Neoplasia_250131_025135 (4).PDF

ONCOGENES Are MUTATIONS of NORMAL genes (PROTO-oncogenes) – Growth Factors – Growth Factor Receptors – Signal Transduction Proteins (RAS) – Nuclear Regulatory Proteins – Cell Cycle Regulators Oncogenes code for è Oncoproteins  PROTO- Mode of Associated Huma...

ONCOGENES Are MUTATIONS of NORMAL genes (PROTO-oncogenes) – Growth Factors – Growth Factor Receptors – Signal Transduction Proteins (RAS) – Nuclear Regulatory Proteins – Cell Cycle Regulators Oncogenes code for è Oncoproteins  PROTO- Mode of Associated Human Category Oncogene Activation Tumor GFs PDGF-β chain SIS Overexpression Astrocytoma Osteosarcoma Fibroblast HST-1 Overexpression Stomach cancer growth factors INT-2 Amplification Bladder cancer Breast cancer Melanoma TGFα TGFα Overexpression Astrocytomas Hepatocellular carcinomas HGF HGF Overexpression Thyroid cancer  PROTO- Mode of Associated Human Category Oncogene Activation Tumor GF Receptors EGF-receptor ERB-B1 Overexpression Squamous cell carcinomas of family (ECFR) lung, gliomas ERB-B2 Amplification Breast and ovarian cancers CSF-1 receptor FMS Point mutation Leukemia Receptor for RET Point mutation Multiple endocrine neoplasia 2A neurotrophic and B, familial medullary thyroid factors carcinomas PDGF receptor PDGF-R Overexpression Gliomas Receptor for stem KIT Point mutation Gastrointestinal stromal tumors cell (steel) factor and other soft tissue tumors  PROTO- Mode of Associated Human Category Oncogene Activation Tumor Signal Transduction Proteins GTP-binding K-RAS Point mutation Colon, lung, and pancreatic tumors H-RAS Point mutation Bladder and kidney tumors N-RAS Point mutation Melanomas, hematologic malignancies Nonreceptor ABL Translocation Chronic myeloid leukemia tyrosine kinase Acute lymphoblastic leukemia RAS signal BRAF Point mutation Melanomas transduction WNT signal β-catenin Point mutation Hepatoblastomas, transduction hepatocellular carcinoma  Mode of PROTO- Activation Associated Human Category Oncogene Tumor Nuclear Regulatory Proteins Transcrip. C-MYC Translocation Burkitt lymphoma activators N-MYC Amplification Neuroblastoma, small cell carcinoma of lung L-MYC Amplification Small cell carcinoma of lung  MYC Encodes for transcription factors Also involved with apoptosis  P53 and RAS p53 RAS n Activates DNA repair H, N, K, etc., varieties proteins Single most common n Sentinel of G1/S abnormality of transition dominant oncogenes in n Initiates apoptosis human tumors n Mutated in more than Present in about 1/3 of 50% of all human all human cancers cancers  Tumor (really “GROWTH”) suppressor genes TGF-β à COLON E-cadherin à STOMACH NF-1,2 à NEURAL TUMORS APC/β-cadherin à GI, MELANOMA SMADs à GI RB à RETINOBLASTOMA P53 à EVERYTHING!! WT-1 à WILMS TUMOR p16 (INK4a) à GI, BREAST (MM if inherited) BRCA-1,2 à BREAST KLF6 à PROSTATE  Evasion of APOPTOSIS nBCL-2 np53 nMYC  DNA REPAIR GENE DEFECTS DNA repair is like a spell checker HNPCC (Hereditary Non-Polyposis Colon Cancer): TGF-β, β-catenin, BAX Xeroderma Pigmentosum: UV fixing gene Ataxia Telangiectasia: ATM gene Bloom Syndrome: defective helicase Fanconi anemia  LIMITLESS REPLICATIVE POTENTIAL TELOMERES determine the limited number of duplications a cell will have, like a cat with nine lives. TELOMERASE, present in >90% of human cancers, changes telomeres so they will have UNLIMITED replicative potential  TUMOR ANGIOGENESIS Q: How close to a blood vessel must a cell be? A: 1-2 mm Activation of VEGF and FGF-b Tumor size is regulated (allowed) by angiogenesis/anti-angiogenesis balance TRANSFORMATIONà GROWTHà BM INVASIONà ANGIOGENESISà INTRAVASATIONà EMBOLIZATIONà ADHESIONà EXTRAVASATIONà METASTATIC GROWTHà etc.  