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105 Cards in this Set
- Front
- Back
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Q: What is the difference between tumor, neoplasm, and cancer?
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-tumor is an abnormal growth of tissue
-neoplasm is an abnormal mass of tissue with excessive and uncontrolled growth, are of epithelial, mesenchymal or combined origin, transformed does not mean benign or malignant -cancer is a general term for malignant neoplasm |
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Q: What are the two basic categories of neoplasm?
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-benign-can involve adjacent tissue but cannot metastasize (it can definitely kill you though)
-malignant-able to invade and damage adjacent tissue and metastasize |
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Q: What are the two basic components of neoplasms?
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-neoplastic cells which are transformed
-supporting stroma which are non-transformed |
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Q: What are some descriptive terms used with tumors?
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-papilloma-benign epithelial neoplasms producing fingerlike or warty projections from epithelial surfaces (papillary)
-polyp-benign tumor that has a big, bulby projection above a mucosal surface -pedunculated-has a skinny stem/stalk -sessile-has a really broad base -invasive-has spike-like projections |
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Q: What are the different suffixes used for the different types of tumors?
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-benign usually with “-oma” suffix (ex: adenoma-glandular tumor)
-malignant mesenchymal (bone, cartilage, blood, fibrous tissue, muscle) origins have “-sarcoma” suffix (ex: liposarcoma) -malignant epithelial origin end in “-carcinoma” (ex: adenocarcinoma) |
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Q: What are some prefixes for the tissue affected by cancers?
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-“adeno-”-glandular cell
-“cyst-”-cyst tumor -“fibro-”-fibrous or connective tissue -“chond-”-cartilaginous tumor -“lipo-”-fatty tissue -“leiomyo-”-smooth muscle -“rhabdomyo-”-striated muscle -“hemangioma-”-vascular endothelial cells |
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Q: What are some examples of benign mixed tumors?
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-pleomorphic adenoma-tumor of salivary gland (epithelial and myoepithelial origin)
-fibroadenoma-found in breasts, involves both fibrous/stromal and glandular origins -mature teratoma/dermoid cyst |
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Q: What are some examples of malignant mixed tumors?
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-malignant mixed tumor of salivary gland
-malignant cystosarcoma phyllodes-a fibroepithelial tumor -immature teratoma, teratocarcinoma |
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Q: What are some exceptions to the nomenclature concerning tumors?
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-sound benign but are not (hepatoma, lymphoma, melanoma, mesothelioma, seminoma
-sound like a neoplasm but are not (hamartoma-disorganized overgrowth of normal tissue that is normal for site (nevi or moles), choristoma-ectopic mass of non-neoplastic tissue that is abnormal for site -neoplasm of bone marrow origin “-emia” (leukemia) -neoplasm of embryonic origin “-blastoma” (neuroblastoma) |
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Q: What are some eponyms concerning tumors?
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-Hodgkin’s disease (lymphoma)
-Ewing’s sarcoma (sarcoma of bone) -Kaposi’s sarcoma (hemangiosarcoma) -Krukenberg’s tumor (metastases to ovaries) |
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Q: What criteria are used in differentiating between benign and malignant tumors?
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-based on morphology and behavior (clinical course) using (1) differentiation and anaplasia, (2) rate of growth, (3) local invastion, and (4) metasteses
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Q: Describe differentiation as a means to differentiate between benign and malignant tumors.
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-Differentiation is the extent to which tumor cells resemble comparable normal cells. Benign tumors usually are well differentiated and closely mimic normal cells. Malignant tumors are generally less well differentiated but range from well to poorly differentiated. Benign or malignant tumor cells may maintain functional attributes such as production of hormones.
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Q: Describe anaplasia as a means to differentiate between benign and malignant tumors.
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-anaplasia (to form backword) is a lack of differentiation (or poor differentiation) and a hallmark of malignant transformation, have tissue architecture that is in disarray
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Q: What are the 5 properties that are characteristic of anaplasia?
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(1) Nuclear and cellular pleomorphism – variation in shape and size
(2) Hyperchromatism – darkly stained nuclei with or without nucleoli (3) Nuclear to cytoplasmic ratio (N/C ratio) increased – enlargement of nuclei (4) Abundant mitoses – proliferative activity (5) Tumor giant cells – large polypoid or multiple nuclei |
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Q: Describe rate of growth as a means to differentiate between benign and malignant tumors.
