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39 Cards in this Set
- Front
- Back
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.Gatekeeper genes
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.directly control
tumor growth |
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.Caretaker genes
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.affect genetic stability
by e.g. causing defective DNA repair |
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.DEFECTS IN DNA REPAIR
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.BRCA-1 and BRCA-2
Hereditary non-polyposis colon cancer syndrome Xeroderma pigmentosum Ataxia telangiectasia Bloom syndrome Fanconi anemia |
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BRCA-1 and BRCA-2
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believed to function in a common
DNA repair pathway Germline mutations lead to breast cancer at an early age (3% of cases) |
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Evasion of Apoptosis
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Follicular B-cell lymphomas (85%)
have a t(14;18) translocation that fuses the BCL2 gene from chromosome 18 with the active IgH locus on chromosome 14 resulting in overproduction of anti-apoptotic BCL2 and indolent accumulation of excess lymphocytes. |
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SUSTAINED ANGIOGENESIS
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Required for tumor to grow over 2 mm
Angiogenesis normally inhibited by thrombospondin-1 (induced by p53) & destruction of HIF-1alpha (by VHL) Tumoral hypoxia calls off VHL, so that HIF-1alpha starts VEGF production & growth of irregular leaky blood vessels mediated by VEGF |
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SUSTAINED ANGIOGENESIS
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Angiogenic switch mediated by HIF-
1alpha, basic FGF, loss of p53, decreased thrombomodulin-1, overcoming anti-angiogenic factors (angiostatin, endostatin, vasculostatin) Anti-VEGF agent bevacizumab hailed as cure for all cancer when developed, but only mildly helpful in most cases |
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CANCER: INVASION: 4 STEPS
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1. Detachment of tumor cells from
each other 2. Degradation of basement membrane & extracellular matrix 3. Attachment of tumor cells to basement membrane 4. Migration |
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CANCER: INVASION
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Detachment of tumor cells from
each other (down-regulation of E-cadherin or mutated catenin) Degradation of basement membrane (type IV collagen) & extracellular matrix by matrix metalloproteinases (esp MMP-9) |
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CANCER: INVASION
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Attachment of tumor cells to exposed
basement membrane components (by laminin and fibronectin receptors) Migration through basement membrane and extracellular matrix (mediated by e.g. autocrine motility factor) |
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METASTASES
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Millions of cancer cells released for
each one that metastasizes Characteristic patterns (e.g. colon to liver, prostate and breast to bone) are due to drainage pathways and organ tropism |
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METASTATIC ORGAN TROPISM:
MECHANISMS |
Differential concentration of
endothelial cell ligands for adhesion molecules in different organs Chemokines (e.g. CXCR4 and CCR7 receptors in breast cancer) |
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TUMOR EMBOLUS
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Tumor cells that invade veins go to
lungs and elicit formation of blood clot around them Fibroblasts organize the clot part of it |
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CHEMICAL CARCINOGENESIS
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Initiators cause mutations, which
become irreversible in the progeny of the mutated cell, if not reversed in it Promoters cause reversible proliferation of initiated cells |
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CHEMICAL CARCINOGENESIS
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Direct chemical carcinogens are
few, generally reactive electrophiles Indirect chemical carcinogens require metabolic activation of procarcinogens commonly by cytochrome P450-dependent mono-oxygenases |
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CHEMICAL CARCINOGENS
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Estrogen
Alcohol Anti-cancer drugs Asbestos Polycyclic & heterocyclic aromatic hydrocarbons Aromatic amines, amides, azo dyes |
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RADIATION CARCINOGENESIS
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Long latent period (years-decades)
Ultraviolet light causes skin cancer Radiation therapy causes sarcomas Nuclear power plant leaks cause thyroid cancer |
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MICROBIAL CARCINOGENESIS
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HCV and HBV, EBV, HPV, Helicobacter pylori
