Insulin-Like Growth Factor Binding Protein-5 Is a Target of Matrix Metalloproteinase-7: Implications for Epithelial-Mesenchymal Signaling

Hemers, Elaine; Duval, Cédric; McCaig, Catherine; Handley, Mark T.; Dockray, Graham J.; Varró, Andrea

doi:10.1158/0008-5472.can-05-0157

Cited by 91 publications

(96 citation statements)

References 47 publications

(52 reference statements)

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“…2 Interestingly, MMP7 stimulates the proliferation of human colonic fibroblasts by cleaving insulin-like growth factor-binding protein 5 (IGFBP5) and subsequent release of insulin-like growth factor (IGF). 15 We therefore speculated that loss of MMP7 might prevent the cleavage of IGFBP5 and subsequent proliferation of fibroblasts in the cis-Apc/Smad4 adenocarcinomas. As shown in Figure 4a, the cleaved form IGFBP5 was increased in the cisApc/Smad4 adenocarcinomas compared with that in the Apc D716 adenomas.…”

Section: Lack Of Mmp7 Does Not Affect Number Of Fibroblasts In Cis-apmentioning

confidence: 99%

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Matrix metalloproteinase 7 is required for tumor formation, but dispensable for invasion and fibrosis in SMAD4-deficient intestinal adenocarcinomas

Kitamura

Biyajima

Aoki

et al. 2009

Laboratory Investigation

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Expression of matrix metalloproteinase 7 (MMP7) is increased in the human colorectal carcinomas, and correlates with malignant progression. However, its contribution to colon cancer pathogenesis is not understood thoroughly. To investigate the roles of MMP7 in colon cancer progression, we introduced an Mmp7 knockout mutation into the cis-Apc/Smad4 mutant mouse, a model of invasive colon cancer in which SMAD4-dependent TGF-b family signaling is inactivated. We demonstrate here that lack of MMP7 reduces the number and size of tumors in the cis-Apc/Smad4 mice. On the other hand, MMP7-deficiency does not affect the depth of tumor invasion, number of stromal fibroblasts or levels of extracellular matrix components in the tumors. These results indicate that MMP7 is required for tumor formation, but not for the invasion or fibrosis of the colon cancer whose SMAD4-dependent TGF-b family signaling is blocked. Accumulating evidence suggest that most colorectal adenomas are initiated by the inactivation of APC gene, and progress into adenocarcinomas through additional genetic alterations in KRAS (for KRAS), TP53 (P53), SMAD4, TGFBR2 (TGF-b type-II receptor), etc. 1 In colorectal carcinomas, marked tumor invasion and expansion of the stroma are well-known features associated with metastasis and poor prognosis. [2][3][4] As a mouse model for colorectal adenocarcinomas, we previously constructed cis-Apc þ /D716 Smad4 þ /À compound mutant (hereafter cis-Apc/Smad4 mice) carrying a knockout allele of the Smad4 gene on the same chromatid as that of Apc. 5 Using these mice, we demonstrated that loss of SMAD4-dependent TGF-b family signaling converts intestinal adenomas to adenocarcinomas. Namely, the cis-Apc/ Smad4 mice develop tumors that show marked invasion and stromal expansion, although the simple Apc mutant (Apc D716 ) mice form only benign adenomas. 5,6 To examine the mechanisms underlying such malignant changes in the cis-Apc/Smad4 tumors, we recently performed DNA microarray analyses and found that the adenocarcinomas expressed much higher levels of CC-chemokine ligand 9 (CCL9) than the Apc D716 adenomas. Further studies revealed that CCL9 released from the cis-Apc/Smad4 tumor epithelia recruits immature myeloid cells (iMCs) that carry its CC-chemokine receptor (CCR1) and express matrix metalloproteinase (MMP) 2 and 9 to help tumor invasion. 7 Although it is the tumor stromal cells that produce most MMPs whose levels are increased in the colon cancer (eg MMP2 and MMP9), the tumor epithelial cells can express another MMP, MMP7. 8 Interestingly, our microarray data 7 showed increased expression of MMP7 in the cis-Apc/Smad4 adenocarcinomas compared with the Apc D716 adenomas. In human colorectal cancer, it has been reported that the level of MMP7 correlates with advanced Dukes stages, poor outcome, invasion and metastasis to the liver. 9-11 Several studies have shown that overexpression of MMP7 increases the invasive ability and metastasis to the liver in some colon cancer cell lines, 9,12,13 although another study suggests ...

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Section: Lack Of Mmp7 Does Not Affect Number Of Fibroblasts In Cis-apmentioning

confidence: 99%

“…14 Interestingly, a recent report suggests that MMP7 can contribute to expansion of the tumor stroma, because recombinant MMP7 stimulates proliferation and migration of human colonic fibroblasts. 15 As these studies relied on cell lines, however, it remains to be determined what actual roles MMP7 plays in colon cancer development in vivo.…”

mentioning

confidence: 99%

Matrix metalloproteinase 7 is required for tumor formation, but dispensable for invasion and fibrosis in SMAD4-deficient intestinal adenocarcinomas

Kitamura

Biyajima

Aoki

et al. 2009

Laboratory Investigation

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“…This suggests that bacteria can alter the tight junctions and penetrate the deeper intercellular spaces down the underlying lamina propria . Moreover, the H. pylori infection increased the MMP‐7 expression, the number of myofibroblasts, and their proliferation and migration 14, 15. High MMP7 expression facilitated cancer invasion and angiogenesis by degrading extracellular matrix macromolecules and connective tissues in vivo.…”

