Yasuda Kazuyo, Torigoe Toshihiko, Mariya Tasuku, Asano Takuya, Kuroda Takafumi, Matsuzaki Junichi, Ikeda Kanae, Yamauchi Makoto, Emori Makoto, Asanuma Hiroko, Hasegawa Tadashi, Saito Tsuyoshi, Hirohashi Yoshihiko, Sato Noriyuki
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
1] Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan [2] Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Lab Invest. 2014 Dec;94(12):1355-69. doi: 10.1038/labinvest.2014.122. Epub 2014 Oct 20.
Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cells within cancer that contribute to cancer initiation and progression. Cancer-associated fibroblasts (CAFs) are stromal fibroblasts surrounding tumor cells, and they have important roles in tumor growth and tumor progression. It has been suggested that stromal fibroblasts and CSCs/CICs might mutually cooperate to enhance their growth and tumorigenic capacity. In this study, we investigated the effects of fibroblasts on tumor-initiating capacity and stem-like properties of ovarian CSCs/CICs. CSCs/CICs were isolated from the ovarian carcinoma cell line HTBoA as aldehyde dehydrogenase 1 high (ALDH1(high)) population by the ALDEFLUOR assay. Histological examination of tumor tissues derived from ALDH1(high) cells revealed few fibrous stroma, whereas those derived from fibroblast-mixed ALDH1(high) cells showed abundant fibrous stroma formation. In vivo tumor-initiating capacity and in vitro sphere-forming capacity of ALDH1(high) cells were enhanced in the presence of fibroblasts. Gene expression analysis revealed that fibroblast-mixed ALDH1(high) cells had enhanced expression of fibroblast growth factor 4 (FGF4) as well as stemness-associated genes such as SOX2 and POU5F1. Sphere-forming capacity of ALDH1(high) cells was suppressed by small-interfering RNA (siRNA)-mediated knockdown of FGFR2, the receptor for FGF4 which was expressed preferentially in ALDH1(high) cells. Taken together, the results indicate that interaction of fibroblasts with ovarian CSCs/CICs enhanced tumor-initiating capacity and stem-like properties through autocrine and paracrine FGF4-FGFR2 signaling.
癌症干细胞（CSCs）/癌症起始细胞（CICs）被定义为癌症中一小部分有助于癌症起始和进展的细胞。癌症相关成纤维细胞（CAFs）是围绕肿瘤细胞的基质成纤维细胞，它们在肿瘤生长和进展中发挥重要作用。有人提出基质成纤维细胞与CSCs/CICs可能相互协作以增强它们的生长和致瘤能力。在本研究中，我们调查了成纤维细胞对卵巢CSCs/CICs的肿瘤起始能力和干细胞样特性的影响。通过ALDEFLUOR检测从卵巢癌细胞系HTBoA中分离出CSCs/CICs作为醛脱氢酶1高表达（ALDH1(high)）群体。对源自ALDH1(high)细胞的肿瘤组织进行组织学检查发现纤维基质很少，而源自成纤维细胞混合的ALDH1(high)细胞的肿瘤组织则显示出丰富的纤维基质形成。在有成纤维细胞存在的情况下，ALDH1(high)细胞的体内肿瘤起始能力和体外成球能力增强。基因表达分析显示，成纤维细胞混合的ALDH1(high)细胞中，成纤维细胞生长因子4（FGF4）以及诸如SOX2和POU5F1等干性相关基因的表达增强。通过小干扰RNA（siRNA）介导敲低FGFR2（FGF4在ALDH1(high)细胞中优先表达的受体）可抑制ALDH1(high)细胞的成球能力。综上所述，结果表明成纤维细胞与卵巢CSCs/CICs的相互作用通过自分泌和旁分泌FGF4-FGFR2信号增强了肿瘤起始能力和干细胞样特性。
