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
Normal mucosa -> hyperplasia -> dysplasia -> carcinoma in situ -> carcinoma
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
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).
- Phorbol esters (eg croton oil) -> skin
- Phenobarbital -> liver
- Saccharin & cyclamate -> bladder
- Bile acids -> colon
- Cigarette smoke -> urinary tract, pancreas, other
- Familial polyposis of colon
- Actinic keratosis
- Atrophic gastritis (PA)
- Chronic cell proliferation of any kind
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)
Spread of tumor cell
- blood vessel
- 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)
Phases of neoplasia
- 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
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
Matrix Metalloproteinase (MMP)
- enzymes degrading extracellular matrix proteins, including collagen, which leads to local invasion or metastasis.
- important for Tumor progression.
- 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
- Interaction w/ host lymphoid cells
- Tumor cell embolus - platelets
- Adhesion to basement membrane
- Metastatic deposit
Certain cancer cells have receptors, ligands found in certain organ/tissue make it simple for the cells to stay there and grow
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.
Vit D converts Hl 60 cells into monocyte-like cells, Vit A variant, retinoic acid converts Hl 60 cells into neutrophil-like cells.
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.
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
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
Certain types of melanoma, colon adenocarcinoma, leukemia, etc are caused by BRAF mutation, and can all be treated with BRAF inhibitor.
A paradigm shift:
classification of cancer according to therapeutic targets rather than cell of origin and morphology
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