Hasina R, Matsumoto K, Matsumoto-Taniura N, Kato I, Sakuda M, Nakamura T
Division of Biochemistry, Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Br J Cancer. 1999 Aug;80(11):1708-17. doi: 10.1038/sj.bjc.6690587.
Invasive potentials of malignant cancer cells are regulated by cell motility factors. To examine the regulation of motility and invasiveness in oral squamous carcinoma, we investigated autocrine- and/or paracrine-acting cell motility factors, using a newly established human cell line (IF cells) from oral squamous cell carcinoma, which has highly invasive and metastatic characteristics. Conditioned medium derived from IF cells stimulated cell scattering and migration of GB-d1 gallbladder carcinoma cells, indicating that IF cells secreted cell motility factors. Using antibodies, IF-derived cell motility factors proved to be transforming growth factor (TGF)-alpha and TGF-beta1. Antibodies against TGF-alpha and TGF-beta1 inhibited autonomous migration of the IF cells. On the other hand, in vitro invasion of IF cells was strongly enhanced by hepatocyte growth factor (HGF) but only slightly by TGF-alpha and TGF-beta1. The conditioned medium from fibroblasts enhanced in vitro invasion of IF cells, an event abrogated by anti-HGF antibody, but not by antibodies against TGF-alpha and TGF-beta1. Importantly, IF cells secreted a factor inducing HGF production in fibroblasts and the factor was identified as interleukin-1, which means that a mutual interaction exists between tumour cells and fibroblasts, as mediated by the HGF/HGF-inducer loop. These results indicate that IF cells utilize TGF-alpha and TGF-beta1 as autocrine-acting motility factors and HGF as a paracrine-acting motility factor, and that invasiveness of IF cells is particularly stimulated by HGF derived from stromal fibroblasts. Utilization of multiple cell motility/invasion factors that act in distinct pathways may confer highly invasive and metastatic potentials in IF oral squamous carcinoma cells.
恶性癌细胞的侵袭潜能受细胞运动因子调控。为研究口腔鳞状细胞癌中运动性和侵袭性的调控机制，我们利用新建立的具有高侵袭和转移特性的口腔鳞状细胞癌人类细胞系（IF细胞），对自分泌和/或旁分泌作用的细胞运动因子进行了研究。IF细胞条件培养基可刺激GB-d1胆囊癌细胞的细胞散射和迁移，表明IF细胞分泌细胞运动因子。利用抗体证实，IF细胞分泌的细胞运动因子为转化生长因子（TGF）-α和TGF-β1。抗TGF-α和TGF-β1抗体可抑制IF细胞的自主迁移。另一方面，肝细胞生长因子（HGF）可显著增强IF细胞的体外侵袭能力，而TGF-α和TGF-β1的作用较弱。成纤维细胞条件培养基可增强IF细胞的体外侵袭能力，抗HGF抗体可消除该作用，而抗TGF-α和TGF-β1抗体则无此作用。重要的是，IF细胞分泌一种可诱导成纤维细胞产生HGF的因子，该因子被鉴定为白细胞介素-1，这意味着肿瘤细胞和成纤维细胞之间存在由HGF/HGF诱导物环路介导的相互作用。这些结果表明，IF细胞利用TGF-α和TGF-β1作为自分泌运动因子，HGF作为旁分泌运动因子，且IF细胞的侵袭性尤其受到基质成纤维细胞来源的HGF的刺激。利用作用于不同途径的多种细胞运动/侵袭因子可能赋予IF口腔鳞状癌细胞高侵袭和转移潜能。
