Kawajiri Hidemi, Yashiro Masakazu, Shinto Osamu, Nakamura Kazunori, Tendo Masashige, Takemura Satoru, Node Manabu, Hamashima Yoshio, Kajimoto Tetsuya, Sawada Tetsuji, Ohira Masaichi, Hirakawa Kosei
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Clin Cancer Res. 2008 May 1;14(9):2850-60. doi: 10.1158/1078-0432.CCR-07-1634.
Transforming growth factor beta receptor (TGFbeta-R) is reported to correlate with the malignant potential of scirrhous gastric carcinoma. The aim of the current study is to clarify the possibility of molecular target therapy with a TGFbeta-R inhibitor, A-77, for the treatment of peritoneal dissemination of scirrhous gastric cancer.
Three scirrhous gastric cancer cell lines and two fibroblasts were used. For in vivo experiments, the A-77 was administered i.p. to mouse models of peritoneal dissemination. The influences of A-77 on the adhesion ability, invasion ability, and the expression of adhesion molecules were examined in vitro.
The A-77 administration resulted in a significantly (P < 0.01) better prognosis for the mice with peritoneal dissemination (median survival time, 51 days), compared with the control (median survival time, 25 days). A-77 therefore significantly (P < 0.01) decreased the weight and number of metastatic nodes. The adhesive ability and invasion ability of cancer cells were significantly decreased by A-77. A-77 decreased the expression of alpha(2), alpha(3), and alpha(5) integrins in gastric cancer cells. The histologic findings showed the degree of fibrosis to be less in the tumors treated by A-77. A-77 decreased the growth of fibroblast and invasion-stimulating activity of fibroblasts on cancer cells.
The TGFbeta-R inhibitor, A-77, decreased the expression of integrins in cancer cells and the proliferation of fibroblasts, which resulted in the decreased adhesive and invasive abilities of scirrhous gastric cancer cells to peritoneum. A-77 is thus considered to be useful for the inhibition of peritoneal dissemination of scirrhous gastric carcinoma.
据报道，转化生长因子β受体（TGFβ-R）与硬癌型胃癌的恶性潜能相关。本研究的目的是阐明使用TGFβ-R抑制剂A-77进行分子靶向治疗硬癌型胃癌腹膜播散的可能性。
使用三种硬癌型胃癌细胞系和两种成纤维细胞。在体内实验中，将A-77腹腔注射到腹膜播散的小鼠模型中。在体外检测A-77对黏附能力、侵袭能力和黏附分子表达的影响。
与对照组（中位生存时间25天）相比，给予A-77的腹膜播散小鼠预后显著更好（P<0.01，中位生存时间51天）。因此，A-77显著降低了转移结节的重量和数量（P<0.01）。A-77显著降低了癌细胞的黏附能力和侵袭能力。A-77降低了胃癌细胞中α2、α3和α5整合素的表达。组织学结果显示，A-77治疗的肿瘤纤维化程度较轻。A-77降低了成纤维细胞的生长以及成纤维细胞对癌细胞的侵袭刺激活性。
TGFβ-R抑制剂A-77降低了癌细胞中整合素的表达和成纤维细胞的增殖，从而导致硬癌型胃癌细胞对腹膜的黏附能力和侵袭能力降低。因此，A-77被认为可用于抑制硬癌型胃癌的腹膜播散。