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-Most malignant tumors grow faster than benign tumors – many exceptions though. Tumor growth may be the imbalance between cell proliferation and cell death. (malignant keeps going and going)
-The rate of growth may change. e.g. Hormone sensitive tumors. -Angiogenesis: Proliferation of non-neoplastic vascular connective tissue. A rapidly growing tumor can out grow its blood supply and become necrotic. Angiogenesis is needed for growth. |
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Q: Describe local invastion as a means to differentiate between benign and malignant tumors.
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-Is it blunt, pushing, or fingerlike? Most benign tumors are cohesive and expansile +/- a capsule. Most have a surrounding compressed fibrous tissue “capsule”. Most malignant neoplasms are invasive, infiltrating and destroying surrounding normal tissue.
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Q: Define Dysplasia.
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-is bad growth, a preneoplastic lesion which may regress, is a disorderly proliferation that is within the spectrum of neoplasia. There is a loss in the uniformity of the individual cells, as well as a loss in their architectural orientation. Can antedate the appearance of carcinoma.
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Q: Define carcinoma in situ.
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When dysplastic changes are marked and involve the full thickness of the epithelium the lesion is called carcinoma in situ (a pre-invasive stage of malignant epithelial tumor where the basement membrane is intact eg. CIS of cervix.)
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Q: Describe metasases as a means to differentiate between benign and malignant tumors.
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-Secondary tumor implants discontinuous with primary tumor. Single most important feature distinguishing benign from malignant tumors. Exceptions include some malignant tumors of brain and basal cell carcinoma of skin
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Q: What are the different types of metastases?
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(1) Lymphatic spread to regional lymph nodes and other parts of body (first lymph node involved (the regional lymph node) will be the one draining that tissue)
(2) Hematogenous (vascular) spread-lung (caval) and liver (portal) are frequent sites of metastases as well as brain, bone marrow and adrenals, remember lymphatic and vascular systems are interconnected, “veinophiliacs” are susceptible to renal cell and hepatocellular carcinoma, not regional or localized, spreads lots throughout, see multiple metastases which enter the systemic circulation (3) transcoelomic spread (seeding of body cavities)-peritoneal, pleural, pericardial and subarachnoid spaces |
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Q: What is the importance of grading and staging cancer?
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-The grade and stage of malignant tumors provides an estimate of aggressiveness. Can be used for planning therapy.
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Q: Describe the system for grading cancers.
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-based on degree of differentiation and mitoses
-I,II, III, IV (IV is worst) -well, moderately or poorly differentiated, undifferentiated -really well differentiated and looks like normal tissue gets a low grade while really ugly then a higher grade |
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Q: Describe the system for staging tumors.
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-based on anatomic extent of tumor including size of tumor, local spread and metastases
-two methods: (1) TNM (tumor, node, metastases) and (2) AJC (American Joint Committee)-takes each tumor type and categorizes them |
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Q: Describe the clonality of tumor growth.
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-majority of tumors arise from a single transformed cell–established by protein or DNA markers (ex: X-linked isoenzyme cell marder G6PD)
-clonality is established by protein or DNA markers (ex: Immunoglobulins, G6PD, Philadelphia chromosome) -polyclonal tumors much less common |
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Q: What are three variables that affect tumor growth?
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-doubling time, growth fraction (GF), and cell production and loss
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Q: Describe doubling time.
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-tumor cells have same five phases (Go, G1, S, G¬2 and M), total cell cycle in many tumors the same or longer than normal cells
-doubling time alone can’t explain progressive and rapid tumor growth -doubling time is usually same or longer in tumor cells |
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Q: Describe growth fraction (GF).
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-proportion of cells within replicative pool (eg not Go)
-most tumor cells are not in replicative pool at a given time, except during early submicroscopic phase -progressive tumor growth alone cannot be blamed on GF |
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Q: Describe cell production and loss.
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-tumor cell accumulation best explained by imbalance cell production and cell loss (apoptosis is key)
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Q: What are the clinical implications of tumor growth?
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-Susceptibility of tumors to chemotherapy – most anti-neoplastic agents act on dividing cells (debulking by radiation and surgery)
-Latent period of tumor – several months to years before the descendants of a transformed cell become clinically detected -Tumor progression and heterogeneity – during the latent period there may be many population doublings. Tumors are genetically unstable and subject to a high rate of mutations. Mutant subclones are heterogeneous with respect to invasiveness, metastatic ability, antigenicity, and responsiveness to chemotherapy. |
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Q: What factors are needed for angiogenesis?
