Presentation on theme: "Oncology Basic Science 12/1/09. Incidence 1.44 million new cancer cases were diagnosed in the United States last year. Also, over one million cases."— Presentation transcript:
Oncology Basic Science 12/1/09
Incidence 1.44 million new cancer cases were diagnosed in the United States last year. Also, over one million cases of basal and squamous cell carcinomas of the skin #2 cause of death in U.S.
Hallmarks of Cancer Hallmarks of Cancer
Tumorigenesis initiation –Initiating events such as gain of function of oncogenes promotion –loss of function of tumor-suppressor genes may lead a single cell to acquire a distinct growth advantage progression –disease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly aggressive behavior. –Most tumors go through a progression from benign lesions to in situ tumors to invasive cancers –Mutations in at least four or five genes are required for formation of a malignant tumor, whereas fewer changes suffice for formation of a benign tumor
Oncogenes Designated by three-letter abbreviations, such as myc or ras. Oncogenes are further designated by the prefix "v- " for virus or "c-" for cell or chromosome, corresponding to the origin of the oncogene when it was first detected. Oncogenes may be –growth factors - platelet-derived growth factor –growth factor receptors - HER2 –intracellular signal transduction molecules - ras –nuclear transcription factors - c-myc
Oncogenes ras (k-ras) –G Protein defect –Colon cancer, pancreatic cancer ret – medullary CA of thyroid erb B –epidermal growth factor receptor –Breast cancer myc (c-myc, n-myc, l-myc) –Transcription factors –Burkitt’s lymphoma, nasopharyngeal CA c-kit – CML, Gastric leiomyoma (GIST) src- tyrosine kinase defect sis- PDGF receptor
Tumor Suppressor Genes Retinoblastoma(RB1) Chromo 13 Cell cycle RetinoblastomaOsteosarcoma P53 Chromo 17 Cell cycle Li-Fraumani- sarcoma, breast, leukemia adrenal, brain APC Chromo 5 Cell adhesion FAP (colon cancer) DCC Chromo 18 Cell adhesion Colon cancer bclApoptosis Breast CA, multiple BRCA I/II Chromo17/13 DNA repair Breast CA
Cancer Invasion in situ cancer vs invasive cancer - tumors that breach the basement membrane –glycoproteins of the ECM bind to tumor cell integrin receptors –Serine, cysteine, and aspartic proteinases and MMPs MMPs comprise a family of metal-dependent endopeptidases Active in alsmost every cancer type
Metastasis Metastasis is an inefficient process Must establish vascularization to sustain the new tumor Only a small subset of cancer cells is able to initiate micrometastases, even smaller - macrometastases.
Metastasis Colon Liver Melanoma Skin, Lung, Small bowel Lung Brain, Heart Sarcoma Lung Breast Brain, Adrenal To Bone Breast, Prostate, Thyroid To Skin Breast, melanoma To Ovary Stomach (Krukenberg) To Small bowel Melanoma
Selected Genes/Cancers Hereditary Retinoblastoma (Rb1) –led to the theory that a single mutation is not sufficient for tumorigenesis. –hereditary retinoblastoma involves two mutations, of which one is germline and one somatic, whereas nonhereditary retinoblastoma is due to two somatic mutations –Knudson's "two-hit" hypothesis. –A "hit" may be a point mutation, a chromosomal deletion referred to as allelic loss, or a loss of heterozygosity, or silencing of an existing gene.
