Extracellular Matrix Metalloproteinase Inducer Stimulates Tumor Angiogenesis by Elevating Vascular Endothelial Cell Growth Factor and Matrix Metalloproteinases

Abstract

Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN expression and activity using recombinant DNA engineering and neutralizing antibodies. In human breast cancer cells, changes in EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production at both RNA and protein levels. In coculture of tumor cells and fibroblasts mimicking tumor-stroma interactions, VEGF expression was induced in an EMMPRIN- and MMP-dependent fashion, and was further enhanced by overexpressing EMMPRIN. Conversely, VEGF expression was inhibited by suppressing EMMPRIN expression in tumor cells, by neutralizing EMMPRIN activity, or by inhibiting MMPs. In vivo, EMMPRIN overexpression stimulated tumor angiogenesis and growth; both were significantly inhibited by antisense suppression of EMMPRIN. Expression of both human and mouse VEGF and MMP, derived from tumor and host cells, respectively, was regulated by EMMPRIN. These results suggest a novel tumor angiogenesis mechanism in which tumor-associated EMMPRIN functionally mediates tumor-stroma interactions and directly contributes to tumor angiogenesis and growth by stimulating VEGF and MMP expression.

Membrane Type 1 Matrix Metalloproteinase (MT1-MMP/MMP-14) Cleaves and Releases a 22-kDa Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Fragment from Tumor Cells

“…In previous in vitro studies, proteolytic cleavage leading to the shedding of EMMPRIN was suggested to occur at the region of the molecule proximal to the plasma membrane (25,29), although the actual fragments released into the CM had not been characterized clearly. The 22-kDa fragment we detected had not been detected in previous studies, perhaps because the 22-kDa fragment cannot be detected by antibodies that recognize the membrane-proximal region of EMMPRIN.…”

“…The other pathway is proteolytic shedding. In addition to inducing MMPs, EMMPRIN is likely to be cleaved and shed by MMPs or other metalloproteinases, because the shedding of EMMPRIN is inhibited by zinc chelators (25,29). Supporting this, MMP-1 and MMP-2 can cleave EMMPRIN at the membrane-proximal region, at least in vitro (29).…”

Origin of carcinoma associated fibroblasts

“…[115][116][117][118] The fibroblast response is hardwired in the genome as part of the cancer's resemblance to a chronic wound, aiming at support of epithelial cell survival and expansion. [119][120][121][122][123][124][125][126][127][128] In addition to parsimony, this hypothesis offers clear predictions to scientifically test against corresponding null hypotheses; (1) That co-culture of cancer cells with normal fibroblasts will induce expression of CAF-specific genes in the fibroblasts, [63][64][65][66][67][68][69][70][71] [63][64][65][66][67][68][69][70][71] Many of the genes shown to be activated in these co-cultures are known markers of CAFs in vivo, such as MMP1, MMP3, collagens, TNC, etc. Evidence that this reciprocal interaction promotes cancer includes the anti-cancer effect of Imatinib, on carcinoma animal models.…”

High incidence of EMMPRIN expression in human tumors

“…Accordingly, MDA-MB-436 human breast cancer cells recombinantly engineered to overexpress EMMPRIN adopt both accelerated growth and increased invasiveness in vivo. 4 More recently, an involvement of tumor-derived EMMPRIN in tumor angiogenesis through stimulation of MMPs and VEGF production was demonstrated by Tang et al, 5 suggesting that EMMPRIN could represent a key player in tumor cell invasion and metastasis.…”