Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression

Abstract

Since its original identification as a leukocyte gelatinase/type V collagenase and tumour type IV collagenase, gelatinase B/matrix metalloproteinase (MMP)-9 is now recognised as playing a central role in many aspects of tumour progression. In this review, we relate current concepts concerning the many ways in which gelatinase B/MMP-9 influences tumour biology. Following a brief outline of the gelatinase B/MMP-9 gene and protein, we analyse the role(s) of gelatinase B/MMP-9 in different phases of the tumorigenic process, and compare the importance of gelatinase B/MMP-9 source in the carcinogenic process. What becomes apparent is the importance of inflammatory cell-derived gelatinase B/MMP-9 in tumour promotion, early progression and triggering of the “angiogenic switch”, the integral relationship between inflammatory, stromal and tumour components with respect to gelatinase B/MMP-9 production and activation, and the fundamental role for gelatinase B/MMP-9 in the formation and maintenance of tumour stem cell and metastatic niches. It is also apparent that gelatinase B/MMP-9 plays important tumour suppressing functions, producing endogenous angiogenesis inhibitors, promoting inflammatory anti-tumour activity, and inducing apoptosis. The fundamental roles of gelatinase B/MMP-9 in cancer biology underpins the need for specific therapeutic inhibitors of gelatinase B/MMP-9 function, the use of which must take into account and substitute for tumour-suppressing gelatinase B/MMP-9 activity and also limit inhibition of physiological gelatinase B/MMP-9 function.

Carcinoma cells induce lumen filling and EMT in epithelial cells by soluble E-cadherin-mediated activation of EGFR

“…Matrix metalloproteinase (MMP)-9, one of the proteases present in the extracellular environment, cleaves the ectodomain of membrane-bound E-cadherin at the MMP cleavage site between amino acids Leu581 and Ser582 to generate a 80-kDa fragment referred to as soluble E-cadherin (sE-cad) (De Wever et al, 2007;Maretzky et al, 2005). MMP-9 levels are elevated in several cancers, and this enzyme appears to be involved in tumor cell initiation and progression, metastatic ability and genetic instability (Farina and Mackay, 2014).…”

TUC338 promotes cell migration and invasion by targeting TIMP1 in cervical cancer

“…TIMP1 participates in the majority of the physiological and pathological processes involved in cell proliferation, migration, matrix remodeling, cell survival and matrix degradation (14)(15)(16)(17)(18). It has also been reported that TIMP1 is overexpressed in colorectal and lung tumors (19,20), and is associated with metastasis and invasion in breast, upper urinary tract and oral squamous cell tumors (19)(20)(21)(22).…”

Roles of Matrix Metalloproteinase-9 in Cancer Metastasis

“…MMP-9 influences the development of several human malignancies by, degradation of collagen IV in the basement membrane and the ECM promotes tumor progression, including invasion, metastasis, growth and angiogenesis (Morrison et al, 2001;Stamenkovic, 2000). MMP-9 is produced and secreted by many types of host stromal cells, inflammatory cells and malignant cells (Coussens and Werb, 1996;Farina and Mackay, 2014). In ovarian cancer cell lesions, it was observed that macrophage infiltration was decreased in MMP-9 deficient mice (Huang et al, 2002).…”

“…MMP-9 plays a central role in tumor progression, including stromal remodeling, eventually metastasis, rheumatoid arthritis, arteriosclerosis and angiogenesis (Farina and Mackay, 2014;Kupferman et al, 2000). MMPs such as MMP-9 are involved in the development of several human malignancies, as degradation of collagen IV in basement membrane and extracellular matrix facilitates tumor progression, including invasion, metastasis, growth and angiogenesis (Groblewska et al, 2012).…”