Module 11 Flashcards
What is Cancer?
- ‘Cancer derives from the Greek for cram, karcinos
- Hippocrates coined the word ‘karcinos’ after observing that distended veins radiating from a breast tumor resembled the legs of a crab
- Abnormal mass of tissue resulting from excessive cell division
- May be benign or malignant
Tumor/Neoplasia
Benign vs Malignant
Benign: cells remain clustered together in a single mass
Malignant = Cancer
- Invade surrounding tissue
- Spread via bloodstream or lymphatics = metastasis
Hallmarks of Cancer
- Growth signal autonomy
- Evasion of growth inhibitory signals
- Avoiding immune destruction
- Unlimited replicative potential
- Tumor-promoting inflammation
- Invasion and metastasis
- Angiogenesis
- Genome instability and mutation
- Evasion of cell death
- Reprogramming energy metabolism
- Growth signal autonomy
Cancer cells can be distinguished from normal cells in cell culture conditions
- Normally, cells grow as a single layer, or monolayer, in a Petri dish due to a property called contact inhibition; contact with neighboring cells inhibits growth.
Cancer cells can be distinguished from normal cells in cell culture conditions (2)
- Transformed cells (cells that have become cancer cells) acquire the following phenotypes:
• they fail to exhibit contact inhibition and instead grow as piles of cells or “foci” against a monolayer of normal cells
• they can grow in conditions of low serum
• they adopt a round morphology rather than a fl at and extended one
• they are able to grow without attaching to a substrate (e.g. the surface of a Petri dish), exhibiting “anchorage independence.
Three distinct phenotypes of cancer cells
- Immortality – indefinite proliferative lifespan
- Transformation – loss of response to normal regulators of cell growth
- Metastasis – ability to break off from a tumor and invade tissues in another location in the body
Normal to Cancer Cell
- Change in phenotype
- Genetic – change in DNA sequence
- Many, but not all, cancer causing agents damage DNA
- Epigenetic – heritable change in gene expression
HOW PROTO-ONCOGENES BECOME ONCOGENES
• Point mutations/deletions in coding sequence —> structural and functional changes
• Point mutations and deletions in regulatory sequences —> over-expression
• Chromosomal translocations —> fusion proteins with novel functions
• Insertional mutagenesis caused by viral integration —> aberrant expression
Gene amplification—>increase in gene dose and protein production
Examples of Inherited Predisposition to Cancer
- RB - Retinoblastoma
- Ip53 - Li-Fraumeni syndrome (various tumors)
- p16/INK4A - Melanoma
- APC - Familial adenomatous polyposis/colon cancer
- NF1, NF2 - Neurofibromatosis 1 and 2
- BRCA1, BRCA2 - Breast and ovarian tumors
Examples of Inherited Predisposition to Cancer 2
- MEN1, RET - Multiple endocrine neoplasia 1 and 2
- MSH2, MLH1, MSH6 - Hereditary nonpolyposis colon cancer
- PTCH - Nevoid basal cell carcinoma syndrome
- PTEN - Cowden syndrome (epithelial cancers)
- LKB1 - Peutz-Jegher syndrome (epithelal cancers)
- VHL - Renal cell carcinomas
Development of cancer occurs in stages
Normal -> Hyperplasia -> Mild dysplasia -> Carcinoma in situ (severe dysplasia) -> Cancer (invasive)
G1 checkpoint signals
- Is the cell big enough?
- Is the DNA damaged?
- Is the environment favorable?
- Is the cell ready to divide again?
G2 checkpoint signals
- DNA replicated once and only once?
- Is the DNA damaged?
- Cell size and nutritional state?
- Is the cell ready to enter mitosis?
M phase checkpoint signals
- Chromosomes attached to opposite poles?
* Is the cell ready to exit mitosis?
Cell Cycle Regulation
• Cyclins – family of proteins whose concentration oscillates during the course of the cell cycle
• Cyclin-Dependent Kinases
- family of enzymes that control progression of the cell cycle
- Exerts its influence by phosphorylation
• Complex = Maturation Promoting Factor (MPF)
Cell Cycle Activation
- Response to mitogen
- Early-response genes
- Delayed-response genes
- Transcription within minutes
- Peaks at 30 min. then drops
- Encode transcription factors (c-Fos and c-Jun)
- c-Fos and c-Jun -> transcription of delayed-response genes
Early-Response Genes
- Stimulated by products of early-response genes
- Include transcription factors such as E2F, cyclins D and E, CDKs
Delayed-Response Genes
E2F Target Genes
- c-Myc, c-Fos
- Thymidine kinase, thymidine synthetase
- Dihydrofolate reductase
- DNA polymerase
- Cyclin E and A
- Dependent on activation of E2F transcription factors
- Allows passage from G1 -> S phase
Restriction Point
- mRNA for replication proteins
- synthesis of replication proteins
- replication of DNA
S Phase
Key points: Cancer
• Cyclin A: required for DNA synthesis • CDK1: required for entry into mitosis • Cyclin B - synthesized during the S phase - Transported from cytoplasm into nucleus just before nuclear membrane breaks down
- Distorts active binding site
- Inserts into ATP-binding site
Cyclin Kinase Inhibitors