibitors Increase proteinase enzyme Increase tissue degradation.

l 3. Attachment: l Normal epithelial cells have receptors help to maintain cells in resting differentiated state. l Ex. : Integrins receptor for laminin & collagens of the basement membrane are present at their basal surface. l In tumor: There are changes in the attachment of tumor cells to ECM proteins. l Loss of adhesion in normal cells leads to induction of apoptosis. l Tumor cells are resistant to apoptosis.

l • 4. Migration: l Locomotion of tumor cells through the degraded basement membranes & matrix. l Involves many receptors & signaling proteins that impinge on actin cytoskeleton. l Such movement is potentiated & directed by: l 1. Tumor cell–derived cytokines such as: l Autocrine motility factors. l 2. Cleavage products of ECM (collagen, laminin). l 3. Chemotactic activity of some growth factors for tumor cells.

Vascular Dissemination & Homing of Tumor Cells: l Most tumor cells circulate as single cells. l Some tumor cells form emboli by aggregating & adhering to platelets so protected from immune cells. l Extravasation of free tumor cells or tumor emboli involves: l 1. Adhesion to vascular endothelium. l 2. Go out through basement membrane to the parenchyma by mechanisms similar to those involved in invasion.

Hallmarks of malignancy 7. Reprogramming of Energy Metabolism: l Cancer cells shift their glucose metabolism into aerobic glycolysis, called: Warburg effect: l Produce 2 molecules of ATP / molecule of glucose. l It is less efficient than mitochondrial oxidative phosphorylation (produce 36 molecule of ATP). l Cancer cells produce less ATP but its production is hundred times faster than normal cells. l So there is increase in glucose uptake, a major feature distinguish tumor cells from normal cells.

l Warburg metabolism: Mode of metabolism favored when rapid growth is required. l Burkitt lymphoma: l 1. The most rapidly growing human cancers. l 2. Tumors cells choose aerobic glycolysis.

Hallmarks of malignancy 8. Evasion of the Immune System: q Tumors cells have ability to avoide destruction by the immune system. q Most tumors arise in immuno-competent hosts. q Tumor cells can trick the immune system so they are not recognized or eliminated. l What l are the nature of tumor antigens and how they might be recognized? Tumor immunity

Hallmarks of malignancy 9. Genomic Instability as Enabler of cancer: l The preceding eight features of malignancy occurs due to genetic alterations or mutation. l How do these mutations arise? l Mutagenic environmental agents: Chemicals, radiation, sunlight DNA damage l They rarely cause cancers due to ability of normal cells to repair any DNA damage occurred. l Defects in the genes encode proteins that repair the damaged DNA Cancer. Ex. : 1. Hereditary Nonpolyposis Colon Cancer Syndrome 2. Xeroderma Pigmentosum.

Hereditary Nonpolyposis Colon Cancer Syndrome l Familial carcinomas of colon. l Results from defects in genes involved in DNA mismatch repair. Ex. : l If there is error in pairing of G with T, (rather l than the normal A with T), the mismatch repair l genes correct the defect. l Mutation in these genes Cancer.

Xeroderma Pigmentosum l Inherited disorder. l Cancers in the sun-exposed skin. l There is defective DNA repair.

Hallmarks of malignancy 10. Tumor-Promoting Inflammation as Enabler of cancer: l Inflammation is protective response against tumor l Can enable malignancy in two ways: l • 1 - Persistent chronic inflammation: l Ex. : Microbial infections or autoimmune reaction. l Increased risk of cancer. l Ex. : Chronic inflammatory diseases of GIT: l Barrett esophagus, ulcerative colitis, H. pylori gastritis, hepatitis B & C & chronic pancreatitis. l

l In chronic tissue injury: l A: Regenerative process as a compensatory proliferation of cells to repair damage, aided by growth factors, cytokines, chemokines produced by immune cells at the site. l Persistent cell replication & reduced apoptosis: Increase risk of genetic mutations. B: Reactive oxygen species formed by inflammatory cells Additional DNA damage in the rapidly dividing cells Carcinogenesis.

l The second way: l • 2 - When inflammation occur in response to tumors. l Many tumors are infiltrated by inflammatory cells (Leukocytes), producing growth factors: l Exert tumor-promoting activity. l Causes additional DNA damage.