Abstract
Blocking tumor vascularization has not yet come to fruition to the extent it was hoped for, as angiogenesis inhibitors have shown only partial success in the clinic. We hypothesized that under-appreciated vascular wall-resident stem and progenitor cells (VW-SPCs) might be involved in tumor vascularization and influence effectiveness of anti-angiogenic therapy. Indeed, in patient samples, we observed that vascular adventitia-resident CD34+ VW-SPCs are recruited to tumors in situ from co-opted vessels. To elucidate this in detail, we established an ex vivo model using concomitant embedding of multi-cellular tumor spheroids (MCTS) and mouse aortic rings (ARs) into collagen gels, similar to the so-called aortic ring assay (ARA). Moreover, ARA was modified by removing the ARs’ adventitia that harbors VW-SPCs. Thus, this model enabled distinguishing the contribution of VW-SPCs from that of mature endothelial cells (ECs) to new vessel formation. Our results show that the formation of capillary-like sprouts is considerably delayed, and their number and network formation were significantly reduced by removing the adventitia. Substituting iPSC-derived neural spheroids for MCTS resulted in distinct sprouting patterns that were also strongly influenced by the presence or absence of VW-SPCs, also underlying the involvement of these cells in non-pathological vascularization. Our data suggest that more comprehensive approaches are needed in order to block all of the mechanisms contributing to tumor vascularization.
Highlights
In order to sustain their continuous growth, tumors have to secure an adequate supply of nutrients and oxygen by inducing vascularization processes
As a first step to investigate the role of adventitial cells on tumor vascularization, we examined histological sections of human tumors by immunohistological staining for
CD34 is a reliable marker for monitoring adventitial vascular wall-resident stem and progenitor cells (VW-SPCs), as the majority of these cells express CD34 but down-regulate it to some extent when they detach from the adventitial niche [8,12]
Summary
In order to sustain their continuous growth, tumors have to secure an adequate supply of nutrients and oxygen by inducing vascularization processes. Under certain conditions, other forms of vascularization can significantly contribute to maintaining tumor supply; Paez-Ribes et al have shown that when angiogenesis is blocked, glioma cells invade into the surrounding parenchyma along existing blood vessels under anti-angiogenics, thereby co-opting these vessels for their metabolic needs [6]. Under therapy-induced acute hypoxic stress, tumors secrete high levels of cytokines like VEGF-A and SDF-1 that mobilize endothelial progenitor cells (EPCs) from the bone marrow [7]. This vasculogenic rescue restores, in parts, tumor perfusion faster than possible with angiogenic sprouting. The contribution of alternative cellular sources to vascularization processes can render anti-angiogenic approaches ineffective, and switching to alternate vascularization pathways can provide an escape mechanism
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