Neoplasia Flashcards
What are the 8 fundamental changes that all cancers display? Also, what are 2 enabling characteristics?
- Self-sufficiency in growth signals (oncogenes)
- Insensitivity to growth-inhibiting signals (tumor suppressor genes)
- Altered cellular metabolism (Warburg effect)
- Evasion of apoptosis (ex. p53 which normally causes apoptosis, BAX/Bcl2)
- Limitless replicate every potential (immortality) (telomerase activity)
- Sustained angiogenesis (VEGF/FGF)
- Ability to invade and metastasize (downregulation of E-cadherins leads to dissociation of attached cells, collagenase to break down Type 4 collagen in BM, fibronectin in ECM for local spread; lymphatic/vascular entrance for metastasis)
- Ability to evade host immune response (ex. downregulates MHCI antigen presentation, no activation of CD8+ T cells)
2 Enabling characteristics: - Inflammation - Genome instability
One of the eight hallmarks of cancer involves self-sufficiency in growth signals. Proto-oncogenes, the normal protein, can be mutated into oncogenes. Oncogenes can then produce oncoproteins, which promotes cell growth in the absence of normal growth promoting signals and dysregulates normal growth checkpoints and controls. Thus, oncogenes can drive the proliferation if cells. What signaling pathway is most frequently mutated? Also, list other pathways that may be mutated.
Most frequently mutated- Receptor tyrosine pathway.
Examples include ERBB1 (lung cancer), ERBB2/HER2 (breast cancer) Others include: - GPCR - JAK/STAT -WNT - Notch - Hedgehog - TGFb/SMAD - NF-kB
Modulation of signal transducers can be mutated and thus lead to a malignant phenotype. Describe the RAS pathway, noting the following components, and their roles:
- RAS (active vs. inactive)
- GAP
- PTEN
- RAF
- PI3K
- MAPK
- Akt
- mTOR
- MYC
- D cylcins
Also, describe the mutations that can occur in the RAS pathway, allowing it to make up 15 to 20% of all tumors.
- RAS point mutation that decreases GTPase activity.
- GAP mutations that leads to unrestrained RAS activity
- RAF mutations that leads to activation of transcription factors
- PI3K mutations that leads to increased cell survival
- PTEN - unregulated PI3K activity
The G1/S checkpoint is most critical for controlling cell cycle progression. List two important tumor supressor genes involved in inhibiting G1/S progression if there is DNA damage. Explain their mechanism of action:
RB and TP53
RB: when RB is inactive, it is hypophosphorylated and bound to the E2F transcription factor. When activated, by cellular damage, etc, RB is unbound from E2F and is hyperphosphorylated. When in its hyperphosphorylated state, E2F can initiate transcription factors.
Note: Both the cyclin D/CDK4 and cyclin D/CDK6 complexes _partially phosphorylates the RB protein._ E2F transcription factor then stimulates the synthesis of Cyclin E, which allows for the full phosphorylation, and INACTIVATION of the RB tumor suppressor protein. This will allow for progression through the G1/S checkpoint.
TP53: normally bound to MDM2, which inhibits its inhibitory effects on cell cycle progression. When unbound, TP53 can activate p21, which is a tumor suppressor protein. Activation is present when cell is damage, pushed into senescence or must undergo apoptosis.
Normally, p53, a tumor suppressor and transcription factor, is found at low levels bound to MDM2. When the cell is stressed, p53 is releaased from MDM2 and can prevent neoplastic transformation by:
- inducing transient cell cycle arrest
- inducing permanent cell cycle arrest
- inducing programmed cell death
The APC gene is a TSG that is important in regulating grwoth promoting signal pathways, and mutation of this join can result in adennmatous polposis coli. The APC gene is found on chromosone 5q21. Recall, that in order for polyps to develop, two-hits must occur (i.e. both copies of APC gene must be lost for adenoma to arise; one hit will simply increase the risk). A germline loss of function is associated with familial adenomatous polyposis.
The APC protein is a part of the WNT signaling pathway.
In this disease, hereditary syndromes only account for 5%, while APC mutations are found in 80% of colorectal cancers. Thus, you shouldn’t suggest familial correlations first.
The APC protein is a part of the WNT signaling pathway. APC is a TSG. Explain how loss of APC can result in cell proliferation. Include mediators such as b-cantenin and TCF.
APC is activated/deactivated in three main states: resting cell, WNT stimulation, and tumor cell with mutated APC:
- resting cell:* w/o WNT stimulation, APC is bound to b-cantenin, a proto-oncogene. Bound with APC, b-cantenin is degraded and unable to act as a trasncription factor in the cell’s nucleus.
