Shenoy Anitha K, Pi Liya, Ligocki Alexander P, Hosaka Koji, Cogle Christopher R, Scott Edward W
Program in Stem Cell Biology and Regenerative Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
Stem Cell Rev Rep. 2023 May;19(4):928-941. doi: 10.1007/s12015-022-10498-7. Epub 2023 Jan 18.
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.
新生血管形成是癌症治疗的关键治疗靶点。然而，抗血管生成疗法的成效有限，因为肿瘤会因激活有助于血管生成的冗余通路而迅速产生耐药性。我们假设同时靶向新生血管形成的不同通路将规避当前的耐药问题，并提供更大的治疗益处。为了验证这一假设，我们使用了两种不同的肿瘤新生血管形成模型，它们具有同样密集的微血管，但对抗SDF-1治疗表现出不同的敏感性。刘易斯肺癌（LLC）主要是一种血管生成性肿瘤，与造血干细胞作为成血管细胞发挥作用有关，可产生循环内皮祖细胞，有助于新血管的形成，并对抗SDF-1治疗有反应。B16F0黑色素瘤是一种血管生成性肿瘤，它从现有血管系统中获取新血管，并且对抗SDF-1治疗耐药。在本研究中，我们观察到血管生成因子Robo1的表达增加，其主要表达于B16F0肿瘤的血管上。通过诱饵受体RoboN阻断Robo1可导致微血管密度降低和肿瘤生长减缓。然而，这与骨髓细胞向B16F0肿瘤的动员有关，从而使新生血管形成模式从血管生成转变为血管发生。联合使用RoboN和单克隆抗SDF-1抗体可有效减缓肿瘤生长，并抑制血管生成和骨髓来源的微血管。