BRCA1, BRCA2 Of women with early-onset breast cancer (aged 40 years or younger), nearly 10% have a germline mutation in BRCA1 or BRCA2. Higher in patients such as in the Ashkenazi Jewish population. Cumulative risks of developing breast cancer and ovarian cancer –BRCA 1– 87% and 44% –BRCA 2- 84% and 27% Responsible for male breast CA
APC Gene and Familial Adenomatous Polyposis Hundreds to thousands of polyps in the colon and rectum. Appear in adolescence progress to colorectal cancer. FAP is associated with benign extracolonic manifestations –congenital hypertrophy –retinal pigment epithelium –epidermoid cysts, and osteomas. Also at risk for –upper intestinal neoplasms (gastric and duodenal polyps, duodenal and periampullary cancer), –hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma), –thyroid carcinomas, desmoid tumors, and medulloblastomas. Gardner’s and Turcot’s
Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Autosomal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. DNA mismatch repair genes HNPCC consists of at least two syndromes: –Lynch syndrome 1- colorectal cancer –Lynch syndrome 2- colorectal cancer + carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas. Amsterdam Criteria
Amsterdam Criteria (3-2-1 rule) At least 3 relatives with an HNPCC-associated cancer: colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis. At least two successive generations should be affected At least one tumor should be diagnosed <50 years of age
Carcinogens Coal Tar – larynx, skin, bronchial CA Beta-naphthylamine – bladder CA Benzene- leukemia Asbestos – Mesothelioma Chinese-style salted fish- Nasopharyngeal carcinoma
Carcinogens Epstein-Barr virus- –Burkitt's lymphoma –Burkitt's lymphoma –Hodgkin's disease –Hodgkin's disease –Nasopharyngeal carcinoma Hepatitis B/C virus- Hepatocellular carcinoma HIV –Kaposi's sarcoma –lymphoma Human papillomavirus 16 and 18 –Cervical cancer –Anal cancer
Cancer Diagnosis Fine-needle aspiration –is easy and relatively safe –disadvantage of not giving information on tissue architecture. Cannot differentiate between an invasive and noninvasive tumor Core-needle biopsy –is more advantageous when the histologic findings will affect the recommended therapy. –performed either by direct palpation or can be guided by an imaging study –disadvantage of introducing sampling error Open biopsies –have the advantage of providing more tissue for histologic evaluation and the disadvantage of being an operative procedure. Incisional biopsies are reserved for very large lesions in which a definitive diagnosis cannot be made by needle biopsy. Excisional biopsies are performed for lesions for which either core biopsy is not possible or the results are nondiagnostic. Should be performed with curative intent.
Staging TNM staging For Absite, review: –Breast Cancer –Colon Cancer –Melanoma –Lung cancer
Prostate-Specific Antigen PSA is the best serum marker available with highest sensitivity PSA levels may be elevated in benign prostate conditions such as prostatitis and benign prostatic hyperplasia, as well as in men with prostate cancer. useful in evaluating treatment and monitoring for recurrence after therapy. In monitoring for recurrence, a trend of increasing levels is more significant than a single absolute elevated value. American Urologic Association and the American Cancer Society both recommend yearly PSA testing for men aged 50 years and older total serum PSA level of 4 ng/mL should be used as a threshold for performing a prostate biopsy
Surgical Management of Primary Tumors The goal of surgical therapy for cancer is to achieve oncologic cure. A curative operation presupposes that the tumor is confined to the organ of origin Patients in whom the primary tumor is not resectable with negative surgical margins are considered to have inoperable disease. –The operability of primary tumors is best determined with imaging studies that can define the extent of local-regional disease. Primary tumors can be resected for palliative reasons, such as improving the quality of life by alleviating pain, infection, or bleeding.
Surgical Management of Lymph Nodes Unlike most carcinomas, soft tissue sarcomas rarely metastasize to the lymph nodes (<5%); therefore lymph node surgery usually is not necessary. generally accepted that a formal lymphadenectomy is likely to minimize the risk of regional recurrence of most cancers On the other hand, there have been opposing opposing views regarding the role of lymphadenectomy in survival of cancer patients.
Surgical Management of Lymph Nodes Relatively new development Lymphatic mapping and sentinel lymph node biopsy were first reported in 1977 by Cabanas for penile cancer Lymphatic mapping –isosulfan blue dye, technetium-labeled sulfur colloid or albumin, or a combination of both techniques to detect sentinel nodes. ***There is no role for sentinel LN BX for clinically palpable nodes
Surgical Management of Distant Metastases depends on the number and sites of metastases, the cancer type, the rate of tumor growth such therapy has resulted in cure in selected cases with isolated metastases to the liver, lung, or brain. 25% 5 year survival for a single colonic met to liver if successfully resected.
Chemotherapy Classified according to the phase of the cell cycle during which they are effective. –Cell-cycle phase–nonspecific agents have a linear dose-response curve, such that the fraction of cells killed increases with the dose of the drug. –Cell-cycle phase–specific drugs have a plateau, and cell kill will not increase with further increases in drug dose Methotrexate and 5-FU are cell cycle specific, all others are non-specific
Radiation Therapy M phase is most vunerable stage of cell cycle for XRT Most damage to DNA is done by formation of oxygen radicals with H2O2 intermediate –More oxygenated tumor = more damage –Large tumors less responsive To a lesser extent, ionizing radiation itself can cause direct DNA damage Most is external beam radiation Brachytherapy: source of radiation delivered directory into operative bed using catheters. Allows high concentrated radiation with fewer side effects.
Radiation Therapy Fractional Doses –Allows repair of normal cells –Allows reoxygenation of tumor –Allows redistribution of tumor cells in cell cycle Radiosensitive tumors: –Seminomas, lymphomas Radioresistant tumors –Epithelial, Sarcomas