High incidence of EMMPRIN expression in human tumors

Abstract

Extracellular matrix metalloproteinase inducer expressed by tumor cells stimulates peritumoral fibroblasts to produce matrix metalloproteinases, thus contributing to tumor invasion and metastasis. To assess its suitability as potential therapeutic target, the overall incidence of EMMPRIN expression in normal and neoplastic tissues was analyzed. EMMPRIN expression was detected immunohistochemically using monoclonal antibodies MEM-M6/1 and HIM6 and tissue microarrays with 2,348 and 608 tissue samples from 129 distinct tumor types and 76 different normal tissues, respectively. Expression and glycosylation state of EMMPRIN in human breast cancer cells were analyzed by Western blot analysis with monoclonal antibodies recognizing distinct carbohydrate structures and biochemical methods. EMMPRIN expression was found in 112 of 129 tumor entities analyzed with malignant tumors being EMMPRIN positive more frequently than benign tumors. A remarkable heterogeneity in EMMPRIN expression between tumor entities was observed. Among others, squamous-cell carcinomas (60-100%), pancreatic (87%), chromophobic kidney (83%), hepatocellular (83%) or medullary breast (83%) adenocarcinomas as well as glioblastoma multiforme (79%) presented with a particular high incidence of EMMPRIN expression. There were a limited number of EMMPRIN-positive normal cell types including proliferatively active and differentiating epithelial cells, germ cells, myocardial cells in the left heart ventricle or vascular endothelial cells of the brain. We could further demonstrate that breast cancer cells expressed EMMPRIN isoforms differing in the presence or absence of Lewis X glycan structures. Our results may assist in defining the suitability of EMMPRIN as therapeutic target and predicting negative side effects. ' 2006 Wiley-Liss, Inc.Key words: extracellular matrix metalloproteinase inducer expression; human normal tissues; human tumors; glycosylation Tumor cell invasion and metastasis requires degradation of extracellular matrix components, which is mainly achieved by various proteolytic enzymes including zinc-dependent matrix metalloproteinases (MMPs). Analysis of MMP expression patterns in tumor specimens revealed that the majority of these enzymes are produced by stromal cells surrounding the tumor rather than by tumor cells themselves. An increasing body of evidence, however, suggests that MMP synthesis is stimulated by tumor cells in a paracrine fashion. This stimulation is at least partially attributed to extracellular matrix metalloproteinase inducer (EMMPRIN, also designated CD147 or basigin), a 58 kDa surface glycoprotein of the immunoglobulin superfamily, originally purified from the plasma membrane of cancer cells. 1 EMMPRIN has been demonstrated to stimulate production of MMP-1, -2, -3, -9, -14, -15 in fibroblasts surrounding tumor cells. 2 As shown by Sun and Hemler, 3 EMMPRIN also appears to participate in the induction of MMP production in tumor cells in an autocrine fashion. Accordingly, MDA-MB-436 human breast cancer cells recombinantly...

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

“…It is believed to have a significant role in the development, differentiation and remodeling of many normal tissues including the lung, thymus, retina, skin, cornea and nervous system (Renno et al, 2002;Betsuyaku et al, 2003;Gabison et al, 2005;Nabeshima et al, 2006). However, it is in the field of cancer that EMMPRIN has garnered most interest because of its consistently high levels of expression on the surface of various tumors, including lung tumors, and because of its correlation with poor prognosis (Caudroy et al, 1999;Davidson et al, 2003;Yan et al, 2005;Riethdorf et al, 2006;Als et al, 2007;Sienel et al, 2008). EMMPRIN expression has also been linked to tumor metastasis as it is one of the most constantly upregulated mRNAs in bone marrow metastatic cells in lung, prostate and breast cancer (Klein et al, 2002;Reimers et al, 2004).…”

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

“…14 It is highly up-regulated in many malignant cancer cells and is thought to contribute to cell survival, invasion, metastasis, and multidrug resistance. 15 Studies targeting Bsg to prevent tumor growth using RNAi techniques have achieved successful outcomes. 16 -19 Along with MMPs, Bsg is also involved in the production of vascular endothelial growth factor and hyaluronan.…”

Target chemotherapy of anti-CD147 antibody-labeled liposome encapsulated GSH-DXR conjugate on CD147 highly expressed carcinoma cells

“…Various physiological processes might be influenced by anti-EMMPRIN therapy (12), such as proliferation and differentiation of epithelial cells (20)(21)(22), fertilization (23), differentiation and activation of immune cells (24)(25)(26), integrinmediated adhesion of myocytes of the left heart ventricle to basement membrane components (27), selective transport processes in endothelial cells to maintain the blood-brainbarrier function (28), erythrocyte maturation (29) or wound healing (30). Accordingly, the side effects of target therapy using CD147 conjugates should be evaluated carefully.…”

“…Involvement of tumor-derived EMMPRIN in tumor angiogenesis through stimulation of MMPs and VEGF production was demonstrated by Tang et al (11), suggesting that CD147 could represent a key molecule in tumor cell invasion and metastasis. To assess its putative role as a target for anticancer therapies, Riethdorf et al (12), analyzed the overall incidence of CD147 expression in a wide spectrum of normal and tumor tissues. They showed that CD147 expression was detected frequently in the vast majority of human malignancies and also in a subset of benign tumors.…”

“…They showed that CD147 expression was detected frequently in the vast majority of human malignancies and also in a subset of benign tumors. Nevertheless, there are some very interesting differences both in the intensity and distribution of CD147 staining among different malignant tumors as well as benign lesions (12). It was predicted that CD147 has the potential to serve as a target for anti-tumor therapy.…”