THE MOLECULAR BASIS OF CANCER Part 2

EVASION OF APOPTOSIS A large family of genes that regulate apoptosis

Slide 8.35

Apoptosis Executioner caspase Regulation of death-receptor-induced gene expression by FLIP.

Apoptotic pathways activated by cytolytic T cells Apoptosis

EVASION OF APOPTOSIS Signaling through the death receptor CD95 (Fas) and by DNA damage. Reduced levels of CD95 in hepatocellular carcinomas. BCL2 in protecting tumor cells from apoptosis in B cell lymphomas of the follicular type t(14:18) in 85% of cases.

LIMITLESS REPLICATIVE POTENTIAL Normal human cells have a capacity of 60 to 70 doublings. Why? Shortening of telomeres at the ends of chromosomes. Activation of the enzyme telomerase which can maintain normal telomere length is seen in 85% to 95% of cancers.

DEVELOPMENT OF SUSTAINED ANGIOGENES Tumors cannot enlarge beyond 1 to 2 mm in diameter or thickness unless thay are vascularized. Neovascularization has a dual effect on tumor growth: 1- perfusion supplies nutrients and oxygen 2- newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting polypeptides such as: - Granulocyte-macrophage colony-stimulating factor (GM-CSF) - Interleukin (IL)-I. - PDGF - insulin-like growth factors

DEVELOPMENT OF SUSTAINED ANGIOGENES Tumors contain factors that are capable of affecting the entire series of events involved in the formation of new capillaries e.g. vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) Tp53 inhibit angiogenesis RAS activation up-regulates VEGF production

DEVELOPMENT OF SUSTAINED ANGIOGENES

Invasion and Metastasis Mechanisms of Invasion and Metastasis Invasion Associated with activated motility Balance between tissue destruction and synthesis Cell surface and extracellular matrix play important roles Metastasis Require acquisition of additional tumor characteristics beyond those necessary for invasion

Invasion and Metastasis Mechanisms of metastases             

Mechanisms of Invasion and Metastasis To produce a hematogenous metastasis a tumor cell must: Homing of tumor cells, chemokine receptors At each step of this metastatic cascade the tumor cells are selected by the basic principle of survival of the fittest which contributes to the phenomenon of tumor progression.

GENOMIC INSTABILITY ENABLER OF MALIGNANCY Ability of normal cells to repair DNA damage. The importance of DNA repair in maintaining the integrity of the genome is highlighted by several inherited disorders in which genes that encode proteins involved in DNA repair are defective.

Hereditary nonpolyposis colon carcinoma (HNPCC) syndrome.

The role of DNA repair genes is in the origin of cancer e.g. if there is an erroneous pairing of G with T rather than the normal A with T, the mismatch repair genes correct the defect. Without these “proofreaders,” errors slowly accumulate in several genes, including protooncogenes and cancer suppressor genes.

GENOMIC INSTABILITY ENABLER OF MALIGNANCY Xeroderma pigmentosum are at increased risk to the development of cancers of the skin exposed to the ultraviolet(UV) light contained in sun rays. UV light causes cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is repaired by the nucleotide excision repair system. Pt. with xeroderma pigmentosum have inherited loss of these genes. Two genes, BRCA1 and BRCA2, account for 80% of cases of familial breast cancer, have a role in DNA repair.

KARYOTOPIC CHANGES IN TUMORS The genetic damage during carcinogenesis may be subtle (e.g. point mutations) or large enough to be detected in a karyotype e.g. - balanced translocation. - deletions. - amplification.

KARYOTOPIC CHANGES IN TUMORS Balanced translocations: Philadelphia (Ph) chromosome in chronic myelogenous leukemia Follicular B-cell lymphomas Burkitt’s lymphoma Deletions :– Deletions of chromosome 13q band 14 are associated with retinoblastoma. Delations of 17p, 5q and 18q all noted in colorectal cancers. Gene amplifications: – N-MYC and HER-2 genes Point mutation: Ras.

HEREDITY Many types of cancer including common forms have hereditary predispositions Lung cancer and smoking, 4x greater in among nonsmoking relatives of lung cancer than nonsmoking relatives of controls

HEREDITY 3 CATEGORIES: Inherited cancer syndromes. Autososmal dominant e.g. familial retinoblastoma and Li-Fraumeni Syndrome. Familial cancers. Evidence of familial clustering, but role of inherited predisposition may not be clear e.g. breast cancer, colon cancer and ovarian cancer. Autosomal recessive syndromes of defective DNA repair, e.g. xeroderma pigmentosa, Ataxia telangiectasia, Bloom syndroom and Fanconi anemia

HEREDITY Inherited cancer syndromes. Autososmal dominant e.g. 1. Li-Fraumeni Syndrome 2. Familial retinoblastoma: 40% are familial 10,000-fold increased risk bilateral other cancers e.g. osteosarcoma 3. Familial adenomatous polyposis: innumerable polyps in colon 100% of pt. develop cancer of colon 4. Multiple endocrine neoplasia 5. Neurofibromatosis 6. von Hippel-Lindau syndrome

(insertional, viral, translocation) amplification or overexpression Mutation (insertional, viral, translocation) Result in : amplification or overexpression “gain of function”

Invasion and Metastasis Mechanisms of Invasion and Metastasis Tumor cells probably penetrate more often into the blood vessel within the tumor rather than the preformed vessels around it. Some tumor vessels have an incomplete endothelial lining and it must be easier for tumor cells to enter such vessels. When the vessel has both a basement membrane and an endothelia lining, penetration takes four steps. 1. Detachment Attachment Lysis Migration (Invasion)