Monday Article #19: Tumour Angiogenesis- Formation of New Blood Vessels in Cancer

Angiogenesis is the formation of new blood vessels from pre-existing vessels. It continues the growth of blood vessels to enable blood supply to larger area of cells. Angiogenesis can occur in health (normal growth and development, wound healing) and diseases such as chronic inflammatory disease and cancer. Tumour angiogenesis will be the focus in this article.

Tumour cells, like all normal cells, require nutrients and oxygen to grow and proliferate as well as removing waste product effectively. A tumour can grow up to 1 - 2 mm3 before going dormant without blood supply. The initiation of formation of new blood vessels from stimulation of pro-angiogenic signalling such as VEGF, angiopoietin and FGF is known as angiogenic switch (Figure 1). Here, the pro-angiogenic signalling becomes dominant to initiate blood vessels formation thus leading to increased growth of tumour cells.

Figure 1 This shows the process of a tumour from being dormant into a developing tumour with vasculature.

Unlike normal physiological angiogenesis for growth and wound healing which are tightly regulated, tumour angiogenesis is dysregulated due to pro-angiogenic signalling becoming constitutively active to stimulate constant growth of tumour blood vessels.

Tumour vasculature are often heterogenous and poorly organized with lack of definite structure of arterioles, capillaries and venules as the constantly forming blood vessels fail to mature. This lead to uneven blood flow and also reduce the efficacy of cancer therapy as most drug delivery are through blood circulation.

Factors regulating Angiogenesis:

There are several factors that regulates tumour angiogenesis, this article will touch on pro-angiogenic factors (VEGF and angiopoietin) and hypoxia.

1. Vascular endothelial growth factor (VEGF) The VEGF family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PIGF) but the major mediator of tumour angiogenesis is VEGF-A. VEGF-A is upregulated when stimulated and binds to VEGF receptor (VEGFR-2) that is highly expressed by blood vessels endothelial cells. Binding of VEGF-A to VEGFR-2 stimulates several pathways leading to increased vascular permeability and vasodilation to allow extravasation of plasma protein. Plasma protein will help in the laying down of a structure for activated endothelial cells to migrate to. VEGF also induces the expression of matrix metalloproteinase (MMP) for the degradation of basal membrane and extracellular matrix to allow migration of endothelial cells and the formation of new capillary sprouts.
   

2. Angiopoietin Angiopoietin works together with VEGF to stabilize new blood vessels. It plays a role in controlling tumour growth and angiogenesis by binding to tyrosine kinase receptor (TIE-2) to induce pre-existing vessel destabilization and pericyte detachment. Pericyte detachment will guide the migration of endothelial cells. Angiopoietin-2 expression is increased in response to hypoxia and VEGF in cancers.
   

3. Hypoxia Due to the increased mass of tumour and lack of blood supply, tumour cells will experience hypoxia which induces the production of pro-angiogenic factors for enhanced blood vessels formation. This is mediated by hypoxia-inducible factors (HIFs) consisting of 2 subunits (HIF-α and HIF-β). HIFs binds to the hypoxia response element on DNA which then induce transcription of VEGF and angiopoietin among others for angiogenesis.

Immune system’s contributions to tumour angiogenesis

The tumour microenvironment consists of a large array of cell types including immune cells such as macrophages. Tumour-associated macrophages (TAMs) in the tumour microenvironment have different phenotypes compared to normal macrophages in which they support and modulate angiogenesis development. TAMs modulate angiogenesis by producing VEGF and releasing angiogenesis-stimulating molecules such as MMPs.

Other immune cells that play a role in angiogenesis includes neutrophils which is a main source of VEGF production and B cells which modulate tumour angiogenesis when STAT3 is activated and expressed on B cells.

Anti-angiogenic therapy:

As tumour cells require blood supply to continue to proliferate, there are several anti-angiogenic therapies aimed to inhibit tumour angiogenesis. Most treatment targets the VEGF signalling pathways such as bevacizumab, sunitinib and cabozantinib. However, these have only been shown limited benefits to some cancers such as liver cancer and colorectal cancer but does not show efficacy in prostate cancer, breast cancer or melanoma. There are also drugs that target the mTOR pathway with anti-angiogenic effects such as everolimus to treat renal cancer and breast cancer. Unfortunately, prolonged treatment using anti-angiogenic therapies causes tumour cells to become resistant towards this treatment which provides an explanation to the various and poor response towards anti-angiogenic therapy.

References:

1. Bergers, G., Benjamin, L. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3, 401–410 (2003). https://doi.org/10.1038/nrc1093

2. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039-2049. doi:10.1056/NEJMra0706596

3. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. 2020;77(9):1745-1770. doi:10.1007/s00018-019-03351-7

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This article was prepared by Jennifer Chang