Tumour vessel remodelling: new opportunities in cancer treatment

Abstract

Tumour growth critically depends on a supportive microenvironment, including the tumour vasculature. Tumour blood vessels are structurally abnormal and functionally anergic which limits drug access and immune responses in solid cancers. Thus, tumour vasculature has been considered an attractive therapeutic target for decades. However, with time, anti-angiogenic therapy has evolved from destruction to structural and functional rehabilitation as understanding of tumour vascular biology became more refined. Vessel remodelling or normalisation strategies which alleviate hypoxia are now coming of age having been shown to have profound effects on the tumour microenvironment. This includes improved tumour perfusion, release from immune suppression and lower metastasis rates. Nevertheless, clinical translation has been slow due to challenges such as the transient nature of current normalisation strategies, limited in vivo monitoring and the heterogeneity of primary and/or metastatic tumour environments, calling for more tailored approaches to vascular remodelling. Despite these setbacks, harnessing vascular plasticity provides unique opportunities for anti-cancer combination therapies in particular anti-angiogenic immunotherapy which are yet to reach their full potential.

Keywords: angiogenesis; cancer and tumours; cancer immunotherapy; extracellular matrix; vessel normalisation.

Figure 1

Distinct cellular features of wild type and normalised tumour blood vessels. Tumour blood vessels consist of endothelial cells (inner layer) and, vascular smooth muscle cells or pericytes (outer layer) which are embedded in basement membrane. (A, left) Representative image of a tumour blood vessel featuring disrupted endothelial cell lining (CD31 endothelial marker in red, arrow heads indicated endothelial gaps) and pericytes (desmin pericyte marker in green) protruding into tumour parenchyma as indicated by arrows. (A, right) Representative image of a normalised tumour blood vessel consistent of compact CD31⁺ endothelium and closely aligned desmin⁺ pericytes. Here, normalisation of the entire vascular bed was achieved by changing the maturity of pericytes only. Confocal images, magnification, 60×. (B, left) Schematic representation of a ‘leaky’ tumour blood vessel featuring endothelial cell gaps and irregularly attached pericytes. (B, right) Schematic representation of a normalised tumour blood vessel with closely aligned endothelial cells and pericytes embedded in basement membrane.

Figure 2

Vessel remodelling strategies to increase tumour perfusion and immune cell penetration. (Left) Therapeutic approaches which aim to destroy or remodel highly angiogenic tumour blood vessels. These approaches are not necessarily mutually exclusive; vessel normalisation and decompression can result in vessel death, and remaining vessels can be normalised during anti-angiogenesis therapy, and induction of high endothelial venules (HEVs) is facilitated on a background of normalised vessels. (Right) Schematic representation of vascular plasticity following therapy and implications for immune cell infiltration. Vascular decompression therapy enlarges blood vessels by alleviating pressure from surrounding extracellular matrix/basement membrane which increases blood flow and potentially immune cell infiltration. Anti-angiogenesis therapy prunes highly proliferative tumour vessels leading to overall blood vessel loss, increase in hypoxia and reduced adaptive immune responses. Vessel normalisation therapy induces a homogeneous vascular network of more quiescent/mature vessels which facilitate infiltration of anti-cancer immune cells. Tertiary lymph node structures, including HEVs, can be therapeutically induced on a background of normalised tumour vessels which increase influx and functionality of adaptive immune cells in the tumour microenvironment.