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-Angiogenesis – necessary for tumor growth beyond 1 to 2 mm and aids in metastasis
-two important angiogenesis factors – fibroblast growth factor (FGF-2), vascular endothelial growth factor (VEGF) -two antiangiogenesis factors – thrombospondin (regulated by TP53) and angiostatin |
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Q: What hormones play a role in tumor growth?
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-tumors of hormonally responsive tissue may maintain their hormone receptors (eg breast and prostate)
-Treatment by hormone manipulation of tumors such as orchiectomy for prostate cancer and estrogen receptor agonist for breast cancer |
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Q: In general, describe the mechanisms of invasion and metastasis.
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-the spread of tumors is a complex process involving sequential steps which can be interrupted at any step by host factors
-interaction between tumor cells and the ECM is dividied into four steps |
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Q: What are the components of the extracellular matrix (ECM)?
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-ECM is divided into two categories: Basement membrane and interstitial connective tissue, ECM components include collagen and adhesion promoting proteins
-Collagen-type I in interstitial connective tissue, type IV in basement membrane -Adhesion promoting proteins-laminin in basement membrane, fibronectin in interstitial connective tissue, both are large multifunctional molecules that bind to other ECM components including collagen, proteoglycans and cells (which are attached to laminin and fibronectin by receptors) |
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Q: What are the four steps involved in the interaction between tumor cells and the ECM?
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1. Cells become less cohesive, e.g. loss of E-cadherins
2. Attachment to matrix components- receptor mediated binding to laminin and fibronectin 3. Degradation of ECM-after attachment tumor cell secrete proteolytic enzymes to create passageways for migration of important enzymes (metalloproteinases) include Type IV collagenases (cleave basement membrane), Interstitial collagenases (cleave type I and III collagen) and Plasmin (degrades non-collagenous matrix proteins) 4. Migration of tumor cells-tumor derived cytokines, cleavage products of the ECM |
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Q: Describe vascular dissemination and homing of tumor cells.
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-Can form emboli with leukocytes and platelets or circulate as single cells
-Eventual site of metastases (organ tropism or poor soil) usually depends on vascular and lymphatic drainage of tumor, tumor adhesion molecules may enhance attachment to tissue ligands, microenvironment factors (e.g. proteases) may inhibit attachment |
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Q: Describe ones predisposition to cancer (epidemiology) and what factors may play a role.
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-Although cancer must ultimately be defined at cellular and molecular levels, epidemiology can contribute substantially to the knowledge about the origin of the cancer.
-factors include cancer incidence, geographic and environment, age, heredity, preneoplastic disorders |
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Q: Describe cancer incidence.
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-cancer incidence and cancer deaths not equivalent
-survival rates vary greatly depending on type of neoplasm -occurs in 1 of 4 or 5 individuals -lung, prostate and colon leading cause of death in US males -lung, breast and colon leading cause of death in US females -the chances of surviving 5 years after diagnosis of cancer vary greatly according to the type of neoplasm (skin > Hodgkin’s disease > non-Hodgikins > lung > pancreas) |
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Q: What are the estimated cancer incidence by site and sex?
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-in males lung (13%), colon and rectum (9%) and prostate (41%) are most common
-in females, lung (13%), colon and rectum (11%), and breast (31%) are most common |
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Q: What are some geographic and environmental factors concerning cancer epidemiology?
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-Nearly all the evidence indicates geographic differences in cancer rates are environmental/cultural rather than due to race.
-reduced incidence of stomach CA in Nisei (2nd generation Japanese-Americans) -some examples of environmental factors include tobacco (lung and other cancers), early intercourse with multiple partners (cervical cancer), and asbestos (mesothelioma) |
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Q: What effect does age have on cancer epidemiology?
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-In general cancer increase with age, mortality peaking between ages 55 and 75 years
-Possible reasons include accumulation of chromosomal mutations and declining immune competence -approx. 10% of children under 15 years die of cancer and types include hemopoietic neoplasms (lymphoma/leukemia), tumors of the CNS, soft tissue and bone sarcomas. -common tumors differ from adults (lymphoblastic leukemia, soft tissue and bone sarcomas, CNS tumors) |
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Q: What effect does heredity have on cancer epidemiology?
