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Molecular model for the evolution of cancers
- First hit - mutation of TS genes (inherited or somatic), at risk
- Second hit - inactivation of the wild type alleles
- Proto-oncogene mutation - eg. adenomas
- If wild-type oncogene exists, senescence
- Homozygous loss of additional TS genes, additional mutations, gross chromosomal alterations -> carcinoma
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Neoplastic progression
Normal mucosa -> hyperplasia -> dysplasia -> carcinoma in situ -> carcinoma
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Development of tumors
- Multiple factors can act together to produce a maximal carcinogenic effect
- Initiation establishes a persistent region of incipient neoplasia; tumors may emerge at a later time
- Progression is not merely an extension of a preexisting lesion
- Progression occurs independently in different tumors in the same animal
- Different characters of a particular tumor undergo progression independently
- Etiologic factors may no longer be present when tumor develops
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Both initiator (for initiation) and promoter (for progression) are necessary for development of tumor. There can be a delay between initiation and progression, but initiator must be applied before promoter, and promoters are inactive in causing tumor on itself (can cause other problems though).
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Tumor pormoters
- Phorbol esters (eg croton oil) -> skin
- Phenobarbital -> liver
- Saccharin & cyclamate -> bladder
- Bile acids -> colon
- Cigarette smoke -> urinary tract, pancreas, other
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PRECANCEROUS LESIONS
- Familial polyposis of colon
- Neurofibromatosis
- Leukoplakia
- Actinic keratosis
- Atrophic gastritis (PA)
- Chronic cell proliferation of any kind
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Grading and staging
- Grading (I-IV or descriptive measures)
- - level of malignancy
- - cytologic differentiation and number of mitotic figures
- Staging (TNM) - spread
- - size of primary lesion (T0-T4)
- - extent in regional lymph nodes (N0-N3)
- - presence or absence of metastasis (M0-M3)
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Spread of tumor cell
- blood vessel
- lymphatics
- intraepithielial (Paget's disease of breast)
- body cavities (Krukenberg tumor - breast cancer, or other cancer cells, spread and settle on the ovaries, causing ovarian cancer)
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Phases of neoplasia
- normal
- hyperplasia - genomic instability
- Intraepithelial neoplasia - clonal expansion (10-30yrs); from focal aberrant proliferation to dysplasia (focal dysplastic proliferation); preinvasive, precancer, premalignant
- Invasive neoplasia - cancer, malignant
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For carcinoma in situ to invade, needs to break through basement membranes
- expressing surface receptors and binding to basement membrane component (laminin)
- Releasing collagenases and other proteases to disrupt and invade BM
- repeated binding to and dissolution of extracellular matrix, tumor cells metastasize
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Matrix Metalloproteinase (MMP)
- enzymes degrading extracellular matrix proteins, including collagen, which leads to local invasion or metastasis.
- important for Tumor progression.
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Metastatic cascade
- Sequential steps involved in the hematogenous spread of a tumor
- Clonal expansion of transformed cell, growth, diversification, angiogenesis
- Metastatic subclone
- Adhesion to and invasion of basement membrane
- Passage through extracellular matrix
- Intravasation
- Interaction w/ host lymphoid cells
- Tumor cell embolus - platelets
- Adhesion to basement membrane
- Extravasation
- Metastatic deposit
- Angiogenesis
- Growth
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Certain cancer cells have receptors, ligands found in certain organ/tissue make it simple for the cells to stay there and grow
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Mechanisms of metastasis development within a
- primary tumor.
- A. rare variant clones develop in the primary tumor
- B. gene expression pattern of most cells of the primary tumor has a metastatic signature
- C. metastatic variants appear in a tumor with a
- metastatic gene signature.
- D. tumor stroma regulates angiogenesis, local
- invasiveness, and resistance to immune elimination, allowing cells of the primary tumor to become metastatic.
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Vit D converts Hl 60 cells into monocyte-like cells, Vit A variant, retinoic acid converts Hl 60 cells into neutrophil-like cells.
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Molecular pathogenesis of acute promyelocytic leukemia and basis for response to all-trans retinoic acid (ATRA).
- RXR, binding partner for normal RARa and PML-RARa
- fusion protein encoded by a chimeric gene created by the (15;17) translocation in acute promyelocytic leukemia.
- For a normal granulocyte progenitor, DNA that’s repressed by the retinoic acid receptor (RARa) has no expression when no retinoic acid binds; when RA binds, and repressor is replaced by activator, gene is expressed and the cells differentiate into short-lived PMNs.
- When translocation gives rise to an abnormal chromosome, PML-RARa forms, the receptor for RA is blocked and Vit A doesn’t work. Blocked differentiation -> acute leukemia.
- ATRA works with the blocked receptor, transcription is activated, cured.
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Cancer stem cells
- subpopulatioin of leukemia and solid tumor cells
- analogous to normal stem cells except that the self-renewal mechanisms are dysregulated.
- Best evidence available is the isolation of leukemia stem cells
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FORCES DRIVING THE PROGRESSION OF THE NEOPLASTIC PHENOTYPE
- 1. Increasing genomic instability within cells that are progressing toward the malignant phenotype:
- - Mitotic aberrations leading to loss or gain of whole chromosomes
- - Loss of domains from within chromosomes
- - Increased susceptibility to spontaneous or induced mutations due to abnormal DNA repair genes
- - Tendency to gene amplification
- 2. Selection of aneuploid immortal cells from the original diploid population
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Certain types of melanoma, colon adenocarcinoma, leukemia, etc are caused by BRAF mutation, and can all be treated with BRAF inhibitor.
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A paradigm shift:
classification of cancer according to therapeutic targets rather than cell of origin and morphology
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Body defense against cancer
- interferons -> virus
- drug-metabolizing enzymes -> chemical carcinogens
- repair enzymes -> DNA damage/mutation
- immune defense -> preneoplastic converting to neoplastic
- Factors limiting spread
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