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Tumor hepatocytes and basement membrane–Producing cells specifically express two different forms of the endostatin precursor, collagen XVIII, in human liver cancers
Author(s) -
Musso Orlando,
Theret Nathalie,
Heljasvaara Ritva,
Rehn Marko,
Turlin Bruno,
Campion JeanPierre,
Pihlajaniemi Taina,
Clement Bruno
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.23189
Subject(s) - endostatin , basement membrane , stromal cell , pathology , extracellular matrix , angiogenesis , biology , cancer cell , hepatic stellate cell , cancer research , type iv collagen , cancer , microbiology and biotechnology , medicine , laminin , genetics
Endostatin is an endogenous inhibitor of angiogenesis and tumor growth in mice, which may be generated by proteolytic cleavage of collagen XVIII. In normal tissues, 2 variants of the endostatin precursor, namely the SHORT and LONG forms, regulate tissue specificity. We analyzed 53 human liver biopsies (18 hepatocellular carcinomas, 16 metastases of colorectal cancer, 3 cholangiocarcinomas, and 16 controls) by RNA dot blots, double‐labeling immunohistochemistry, and in situ hybridization, using common and variant‐specific probes. Tumor hepatocytes expressed the LONG form, whereas cholangiocarcinoma cells expressed the SHORT form, which was deposited in tumor basement membranes. Metastatic colorectal carcinoma cells did not express collagen XVIII. In the stromal compartment of primary and metastatic cancers, myofibroblasts and vascular endothelial cells expressed the SHORT form. Both basement membrane components, collagen IV and the SHORT collagen XVIII form, were codistributed and their mRNA levels strongly correlated (R = .75, P < .001). In addition, freshly isolated human hepatocytes expressed the LONG form and culture‐activated stellate cells the SHORT form. Moreover, the full‐length LONG form is a plasma protein. Thus, the LONG form is a hepatocyte‐specific variant, and the SHORT form is a major component of the tumor extracellular matrix in primary and metastatic liver cancers. In the clinical context, the global expression of the endogenous endostatin precursor, collagen XVIII, in liver cancer results from the combined expression profiles of tumor cells, stromal cells, and nontumor hepatocytes at the advancing edge of the tumor, particular to each type of cancer.