Oncogenesis and metabolism in cancer self study flashcards
bcr-abl
Fusion oncogene. Example of uninhibited tyrosine kinase activity. Activates all downstream signals.
Is carcinogenesis usually somatic or germ line?
Usually somatic (nonheritable)
What are germ line mutations?
Present in egg or sperm, heritable
What are somatic mutations?
Occur in nongermline tissues, nonheritable. May be caused by intefections, toxins.
Early onset bilateral cancers are associated with what?
Germline mutations
Knudson 2 hit hypothesis
Usually underlying germline mutation (1st hit) and later onset somatic mutation (2nd hit)
What happens if you give an identical twin a stem cell transplant?
Perfect match but more risk of relapse because immune systems identical
T-cell depletion in donor bone marrow
Cause more relapses, suggesting donor t-cells help eradicate cancer cells
Tumor vaccines
Use patient’s own cells to prevent cancer recurrence
6 hallmarks of cancer
- Sustaining proliferative signaling 2. Resisting cell death 3. Inducing angiogenesis 4. Enabling replicative immortality 5. Evading growth suppressors 6. Activating invasion and metastasis
2 emerging hallmarks of cancer
- Deregulating cellular energetics 2. Genome instability and mutation
2 enabling characteristics of cancer
- Avoiding immune destruction 2. Tumor-promoting inflammation
Immune system and cancer
Plays critical role in suveillance of, prevention of, and elimination of cancer and pre-cancerous cells. More profound immune dyfunction means higher cancer risk.
What are the 2 most common cancers associated with immunodeficiency?
- Leukemias 2. Lymphomas
What predisposes someone to leukemia?
Damage to bone marrow
Chromosome instability and cancer
Fragile chromosomes greatly increase chromosomal mutations and DNA damage. In damaged DNA failure to undergo apoptosis allows persistence of mutations which can lead to cancer.
p53
Guardian of the genome. Arrests cell in G1 and G2 when DNA damage is detected to give cell time to repair or die
p53 in cancer
If mutation in p53 the probability of survival for more than a few years is extremely low.
BRCA1 and NBS in breast cancer
Participate in DNA repair
ATM
Mediates response to DNA damage and cell cycle progression. Detects the DNA damage so p53 can drive cell to repair or apoptosis.
2 things oncogenes control
- Cell proliferation 2. Apoptosis (or both)
Oncogene product 3 categories
- Transcription factors 2. Tyrosine Kinase activity (often growth factor receptors and activate downstream targets) 3. Chromatin remodelers “Imprinting”
Transcription activators
Potent for very active genes (like Immunoglobin genes). Can inappropriately activate oncogenes that can lead to cancer.
Philadelphia chromosome
Discovered by Janet Rowley. Chromosome 9 and chromosome 22 switched places which is called chronic myelogenous leukemia (CML). This started to convice scientific community that cancer is genetic.
Imatinib AKA “Gleevec” AKA STI
Drug which has lock and key fit for abnormal Bcr-abl protein. Had 40-50% cure rate and turned it into a 98% cure rate.
Imprinting
Example of chromatin remodeling. Methylation which changes transcription of a gene, turning off the promoter.
Uninhibited activity of growth factors
Can happen through imprinting and loss of heterozygosity
Loss of heterozygousity
One allele vanishes and only one parent’s allele is expressed—uniparental disomy
Unilateral disomy
Two copies from the SAME parent instead of one copy from each parent
Is suppressing the suppressor (p53 and Rb) or activating the activator worse for cancer?
Suppressing the supressor (taking away the defense) because the tumor suppressor gene can fix the problems caused by the activator
What does loss of tumor suppressors do?
Leads to overexpression of oncogenes
Vascular endothelial growth factor (VEGF)
Stimulates formation of vasculature for new tumor site (there is a drug that targets this)
Angiogenesis
New blood vessels (does NOT happen normally)
Wrong number of chromosomes and embryologic defects
Increased risk of cancer
What is the difference between embryology and cancer?
Embryology is “regulated” growth vs cancer is dysregulated
Malignant tumors are characterized by what 4 things?
- Upregulated cell division 2. Immortality, resistance to apoptosis 3. Ability to metastasize 4. Induce angiogenesis (make new blood vessels)
Tumor cells and energy needs
Main energy source is glucose-will take it under any conditions. Tumor cells are not responsive to insulin or glucagon. Tumor cells also have high AA requirements for building proteins.
Source of glucose for tumor cells
Blood (glycogen breakdown oe glucose synthesis in liver). Glycolysis highly upregulated; some glycolytic enzymes become much more efficient variants.
Source of amino acids for tumor cells
Skeletal muscle
Cancer cachexia and 4 causes
Unexplained weight loss in cancer patients possibly caused by: 1. Decreased appetite 2. Increased energy need of cancer cells 3. Secretion of factors that stimulate skeletal muscle/fat tissue wasting 4. Endocrine imbalance (insulin resistance, higher cortisol, higher BMR)
5 factors released by cancer cells which moderate metabolism
- ACTH 2. Nerve growth factor 3. Insulin-like growth factor 4. Proteolysis inducing factor 5. Lipid mobilizing factor
Host response to tumor
Release of IL-1, IL-6, interferon-gamma, tumor necrosis factor-alpha by immune cells which cause fever, proteolysis (breakdown of proteins), lipolysis