- WNT activation:* when WNT stimulates the WNT receptor, the formation of the APC/b-cantenin destruction complex is blocked and b-cantenin is allowed to accumulate. B-cantenin will enter the nucleus and form a transcription activation complex with TCF. This complex will ultimately promote growth of colonic epithelial cells, including synthesis of c-Myc and cyclin D1.
- Loss of APC:* cell behaves as if they are being continuously stimulated by WNT due to the overaccumulation of b-cantenin.
B-cantenin is not only important for promoting cell growth/viability, but it’s also important for initiating repair after damage to the endothelial adhesion molecules. Explain this mechanism of action with regards to b-cantenin and E-cadherin.
E-cadherin-mediated cell–cell adhesion is frequently lost during the development of malignant epithelial cancers. E-cadherin downregulates β-catenin/Tcf-mediated transcriptional activity by sequestrating β-catenin into E-cadherin cell-adhesion complexes even in the presence of activated Wnt signaling. Thus, sequestration of b-cantenin by E-cadherin may play a small role in minimizing the malignant phenotype that can occur by unregulated/accumulated b-cantenin. Loss of b-cantenin inhibition by mutation of E-cadherin/b-cantenin axis is a key characteristic of carcinomas.
PTEN is a TSG that normally encodes a phosphatase and serves as a break on the PI3K/AKT portion of the tyrosine kinase pathway. Recall the effect that this portion of the pathway has in creating the malignant phenotype. Also, what disease is associated with a mutated PTEN.
Cowden syndrome is associated with a mutation of PTEN. The PI3K pathway is a portion of the RAS tyrosine kinase signaling pathway that promotes pro-growth metabolism and increased protein synthesis.
Not that in Coeden syndrome, there is an accumulation of benign growth called hamartomas; there is also a high risk of breast and endometrail carcinoma.
Tumor suppressor gene NF1 is important for producing proteins that regulate the activity of GAP (GTPase activating protein). Neurofibrin is important for accelerating GTP hydrolysis on Ras proteins. Thus, with loss of neurofibromin, RAS is trapped in an active state. Neurofibomatosis requires “2-hits” of mutations to the two alleles to result in disease. 50% of NF type 1 cases are due to sporadic mutations. NF1, benign tumors are called neurofibromas.
Tumor suppressor gene NF2 is important for producing neurofibrin 2 (merlin). Merlin is important for maintaining stable cell-to-cell junctions. Thus, damage to merlin can result in a cell becoming insensitive to normal growth arrest signals generated by cell-to-cell contact. Neurofibomatosis type 2 requires “2-hits” of mutations to the two alleles to result in disease. 50% of NF type 2 cases are due to sporadic mutations. NF1, tumors are called schwannomas.
WT1 is a TSG and is a transcriptional regulator of mesenchymal to epithelial transition. Loss of function mutations can lead to Wilms tumor. What tissues in the body depend on propoer transcriptional activation from WNT?
Encoded WT1 protein is a transcriptional activators of genes involved in renal and gonadal differentiation.
VHL (von Hippel-Lindau) encodes a protein that plays a role in ubiquitin-proteasome degradation. VHL causes an increased incidence of renal cell carcinoma and pheochromocytoma.
What is the cause of Peutz-Jeghers syndrome?
STKll, is gene that encodes a serine/threonin kinase 11 enzyme, which is important for promoting apoptosis. This syndrome is characterized by benign hamartomatous polyps of the GI tract, increased risk of GI and pancreatic cancers, and mucocutaneous hyperpigmentation.
Alteration of cellular metabolism is a hallmark of cancer cells. Describe why cells utilize the Warburg effect for energy production.
Oxidative phosphorylation provides a lot of ATP, but it doesn’t produce the carbon-based metabolic intermediates that cancer cells need. Thus, cancer cells become “fixed” and will rely on glycolysis for energy production. Glycolysis will only produce 2 ATP (Glucose > pyruvate > lactate).
Evasion of apoptosis is a hallmark of cancer cells. Describe the mechanism by which a cell will normally undergo apoptosis. Include mention of the mitochondrial and death-receptor pathways.
Epidemiology:
Canceer is the 2nd leading cause of death in both adults and children. What are the top three most common cancers by incidence and mortality?
- breast/prostate (highest incidence)
- lung (highest mortality in both sexes)
- colorectal
cardiovascular disease is the leading cause of deaths in adults.
