新生血管化是癌症治疗的关键治疗靶点。然而，抗血管生成疗法的成功效果有限，因为肿瘤通过激活多余的血管生成通路快速产生耐药性。我们假设同时针对新生血管生成的不同通路将避免当前的耐药性问题，并提供增强的治疗效果。为了测试这一假设，我们利用了两个不同的肿瘤新生血管生成模型，这些模型展示了同样密集的微血管结构，但对抗SDF-1治疗的敏感性存在差异。刘易斯肺癌（LLC）主要是一种由HSC作为hemangioblast功能生成的循环内皮祖细胞，有助于形成新的血管，对抗SDF-1治疗有反应。B16F0黑色素瘤是一种从现有血管生成新的血管的血管生成性肿瘤，对抗SDF-1治疗具有耐药性。在这项研究中，我们观察到具有血管生成因子Robo1的表达增加，它主要表达在B16F0肿瘤的血管上。通过假受体RoboN阻断Robo1，导致微血管密度和肿瘤生长降低。然而，这与BM细胞进入B16F0肿瘤相关，从而将新生血管成形的方式从血管生成性变为血管发生性。使用RoboN和单克隆抗SDF-1抗体的联合治疗有效地减缓了肿瘤生长并抑制了血管生成和BM源微血管。 © 2023。作者在Springer Science+Business Media，LLC的专有许可下，隶属于Springer Nature。

Neovascularization is a key therapeutic target for cancer treatment. However, anti-angiogenic therapies have shown modest success, as tumors develop rapid resistance to treatment owing to activation of redundant pathways that aid vascularization. We hypothesized that simultaneously targeting different pathways of neovascularization will circumvent the current issue of drug resistance and offer enhanced therapeutic benefits. To test this hypothesis, we made use of two distinct models of tumor-neovascularization, which exhibit equally dense microvasculature but show disparate sensitivity to anti-SDF-1 treatment. Lewis lung carcinoma (LLC) is primarily a vasculogenic-tumor that is associated with HSC functioning as a hemangioblast to generate circulating Endothelial Progenitor Cells contributing to formation of new blood vessels, and responds to anti-SDF-1 treatment. B16F0 melanoma is an angiogenic-tumor that derives new blood vessels from existing vasculature and is resistant to anti-SDF-1 therapy. In this study, we observed increased expression of the angiogenic-factor, Robo1 predominantly expressed on the blood vessels of B16F0 tumor. Blockade of Robo1 by the decoy receptor, RoboN, resulted in reduced microvascular-density and tumor-growth. However, this was associated with mobilization of BM-cells into the B16F0 tumor, thus switching the mode of neovascularization from angiogenic to vasculogenic. The use of a combinatorial treatment of RoboN and the monoclonal anti-SDF-1 antibody effectively attenuated tumor-growth and inhibited both angiogenic and BM-derived microvessels.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.