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104 Cards in this Set
- Front
- Back
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cancer arises from...
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an accumulation of gene mutations that promote uncontrolled growth and invasive properties
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types of CA-related genetic changes
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point mutation
chromosomal changes - oncogene activatged by translocation gene amplification epigenetic changes |
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environmental CA-causing agents
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chemicals
radiation viruses bacteria |
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carcinogenic chemicals
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direct-acting alkylating agents
polycyclic aromatic hydrocarbons aromatic amines and Azo dyes nitrosamines and amides |
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important points about carcinogenic chemicals
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chemical carcinogenesis is does dependent
multi-step process most carcinogens are metabolically activated or inactivated in vivo |
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carcinogenic radiation
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UV rays -->
squamous cell carcinomas basal cell carcinoma malignant melanoma ionizing radiation: gamma-rays, X-rays --> leukemia and many other solid tumors, thyroid carcinomas |
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oncogenic DNA viruses
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HPV
EBV HBV & HCV |
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HPV E6 carcinogenesis
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inhibits p53
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HPV E7
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inhibits p53, p21 and pRB
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cancers caused by EBV
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Burkitt lymphoma
B cell lymphoma Hodgkin lymphoma nasopharyngeal carcinoma |
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how do HBV & HCV cause cancer?
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induce injury to liver cells (inflammation, cell death) and extensive regeneration
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oncogenic RNA viruses
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Human T cell leukemia virus type 1
--> T cell leukemia/lymphoma |
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Carcinogenic bacteria
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helicobacter pylori --> gastric lymphoma
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2 categories of gene mutations
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mutations of pathological important
polymorphisms |
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single nucleotide polymorphism (SNP)
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DNA sequence variation differing btw members of a species
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epigenetic changes
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any process that alters gene activity without changing DNA sequence
e.g.: DNA methylation |
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tumors are _____, but malignant tumors are ____
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tumors are monoclonal, but malignant tumors are heterogenous
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2 models of tumorigenesis
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stochastic model - every CA cell has the capacity to regenerate a tumor, but the probability of this event for any given cell is low
cancer stem cell model - v. small subset of cells w/in tumor pop. actually has capacity to initate and sustain tumor growth |
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problems with canonical (stochastic) model
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cells derived from tumors frequently heterogenous wrt proliferation potential and phenotypic markers
several mustations required for cell to become cancerous, but cells from which CA arises are often short-lived |
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2 qualities a CA stem cell must possess
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self-renewal
differentiation |
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CA stem cell hypotheis predicts what?
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long-lived stem cells more likely to accumulate initial mutations leading to cancer than their short-lived differentiated progeny
TACs are immediate duaghters of somatic stem cells - inhereit parental muations and may serve as targes for final transforming events |
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oncogene mutations
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gain-of-function mutation
mutant alleles are considered dominant - transformed cells despite normal counterpart - only need one mutatnt allele to develop cancer |
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4 examples of oncogenes
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Ras
C-myc C-Abl ERBB2/HER2 |
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tumor suppressor gene
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also known as recessive or anti-oncogenes
both normal allels often be mutated to develp cancer mutations in tumor suppressor genes can have haploinsufficent, gain-of-function and dominant negative a third hit may be required |
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two-hit hypothesis, aka:
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Knudson hypothesis
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haploinsufficiency
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situation in which the total level of a tumor suppressor produced by teh cell is about half the normal level - not sufficient to permit the cell to function normally
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role of cyclins and cyclin dependent kinases (CDK)
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regulate transitions out of G1 and G2 phases
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G1 cyclin & CDK
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cyclin D
Cdk4 |
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S phase cyclins & CDK
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cyclins E and A
Cdk2 |
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mitotic cyclins & CDK
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cyclins B and A
Cdk1 |
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DNA repair genes
function |
repair DNA damage and prevent mutations in gnees that regulate cell growth and PCD
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Pro-apoptotic factors:
Anti-apoptotic factors: |
Pro: Bad, Bax, etc.
Anti: BCL-2 (B cell lymphoma) |
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Telomeres - overview
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repetitive DNA on ends of chromosomes
mostly duplex, but extreme tip is 3' ssDNA overhand of G-cluster strand (synthezed by telomerase) 3' overhand extended during S phase heart muscle cells do not continually divide, so their telomeres do not shorten with age |
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telomeres and aging
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30-200 telomeric bps lost w/ each cell division
once body fully formed, telomerase is repressed in many somatic cells and telomeres shorten as cells reporduce when tolomeres decline to threshold level, a signal is emitted that prevents the cell from dividing further |
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what happends to telomerase in CA cells?