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-Heredity plays a role in the development of cancer even in the presence of closely defined environmental factors
-include familial cancers, inherited cancer syndromes and chromosomal instability syndromes |
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Q: Describe familial cancers.
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-close relative of cancer patients have a higher incidence of the same type of neoplasm
non-random chromosomal abnormalities (e.g. BRCA1 & BRCA2- breast and ovarian cancer) |
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Q: Describe inherited cancer syndromes.
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-40% of childhood retinoblastomas are familial and shows an autosomal dominant pattern
-familial adenomatous polyposis is autosomal dominant trait – almost all develop colon cancer in later life |
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Q: Describe chromosomal instability syndromes.
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-inherited as autosomal recessive
-defect in DNA repair with increase risk of variety of cancers (ex Xerodermal pigmentosum (skin cancer secondary to UV)) |
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Q: Describe acquired preneoplastic disorders.
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-Certain clinical conditions are associated with increased risk of tumors including: (1) atrophic gastritis of pernicious anemia (stomach cancer), (2) chronic ulcerative colitis (carcinoma of colon), (3) leukoplakia of oral genital mucosa (squamous cell cancers), (4) persistent regenerative cell replication – cirrhosis/hepatocellular carcinomas, and (5) hyperplastic and dysplastic proliferation (atypical endometrial hyperplasia/carcinoma)
-Development of malignant tumor from a benign one is uncommon with a few exceptions – villous adenomas of colon can develop into cancer |
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Q: What is the molecular basis for carcinogenesis?
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1. non-lethal damage lies at the heart of carcinogenesis. Genetic damage or mutations may be acquired from environmental agents such as chemicals and radiation
2. Three classes of normal regulatory genes are the targets of genetic damage (growth promoting proto-oncogenes (“dominant”), growth inhibiting cancer suppressor genes (anti-oncogenes) (“recessive”), and genes that regulate programmed cell death or apoptosis (“recessive or dominant”) 3. Genes that regulate DNA repair are important in carcinogenesis-defects lead to mutations and possible neoplastic transformation 4. Carcinogenesis is a multi-step process at the phenotypic and genetic level – tumor progression |
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Q: Define oncogenes and proto-oncogenes.
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-Oncogenes are genes whose products (oncoproteins) are associated with neoplastic transformation
-Proto-oncogenes are normal genes that affect growth and differentiation, they can be converted into oncogenes by retroviral transduction (V-oncs) or changes in situ that effect their expression and/or function, thereby converting them into C-oncs |
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Q: What are the protein products of oncogenes?
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-Oncoproteins resemble normal protooncogene products, however, they are not regulated by normal growth factors and external signals.
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Q: What are some of the properties of malignant phenotype cancer?
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-self-sufficiency in growth signals
-insensitivity to growth-inhibitory signals -evasion of apoptosis -limitless replicative potential (i.e., overcoming cellular senescence) -sustained angiogenesis -ability to invade and metastasize |
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Q: What are the five basic groups/categories of oncogenes?
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-the categories are based on their role in the signal transduction cascade and cell cycle regulation
-include growth factors, growth factor receptors, signal transducting proteins, nuclear transcription factors, and cyclins and cyclin dependent kinases |
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Q: Describe growth factors as a category of oncogenes.
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-Over production of growth factor (e.g. platelet derived growth factor (PDGF) from protooncogene SIS (many glioblastomas))
-More often a normal growth factor gene but products of other oncogenes may cause over expression of growth factor. e.g. RAS products cause over expression of transforming growth factor alpha (TGF–alpha),(many sarcomas) |
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Q: Describe growth factor receptors as a category of oncogenes.
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-mutant receptor delivers continuous mitogenic signals to cells in absence of growth factors
-over expression is more common. e.g. HER2 (ERBB2) an EGF receptor in 15% to 30% of breast cancer, adenocarcinoma of lung, ovary and salivary glands. ERBB1 in 80% of squamous cell lung CA. |
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Q: Describe signal-transducting proteins as a category of oncogenes.
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-mimic normal cytoplasmic signal transducing proteins which are usually on inner side of plasma membrane. They receive message from activated GF receptors then transmit them to the nucleus.
-2 important in this category RAS and ABL |
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Q: Describe RAS.
