By Themis Halka
In recent years, the role of vasculature in tumours has drawn great interest. Vasculature has key roles in growth and survival, through transport of nutrients and oxygen. In the past, strategies to prevent tumour growth have focused on preventing development of vasculature– but a new focus of research now aims to restore normal vasculature in the tumour environment.
The vasculature in tumours is highly abnormal.1 Normal angiogenesis results in mature blood vessels, where all the appropriate cells have been recruited in an organised fashion – but this is not the case for tumour angiogenesis. Tumour vasculatures are in general highly disorganised, irregularly shaped, excessively branched and leaky.2 This is due to abnormal cell-cell attachment between endothelial cells and the basement membrane, whose composition is often altered in the tumour microenvironment.1 Numerous factors are involved in this abnormal vasculature development in tumours; however one cell type in particular has emerged as a key potential regulator of this angiogenic process: pericytes.
Pericytes can be described as mural cells that are embedded in the endothelial basement membrane.1 They play a supportive role that is crucial to angiogenesis, promoting stabilisation and maturation of the vasculature. In fact, their strong interaction with endothelial cells is thought to be involved in the progression and remodelling of the vasculature, the stability and cohesion of the endothelial cell lining, and also in the recruitment of the necessary elements in the basement membrane.3 In various tumour vasculatures, pericytes have been found to be abnormally recruited. They were more disorderly arranged, showing an altered morphology and a looser vessel attachment.3 This abnormality is likely to have an impact on their function of maturing and stabilising the blood vessels. Therefore, pericytes gradually emerge as a target for cancer therapy: restoring their recruitment and function could help ensure the normality of the tumour vasculature.
Vasculature normalisation consists in restoring the normal structure and function in blood vessels.4 This is an emerging concept in cancer therapy, particularly as it has been discovered that the leaky and disorganised vasculature in tumours is a driver of metastasis. In order to metastasise, or migrate to other sites in the body, one strategy tumour cells deploy is to use the blood vessels for transport. To achieve that, tumour cells first need to enter the blood vessels, by a process named intravasation. This intravasation is facilitated by the abnormally leaky tumour vasculature.3
To initiate metastasis, tumour cells need to undergo endothelial to mesenchymal transition (EMT) which allows them to detach and become motile. This differentiation can be initiated by a combination of factors, such as hypoxia. Hypoxia, the depletion of oxygen delivery to tissue, is present in numerous tumour vasculatures due to the irregular shape and abnormal organisation of the tumour.4 While some regions of the tumour will be importantly vascularised, other regions will receive only few nutrients and oxygen: this will drive their transition to the mesenchymal phenotype and help them to start migrating.
Normalising the vasculature could therefore help reduce the permeability of blood vessels and maintain a steady oxygenation of the tumour cells. This would reduce metastasis, but also improve the effects of existing cancer therapies, like chemotherapy and radiotherapy, by allowing easier access to the tumour cells.4
Pericytes are a thoroughly investigated target for tumour vasculature normalisation. In fact, redeveloping an appropriate pericyte recruitment and coverage could promote normalised tumour vascularisation which would support the steady oxygenation of tissue, reducing hypoxia.5 In addition, enhancing pericyte recruitment could also strengthen the endothelial lining of blood vessels, thereby reducing the leakage of blood vessels and blocking tumour cells from accomplishing intravasation. Several studies in this area support this theory: in colorectal and renal cancers for example, an elevated micro-vessel pericyte coverage was found to correlate with a well-differentiated tumour with low rates of distant metastasis, and an improved overall survival.6
Several targets for enhancing pericyte recruitment are being investigated. Pericyte recruitment is influenced by numerous factors. PDGF, released by endothelial cells, is an important driver of pericyte recruitment.7 The delivery of PDGF agonists could potentially help the development of mature blood vessels. Another protein with an interesting role in recruiting pericytes is Angiopoietin 1. It contributes to recruiting pericytes through binding with the Tie-2 receptor expressed by pericytes. However, in the tumour environment, Angiopoietin 1 is in competition with Angiopoietin 2, an antagonist to the Tie-2 receptor. Angiopoietin 2 secretion is regulated by cancer-derived modulators, and causes reduced binding of Angiopoietin 1 with Tie-2 in tumours. Inhibiting Angiopoietin 2 in the tumour environment could help maintain pericyte coverage by allowing Angiopoietin 1 to interact with Tie-2.1,7
Promoting pericyte recruitment aims to normalise the tumour vasculature. However, as mentioned, this opposes strategies that target tumour vasculature: the anti-angiogenic therapies, which aim to prevent angiogenesis. Anti-angiogenic therapies are often based on preventing endothelial cells from dividing and sprouting to generate new vessels.1 This can be partially achieved by blocking the release of vascular endothelial growth factor (VEGF) which stimulates endothelial cells. However, as pericytes can release VEGF, they often oppose the effect of anti-angiogenic therapies.8 It is therefore necessary to choose between enhancing or inhibiting pericyte coverage. Put simply, it is a question of timing, where therapies are chosen depending on whether it is appropriate to prevent angiogenesis, or metastasis.
Normalising tumour vasculature through targeting pericytes is a promising target. This relatively new approach of enhancing pericyte function in cancer patients offers new possibilities to prevent metastasis – for example, in cases where angiogenesis has already occurred, and the tumour is vascularised. Preclinical/clinical trials are currently being undertaken to better control this therapeutic strategy, and to better understand its medical implications. Whilst deployment to cancer patients may not be seen for some time, there is great excitement for this target in addressing tumour metastasis.
References:
- Chen Z, Xu XH, Hu J. Role of pericytes in angiogenesis: focus on cancer angiogenesis and anti-angiogenic therapy. Neoplasma. 2016;63(2):173-82. doi: 10.4149/201_150704N369. PMID: 26774138.
- Ruoslahti E. Specialization of tumour vasculature. Nature Reviews Cancer. 2002; vol. 2, pp. 83–90.
- Ribeiro A, Okamoto O. Combined Effects of Pericytes in the Tumour Microenvironment. Stem Cells International. 2015.
- Meng MB, Zaorsky N, Deng L, Wang HH, Chao J, Zhao LJ et al. Pericytes: a double-edged sword in cancer therapy. Future Oncology 2015: 11(1); 169-179.
- Goel S, Duda DG, Xu L, Munn LL, Boucher Y et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 2011; 91: 1071–1121. http://dx.doi. org/10.1152/physrev.00038.2010
- Yonenaga Y, Mori A, Onodera H et al. Absence of smooth muscle actin-positive pericyte coverage of tumour vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncolog. 2005: 69(2); 159–166.
- Kang E, Shin JW. Pericyte-targeting drug delivery and tissue engineering. Int J Nanomedicine. 2016;11:2397-2406. Published 2016 May 27. doi:10.2147/IJN.S105274
- Raza A, Franklin MJ, Dudek AZ. Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol 2010; 85: 593–598. http://dx.doi.org/10.1002/ ajh.21745
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