Angiogenesis and Platelets Flashcards
Describe how platelets interact with tumour cells and state how this helps metastasis
Platelets bind to cancer cells which allows tumour cells to spread to distant organs. platelets activate and secrete granual content. aiiib(beta)3 is the primary intergrin on platelets. Platelet promote tumour migration through the EC layer in an integrin dependent fashion. platelet activation can occur by tumour cells releasing ADP, thrombin and PAF- these interact with P2Y12 & PAR1 which trigger platelet activation
explain how platelets induce cancer cell proliferation
-when cancer tells enter circulation they are subject to NK cells which immuosurviellence and release immunoregulatory cytokines that regulative adapative immune response.
-plateletes act as a physical shield and induce molecular mimicry (the transfer of MHC1 to tumour cell surface allowing evasion of the NK cells).
-activated platelets release TGF-b which also inhibit NK function
describe a method to measure platelet-cancer binding
Effect of platelets, thrombin, eptifibatide (GP IIb/IIIa inhibitor) , and RGDWE peptides on migration of MDA-MB-231 cells through HUVEC monolayers
what are some mechanisms that promote TCIPA
Release of pro-coagulant factors (e.g., ADP, thrombin) from tumor cells activates platelets.
Expression of adhesion molecules like P-selectin and integrins on tumor cells facilitates binding to platelets.
Platelet activation leads to the release of growth factors (e.g., VEGF, PDGF), supporting tumor progression.
Platelet-tumor cell interactions protect tumor cells from immune surveillance and enhance metastatic spread.
Tumor-derived microparticles further stimulate platelet aggregation and facilitate tumor cell survival in circulation.
how do migration and invasion assays work
Migration and invasion assays assess cell movement and ability to penetrate extracellular matrices. In migration assays, cells are placed in a well with a gap (e.g., in a wound healing or Boyden chamber assay) and monitored for movement toward a chemoattractant. In invasion assays, cells are placed on a membrane coated with extracellular matrix proteins (e.g., Matrigel) in a Boyden chamber, and their ability to invade through the matrix toward a chemoattractant is measured. Both assays quantify cell migration/invasion based on cell number or area covered after a set time.
what is angiogenesis
- the development of new blood vessels
- without oxygen necorsis occurs; a necrotic core develops
- this process requires the migration and growth of endothelial cells.
- cancer secretes stimulants to endothelial cells to grow and migrate them to the site of a tumour. the structure made is leaky, tortuous and allows direct entry to the circulation
explain how VEGF induces angiogenesis
- important infucer,
-Angiopoietin and cognate Tie receptors and ephrin’s and ephrin receptors also play a key role - There are 5 VEGF family members (A-D and placental growth factor PlGF
1 is a decoy recpetor - 2 is the driver of angiogenesis
-3 is mainly inovlved in the development of the lymphatic system
NPRs are another class expressed w cancer and seem to play a role in tumpur cell incasion, they also regulate VEGFR1-2. - VEGF-A induces endothelial growth, permeability and leakage, sprouting is lead by tips which sense the envieonemnt and direct the sprouting process
-The RAS-Raf-MEK-ERK signalling cascade is activated switching on several genes associated with proliferation and matrix metalloprotease production
describe other forms of vessel formation and how we can target these processes
splitting angiogenesis- where an already existing blood vessel in two; indcued by VEGF and PDGF
- VASCULOGENESIS- differentiation of endothelial progenitor cells (EPCs) in a process coined vasculogenesis
In preclinical glioma models, it has been shown that revascularization that occurs during glioma recurrence after irradiation is mediated by vasculogenesis and not angiogenesis.
what si the angiogenic switch
- a time resticted event where during the time of tumour progress he balance between pro- and anti-angiogenic factors tilts towards a pro-angiogenic outcome,
what is the relation of hypoxia and angiogenesis
Oxygen levels regulate HIF at the protein rather than mRNA level- both HIF components (HIF-1α and HIF-1 β are constitutively expressed
The von Hippel-Lindau (VHL) tumour suppressor protein binds to hydroxylated HIF-1α enabling ubiquitination (a marker for proteosomal degradation to occur) of HIF-1α
Under hypoxia VHL cannot bind HIF-1α, it is stabilised, dimerises and binds to the hypoxia response element in target genes (such as in the VEGF promotor)
describe antiogenic therapy
does not directly target the cancer but is designed to prevent tumours from forming blood vessels to stop their growth. though it is limited
Despite promising results showed by pre-clinical studies, anti-VEGF monotherapy such as bevacizumab, sunitinib and aflibercept have only provided limited benefits in certain tumour types including advanced-stage renal cell carcinoma, hepatocellular carcinoma and colorectal carcinoma and have not shown efficacy in pancreatic adenocarcinoma, prostate cancer, breast cancer or melanoma
RESISTANCE: VEGF independant pathways can be developed2. only partially normalize blood vessels, leaving dysfunctional ones that still support tumor growth3. like FGF and PDGF, can bypass VEGF inhibition.
why ERk inhibitoes may be sued as potential angiogenesis inhibitor
ERK inhibitors may be used as potential angiogenesis inhibitors because the ERK signaling pathway plays a key role in endothelial cell proliferation, migration, and tube formation, processes critical for angiogenesis. By inhibiting ERK, these drugs can prevent abnormal blood vessel formation, which is essential in conditions like cancer and diabetic retinopathy.
how do vessels created by angiogeneis and vascular mimicry differ ?
1.Vessels formed by angiogenesis arise through the proliferation and migration of endothelial cells, creating true blood vessels with lumens.
2. In contrast, vascular mimicry occurs when tumor cells themselves form vessel-like structures without endothelial involvement, lacking typical blood vessel features but still facilitating tumor blood supply.
Describe some of the consequences of tumour hypoxia
t promotes the activation of hypoxia-inducible factors (HIFs), stimulating angiogenesis, immune evasion, and metabolic changes to support tumor survival. Hypoxia also enhances the expression of genes associated with resistance to therapies, making tumors more aggressive. Furthermore, it contributes to genomic instability, facilitating tumor progression, metastasis, and a more hostile microenvironment, which ultimately compromises the effectiveness of treatment strategies like chemotherapy and radiation.
How do we know platelets bind to cancer cells? What are the mechanisms supporting this?
Evidence comes from experimental studies showing platelet aggregation on cancer cells, observed via microscopy and flow cytometry. Key mechanisms include the interaction of platelet glycoprotein IIb/IIIa with integrins on tumor cells, and P-selectin binding to PSGL-1 on cancer cells. Tumor-secreted factors like thrombin, VEGF, and ADP also enhance platelet-tumor adhesion. Additionally, platelet activation leads to the release of pro-inflammatory cytokines and growth factors, further promoting tumor cell survival, immune evasion, and metastasis.
