Lecture 2: Multistep tumor progression Flashcards
Approximate shift between cigarette consumption and lung cancer
~20 years
Three main types of carcinogens
- Chemical agents
- Physical agents (UV, X-rays)
- Viral agents
Goal and method of the Ames test
Are carcinogens also potent mutagens ?
Test the ability of the compounds to enable new capabilities in Salmonella bacteria through mutagenesis
Result of the Ames test
Carcinogens ARE mutagens
Hyperplasia
Cells deviate minimally from normal tissues but contain an excessive number of cells
Adenomas
Hyperplasias that develop from the cells that line the lumen of glands, not yet invasive
Polyps
Contain all cell types found in the normal tissue but with substantial expansion -> macroscopic mass that can protrude externally (lumen of the intestine)
Not invasive
Dysplasia
Cytologically abnormal (atypia)
Alteration of the overall architecture of the tissue
Transitional state between benign and premalignant growth
Invasive adenocarcinomas
Malignant tumors: cells growths that invade underlying tissue
Usual progress of tumors of epithelial origin
Hyperplasia/displasia => Carcinoma in situ => Invasive carcinoma
Progression in colorectal cancer
Normal colonic crypts => Hyperplasia => adenoma => carcinoma => metastasis
Histological evidence for multi-step progression in colorectal cancer
Adenoma turns into malignant tumor mass invading the muscle cells
Reason for delay in twins developing cancer
First mutation is always the same, but independent, random and critical secondary mutations needed to develop the cancer
Two most common mutated genes causing cancer
Ras and Myc
Why are carcinogen mutations kept during evolution
Confer a selective advantage to cells by allowing them to divide
3 Mutations sufficient to transform mouse cells
Ras, pRb, p53
5 Mutations required to transform human cells
Ras, pRb, p53, telomeres, PP2A
Defs of: immortalization, Transformation
Immortalization: cells proliferate in vitro and don’t undergo senescence
Transformation: cells can form tumors
Tumor initiator
Generally a mutagen, causes genetic or epigenetic changes (mutations) in normal cells that are necessary (but often not sufficient) for tumor development
Tumor promoter
Fosters the growth (proliferation) of “initiated” cancer cells, enabling their acquisition of additional features, also genetic, leading to cancer. A tumor promoter may not be a mutagen
Skin carcinogenesis model : Effect of painting once with initiator or multiple paintings with promoter
No change
Effect of painting once with initiator + multiple paintings with promoter (same site)
Papilloma
Effect of painting once with initiator + multiple paintings with promoter (diff site)
No change
Effect of painting once with initiator + multiple paintings with promoter (same site) => stop promoter painting
Papilloma develops and goes away
Effect of painting once with initiator + multiple paintings with promoter (same site) => additional extensive promoter painting => stop promoter painting
Papilloma develops and doesn’t go away
Effect of painting once with initiator + multiple paintings with promoter (same site) => paint papilloma with initiator
Papilloma turns into a carcinoma
Tumor initiator and promoter for skin carcinogenesis (and their effect)
Initiator: DMBA, causes oncogenic RAS proteins and mutation in p53
Promoter : TPA
Alcohol and tobacco (which one initiator and promoter)
Alcohol = promoter, tobacco = initiator
