molecular biology of neoplasia II - lecture notes - julia Flashcards Preview

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Flashcards in molecular biology of neoplasia II - lecture notes - julia Deck (24)
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1
Q

review: what are the different mechansism by which a cell can undergo apoptosis?

A
  • death receptor pathway
  • fasL, TNF, TRAIL => activation of death receptors
  • activates FADD
  • activates caspase-8
  • activates caspase-3
  • apoptosis
  • stress pathway
  • bcl2 is inactivated and so stops inactivating Bax
  • bax activates cyt c/apaf1 and omi/diablo
  • ctyc/apaf-1 activate caspase 9
  • omi/diablo inhibit IAP, which normally inhibits caspase 9 and casease 3,7
  • caspase 9 activates caspase 3,7
  • apoptosis
2
Q

what are some possible triggers of the stress pathway of apoptosis?

A
  • chemo
  • XRT
  • hypoxia
  • genetic damage
  • GF or cytokine withdrawl
  • loss of cohesion/adhesion
3
Q

what are modulators of the stress apoptosis pathway?

A
  • Bcl-2/Bax family
4
Q

what is bcl-2? how is it involved in cancer?

A
  • modulator of the stress pathway of apoptosis
  • mitochondiral membrane protein that blocks apoptosis
  • in follicular lymphomas, have a t(14;18) chromosomal translocation => abnormally high levels of bcl-2 protein => lack of normal apoptosis in response to abnormal cells
5
Q

how do normal and cancer cells differ in terms of senescence and immortalization?

A
  • normal cells in culture have finite replicative potential
  • senescence = after a certain number of replications, cells stop growing
  • if a cell has disabled pRb and p53, senescence will be circumvented => cells continue replicating until enter crisis = massive cell death, karyotypic disarray, end-to-end fusion of chromsomes
  • sometimes get variant cell that doesn’t go into crisis and can multiply without limit = immortialization
6
Q

how is telomerase involved in neoplasia?

A
  • not present in most normal cells (except germ cells and stem cells)
  • levels higher in malignant than benign neoplasms though some malignant neoplasms lack detectable telomerase activity (may be alternate methods of telomere stabilization or lengthening)
7
Q

what are the steps of new vessel growth into an new area?

A
  1. perivascular detatchment and vessel dilation
  2. onset of angiogenic sprouting
  3. continuous sprouting - new vessel formation and maturation, recruitment of perivascular cells
  4. tumor vasculature is established

these vessels probably won’t appear perfectly normal because growth not that well regulated - perfectly functional though

8
Q

what controls angiogenesis?

A
  • dependent on local ratio of angiogenic inducers (VEGF) to anti-angiogenic agents
  • normally ratio is low - no vascular proliferation
  • but angiogenic switch can occur and angiogenesis will occur
9
Q

what can cause an angiogenic switch? (5)

A
  • physiologic circumstances
  • wound healing
  • normal development
  • physiologic hyperplasia
  • pathologic conditions
  • tumorigenesis
  • subclone develops ability to stimulate angiogenesis due to clonal progression
10
Q

what are factors that increase angiogenesis (inhibitors)?

A
  • thrombospondin-1
  • statins
  • angiostatin
  • endostatin
  • canstatin
  • turnstatin
11
Q

what things activate angiogenesis?

A
  • vegfs
  • fgfs
  • pdgfb
  • egf
  • lpa
12
Q

how can angiogenesis be targeted in therapies for tumors?

A
  • give with low dose standard cytotoxic therapy
  • targets vascular endothelial cells
  • regressed to dormant microscopic lesions with endostatin treatment even though tumor cells were proliferating but get high rate of apoptosis of tumor cells
  • apparently these haven’t panned out in clinic though for “various reasons”…
13
Q

how many tumor cells metastasize?

A
  • millions of tumor cells are shed into the circulation daily
  • but only 1 in 10,000 survive to initiate a metastatic focus
14
Q

what are the steps in establishment of a metastatic focus? what must the tumor cells be able to do?

A
  1. decreased cellular cohesion (dyscoheision - due to change in cadherins)
  2. matrix degradation by release of MMPs, TIMPs
  3. changes in cell-matrix attachments (changes in integrins)
  4. cells must be able to break through the basement membrane and get through the vascular endothelium
  5. must be able to evade the immune system, platelets, etc
  6. must be able to adhere to the vessel wall
  7. must be able to get out of the vessel (extravascation)
  8. angiogenesis
  9. proliferation
15
Q

what do cadherins do? how do they mediate cell-cell cohesion?

A
  • mediate homotypic cell-cell interactions at adherens junctions
  • complexed with cytoskeleton via catenins
  • involved in signaling pathway that regulates cell proliferation, apoptosis, differentiation, and cell motility
  • loss correlates with increased invasiveness and metastatic potential
16
Q

what do integrins do and how must they change for metastasis?

A
  • transmembrane receptors for basement membrane components and other ECM molecules
  • focal adhesion kinase pathways regulate apoptosis, proliferation, and cell motility
  • tumor cells have integrin switching = altered integrin expression patterns =>
  • decreases adhesion to the basement membrane
  • increased adhesion to the ECM
  • increased migration over the ECM
17
Q

what are some examples of proteins that integrins detect?

A
  • collagens
  • laminin
  • tenascin
  • fibronectin
  • vitronectin
18
Q

what proteins are involved in matrix degradation? what is different in cancer tissue?

A
  • proteolytic enzymes: matrix metalloproteinases (MMPs) and collagenases
  • these destroy the local basement membrane and ECM to allow tumor cells to invade
  • expression of tissue inhibitors of metalloproteinases (TIMPs) is down regulated in cancer
19
Q

what factors direct migration of tumor cells?

A
  • autocrine and paracrine factors:
  • growth factors (IGFs, FGFs, TGF-beta) - all stimulate tumor cell motility
  • hepatocyte growth factor = ligand for c-met protooncogene
  • cytokines (interleukin-8, histamine)
  • extracellular matrix factors
  • intact ECM molecules (vitronectin, fibronectin, laminin, type I collagen)
  • fragments of ECM molecules released from the matrix by MMPs
20
Q

how can antiadhesive agents be targeted as a therapy for cancer?

A
  • peptidomimetrics and monoclonal antibodies targeted at integrins
  • antagonists of alphavbeta3 (vitaxin) induce vascular cell apoptosis and inhibit angiogenesis by blocking endothelial cell matrix interactions
21
Q

how can matrix metalloprteinase inhibitors be used theraputically in treatment of neoplasm?

A
  • blocks degradation of matrix
  • blocks action of proteases and growth factors
  • have been found to have anti-invasive properties in vitro and anti-angiogenic properties in vivo
22
Q

how are anti-motility agents being used theraputically to treat neoplasm?

A
  • taxanes block microtubule cycling
  • inhibitor of ca influx is used (carboxyamido-triazole)
23
Q

what are typical genetic steps toward colon cancer development?

A

certain genes have a high probability of mutating at each definable stage of colon cancer progression

  1. starts with loss of APC gene on chromosome 5 => small benign polyp
  2. oncogenic mutation of ras gene on chromosme 12 => large benign polyp
  3. loss of p53 on chromosome 17 and loss of a gene on chromosme 18 (possible DCC) => cancer
24
Q

what would be the genetic profile of the tissue surrounding a tumor?

A
  • benign tissue around the malignant tissue frequently contains many of the same set of mutations found in the tumor but lacks at least one mutation that is found in the tumor tissue