Thaker Premal H, Han Liz Y, Kamat Aparna A, Arevalo Jesusa M, Takahashi Rie, Lu Chunhua, Jennings Nicholas B, Armaiz-Pena Guillermo, Bankson James A, Ravoori Murali, Merritt William M, Lin Yvonne G, Mangala Lingegowda S, Kim Tae Jin, Coleman Robert L, Landen Charles N, Li Yang, Felix Edward, Sanguino Angela M, Newman Robert A, Lloyd Mary, Gershenson David M, Kundra Vikas, Lopez-Berestein Gabriel, Lutgendorf Susan K, Cole Steven W, Sood Anil K
Department of Gynecologic Oncology, University of Texas (U.T.) M.D. Anderson Cancer Center, 1155 Herman Pressler, Unit 1362, Houston, Texas 77030, USA.
Nat Med. 2006 Aug;12(8):939-44. doi: 10.1038/nm1447. Epub 2006 Jul 23.
Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.
应激可改变免疫、神经化学和内分泌功能，但其在癌症进展中的作用尚未完全明确。在此，我们表明，在原位小鼠模型中，慢性行为应激会导致组织儿茶酚胺水平升高、肿瘤负荷增加以及卵巢癌细胞侵袭性生长增强。这些效应主要通过β₂肾上腺素能受体（由ADRB2编码）激活肿瘤细胞环磷酸腺苷（cAMP）-蛋白激酶A（PKA）信号通路介导。应激动物体内的肿瘤显示血管生成显著增加，血管内皮生长因子（VEGF）、基质金属蛋白酶2（MMP2）和基质金属蛋白酶9（MMP9）的表达增强，并且我们发现血管生成过程介导了应激对体内肿瘤生长的影响。这些数据确定cAMP-PKA信号通路的β-肾上腺素能激活是行为应激在体内增强肿瘤血管生成从而促进恶性细胞生长的主要机制。这些数据还表明，阻断ADRB介导的血管生成可能对卵巢癌的治疗具有重要意义。
