Prognostic impact of extracellular matrix metalloprotease inducer: immunohistochemical analyses of colorectal tumors and immunocytochemical screening of disseminated tumor cells in bone marrow from patients with gastrointestinal cancer

Abstract

Background: Extracellular matrix metalloprotease inducer (EMMPRIN) induces matrix metalloproteinase (MMP) expression, tumor-stroma cell interaction, and invasion/angiogenesis. The objectives of the current study were to find the first evidence of a prognostic impact of total and relative EMMPRIN expression in colorectal cancer cells and to analyze EMMPRIN in bone marrow-disseminated tumor cells and normal cells from 2 different gastrointestinal cancer entities.

Methods: Tumors and normal tissues from 40 patients with colorectal cancer who were followed prospectively (median follow-up, 31 months) were analyzed for EMMPRIN by immunohistochemistry. Bone marrow from 51 patients (13 patients with gastric cancer and 38 patients with colorectal cancer) with evidence of disseminated tumor cells was screened for EMMPRIN in tumor cells and normal cells (cytokeratin 18/EMMPRIN double immunocytochemistry).

Results: A significant correlation between poor disease-specific survival (P=.037; Kaplan-Meier method; Mantel-Cox log-rank tests) and an increased ratio of EMMPRIN in tumor cells versus corresponding normal epithelial cells were observed. Furthermore, the relative increase of EMMPRIN was associated with a trend toward poor overall and recurrence-free survival. High relative EMMPRIN expression was associated significantly with positive metastasis status (M1) (P=.001) and with a trend towards advanced pathologic tumor classification. Sixteen percent of disseminated tumor cells in bone marrow samples from patients with colorectal cancer and 48.5% of disseminated tumor cells in bone marrow samples from patients with gastric cancer stained positive for EMMPRIN, and EMMPRIN on micrometastatic cells was associated significantly with parameters of tumor progression (M status, noncurative resectability). A minority of normal bone marrow cells were stained for EMMPRIN, suggesting their suitability for molecular targeting.

Conclusions: To the authors' knowledge, this study was the first to indicate that increased relative EMMPRIN protein in tumor-specific cells compared with normal cells predicts poor disease-specific survival in patients with colorectal cancer and that EMMPRIN in primary and bone marrow-disseminated tumor cells is associated with clinical markers of tumor progression in patients with colorectal/gastric cancer.