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The Biology of Cancer December 12, 2006 Cancer: A Cellular Disease Principles of Cellular Growth • Ability to produce exact replica – essential component of life • Normal cellular regulation – Balance between division and death (apoptosis) – Limits on proliferation • Physical boundaries (e.g. basement membrane) • Tissue pressure contact inhibition – Cell cycle regulation • Error correction – Lack of fidelity in cellular reproduction genetic instability – Repair genes – Immune mechanisms: removal of non-self cells – Apoptosis G0: Rest phase G2: Preparation for Mitosis Functional phases Preparatory phases M phase: G1: Preparation for Synthesis Cell Cycle Check Points • Events of cell cycle highly ordered: – different extra cellular/intracellular events • Progression through cell cycle controlled by: – regulation of gene products – checkpoints genes Normal cellular stop signals • Cellular hypoxia (outgrowth of blood supply) • Decreased availability of nutrients • Alternation in cytokine/hormonal milieu • Accumulation in toxic metabolites • Inhibitition of cell-cell contact Cancel: Cellular Derangements • In-exact replica – Genetic instability – Loss of certain function, gain of others • Abnormal cellular regulation: Loss of Balance – – – – Enhanced proliferation Disruption of Physical boundaries Increased tissue pressure, loss of contact inhibition Inhibition of apoptosis (programmed cell death) • Loss of error correction – – – – – Lack of fidelity in cellular reproduction genetic instability Loss of Repair genes Immune inhibition (anergy) Inhibition of apoptosis Selective advantage certain clones Cell Cycle Extra cellular Signals • Complex regulation and division not in a vacuum • Cell integrate signals into control mechanisms: – Nutrient status – Cell to cell contact – Extra cellular peptides • Growth factors cause cells in G0 phase through cell cycle • Continued growth factor exposure • Cytokines: – – – – soluble mediators of cell to cell communication interleukins, interferon, CSF bind to receptors on surface of cells cascade of biochemical signals activation/suppressing of genes CARCINOGENESIS Summary of the carcinogenic process. Invasiveness Initiation Promotion Progression Metastasis (eg Vogelstein model for colon cancer) Normal adenoma I adenoma II APC gene Chr 5q Ras mutation transformation to hyperproliferation proliferation signal left on adenoma III DCC gene 8q21 allelic loss carcinoma P53 Chr 17p tumour suppressor loss of tumour involved in suppressor and differentiation apoptosis Causes of Cancer Factor or Class of Factors Percent of all Cancer Deaths Tobacco 30% Diet 35% Reproductive and sexual behaviour 7% Occupation 4% Alcohol 3% Pollution 2% Geophysical factors 3% Industrial products 1% Medicines and medical procedures 1% Inherited <5% Life-cycle • 1cm3 -> 1g tumor ( 109) cells – 1 cm the limit of clinical detection – 30 doublings occurred prior to clinical detection • Only 10 more doublings (3 logs) – 1kg of tumor – terminal disease • Pre-clinical phase 75% of “life of tumor” Death: 1 kg 10 doublings CT or U/S: 1 cm 30 doublings Single cell Cellular proliferation of tumors • Heterogeneous as a result of: – variability in blood supply/nutrients – Clonal variation Clonal Selection • Increased volume as a result: – Increased division – Decreased death Principles of Metastases • Principle cause of death • Mainly routes of dissemination: – via blood steam – lymphatic • Are flow and organ specific • Establishment of metastases is inefficient: – subpopulation/clone have the abilities to metastases – generally most malignant/aggressive Steps in Metastatic Cascade • Escape • Travel through the blood/lymphatic system • Arrest/attachment • Establishment of clone Metastases: Escape • May be biologically facilitated by: – ability to commit vascular invasion – cell necrosis – molecules of the cell surface – protease ( enzyme) secretion by tumor Metastases: Travel • Blood supply ( angiogenesis) must be adequate • Adequate lymphatic drainage • Special circulatory circumstances Angiogenesis • Concept first put forward by Folkman • Tumour produces factors to induce / generate its own blood supply • VEGF one of the most important mediators • Interacts with endothelial cell receptors : – VEGFR-1 and VEGFR-2 • Essential for normal embryonic vasculogenesis • VEGF upregulated in many cancer types Growth factors eg TGFb, estrogen Collagenases ras Growth factors receptors CDK’seg EGFR, eRBb2 Angiogenic factors Eg VEGF Cancer Promotion Autocrine promotion Eg. contact inhibition Chemotherapy Principles of Chemotherapy • Exponential relationship between dose and kill – small decrease in drug dose results in large increase in cell survival • Cycling cells at greatest risk • Multiple courses of therapy – each treatment kills same proportion (not number) of cells – e.g.: 3 log killed 1010 to 107 1 log regrowth between cycles Mechanisms of resistance • Tumor sanctuaries • Drug exposure/Selection pressure – chemotherapeutic agents selects for resistant cells • Resistance within a tumor a function of: – inherent genetic instability of a tumor – size of tumor ( # cells) Goldie-Coldman hypothesis (chance resistance a size) Stop Block Turn Stop growth off new the Stimulate Chemotherapy destruction of blood renegade factor vessel immune barriers “grow” receptors formation signal system •Herceptin •Endostatin •Farnesyl •Matrix •Interferon transferase metalloproteinase •Rituxan •Angiostatin •MoAb’s inhibitors inhibitors •Tamoxifen •COX2 inhibitors Blood supply as the Target VEGF X e.g. bevacizumab / Avastin® X Cell membrane Tyrosine Kinase VEGFR - 2 VEGF trap X X Signal Transduction Blood supply as target: Bevacizumab in colon cancer Generalized Staging Principles: TNM • Stage I – Organ confinement • Stage II – Locally advanced / larger / penetration • Stage III – Nodal involvement • Stage IV – Metastatic Look for: Molecular staging elements Lymph Nodes • Prognosticator – E.g. colon N0 25% recurrence (less than 4 negative nodes 50%) N1 (1-3 nodes) 60% recurrence N2 (4+ nodes) 70% recurrence • Source of disease – Axillary dissection as a therapeutic intervention – TME • Techniques for analysis – Toluene fat dissolving techniques (yield) – Immunohistochemistry for cytokeratins • The sentinel node – Extensive focused analysis Pattern Recognition • Colon – – – – Mesenteric nodes Drains through portal vein: first stop liver Of those stage IV, 90 have liver mets, 70 only liver Other sites peritoneal, nodes > lung >> [bone/brain] • Lung – Mediastinal nodes – Pleural effusions – Lung, Liver, adrenal, bone, brain • Breast – Axillary nodes – Lung, liver, bone, brain • Kidney or Melanoma anywhere! Unknown primary • Peritoneal + ovarian masses – Ovarian, PPC, Stomach, colon • Axillary nodes – Breast, lymphoma • Brain metastases – Lung, breast>> kidney.. • Bone metastases – “Buy The Kid Long Pants” The curable metastasis • Surgery Colon cancer – 35% 5yOS after complete resection of liver, lung or splenic metastases • Chemotherapy for testicular cancer or lymphoma Thank-you for your attention!