Department of Urology, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan.
Department of Health Sciences, Prefectural University of Hiroshima, Hiroshima, Japan.
Cancer Med. 2017 Oct;6(10):2308-2320. doi: 10.1002/cam4.1124. Epub 2017 Aug 23.
Tumor growth and metastasis are determined not by cancer cells alone but also by a variety of stromal cells, various populations of which overexpress platelet-derived growth factor receptors (PDGF-Rs). In addition, activation of PI3K-AKT-mammalian target of rapamycin (mTOR) signaling is frequently observed in many cancer types as well. mTOR comprises a serine/threonine kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. In this study, we investigated the impact of molecular-targeting agents including PDGF-R and mTOR inhibitors on the tumor stroma of human kidney cancer and examined the efficacy of combination therapy with these agents against this disease. Treatment with sunitinib did not suppress tumor growth, but significantly decreased stromal reactivity, microvessel density, and pericyte coverage of tumor microvessels in an orthotopic mouse model. In contrast, treatment with everolimus decreased tumor growth and microvessel density but not stromal reactivity. However, sunitinib and everolimus in combination reduced both the growth rate and stromal reaction. These findings suggest that target molecule-based inhibition of the cancer-stromal cell interaction appears promising as an effective antitumor therapy.
肿瘤的生长和转移不仅取决于癌细胞，还取决于多种基质细胞，其中各种细胞群体过度表达血小板衍生生长因子受体 (PDGF-Rs)。此外，PI3K-AKT-雷帕霉素靶蛋白 (mTOR) 信号通路的激活在许多癌症类型中也经常观察到。mTOR 由一种丝氨酸/苏氨酸激酶组成，它会增加刺激关键细胞过程的蛋白质的产生，如细胞生长和增殖、细胞代谢和血管生成。在这项研究中，我们研究了包括 PDGF-R 和 mTOR 抑制剂在内的分子靶向药物对人类肾癌肿瘤基质的影响，并检查了这些药物联合治疗这种疾病的疗效。舒尼替尼治疗并没有抑制肿瘤生长，但在原位小鼠模型中，显著降低了基质反应性、微血管密度和肿瘤微血管周细胞的覆盖率。相比之下，依维莫司治疗降低了肿瘤生长和微血管密度，但没有降低基质反应性。然而，舒尼替尼和依维莫司联合使用可降低生长速度和基质反应。这些发现表明，基于靶向分子的抑制肿瘤-基质细胞相互作用似乎是一种有效的抗肿瘤治疗方法。
