Ch. 11: Multi-Step Tumorigenesis Flashcards
Cancer risk _______ with age.
Interpretation- ….
- increases
- It takes time for cancer to form.
Can we estimate how long it takes for cancer to
form?
Generally, not really.
* Dependent on random mutational events (hard to predict)
* But we can do so here, with lung cancer risk and a known source of cancer (smoking tobacco)
Why do cancers take a long time to form?
Hypothesis-
* Cancer formation is a multi-step process
* A sequence of unlikely events must occur for a tumor to form
* As we grow older we accumulate cells at many places in our bodies that have undergone some but not all steps of tumor progression
* Autopsy reports show that ~65% of individuals carry undiagnosed tumors, independent of the cause of death
Histopathology
examining tissues under a microscope to study disease
What suggests cancers develop in a multi-step process?
A spectrum of tissue morphologies exist between
normal and highly malignant
* Suggests, cancers develop in a multi-step process
Hyperplasia
Individual cells look normal but there is evidence of increased
cell divisions. Usually, the tissue looks thicker.
Dysplasia
- Loss of well-ordered single layer of cells
- Morphology looks subtly different than normal
In situ cancer
- More severely abnormal growth
- Benign- stay in the tissue of origin
- Usually not diagnosed as a cancer
Metastatic Cancer
- More severely abnormal growth
- Evidence of malignancy- cells have migrated out of the tissue of origin, into distant sites of the body
- Diagnosed as cancer
Progression does not inevitably happen
- Impact on early screening
- Unnecessarily overtreating patients with pre-metastatic lesions that may not ever develop to cancer.
- Active area of research- Identify which early lesions are
a high risk to develop into metastatic cancer
Prediction: Genetic mutations accumulate as progression proceeds
Experiment: Determine if there is an increase in mutations in tissues at each stage of progression
Results: ?
Updates Results: ?
Results: Mutations accumulate as cancer progresses
* Colon cancer at the following progression stages:
* Small adenoma, mid-size adenoma, large adenoma, carcinomas
Results:
- Common genes/regions were mutated at specific stages in colorectal cancer progression
* Common genes/regions were mutated at specific stages in colorectal cancer progression
- Interpretations:
- LOH Chr. 5q was seen in all stages of cancer progression
- Activated K-ras was seen in intermediate adenomas and all stages of progression after that
- Carcinomas have all of these mutations: LOH Chr. 5q, activation of K-ras, LOH Chr 18q, and LOH Chr. 17p
Updated results: Pathways involved in colon carcinoma progression
* Since the original study, researchers have further characterized the molecules and pathways effected by each mutation.
* Generally, carcinoma tumor progression involves the following genetic mutations in the following order of progression (slide 23)
A model of all the pathways mutated in colon carcinoma progression
- In reality, there is more than 1 way colon cancers develop
- In general, genes in 4 major
pathways are mutated - B-catenin mutations occur
relatively early in progression - TP53 mutations occur relatively late in progression
- Some mutations are more
frequent than others - Some mutations are more likely to occur together (Ex- B-raf and SMAD4)
Genes that are commonly mutated during cancer
progression contribute to…
common phenotypes of cancer
Cancer development through a lens of evolution (slides 27-31)
- Each individual cell in a tissue is in competition with other individual cells
- If a cell happens to get a mutation that increases its fitness relative to other cells then it will accumulate in
higher numbers compared to non-mutated cells - Idea- a random mutation in 1 cell gives it a proliferative advantage compared to other cells.
- This cell and it’s descendants will come to dominate the tissue.
- When this cell and it’s descendants gets to large numbers; a second mutation is mathematically possible.
- If the second mutation gives an additional fitness advantage, then it and its descendants will come to dominate the tissue
- When this cell and it’s descendants gets to large numbers; a third mutation is mathematically possible.
- If the second mutation gives an additional fitness advantage, then it and its descendants will come to dominate the tissue.
- Clonal expansion: when a single cell contributes to a population of cells.
- Idea: Cancer progression involves a number of clonal expansions.
- Each mutation must be
complementary, act on a separate molecular pathway, and confer an increased fitness relative to the prior mutation
Clonal Expansion
when a single cell contributes to a population of cells
