Immunoelectron microscopic localization of transforming growth factor beta 1 and latent transforming growth factor beta 1 binding protein in human gastrointestinal carcinomas: qualitative difference between cancer cells and stromal cells.

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.