Invasion Factors nDetachment ("loosening up") of the tumor cells from each other nAttachment to matrix components nDegradation of ECM, e.g., collagenase, etc. nMigration of tumor cells METASTATIC GENES? NM23 KAI-1 KiSS  CHROMOSOME CHANGES in CANCER TRANSLOCATIONS and INVERSIONS Occur in MOST Lymphomas/Leukemias Occur in MANY (and growing numbers) of NON- hematologic malignancies also Malignancy Translocation Affected Genes Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34 bcr 22q11 Acute leukemias (AML and ALL) (4;11)(q21;q23) AF4 4q21 MLL 11q23 (6;11)(q27;q23) AF6 6q27 MLL 11q23 Burkitt lymphoma (8;14)(q24;q32) c-myc 8q24 IgH 14q32 Mantle cell lymphoma (11;14)(q13;q32) Cyclin D 11q13 IgH 14q32 Follicular lymphoma (14;18)(q32;q21) IgH 14q32 bcl-2 18q21 T-cell acute lymphoblastic leukemia (8;14)(q24;q11) c-myc 8q24 TCR-α 14q11 (10;14)(q24;q11) Hox 11 10q24 TCR-α 14q11 Ewing sarcoma (11;22)(q24;q12) Fl-1 11q24 EWS 22q12  Carcinogenesis is “MULTISTEP” NO single oncogene causes cancer BOTH several oncogenes AND several tumor suppressor genes must be involved Gatekeeper/Caretaker concept – Gatekeepers: ONCOGENES and TUMOR SUPPRESSOR GENES – Caretakers: DNA REPAIR GENES Tumor “PROGRESSION” – ANGIOGENESIS – HETEROGENEITY from original single cell  Carcinogenesis: The USUAL (3) Suspects Initiation/Promotion concept: – BOTH initiators AND promotors are needed – NEITHER can cause cancer by itself – INITIATORS (carcinogens) cause MUTATIONS – PROMOTORS are NOT carcinogenic by themselves, and MUST take effect AFTER initiation, NOT before – PROMOTORS enhance the proliferation of initiated cells  Q: WHO are the usual suspects? Inflammation? Teratogenesis? Immune Suppression? Neoplasia? Mutations?  A: The SAME 3 that are ALWAYS blamed! 1) Chemicals 2) Radiation 3) Infectious Pathogens  CHEMICAL CARCINOGENS: INITIATORS DIRECT “PRO”CARCINOGENS β-Propiolactone Polycyclic and Heterocyclic Dimethyl sulfate Aromatic Hydrocarbons Diepoxybutane Aromatic Amines, Amides, Azo Dyes Anticancer drugs (cyclophosphamide, Natural Plant and Microbial chlorambucil, Products nitrosoureas, and others) – Aflatoxin B1à Hepatomas – Griseofulvinà Antifungal Acylating Agents – Cycasinà from cycads – 1-Acetyl-imidazole – Safroleà from sassafras – Dimethylcarbamyl chloride – Betel nutsà Oral SCC  CHEMICAL CARCINOGENS: INITIATORS OTHERS Nitrosamine and amides (tar, nitrites) - JAPAN Vinyl chlorideà angiosarcoma Nickel Chromium Insecticides Fungicides PolyChlorinated Biphenyls (PCBs) – MF?  