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Laminin 2-Chain Fragment in the Circulation

A Prognostic Indicator of Epithelial Tumor Invasion

Diagnostic Department, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki 300-2635 [M. K.]; Division of Gastroenterology, National Kyushu Cancer Center, Fukuoka 815-1347 [A. F.]; Institute for Protein Research, Osaka University, Suita, Osaka 565-0871 [N. S., K. S.]; and Sekiguchi Biomatrix Signaling Project, ERATO, Japan Science and Technology Corporation, Nagakute, Aichi 480-1195 [N. S., K. S.], Japan

Laminin (LN) 5, the major component of epithelial-derived extracellular matrix (ECM), plays a major role in cell adhesion and motility. Previous reports stated that proteolytic processing of the NH₂-terminal region of the 2 chain enhances cell motility on LN5, indicating that the degraded 2 chain NH₂-terminal region would be shed from the ECM. However, soluble LN 2 NH₂-terminal fragment (G2F) have not been detected in biological fluids. Here, we developed a double-monoclonal electrochemiluminescence immunoassay for human G2F and detected its presence in the normal human circulation (mean ± SD: 39.2 ± 10.3 ng/ml; n = 10). We also measured serum levels of G2F in nude mice orthotopically transplanted with three different human pancreatic carcinoma cell lines: MIApaca-II (secreting no LN5), HPAC (secreting the 3ß32 heterotrimer of LN5), or KP-1 (secreting the monomeric 2 chain of LN5). Serum levels of G2F drastically increased in the nude mice transplanted with HPAC (mean ± SD: 351 ± 33 ng/ml, 5 weeks after transplantation), the most invasive tumor cells to generate extensive peritoneal dissemination in vivo. A moderate increase in serum levels of G2F was also observed in mice transplanted with KP-1 (87.9 ± 82 ng/ml, 5 weeks after transplantation), but no antigen was detected in the sera of MIApaca-II-transplanted mice. Therefore, circulating G2F was demonstrated to be a sensitive marker for LN5 production of primary pancreatic carcinomas, even if it was produced only as a monomeric 2 chain. In 11 established human pancreatic tumor cell lines (6 of LN5-producing cells and 5 of nonproducing cells), LN5-secreting cells have significantly higher levels of cell surface expression of ß4 integrin than nonsecreting cells. Thus, LN5 secretion is accompanied by cell surface expression of 6ß4 integrin, participating in hemidesmosome reorganization to form invading edges of malignant epithelial carcinomas. These data reveal that the level of circulating G2F is a new, prognostic, tumor-characterizing marker for estimating the invasiveness and malignancy of epithelial carcinomas in cancer patients.

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