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HCV (& HBV) cause
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hepatic cancer
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EBV causes
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lymphoma
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HPV causes
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uterine cervical cancer
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Helicobacter pylori
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causes gastric
carcinoma and lymphoma |
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ANTI-TUMOR IMMUNE
SURVEILLANCE: TUMOR ANTIGENS |
Mutated oncogene products
Products of other mutated genes Overly or aberrantly expressed proteins Oncogenic viral products |
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ANTI-TUMOR IMMUNE
SURVEILLANCE: TUMOR ANTIGENS |
Oncofetal antigens (e.g. CEA, AFP)
Altered cell surface glycolipids or glycoproteins (e.g. CA-125, CA-19-9) Cell type specific differentiation antigens |
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IMMUNE SURVEILLANCE:
EFFECTOR MECHANISMS |
Principal: CD8+ cytotoxic lymphocytes
Other: Natural killer cells (activated by IL-2) Macrophages (activated) Antibodies |
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IMMUNE SURVEILLANCE:
RESISTANCE MECHANISMS |
Selective outgrowth of Ag-neg cells,
Decreased MHC molecules Lack of co-stimulation Antigen masking Apoptosis of cytotoxic lymphocytes Immunodeficiency |
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DIRECT EFFECTS OF TUMORS
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•Impingement on adjacent structures
•Obstruction (e.g. of intestine) •Functional activity (e.g. hormones) •Surface ulceration +/- bleeding +/- infection •Infarction +/- rupture |
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PARANEOPLASTIC SYNDROMES
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Symptoms not attributable to direct
effects of tumor (or hormones native to the primary tumor organ) Occur in about 10% of cancer patients Not counting cachexia (wasting) [in a class by itself] |
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PARANEOPLASTIC SYNDROMES
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Can be the earliest manifestation of
occult tumor Can be sickening, even fatal by themselves May mimic metastatic disease |
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PARANEOPLASTIC SYNDROMES
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Hypercalcemia (most common)
Cushing syndrome (ACTH) Syndrome of inappropriate ADH Hypoglycemia (insulin) Carcinoid syndrome (serotonin) Eaton-Lambert syndrome (myasthenia) |
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HYPERCALCEMIA OF MALIGNANCY
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Symptoms: nausea, vomiting,
constipation, polyuria, disorientation, lethargy, seizures Mechanisms: parathyroid hormonerelated protein (PTHRP), etc. Treatments: hydration, biphosphonates |
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CUSHING SYNDROME
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Signs & symptoms: weight gain, central
obesity, moon face (fat deposition), weakness, hirsutism, hypertension, glucose intolerance, depression, psychosis, broad red abdominal striae, buffalo hump dorsal neck fat deposition, plethora, osteoporosis, menstrual irregularity, muscle wasting, etc., etc. |
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CARCINOID SYNDROME
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Symptoms: attacks of cutaneous
flushing (deep red erythema of face and neck) [may go on to persistent erythema or cyanosis], diarrhea, cramps, nausea, vomiting, cough, etc. |
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PARANEOPLASTIC SYNDROMES
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Acanthosis nigricans
Dermatomyositis Hypertrophic osteoarthropathy Migratory thrombophlebitis (Trousseau syndrome) Marantic (non-bacterial thrombotic) endocarditis |
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TUMOR STAGE
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Anatomic extent of tumor, including
primary tumor size, extent of lymph node and distant metastases |
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TUMOR GRADE
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Qualitative assessment of the
differentiation of a tumor (extent to which it resembles normal tissue at primary site) |
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DIAGNOSIS OF CANCER: 2 STAGES
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1. DISCOVERY
Symptoms, Signs, Radiology Serum markers 2. SPECIFIC DIAGNOSIS Biopsy (most common, usually best) |
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DIAGNOSIS OF CANCER:
DISCOVERY |
Symptoms, Signs, Radiology
Serum markers (e.g. PSA, CA-125, CA-19-9, HCG, AFP, CEA, Immunoglobulins) |
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DIAGNOSIS OF CANCER:
SPECIFIC DIAGNOSIS |
Biopsy (most common, usually best)
Fine needle aspiration cytology Exfoliative cytology +/- immunohistochemistry +/- flow cytometry +/- molecular testing |