CHEMICAL CARCINOGENS: PROMOTORS HORMONES PHORBOL ESTERS (TPA), activate kinase C PHENOLS DRUGS “Initiated” cells respond and proliferate FASTER to promotors than normal cells  RADIATION CARCINOGENS nUV: BCC, SCC, MM nIONIZING: photons and particulate n Hematopoetic and Thyroid (90%/15yrs) tumors in fallout victims n Solid tumors either less susceptible or require a longer latency period than LEUK/LYMPH n BCCs in Therapeutic Radiation  VIRAL CARCINOGENESIS HPVà SCC EBVà Burkitt Lymphoma HBVà Hepatocellular Carcinoma (Hepatoma) HTLV1à T-Cell Malignancies KSHVà Kaposi Sarcoma  H. pylori CARCINOGENESIS 100% of gastric lymphomas (i.e., M.A.L.T.-omas) Gastric CARCINOMAS also!  HOST DEFENSES IMMUNE SURVEILLENCE CONCEPT CD8+ T-Cells NK cells MACROPHAGES ANTIBODIES CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells  Effects of TUMOR on the HOST Locationà anatomic ENCROACHMENT HORMONE production Bleeding, Infection ACUTE symptoms, e.g., rupture, infarction METASTASES  CACHEXIA Reduced diet: Fat loss>Muscle loss Cachexia: Fat lost + Muscle loss TNF IL-1 PIF (Proteolysis Inducing Factor)  PARA-Neoplastic Syndromes Endocrine Nerve/Muscle, e.g., myasthenia w. lung ca. Skin: e.g., acanthosis nigricans, dermatomyositis Bone/Joint/Soft tissue: HPOA (Hypertrophic Pulmonary OsteoArthropathy) Vascular: Trousseau, Endocarditis Hematologic: Anemias Renal: e.g., Nephrotic Syndrome  ENDOCRINE Cushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance Pancreatic carcinoma Neural tumors Syndrome of inappropriate Small cell carcinoma of lung; Antidiuretic hormone or atrial antidiuretic hormone intracranial neoplasms natriuretic hormones secretion Parathyroid hormone-related protein Hypercalcemia Squamous cell carcinoma of lung (PTHRP), TGF-α, TNF, IL-1 Breast carcinoma Renal carcinoma Adult T-cell leukemia/lymphoma Ovarian carcinoma Hypoglycemia Fibrosarcoma Insulin or insulin-like substance Other mesenchymal sarcomas Hepatocellular carcinoma Carcinoid syndrome Bronchial adenoma (carcinoid) Serotonin, bradykinin Pancreatic carcinoma Gastric carcinoma Polycythemia Renal carcinoma Erythropoietin Cerebellar hemangioma Hepatocellular carcinoma  GRADING/STAGING GRADING: HOW “DIFFERENTIATED” ARE THE CELLS? STAGING: HOW MUCH ANATOMIC EXTENSION? Which one of the above do you think is more important?  WELL? MODERATE? POOR? GRADING for Squamous Cell Carcinoma ADENOCARCINOMA GRADING Let’s have some FUN!  LAB DIAGNOSIS BIOPSY CYTOLOGY: (exfoliative) CYTOLOGY: (FNA, Fine Needle Aspirate) IMMUNOHISTOCHEMISTRY Categorization of undifferentiated tumors Leukemias/Lymphomas Site of origin Receptors, e.g., ERA, PRA  TUMOR MARKERS HORMONES: (Paraneoplastic Syndromes) “ONCO”FETAL: AFP, CEA ISOENZYMES: PAP, NSE PROTEINS: PSA, PSMA GLYCOPROTEINS: CA-125, CA-19-5, CA-15-3 MOLECULAR: p53, RAS NOTE: These SAME substances which can be measured in the blood, also can be stained by immunochemical methods in tissue MICRO-ARRAYS THOUSANDS of genes identified from tumors give the cells their own identity and FINGERPRINT and may give important prognostic information as well as guidelines for therapy. Some say this may replace standard histopathologic identifications of tumors. What do you think?  How do tumor cells escape immune surveillance? Mutation ↓ MHC molecules on tumor cell surface Lack of CO-stimulation molecules, e.g., (CD28, ICOS) Immunosuppressive agents Antigen masking Apoptosis of cytotoxic T-Cells (CD8), i.e., the damn tumor cell KILLS the T-cell! Immunomodulating therapy Immunomodulating therapy