Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2784-9. doi: 10.1073/pnas.1018866109. Epub 2012 Jan 23.
Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.
抗血管生成治疗被认为对癌症的治疗具有重要的潜力。然而，最近的临床试验显示，抗血管生成药物在延长患者生存方面的疗效有限，这使得此类治疗方法的疗效，特别是在乳腺癌患者中的疗效受到了质疑。使用临床前模型的新研究进一步表明，抗血管生成药物实际上会增加乳腺癌细胞的侵袭性和转移性。我们证明，通过在人乳腺癌异种移植瘤中产生肿瘤内缺氧，抗血管生成药物舒尼替尼和贝伐珠单抗增加了癌症干细胞的数量。体外研究表明，缺氧驱动的干细胞/祖细胞富集主要是由缺氧诱导因子 1α介导的。我们进一步表明，在体外缺氧条件下以及在舒尼替尼治疗的小鼠异种移植瘤中，Akt/β-catenin 癌症干细胞调节途径在乳腺癌细胞中被激活。这些研究表明，缺氧驱动的癌症干细胞刺激限制了抗血管生成药物的有效性，并表明为了改善患者的预后，这些药物可能需要与针对癌症干细胞的药物联合使用。
