Critical role of type IV collagens in the growth of bile duct carcinoma. In vivo and in vitro studies

Most extrahepatic bile duct carcinomas (EBDC) are characterized by a striking stromal response (desmoplasia). Our previous studies showed deposition of type IV collagen in the desmoplastic stroma beyond the basement membrane. Although type IV collagen is expressed in EBDC, little is known about the pattern of deposition in tumor stroma and how this matrix component influences the behavior of tumor cells. With the progression of desmoplasia in EBDC, different changes occurred in the quantity and localization of type IV collagen from that of type I collagen. Type I collagen was diffusely distributed in the stroma and appeared to be concentrated in the center of the tumors. In contrast, type IV collagen was deposited in the interstitium alongside carcinoma cells at the tumors' periphery. Weak or no type IV collagen deposition was detected in the more central portion of the tumors containing sclerotic collagens. To investigate the role of stromal type IV collagen in tumor cell proliferation, EBDC cell lines were cultured in a three-dimensional matrix containing varying compositions of type I collagen and type IV collagen. They were also assayed for cell adhesion and migration using in vitro models. Type IV collagen more extensively stimulated tumor cell proliferation, adhesion and migration in a dose-dependent manner than did type I collagen. All of these results suggest that modified tumor stroma with the presence of type IV collagen in EBDC provides a better environment for tumor growth and invasion.