cell communication and balancing tumour growth Flashcards
TGF beta
complex, dual natured role during tumour progression
- tumour suppressor in pre malignant cells
- tumour promoter in overtly malignant cells
cancer cell clones with inactivated or subverted SMAD pathways can avoid the tumour suppressive effects of TGF-beta, promoting the invasiveness and immune evasion
genetically engineered mouse model
- selective inactivation of TGF-beta receptor in stromal fibroblasts
- stromal cells are no longer susceptible to TGF-beta-mediated growth inhibition
- hyperproliferating fibroblasts drive nearby epithelial cells to proliferate
- proliferative epithelial cell layers develop into carcinomas
- power of stromal cells to stimulate epithelial cell proliferation, leading to neoplastic transformation of the epithelial cells
how do CAFs accelerate tumour growth
- myofibroblasts release stroma derived factor 1
- this chemokine recruits endothelial progenitor cells into the tumour stroma
- myofibroblasts release VEGF
- this growth factor induces differentiation of recruited cells into endothelial cells
- the resulting access to the circulation then facilitates tumour growth
- the density of myofibroblasts in the tumour stroma is correlated with aggressiveness of disease in some cancers
- this suggests that CAFs play a critical role in driving aggressive tumour growth
what do macrophages release
- secrete MMPs
- release mitogenic and angiogenic factors
mechanisms of aquired resistant to anti- angiogenesis therapy
endothelial cell radioresistance: hypoxic activation of HIF-1 renders endothelial cells resistant to irradiation
vacular mimicry: a fraction of tumour vessels are lined by malignant cells and are thus unresponsive to anti-angiogenic agents
anagiogenic switch - the outgrowth of tumour cell clones expressing elevated levels of certain angiogenic factors may be naturally favoured
vascular independence: mutant tumour cell clones are able to survive in hypoxic tumours
stromal cells: VEGF null tumours recruit pro angiogenic stromal cells such as as myofibroblasts via upregulation of PDGF-A and myeloid cells
how can pericytes cause resistance to anti angiogenesis therapy
pre existing vessels are covered by a full complement of supporting pericytes so not readily pruned by anti-angiogenic drugs
targeting pericytes
pericytes provide survival functions to endothelial cells
- endothelial cells are partially resistant to VEGF-R inhibition and are less sensitive to chemotherapy
- targeting pericytes via PDGF receptor inhibitors
- causes impaired support or protection by pericytes
- so endothelial cells are very sensitive to VEGF-R inhibition and chemotherapy
anti VEGF-R drug SU5416
able to block early stage angiogenic switch
no effect on late stage, well established tumours
anti PDGF - R drug SU6668
relatively weak at preventing early stage angiogenic switch
far more potent than anti VEGF-R drug SU5416 in treating advanced tumours
combination of these drugs more effective in reducing tumour volume
anti PDGF - R drug SU6668 and anti VEGF-R drug SU5416
both have been abandoned clinically because of limited efficacy in phase II or phase III clinical trials
this demonstrates the limited power of mouse models of cancer pathogenesis to predict human clinical responses
the effects of the SASP depending on tumour stage
- in pre-cancerous tissues, the effects of the SASP are predominantly tumour-suppressive
- major tumour - suppressive effects including autocrine and paracrine senescence and induction of immunosurveillance
- in advanced cancerous tissues, the SASP factors from stromal cells such as CAFs can promote tumour growth
Senolytic drugs in cancer therapy
- the modes of action of major senolytic drugs exhibiting confirmed anti cancer activites
- senolytic drugs are currently ebing developed to target senescent cells to eliminate their deleterious effects
