Mizoi T, Ohtani H, Miyazono K, Miyazawa M, Matsuno S, Nagura H
Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.
Cancer Res. 1993 Jan 1;53(1):183-90.
Transforming growth factor beta 1 (TGF-beta 1) is secreted as an inactive complex associated with latent TGF-beta 1 binding protein (LTBP). Tissue localization of these proteins has not been fully understood in human pathological conditions. We examined the immunohistochemical localization of TGF-beta 1 precursor (proTGF-beta 1) and LTBP in carcinomas and granulation tissue in the human gastrointestinal tract at the light and electron microscopic levels. In normal tissue, endothelial cells and granulocytes sporadically showed immunoreactivity for proTGF-beta 1, while epithelial cells were all negative. In cancer tissue, both cancer cells and stromal cells (fibroblasts, macrophages, and endothelial cells) were positive for proTGF-beta 1, more frequently in diffuse-type gastric carcinomas than in differentiated-type adenocarcinomas. Immunoelectron microscopy revealed that proTGF-beta 1 was localized in rough endoplasmic reticulum and perinuclear cisternae in fibroblasts, macrophages, and endothelial cells in cancer stroma and in fibrous granulation tissue. In contrast, the intracellular localization of proTGF-beta 1 in carcinoma cells was predominantly observed in the cytosol (cytoplasmic matrix). This finding suggests disarranged or blocked intracellular transportation of proTGF-beta 1 in cancer cells. The immunoreactivity for LTBP was not observed in the normal epithelial cells. It was localized in cancer stroma, not in cancer cells. Ultrastructurally, LTBP was located in the extracellular matrix around fibroblasts and smooth muscle cells. The intracellular immunoreactivity for LTBP was observed in rough endoplasmic reticulum of fibroblasts and smooth muscle cells, the same as in granulation tissue. These results suggest that gastrointestinal carcinoma cells produce no or a small amount of LTBP in vivo. Our investigation suggests that extensive fibrosis in both cancer stroma and granulation tissues may be promoted by TGF-beta 1 mainly secreted from stromal cells.
转化生长因子β1（TGF-β1）以与潜伏性TGF-β1结合蛋白（LTBP）相关的无活性复合物形式分泌。在人类病理状况下，这些蛋白的组织定位尚未完全明确。我们在光学和电子显微镜水平上，研究了TGF-β1前体（proTGF-β1）和LTBP在人胃肠道癌组织和肉芽组织中的免疫组织化学定位。在正常组织中，内皮细胞和粒细胞偶尔显示出对proTGF-β1的免疫反应性，而上皮细胞均为阴性。在癌组织中，癌细胞和基质细胞（成纤维细胞、巨噬细胞和内皮细胞）对proTGF-β1呈阳性，弥漫型胃癌中的阳性情况比分化型腺癌更常见。免疫电子显微镜显示，proTGF-β1定位于癌基质和成纤维肉芽组织中的成纤维细胞、巨噬细胞和内皮细胞的粗面内质网和核周池。相比之下，癌细胞中proTGF-β1的细胞内定位主要见于胞质溶胶（细胞质基质）。这一发现表明癌细胞中proTGF-β1的细胞内运输紊乱或受阻。正常上皮细胞中未观察到LTBP的免疫反应性。它定位于癌基质，而非癌细胞。超微结构上，LTBP位于成纤维细胞和平滑肌细胞周围的细胞外基质中。在成纤维细胞和平滑肌细胞的粗面内质网中观察到LTBP的细胞内免疫反应性，与肉芽组织中的情况相同。这些结果表明，胃肠道癌细胞在体内不产生或仅产生少量LTBP。我们的研究表明，癌基质和肉芽组织中的广泛纤维化可能主要由基质细胞分泌的TGF-β1所促进。
