TME and balancing tumour growth 2

• Describe the dual action of TGF-beta in tumours

  Tumour suppressor in pre-malignant cells:

  • Promotes apoptosis and inflammation

  Tumour promoter in overtly malignant cells:

  • LOF mutation in TGF-beta receptor or SMAD pathway allows cancer cells to avoid the tumour suppressive effects of TGF-beta and promotes invasiveness and immune evasion
• How do CAFs accelerate tumour growth?

  • Myofibroblasts release stroma derived growth factor 1, which recruits endothelial progenitor cells into the tumour stroma
  • Myofibroblasts release VEGF, which induces differentiation of recruited cells into endothelial cells, which then form the tumour neovasculature
  • The resulting access to the circulation then facilitates tumour growth
• How do tumour cells acquire resistance to anti-angiogenesis therapy?

  • Vascular mimicry: a fraction of tumour vessels are lined by malignant cells and thus unresponsive to anti-angiogenic agents.
  • Stromal cells: VEGF null tumours recruit pro-angiogenic stromal cells such as myofibroblasts via upregulation of PDGF-A and myeloid cells
  • Mature robust vessels: pre-existing vessels are covered by a full complement of supporting Pericytes, which are not so readily pruned by anti-angiogenic drugs
• Describe VEGF-R inhibition

  Endothelial cells are partially resistant to VEGF-R inhibition and therefore less sensitive to chemotherapy. Instead VEGF-R inhibitors target Pericytes, which impaired their protection to endothelial cells, making endothelial cells more sensitive to chemotherapy.
• Describe combination therapies

  Anti-VEGF-R drugs are able to block early stage angiogenic switch and anti-PDGF-R drugs are most potent as treating advanced tumours. When used in combination, they can decrease tumour volume by a greater amount than when used independently in mouse models.
• Describe senolytic drugs in cancer therapy

  This is a certain class of drug that induces cell death in senescent cells and are currently being developed to target senescent cells to eliminate their deleterious effects.