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teolmerase activated
keeps rebuilding telomeres long past cell's normal lifetime --> immortalization of cells |
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HTERT
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catalytic subunit of telomerase that is overexpressed in most CA cells
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telomere associated proteins that are part of the telomere structure and have essential roles in controlling telomere length
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TFR1
TRF2 POT1 RAP1 |
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6 essential alterations for malignant transformation
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self-sufficiency in growth signals
insensitivity to inhibitory growth signals escaping apoptosis unlimited replicative potential sustained angiogenesis tissue invasion and metastasis |
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neoplasia
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new growth
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tumor
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originally defined as swelling caused by inflammation
now equated with neoplasm |
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cancer
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common term for all malignant tumors
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hyperplasia
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increase in number of cells in organ/tissue
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hyperplasia vs. neoplasia
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Hyperplasia:
- direct response to a stimulus - involves parenchymal and stromal tissue - diffuse - organized - typical morphology - regress if stimulus removed Neoplasia: - independent of extracellular stimulus - parenchymal cells only - focal - disorganized - atypical morphology - continues to grow after stimulus removed |
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tumors are composed of...
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parenchyma - epithelial or mesenchymal cells
supportive stroma |
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mesenchymal tumor nomenclature
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benign - suffix "-oma" added to cell of origin, e.g.: fibroma
malignant - "sarcoma" added to cell of origin, e.g.: fibrosarcoma |
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Nomenclature of benign epithelial tumors
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Benign (-oma)
- cell of origin: adrenal adenoma - microscopic architecture: adenoma, papilloma - macroscopic patterns: polyp |
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nomenclature of malignant epithelial tumors
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Malignant (carcinoma)
- cell of origin: squamous cell carcinoma - microscopic architecture: adenocarcinoma - macroscopic patterns: polypoid carcinoma |
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mixed tumor, pleomorphic (salivary gland)
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composed of cells representative of a single germ layer
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teratoma
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cells representative of more than one germ layer
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Hamartoma
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aberrant differentiation of mature spcialized cells or tissue indigenous to the particular site
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exceptions to the oncological nomenclature:
lymphoma |
malignancy of lymphoid tissue
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exceptions to the oncological nomenclature:
leukemia |
malignancy of hematopoietic stem cells
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exceptions to the oncological nomenclature:
glioma |
malignancy of CNS glial cells
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exceptions to the oncological nomenclature:
melanoma |
malignancy of melanocytes
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exceptions to the oncological nomenclature:
heatpoma |
hepatocellular carcinoma
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exceptions to the oncological nomenclature:
seminoma |
malignancy of testicular germ cells
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4 characteristics of malignant tumors
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malignant change in the target cell
growth of the transformed cells local invasion distant metastases |
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differentiation in tumor growth
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the extent to which neoplastic cells resemble comparable normal cells (morphologically, functionally)
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anaplasia in tumor growth
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lack of differentiation
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benign tumors are generally ____- differentiated, while malignant tumors...
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benign tumors are generally WELL-differentiated, while malignant tumors range from well differentiated to anaplastic
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4 morphologic marks of anaplasia
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pleomorphism
abnormal nuclear morphology mitoses loss of polarity |
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Dysplasia
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disordered growth
found in epithelia, NOT mesenchyma constellation of changes - loss of uniformity - loss of architectural orientation - pleomorphism - hyperchromatic, large nuclei - mitotic figures |
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carcinoma in situ
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pre-invasive lesion
dysplastic changes are marked involve entire thickness of the epithelium remains confined to normal tissue |
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determinants of tumor growth rate
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doubling time
growth fraction cell loss rate cell turnover tumor differentiation |
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hallmark of malignant tumors
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local invasion and metastases
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3 patterns of metastases
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direct seeding of a surface or body cavity
lymphatic hematogenous |
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common tumors
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Men: prostate, lung, colorectal
Women: breast, lung, colorectal Children: acute leukemia, neuoblastoma, Wilms' tumor, retinoblastoma |
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which is more important to CA dispositions, environmental or racial factors?