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-RAS is single most common oncogene in human tumors (30%)
-RAS binds GTP (active) and GDP (inactive) -Active RAS activates several cytoplasmic kinases → signaling nucleus to proliferate -RAS has intrinsic GTPase activity which inactivates itself |
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Q: Describe ABL.
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-like RAS encodes a plasma membrane associated signal transducer protein, also involved in apoptosis.
-normally regulated on chromosome 9 but translocated to chromosome 22 it is not regulated -a hybrid of ABL and break point cluster (BCR) on 22 encodes a potent tyrosine kinase which promotes growth -BCR-ABL is associated with chronic myelogenous leukemia (Ph1) |
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Q: Describe nuclear transcription factors as a category of oncogenes.
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-MYC binds to DNA to activate several growth related genes including cyclin D1 which starts the cell cycle
-MYC most commonly associated with human tumors and expressed in virtually all normal cells -persistent or over expression resulting in sustained proliferation -Burkitt’s lymphoma/MYC, neuroblastoma/N-MYC, small cell carcinoma of lung/L- MYC |
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Q: Describe cyclins and cyclin dependent kinases as a category of oncogenes.
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-The orderly progression of cells through the cell cycle is achieved by cyclin dependent kinases (CDK’s) which bind to cyclins, activating the former. There are different cyclins for distinct portions of the cell cycle. G¬1 to S phase an important check point regulated by D cyclins – and appropriate CDK’s are activated. This check point guarded by the retinoblastoma protein (RB). CDK’s can be controlled by CDK inhibitors (CDKI’s). D/CDK4 phosphorylates RB and allows cell to enter S. Over amplification and expression of D cyclins will cause cells to enter S unregulated breast, esophagus, liver and lymphoid malignancies. Over expression of CDK4 the catalytic component of D/CDK4 complex leads to a similar outcome (melanomas, sarcomas, and glioblastomas)
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Q: What are the three mechanisms that proto-oncogenes may be converted to oncogenes?
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-point mutations, chromosomal translocations, and gene amplification
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Q: Describe how point mutations can convert proto-oncogenes to oncogenes.
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-ras oncogene best example of activation by point mutation, usually reduces GAP induced hydrolysis of GTP, large number of tumors involved (90% pancreatic adenocarcinoma, 50% colon and thyroid cancer, 30% lung and myeloid leukemias), infrequent in breast and ovarian cancers
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Q: Describe how chromosomal translocations can convert proto-oncogenes to oncogenes.
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-Activate proto-oncogenes by two mechanisms: (1) placement of gene next to a strong promotor/enhancer element. In Burkitt’s lymphoma the t(8
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Q: Describe how gene amplification can convert proto-oncogenes to oncogenes.
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-Reduplication of proto-oncogenes can lead to increased expression, N-MYC amplification (3 to 300) copies in neuroblastomas and HER2 in breast carcinoma. Both associated with poor prognosis.
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Q: What are some proteins that are produced by tumor suppressor genes?
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-Cancer may be promoted due to the inactivation of genes who’s products suppress cell proliferation. Include (1) Growth inhibitory factors (factors which bind to the cell membrane receptors to transmit inhibitory signals), (2) Molecules that regulate cell adhesion, (3) Molecules that regulate signal transduction (down regulation of growth promoting signals), and (4) Molecules which regulate nuclear transcription and cell cycle.
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Q: What is the prototype cancer suppressor gene?
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-retinoblastoma on chromosome 13q14
-Binds to DNA and sequesters transcription factors (E2F) in hypophosphorylated/active state -D/CDK4, D/CDK6 and E/CDK2 phosphorylate/inactivate RB, releasing transcription factors then cell can enter S phase -RB associated with pathogenesis of childhood tumor retinoblastoma where 40% are familial, autosomal dominant and the rest are sporadic |
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Q: What is the two-hit hypothesis for RB?
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1. two normal RB loci must be inactivated (two hits) for retinoblastoma
2. familial cases inherit one defective gene. Only “one hit” mutation required for retinoblastoma |
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Q: Describe the genetics assoacited with the two hit hypothesis for RB.
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-Both alleles can be detected by molecular studies (point mutations) or cytogenetic studies deletion of 13q14, Patients with familial retinoblastoma also have increased risk of osteosarcomas and soft tissue sarcomas. Mutations in genes regulating RB can mimic RB loss, e.g. p16(CDKN2A), cyclin D, CDK4
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Q: Describe adenomatous Polyposis Coli-beta catenin pathway.
