Institute of Anatomy and Cell Biology, Julius-Maximilians-University, 97070 Würzburg, Germany.
Institute of Pathology, Julius-Maximilians-University, 97070 Würzburg, Germany.
Cells. 2021 Jul 7;10(7):1719. doi: 10.3390/cells10071719.
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.
阻断肿瘤血管生成的效果并不如预期，因为血管生成抑制剂在临床上仅取得部分成功。我们假设，被低估的血管壁驻留的干细胞和祖细胞（VW-SPCs）可能参与肿瘤血管生成，并影响抗血管生成治疗的效果。事实上，在患者样本中，我们观察到血管外膜驻留的 CD34 VW-SPCs 从被募集的血管原位招募到肿瘤中。为了详细阐明这一点，我们建立了一种使用多细胞肿瘤球体（MCTS）和小鼠主动脉环（AR）同时嵌入胶原凝胶的体外模型，类似于所谓的主动脉环测定（ARA）。此外，ARA 通过去除含有 VW-SPCs 的 AR 外膜进行了修改。因此，该模型能够区分 VW-SPCs 与成熟内皮细胞（ECs）对新血管形成的贡献。我们的结果表明，去除外膜会显著延迟毛细血管样芽的形成，并且其数量和网络形成明显减少。用 iPSC 衍生的神经球体代替 MCTS 会导致明显不同的发芽模式，而 VW-SPCs 的存在与否也会强烈影响这些模式，这也表明这些细胞参与了非病理性血管生成。我们的数据表明，需要更全面的方法来阻断所有参与肿瘤血管生成的机制。