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environmental
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occupational carcinogenic hazards
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asbestos
vinyl chloride 2-naphthylamine |
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genetic predisposition to cancer
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8-10% of cancers are linked to inherited predisposition
autosomal dominant defective DNA repaire syndromes - autosomal recessive: XP, AT, Bloom - autosomal dominant: HNPCC familial cancers - no clear pattern of transmission, exc. for BRCA1, 2 & HNPCC, APC (colon) |
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inherited autosomal recessive syndromes of defective DNA repair
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seroderma pigmentosum
ataxia-telangiectasia bloom syndrom fanconi anemia |
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nonhereditary predisposing conditions to cancer
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chronic inflammation
- production of cytokines - increasing tissue stem cells pool - promot genomic instability (ROS production) precancerous conditions - chronic atrophic gastritis - solar keratosis - ulcerative colitis - leukoplakia - colonic villous adenoma |
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chemical carcinogenesis
initiation - mutation - |
initiation - irreversible, but not sufficent for tumor formation
mutation - result of initiation; rapid, irreversible |
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chemical carcinogenesis
promotion |
nontumorogenic
does not affect DNA reversbile affects initiated cells only time and dose-dependent |
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chemical carcinogens - initiators
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highly reactive electrophiles
react with cellular nucleophilic sites nonenzymatic reaction results in formation of covalent adducts interaction is nonlethal in initiated cells |
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exogenous carcinogenic promoters
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alcohol
cigarette smoke viral dietary fat drugs |
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endogenous carcinogenic promoters
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hormones
bile salts |
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molecular targets of chemical carcinogens
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RAS: chemically-induced tumors
p53: viral-associated cancers |
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carcinogenesis by UV rays
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UVB
formation of pyrimidine dimers in DNA repaired by nucleotide exceision repair (NER) pathway excessive sun exposure overwhelms NER RAS/p53 mutations |
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xeroderma pigmentosum
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autosomal recessive
mutated NER pathway inability to repair UV-induced DNA damage extreme photosensitivity 2000-fold increased risk of skin cancer in exposed areas |
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ionizing radiation
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all forms are carcinogenic
risk much higher if exposed to other carcinogens |
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carcinogenic RNA viruses
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HCV: HCC, splenic marginal zone lymphoma
HTLV-1: T cell leukemia |
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carcinogenesis via helicobacter pylori
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gastric lymphoma of MALT type
gastric adenocarcinoma of intestinal type pathogenic strains - CagA gene - secretory system injects CagA protein into host cells - VacA gene --> PCD |
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effects of tumors on host
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local effects
hormonal effects cancer cachexia - loss of body fat and lean body mass + TNF, IL-1, IFNgamma |
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paraneoplastic syndrome
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symptom complex not explained by local effect or distant spread of tumor
may represent the earliest manifestation of an occult neoplasm may represent significant clinical problems does not affect the stage or treatment outcome |
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6 paraneoplastic syndromes
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cushing syndrome - small cell lung cancer
SIADH - small cell lung CA hypercalcemia - non-small cell lung CA erthyrocytosis - cerebellar hemangioma myasthenia - lung CA hypertrophic osteoarthropathy (clubbing) - lung CA |
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grading of tumors
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based on degree of differentiation
- I: well-differentiated - II: moderately differentiated - III: poorly differentiated - IV: anaplastic does not always correlate with biologic behavior |
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staging of tumors
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TNM system:
T (tumor): 1-4, based on size or depth of invasion N (nodes): 1-3, based on number and location M (metastases): 0 (absent), 1 (present) |
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TNM staging does not apply to which three cancers
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acute or chronic leukemia
multiple myeloma lymphoma (Ann Arbor staging system) |
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3 histologic and cytologic methods of lab diagnosis of CA
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excision or biopsy
needle aspiration cytologic smears |
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role of IHC in lab diagnosis of CA
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ID of cellular elements or surface markers by monoclonal Abs
categorization of undifferentiated CAs categorization of leukemias and lymphomas (now by flow cytometry) determining origin of metastatic CA detection of molecules w/ prognostic or therapeutic significance (ER, PgR, HER2/Neu) |
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FISH
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fluorescent in situ hybridization
HER2/Neu chromosomal abnormalities |
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PCR
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BCR/Abl
PML/RARalpha |
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detection of minimal residual disease done by which method?
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PCR/RT-PCR
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Flow cytometry identifies what?
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DNA content and ploidy
cell suface markers |
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tumor markers - overview
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cell products that can be measured in the blood/body fluids
not used as 1* diagnostic modality lack of Se/Sp some helpful in following progress of therapy screening and early detection (PSA only) |
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prostate cancer tumor markers
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PSA
PAP (prostatic acid phsophatase) |
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ovarian cancer tumor marker
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CA-125
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marker for colon cancer, pancreatic cancer
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CA-19-9
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alpha-fetoprotein (AFP) = marker for which CAs?
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liver cell CA
nonseminomatous germ cell tumors of testis |
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beta-HCG = tumor marker for what?
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trophoblastic tumors
nonseminomatous testicular tumors |
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calcitonin = tumor marker for waht?
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medullary carcinoma of thyroid
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catecholamine = tumor marker for what?
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pheocyromocytoma
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carcinoembryonic antigen (CEA) = tumor marker for what?
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carcinomas of colon, pancreas, lung, stomach, heart
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