Melanoma Tumour Vascularization and Tissue-Resident Endothelial Progenitor Cells

Abstract

The aggressiveness of solid cancers, such as melanoma, relies on their metastatic potential. It has become evident that this key cause of mortality is largely conferred by the tumour-associated stromal cells, especially endothelial cells. In addition to their essential role in the formation of the tumour vasculature, endothelial cells significantly contribute to the establishment of the tumour microenvironment, thus enabling the dissemination of cancer cells. Melanoma tumour vascularization occurs through diverse biological processes. Vasculogenesis is the formation of de novo blood vessels from endothelial progenitor cells (EPCs), and recent research has shown the role of EPCs in melanoma tumour vascularization. A more detailed understanding of the complex role of EPCs and how they contribute to the abnormal vessel structures in tumours is of importance. Moreover, anti-angiogenic drugs have a limited effect on melanoma tumour vascularization, and the role of these drugs on EPCs remains to be clarified. Overall, targeting cancer vasculature remains a challenge, and the role of anti-angiogenic drugs and combination therapies in melanoma, a focus of this review, is an area of extensive exploration.

Lymphatic expression of the proliferation marker Ki67 is linked to sentinel node positivity, recurrence and mortality in primary cutaneous melanoma

“…In our secondary analyses, the association between D2‐40 + /Ki67 + positivity and melanoma‐specific mortality only held in SLN‐negative patients, potentially because SLN‐positive tumours‐by virtue of having disseminated already—are not further distinguished by explicit confirmation of new lymphatic vessels. Notably, CD31 + /Ki67 + expression was not prognostic in this cohort, and it is plausible that investigation of immature endovascular progenitors or endothelial‐mesenchymal transition would provide more insight into tumour‐related angiogenesis than proliferation assays alone 13,14 …”

“…12 Tumour vascularization can also be driven by hypoxia-independent mechanisms, and frequently involves non-angiogenic processes, such as vasculogenesis and vasculogenic mimicry. 13,14 Although thicker melanomas generally exhibit higher levels of vascular 15,16 and lymphatic 17,18 vessel density than thin melanomas, there is considerable variation in the extent of lymphovascularity among individual tumours. 12 Therefore, a potential approach to risk stratification involves evaluation of the tumour vasculature through endothelial markers such as CD31 (general endothelium, with higher specificity towards vascular endothelium) and D2-40 (podoplanin; specific to lymphatic endothelium).…”

“…Notably, CD31 + /Ki67 + expression was not prognostic in this cohort, and it is plausible that investigation of immature endovascular progenitors or endothelial-mesenchymal transition would provide more insight into tumour-related angiogenesis than proliferation assays alone. 13,14 The majority of previous studies in this field have focused on either lymphovascular invasion 29,30 or single-marker measures of lymphovascular density, including CD31, 21 D2-40, 17 FGF2, 31 and VEGF-C. 16 By comparison, our use of Ki67 as a complement to existing endothelial markers enables differentiation of active tumour lymphangiogenesis from the quiescent physiological vasculature. 32 In a similar study on D2-40 + /Ki67 + and CD34 + /Ki67 + co-expression in melanoma, Pastushenko et al used the Chalkley method to identify the proportion of vascular or lymphatic endothelium with angiogenic potential.…”

“…Classically, hypoxia and chronic inflammation induce melanoma cells to secrete pro‐angiogenic mediators such as the fibroblast (FGF) and vascular endothelial growth factors (VEGF), which in turn stimulate extension of new blood and lymphatic vessels from the existing lymphovascular network 12 . Tumour vascularization can also be driven by hypoxia‐independent mechanisms, and frequently involves non‐angiogenic processes, such as vasculogenesis and vasculogenic mimicry 13,14 …”

Tumour associated endothelial cells: origin, characteristics and role in metastasis and anti-angiogenic resistance

“…Within the vasculature, tumour cells come into direct contact with tumour-associated endothelial cells (TECs). Tumour-endothelial interactions not only promote malignant vascularisation but also influence the proliferative and metastatic potential of the malignant cells ( Hashemi et al, 2022 ).…”