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-APC has antiproliferative effects regulating catenin levels, beta catenin binds E cadherin but also promotes cell proliferation in nucleus
-APC promotes destruction of beta catenins, inactivation of APC results in increased beta catenins, which increases cyclin D and MYC via WNT signaling |
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Q: What happens with a defective APC?
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-adenomatous polyposis coli-one defective APC inherited, loss of the second APC leads to hundreds + of colon adenomas (polyps) by 20 years
-very high risk of developing adenocarcinoma of colon, but additional mutations are required |
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Q: Describe sporadic colon carcinoma.
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-70 to 80% have APC mutations, colon cancers with normal APC may have abnormal catenins which are not degraded by APC
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Q: Describe TP53.
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-it is the guardian of the genome, one of the most commonly mutated genes seen in virtually all types of human cancers
-multiple complex functions involving antiproliferation and apoptosis -TP53 senses DNA damage arresting cell in G1 and inducing DNA repair, it increases transcription of CDKI CDKN1A (p21) preventing phosphorylation of RB and induces GADD45 (growth arrest and DNA damage) which aids DNA repair -If DNA cannot be repaired apoptosis genes such as BAX are induced |
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Q: What is Li Fraumeni syndrome?
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-can inherit one mutant TP53 or RB
-markedly increased risk of multiple types of malignancies -TP53 can be inactivated by certain DNA viruses such as oncogenic HPV, hepatitis B virus, and possibly EBV |
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Q: What are some genes that regulate apoptosis?
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-Accumulation of tumor cells can result from mutations in apoptosis genes, some genes that regulate apoptosis: BCL2, BAX, BCL-X, BAG, BAD
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Q: Describe BCL2.
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-BCL2 is an anti-apoptosis gene in chromosome 18, when translocated to Ig locus on 14 it is activated. 80% of follicular lymphomas. Results in decreased cell death not over proliferation therefore tend to be “indolent”
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Q: Describe BAX.
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-BAX opposes BCL2 action therefore accelerates death, as noted, TP53 is an apoptosis inducing gene and appears to exert this effect by increasing transcription of BAX, if TP53 is mutated the effectiveness of chemotherapy may be reduced
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Q: Describe hereditary nonpolyposis colon carcinoma (HNPCC) syndrome.
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-carcinomas of cecum and proximal colon, DNA mismatch repair is defective and errors/mutations accumulate, five separate genes involved, usually a second “hit” needed, also associated with endometrial, ovarian carcinomas, other GI CA.
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Q: Describe Xeroderma pigmentosum.
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-several genes are involved in DNA excisional repair, UV causes pyrimidine dimers which are repaired by nucleotide excision repair system, increased risk of skin cancer
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Q: What types of defects are found in familial breast cancer?
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-BRCA1 & BRCA2 are seen in 80% of familial breast CA, 1 in ovarian and prostate CA, 2 in ovarian, prostate, bile duct, pancreas, stomach CA and melanoma
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Q: What are some karyotypic changes that occur in tumor cells?
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-Many neoplasms are associated with non-random chromosomal abnormalities which are important and possibly primary events in neoplastic transformation
-Three types of non-random chromosomal abnormalities in cancer |
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Q: What are the three types of non-random chromosomal abnormalities in cancer?
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1. Balanced translocations: Philadelphia chromosome (Ph1) ([t(9
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Q: Describe viral oncogenesis.
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-A variety of RNA and DNA viruses have been proven oncogenic in humans, RNA oncogenic viruses are all retroviruses, which transform cells by two mechanisms
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Q: What are the different mechanisms of how RNA oncogenic viruses transform cells?
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1. Acute transforming retroviruses contain a viral oncogene such as vSRC, vABL, and vMYB. Remember v-oncs are derived from proto-oncogenes
2. Slow transforming retroviruses do not contain v-oncs but proviral DNA can insert near a proto-oncogene. With a strong retroviral promotor the adjacent proto-oncogene is over expressed “insertional mutagenesis” |
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Q: Describe Human T-cell Leukemia Virus Type I (HTLV-1).
