HB-EGF and PDGF Mediate Reciprocal Interactions of Carcinoma Cells with Cancer-Associated Fibroblasts to Support Progression of Uterine Cervical Cancers
HB-EGF and PDGF Mediate Reciprocal Interactions of Carcinoma Cells with Cancer-Associated Fibroblasts to Support Progression of Uterine Cervical Cancers
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DOI：
10.1158/0008-5472.can-11-0034
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发表时间：
2011-11-01
期刊：
影响因子：
11.2
通讯作者：
Mekada, Eisuke
中科院分区：
文献类型：
--
作者：
Murata, Takuya;Mizushima, Hiroto;Mekada, Eisuke
肿瘤间质驱动癌症的生长和进展。肝素结合表皮生长因子样生长因子（HB-EGF）是一种EGF受体配体，以自分泌或旁分泌方式刺激细胞生长。虽然HB-EGF在癌细胞中的表达升高及其对肿瘤进展的贡献已被充分证明，但HB-EGF在肿瘤基质中表达的作用尚未阐明。在这里，我们发现HB-EGF在基质成纤维细胞中表达，促进癌细胞增殖。在子宫颈癌中，HB-EGF在癌上皮近端的基质中被化学检测到。从宫颈癌患者肿瘤组织中分离的成纤维细胞与宫颈癌细胞共培养可促进宫颈癌细胞的体外增殖。抑制HB-EGF功能或血小板衍生生长因子（PDGF）抑制剂治疗可消除宫颈癌相关成纤维细胞（CCF）共培养增强的癌细胞生长。此外，CCF或小鼠胚胎成纤维细胞的共移植增强了小鼠异种移植模型中的肿瘤形成，但与HB-EGF缺陷小鼠的胚胎成纤维细胞的共移植没有增强。相反，来自癌细胞的条件培养基诱导CCF中的HB-EGF表达。机制研究表明，PDGF是主要因素负责。总之，我们的研究结果表明，HB-EGF和PDGF介导癌细胞与癌症相关成纤维细胞的相互作用，以旁分泌方式促进癌细胞增殖，这对新型组合癌症疗法具有重要意义。Cancer Res; 71（21）; 6633-42.（C）2011年《非洲标准化评论》。
Tumor stroma drives the growth and progression of cancers. A heparin-binding epidermal growth factor-like growth factor, HB-EGF, is an EGF receptor ligand that stimulates cell growth in an autocrine or paracrine fashion. While elevated expression of HB-EGF in cancer cells and its contribution to tumor progression are well documented, the effects of HB-EGF expression in the tumor stroma have not been clarified. Here, we show that HB-EGF is expressed in stromal fibroblasts where it promotes cancer cell proliferation. In uterine cervical cancers, HB-EGF was detected immunohistochemically in the stroma proximal to the cancer epithelium. Proliferation of cervical cancer cells in vitro was enhanced by coculture with fibroblasts isolated from tumor tissues of patients with cervical cancer. Inhibition of HB-EGF function or treatment with platelet-derived growth factor (PDGF) inhibitors abrogated cancer cell growth enhanced by cervical cancer-associated fibroblast (CCF) coculture. Furthermore, tumor formation in a mouse xenograft model was enhanced by cotransplantation of CCF or mouse embryonic fibroblasts, but not with embryonic fibroblasts from HB-EGF-deficient mice. Conversely, conditioned medium from cancer cells induced HB-EGF expression in CCF. Mechanistic investigations established that PDGF was the primary factor responsible. Together, our findings indicate that HB-EGF and PDGF reciprocally mediate the interaction of cancer cells with cancer-associated fibroblasts, promoting cancer cell proliferation in a paracrine manner that has implications for novel combinatorial cancer therapies. Cancer Res; 71(21); 6633-42. (C)2011 AACR.