Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
Carcinogenesis. 2012 Jan;33(1):20-9. doi: 10.1093/carcin/bgr230. Epub 2011 Oct 21.
Omentum metastasis is a common occurrence in epithelial ovarian cancer (EOC), which is often accompanied by ascites that facilitates the spread of EOC cells. A subpopulation of fibroblasts-the cancer-associated fibroblasts (CAFs) are important promoters of tumor progression. We have shown previously that CAFs exist not only in omentum with EOC metastasis but also in omentum without metastasis. In the present study, using primary human fibroblasts isolated from normal omentum (NFs) and omentum with ovarian cancer metastasis (CAFs), we established in vitro coculture models and a 3D culture model mimicking human omentum structure for investigation of interactions between fibroblasts and cancer cells. We demonstrate that EOC cells activate NFs and promote their proliferation via transforming growth factor-β1 (TGF-β1) signaling, and the activated fibroblasts contribute to the invasion and adhesion of EOC cells. Moreover, EOC cells and NFs coculture led to overexpression of hepatocyte growth factor (HGF) and matrix metalloproteinase-2 (MMP-2) and adhesion and invasion of EOC cells could be partially suppressed by blocking the function of HGF or MMP-2. Additionally, mouse peritoneal dissemination models of EOC confirmed the activation of fibroblasts by cancer cells and the tumor growth- and metastasis-promoting effects of activated fibroblasts in vivo. Our findings indicate that activated fibroblasts in omentum form a congenial environment to promote EOC cells implantation. It is an intriguing concept that targeting the activation of omentum fibroblast through the inhibition of TGF-β1 signaling can be used as a new therapeutic strategy against ovarian cancer omentum metastases, which needs further study.
大网膜转移是上皮性卵巢癌（EOC）的常见现象，常伴有腹水，有利于 EOC 细胞的扩散。成纤维细胞的一个亚群——癌症相关成纤维细胞（CAFs）是肿瘤进展的重要促进者。我们之前已经表明，CAFs 不仅存在于有 EOC 转移的大网膜中，也存在于没有转移的大网膜中。在本研究中，我们使用从正常大网膜（NFs）和卵巢癌转移的大网膜（CAFs）中分离的原代人成纤维细胞，建立了体外共培养模型和模拟人网膜结构的 3D 培养模型，以研究成纤维细胞和癌细胞之间的相互作用。我们证明 EOC 细胞通过转化生长因子-β1（TGF-β1）信号激活 NFs 并促进其增殖，而激活的成纤维细胞有助于 EOC 细胞的侵袭和黏附。此外，EOC 细胞与 NFs 的共培养导致肝细胞生长因子（HGF）和基质金属蛋白酶-2（MMP-2）的过度表达，并且通过阻断 HGF 或 MMP-2 的功能可以部分抑制 EOC 细胞的黏附和侵袭。此外，EOC 细胞的小鼠腹膜扩散模型证实了癌细胞对成纤维细胞的激活以及激活的成纤维细胞在体内对肿瘤生长和转移的促进作用。我们的研究结果表明，大网膜中激活的成纤维细胞形成了有利于 EOC 细胞植入的有利环境。通过抑制 TGF-β1 信号来靶向激活大网膜成纤维细胞可以作为一种针对卵巢癌大网膜转移的新治疗策略，这需要进一步研究。