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-Associated with T-cell leukemia/lymphoma endemic in Japan and Caribbean basin, only 1% infected develop leukemia/lymphoma after 20-30 years, no v-oncs nor is it inserted next to proto-oncogenes, contains TAX (gene essential for viral replication and can activate transcription of host genes including IL-2 (a T-cell growth factor) and it’s receptor and granulocyte macrophage colony stimulator (GM-CSF). Macrophages can make IL-1, another T-cell mitogen), can repress CDKI CDKN2A/p16
-Prolonged proliferation → mutation → monoclonal, neoplastic T cell proliferation |
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Q: What are some examples of DNA oncogenic viruses?
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-human papilloma viruses (HPV), Epstein-barr virus (EBV), hepatitis B virus (HBV)
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Q: Describe HPV.
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-there are 80+ types (1, 2, 4 and 7 cause benign papillomas (warts), 16 and 18 present in almost all of invasive squamous cell carcinoma and CIS of cervix, 6 and 11 low malignant potential)
-Two proteins are produced which can simulate the loss of two important tumor suppressor genes (E6 binds to and inactivates TP53 which mediates degradation of BAX and activates telomerase, E7 binds to and inactivates RB which inactivates certain CDK1’s and high risk HPV may bind and activate cyclins E and A -Full malignant potential requires other environmental factors |
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Q: Describe EBV.
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-Associated with four human tumors:
1. Burkitt’s lymphoma – EBV causes B cell proliferation and with concomitant impaired immune response (eg malaria) with decreased immunoregulation. Cells are at risk for mutations such as t(8,14) associated with MYC gene. Nonendemic areas only 20% have EBV genome but all have the specific translocation. Endemic in Africa. 2. B cells lymphomas in the immunosuppressed (including AIDS) 3. Hodgkin’s disease 4. Nasopharyngeal cancer – endemic in Southern China |
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Q: Describe HBV.
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-HBV linked with hepatocellular carcinoma (90%), its roll is unclear but probably multifactorial, Injury and regeneration predispose to mutations with environmental agents
-HBx- protein disrupts growth control by activating proto-oncogenes, may bind to and inactivate p53 |
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Q: Describe chemical carcinogens.
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-Diverse structures both natural and synthetic, direct acting CC’s require no activation, but more common are indirect acting CC’s which become active after metabolic conversion e.g. microsomal Cytochrome P450, all chemical carcinogens are electrophiles that react with the electron rich atoms in RNA, DNA and proteins, carcinogenicity of some chemicals augmented by agents which have little if no cancerous activity called “promotors” many carcinogens have no requirement for promoting agents, CC can act with other carcinogens e.g. viruses and radiation
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Q: Describe alkylating agents as chemical carcinogens.
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-Alkylating agents are direct acting and can be used in cancer and immunosuppressive therapy. Treated patients are at increased risk of developing 2o malignancies later, especially leukemia
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Q: Describe aromatic hydrocarbons as chemical carcinogens.
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-Aromatic hydrocarbons are indirect acting and are in cigarette smoke, cooked animal fat and fossil fuels
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Q: Describe azo dyes and aromatic agents as chemical carcinogens.
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-beta-naphthylamine, used in aniline dye and rubber industry associated with a 50x risk of bladder cancer, indirect acting
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Q: Describe miscellaneous potent carcinogens as chemical carcinogens.
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-Miscellaneous potent carcinogens include vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides and polychlorinated biphenyls (PCBs). Indirect acting
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Q: What is the mechanism of action of carcinogens?
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-Chemical carcinogens are mutagenic, ras mutations most common in rodents
-TPA (tetra-decanoylphorbol-acetate) a phorbol ester promotor is a powerful activator of protein kinase C, may induce cellular proliferation. -Carcinogen induced damage does not always lead to cancer, remember DNA can be repaired |
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Q: Describe radiation carcinogensis.
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-Radiant energy in the form of ionizing and ultraviolet radiation can cause cancer by chromosome breakage, translocations and point mutations, radiation induced cancer has an extremely long latent period, infancy/childhood irradiation of the head and neck 9% develop thyroid carcinomas, UV radiation (Sun, tanning beds) can cause melanomas, squamous and basal cell carcinomas of the skin. Especially true in the fair skinned in at risk locals eg New Zealand, Australia and Venus, UV damages DNA by producing pyrimidine dimers, which are repaired by the DNA excision, repair mechanism, those with xeroderma pigmentosum have a higher risk of skin cancer
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Q: What is the role of tumor specific antigens (TSA) in illiciting immune response to tumors?