Section: Introductionmentioning

confidence: 99%

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

et al. 2018

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BackgroundMajor human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori‐infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA−vacA−) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer‐associated fibroblasts (CAFs) able to induce epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM‐1).Materials and MethodsThe panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)‐infected fibroblasts by RT‐PCR. After insert coculture of differentiated fibroblasts with RGM‐1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT‐associated genes was analyzed by RT‐PCR.ResultsThe mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA−vacA−) strain. Following coculture with CAFs, RGM‐1 cells showed significant decrease in E‐cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFβR, HGFR, FGFR, N‐cadherin, vimentin, α‐SMA, VEGF, and integrin‐β1.Conclusion Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM‐1 epithelial cell line.

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“…19 Additionally, MMP-7 induces cell proliferation through cleavage of heparin binding epidermal growth factor (HB-EGF) precursor, 20 a disintegrin and metalloproteinase family (ADAM) member, ADAM28 21 and degradation of all 6 insulin growth factor binding proteins (IGFBP-1 to -6), increasing the bioavailability of IGF and thus favoring cancer cell growth and survival. 22,23 Matrilysin can regulate angiogenesis either by inducing a direct proliferative effect on vascular endothelial cells 24 or producing angiogenesis inhibitors (angiostatin, endostatin and neostatin-7) 25 or enriching the variety of angiogenesis mediators, such as the soluble vascular endothelial growth factor (sVEGF). 26 Immunoevasion due to MMP-7 would be related to FASL cleavage 16,17 or to IgG degradation.…”

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confidence: 99%

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Maurel

Nadal

García-Albéniz

et al. 2007

Intl Journal of Cancer

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Metalloproteinase 7 (MMP-7) plays an important role in tumor growth, invasion and dissemination, and is secreted to the media. Because of the close implication of MMP-7 in cancer biology, we sought to define the prognostic significance of serum levels of MMP-7 in metastatic colorectal cancer (CRC) and explore its possible impact in the daily clinical practice. MMP-7 expression was determined by enzyme-linked immunoabsorbent assay. We assessed serum MMP-7 levels in 87 healthy controls, 96 patients with nonmetastatic CRC and 120 patients with advanced CRC. Clinical information was gathered from patient files. Cox proportional hazards model was used to assess survival. MMP-7 and the variables associated with prognosis were entered and a backward elimination method was employed to adjust the model. Inclusion criteria was p 0.05 and exclusion criteria was p 0.10. Advanced CRC patients have a significant higher mean serum MMP-7 levels (13.4 ng/ml) than those in nonmetastatic CRC (5.5 ng/ml; p < 0.001) and healthy controls (4.2 ng/ml; p < 0.001). In metastatic patients, after adjusting for other prognostic variables, MMP-7 (entered as a continuous variable) is associated with decreased survival (HR 1.016, IC 95% 1.002-1.031). Serum MMP-7 levels are significantly elevated in patients with advanced CRC. In conclusion, MMP-7 is an independent prognostic factor for survival in advanced CRC. In our sample, the risk of death associated to MMP-7 increase is much higher than the risk of death associated to lactate dehydrogenase elevation. ' 2007 Wiley-Liss, Inc.Key words: colorectal cancer; prognosis; matrix metalloproteinases Widely accepted prognostic factors in advanced colorectal cancer (CRC) are performance status (PS), serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels. 1-4 Despite of it, novel markers and useful prognostic indexes are needed to better classify these patients for clinical practice.Matrylisin (MMP-7) is a proteolytic enzyme belonging to Matrix Metalloproteinase (MMPs) family. [5][6][7] It is constitutively expressed in the ductal and glandular epithelium of many tissues. 8 In the lung and intestine it plays a role activating antibacterial peptides such as prodefensins. 9 MMP-7 is synthesized and secreted by tumor epithelial cells as a 28-KDa proenzyme that can be activated through proteolytic removal of a 9-KDa prodomain from the N-terminus. The soluble activated form binds to the tumor epithelial cell surface. Both active forms, the soluble and the membranebounded, have proteolytic activity. Its expression is regulated by transcription factors such as AP-1, PEA3 and b-catenin/ tcf4 complex. [10][11][12] By degrading elastin, laminin, proteoglycans, osteopontin, fibronectin and type IV collagen, MMP-7 gains the capacity to invade. Matrilysin can also promote tumor invasion by activating other MMPs (MMP-2 and MMP-9), through ectodomain shedding of E-cadherin. 13 and receptor activator of nuclear factor-kappa B ligand (RANKL) 14 or through cleavage of adhesion molecules, such as integri...

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Insulin-Like Growth Factor Binding Protein-5 Is a Target of Matrix Metalloproteinase-7: Implications for Epithelial-Mesenchymal Signaling

Cited by 91 publications

References 47 publications

Matrix metalloproteinase 7 is required for tumor formation, but dispensable for invasion and fibrosis in SMAD4-deficient intestinal adenocarcinomas

Matrix metalloproteinase 7 is required for tumor formation, but dispensable for invasion and fibrosis in SMAD4-deficient intestinal adenocarcinomas

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

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