RRC ID 39340
Author Kataoka H, Uchino H, Iwamura T, Seiki M, Nabeshima K, Koono M.
Title Enhanced tumor growth and invasiveness in vivo by a carboxyl-terminal fragment of alpha1-proteinase inhibitor generated by matrix metalloproteinases: a possible modulatory role in natural killer cytotoxicity.
Journal Am. J. Pathol.
Abstract Matrix metalloproteinases (MMPs) are believed to contribute to the complex process of cancer progression. They also exhibit an alpha1-proteinase inhibitor (alphaPI)-degrading activity generating a carboxyl-terminal fragment of approximately 5 kd (alphaPI-C). This study reports that overexpression of alphaPI-C in S2-020, a cloned subline derived from the human pancreas adenocarcinoma cell line SUIT-2, potentiates the growth capability of the cells in nude mice. After stable transfection of a vector containing a chimeric cDNA encoding a signal peptide sequence of tissue inhibitor of metalloproteinase-1 followed by cDNA for alphaPI-C into S2-020 cells, three clones that stably secrete alphaPI-C were obtained. The ectopic expression of alphaPI-C did not alter in vitro cellular growth. However, subcutaneous injection of the alphaPI-C-secreting clones resulted in tumors that were 1.5 to 3-fold larger than those of control clones with an increased tendency to invasiveness and lymph node metastasis. These effects could be a result of modulation of natural killer (NK) cell-mediated control of tumor growth in nude mice, as the growth advantage of alphaPI-C-secreting clones was not observed in NK-depleted mice, and alphaPI-C-secreting clones showed decreased NK sensitivity in vitro. In addition, production of alphaPI and generation of the cleaved form of alphaPI by MMP were observed in various human tumor cell lines and in a highly metastatic subline of SUIT-2 in vitro. These results provide experimental evidence that the alphaPI-degrading activity of MMPs may play a role in tumor progression not only via the inactivation of alphaPI but also via the generation of alphaPI-C.
Volume 154(2)
Pages 457-68
Published 1999-2
DOI 10.1016/s0002-9440(10)65292-3
PII S0002-9440(10)65292-3
PMID 10027404
PMC PMC1849991
MeSH Adenocarcinoma / enzymology Adenocarcinoma / pathology* Amino Acid Sequence Animals Base Sequence Clone Cells Cytotoxicity, Immunologic* DNA Primers / chemistry Genetic Vectors Humans Killer Cells, Natural / metabolism* Metalloendopeptidases / genetics Metalloendopeptidases / metabolism* Mice Mice, Nude Molecular Sequence Data Neoplasm Invasiveness Neoplasm Transplantation Neoplasms, Experimental / secondary Pancreatic Neoplasms / enzymology Pancreatic Neoplasms / pathology* Peptide Fragments / genetics Peptide Fragments / metabolism Tumor Cells, Cultured alpha 1-Antitrypsin / genetics alpha 1-Antitrypsin / metabolism*
IF 4.069
Times Cited 53
Human and Animal Cells