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-Present only on tumor cells and not normal cells
-Can be recognized by cytotoxic T-cells by class I MCH molecules -Melanoma associated antigen 1 (MAGE1) on 40% melanomas, 20% breast carcinomas, 35% non-small cell carcinomas and normal testes -Pancreas and breast carcinomas may have abnormally glycosylated mucus which is recognized by T-cells |
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Q: What is the role of tumor associated antigens (TAA) in illiciting immune response to tumors?
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-Present on tumors but also on some normal cells-differentiation specific antigens
-CALLA (CD10) is on early B cells and B cell malignancies -Prostate specific antigen (PSA) is on normal and neoplastic prostate, HER-2 over expressed in breast carcinomas |
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Q: Describe the antitumor effector mechanism of cytotoxic T lymphocytes.
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-play a roll particularly in virus associated neoplasms
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Q: Describe natural killer cells (NK) role in antitumor effector mechanisms.
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-are capable of destroying tumor cells without prior sensitization and may be the first line of defense against tumors, T and NK cells provide complimentary antitumor mechanisms, no tumor MCH, no problem because NKs are inhibited by MCH 1, can also participate in antibody dependent cellular toxicity (ADCC)
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Q: Describe macrophages roles in antitumor effector mechanisms.
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-are activated by interferon-gamma (INF-gamma) which is produced by NK and T cells, can kill tumors the same way as microbes or by secretion of tumor necrosis factor gamma may be lytic to some tumors
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Q: What do humoral mechanisms do in antitumor effector mechanisms?
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-activate compliment and induction of ADCC by NK cells
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Q: Describe the importance of immunosurveillance and ways tumors escape immunosurveillance.
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-Immunodeficient hosts have a higher rate of cancer (HIV, X linked lymphoproliferative disorder (XLP) with EBV develop a severe mononucleosis and may develop lymphoma)
-some ways tumors escape immunosurveillance include (1) selective outgrowth of antigen negative variants, (2) reduced or loss of histocompatibility antigens, (3) may have antigen peptide and MHC-1 but no co-stimulatory molecules preventing T cell sensitization, and (4) immunosuppression by many oncogenic agents and some tumor products e.g. transforming growth factor (TGF-β) |
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Q: What are the clinical features of neoplasia?
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-Tumors, benign and malignant can threaten host (location is critical), tumor hormone production can cause problems eg pancreatic β cell tumor can cause hypoglycemia/hyperinsulinemia
-Cancer cachexia is a progressive loss of weight, weakness, anorexia, and anemia (origin is multifactorial but a novel protein has been found that causes weight loss with muscle breakdown, calorie expenditure remains high and basal metabolic rate increased which may be due to TNF – α and other cytokines) |
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Q: Describe paraneoplastic syndromes.
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-are not explained by tumor spread or hormones normally expressed from the tissue of origin
-present in 10-15% of those with cancer, can be severe or lethal and may mimic metastatic disease, may be first manifestation of an occult neoplasm, most common syndromes include: Cushing’s syndrome, nonbacterial thrombotic endocarditis and venous thrombosis and hypercalcemia -Hypercalcemia is multifactorial and may involve parathyroid hormone related protein (PTHrP) as in SCC of lung, TGFα which activates osteoclasts or active vitamin D -Widespread bone metastases cause hypercalcemia however it is not considered a paraneoplastic process -Clubbing of fingers and hypertrophic osteoarthropathy in lung cancer |
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Q: What are some pathologic techniques used to diagnose cancer?
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1. Open biopsy – histologic
2. Fine needle aspiration – cytologic and histologic 3. Papanicolaou or cytology smears – all positive findings best confirmed by biopsy and histologic examination 4. Core needle biopsy 5. Other techniques including flow cytometry (antigens and ploidy), immunohistochemistry and other special stains, DNA probe analysis (eg southern blot), PCR, or Fluorescent in situ hybridization (FISH) for karyotypic abnormalities |
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Q: What are some biochemical assays for determining cancer?
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-Biochemical assays for tumor enzymes, hormones or other markers may not be able to diagnose cancer however they may indicate at risk individuals and be used for therapy monitoring
-include PSA, CEA and alpha-fetoprotein, benign entities may elevate markers as well |
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Q: What are some other syndromes with defects in DNA repair?
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-ataxia telangiectasia, Fanconi anemia, Bloom syndrome
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Q: What are the three different classes of carcinogenic agents?
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-chemicals, radiant energy and oncogenic viruses
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