Gray Institute for Radiation Oncology and Biology, Oxford University, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK.
Cancer Metastasis Rev. 2012 Dec;31(3-4):823-42. doi: 10.1007/s10555-012-9394-4.
Tumor cells exploit their microenvironment by growth factors and cytokines such as vascular endothelial growth factor (VEGF) to stimulate abnormal vessel formation that is leaky and tortuous, causing irregular blood flow. The combination of poor perfusion, raised interstitial fluid pressure and areas of vascular collapse leads to hypoxia within tumor. The latter activates factors such as hypoxia inducible factor 1 (HIF-1) that serve to make cancer cells more aggressive and also markedly influences the response of malignant tumors to conventional irradiation and chemotherapy. Accumulating data now suggest that blockade of oncogenic signaling, for example by PI3K/Akt/mTOR inhibitors, might consist a promising strategy since these agents do not only possess antitumor effects but can also alter tumor vasculature and oxygenation to improve the response to radiation and chemotherapy. In many cases, these changes are related to downregulation of HIF-1α and VEGF. Here, we review the pathophysiology of tumor microenvironment (TME) and how it adversely affects cancer treatment. The complex interaction of tumor vasculature and radiotherapy is examined together the preclinical evidence supporting a proinvasive/metastatic role for ionising radiation. We will discuss the expanding role of oncogenic signaling, especially PI3K/Akt/mTOR, on tumor angiogenesis. Special emphasis will be paid to the potential of different oncogenic pathways blockade and other indirect antivascular strategies to alter the TME for the benefit of cancer treatment, as an alternative to the classical angiogenetic treatment.
肿瘤细胞通过生长因子和细胞因子（如血管内皮生长因子[VEGF]）来利用其微环境，刺激异常的血管形成，这些血管是渗漏和扭曲的，导致血流不规则。灌注不良、间质液压力升高和血管塌陷区域的组合导致肿瘤内缺氧。后者激活了缺氧诱导因子 1（HIF-1）等因素，使癌细胞更具侵袭性，并且还显著影响恶性肿瘤对常规放疗和化疗的反应。越来越多的证据表明，阻断致癌信号，例如通过 PI3K/Akt/mTOR 抑制剂，可能是一种有前途的策略，因为这些药物不仅具有抗肿瘤作用，而且可以改变肿瘤血管和氧合作用，从而提高对放疗和化疗的反应。在许多情况下，这些变化与 HIF-1α 和 VEGF 的下调有关。在这里，我们回顾了肿瘤微环境（TME）的病理生理学以及它如何对癌症治疗产生不利影响。我们一起检查了肿瘤血管与放疗的复杂相互作用，并支持电离辐射具有促进侵袭/转移作用的临床前证据。我们将讨论致癌信号，特别是 PI3K/Akt/mTOR 的作用在肿瘤血管生成中的扩展作用。特别强调不同致癌途径阻断和其他间接抗血管生成策略的潜力，以改变 TME ，从而使癌症治疗受益，作为经典血管生成治疗的替代方法。
