Tumor cell expression of MMP3 as a prognostic factor for poor survival in pancreatic, pulmonary, and mammary carcinoma

Mehner, Christine; Miller, Erin; Nassar, Aziza; Bamlet, William R.; Radisky, Evette S.; Radisky, Derek C.

doi:10.18632/genesandcancer.90

Cited by 80 publications

(59 citation statements)

References 70 publications

(68 reference statements)

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“…However, MMP-3 was upregulated in prostate cancer cells but downregulated in CAFs isolated from prostate stroma (primary culture) or derived from bone marrow stroma (3D coculture). In prostate cancer specimens, localization of MMP-3 staining was found primarily in tumor cells and much less in the surrounding stroma, similar to the observations in pancreatic, breast, and lung carcinomas 23 , 32 , implying that MMP-3 expression is stage- and cell type-dependent during cancer progression. Physiologically, the stroma of normal tissues functions as a physical barrier against carcinogenesis.…”

Section: Discussionsupporting

confidence: 77%

Reactive oxygen species–mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression

Hsieh

Liu

Chen

et al. 2017

Sci Rep

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Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

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Section: Discussionsupporting

confidence: 77%

Reactive oxygen species–mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression

Hsieh

Liu

Chen

et al. 2017

Sci Rep

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“…Tumor cells show even higher intracellular gelatinolytic activity (likely from MMP-2) particularly at the invasive tumor front, yet apoptosis is not induced[131]. Like MMP-2, MMP-3 shows intracellular activity being highly associated with apoptosis, except in cancer[132–134]. MMP-1, MMP-7, MMP-8, and MMP-9 are also rarely activated intracellularly in healthy cells during times of cellular stress[135], but reliable cancer-related intracellular activity studies regarding these MMPs are scarce.…”

Section: Matrix Metalloproteinases In Cancer: Why Are They Worthwhilementioning

confidence: 99%

Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression

Isaacson

Jensen

Subrahmanyam

et al. 2017

Journal of Controlled Release

112

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While commonly known for degradation of the extracellular matrix, matrix metalloproteinases (MMPs) exhibit broad potential for use in targeting of bioactive and imaging agents in cancer treatment. MMPs are upregulated at all stages of expression in cancers. A comprehensive analysis of published literature on expression of all MMP subtypes at the genetic, protein, and activity levels in normal and diseased tissues indicate targeting applicability in a variety of cancers. This expression significantly increases at advanced cancer stages, providing an improved opportunity for controlled release in higher-stage patients. Since MMPs are integral at every stage of metastasis, MMP roles in cancer are discussed with a focus on MMP distribution and mobility within cells and tumors for cancer targeting applications. Several strategies for MMP utilization in targeting – such as matrix degradation, MMP cleavage, MMP binding, and MMP-induced environmental changes – are addressed.

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“…It has been shown that MMP3 and CCN2 (aka connective tissue growth factor (CTGF)) are often increased in tumor-stroma tissues or patients' serum, and are thus biomarkers correlated with poor prognosis in cancer [18][19][20][21][22]. It has been also shown that MMP3 and CCN2/CTGF promote tumor progression through processes including rapid metastasis and tumor-stroma interactions [23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

Okusha

Eguchi

Tran

et al. 2020

Cancers

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Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites.

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Tumor cell expression of MMP3 as a prognostic factor for poor survival in pancreatic, pulmonary, and mammary carcinoma

Cited by 80 publications

References 70 publications

Reactive oxygen species–mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression

Reactive oxygen species–mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression

Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

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