MMP-10 Is Overexpressed, Proteolytically Active, and a Potential Target for Therapeutic Intervention in Human Lung Carcinomas

Abstract

Matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix is a major factor for tumor development and expansion. This study analysed MMP-10 protein expression and activity in human lung tumors of various grade, stage, and type to address the relationship between MMP-10 and tumor characteristics and to evaluate MMP-10 as a therapeutic target in non small cell lung carcinoma (NSCLC). Unlike the majority of MMPs, MMP-10 was located in the tumor mass as opposed to tumor stroma. MMP-10 protein was observed at low levels in normal human lung tissues and at significantly higher levels in all types of NSCLC. No correlation was observed between MMP-10 protein expression and tumor type, stage, or lymph node invasion. To discriminate between active and inactive forms of MMP-10 in samples of human NSCLC, we have developed an ex vivo fluorescent assay. Measurable MMP-10 activity was detected in 42 of 50 specimens of lung cancer and only 2 of 10 specimens of histologically normal lung tissue. No relationship was observed between MMP-10 activity levels and clinicopathologic characteristics. Our results suggest that MMP-10 is expressed and active at high levels in human NSCLC compared to normal lung tissues, and, as such, is a potential target for the development of novel therapeutics for lung cancer treatment.

Expression of matrix metalloproteinase-10 in human bladder transitional cell carcinoma

“…In contrast to other MMPs, MMP-10 localises predominantly to the tumor epithelial mass rather than the tumor stroma 28 . This epithelial localization is substantiated by similar observations in human skin carcinomas 13 and our studies in lung carcinomas 9 . With reference to bladder carcinoma, MMP-13 expression is also predominantly in the tumor cells rather than tumor stroma 20 .…”

“…Localization of MMP-10 was assessed by immunohistochemistry of human bladder TCC and histologically normal bladder tissue, as previously described in our laboratory 9 . Following inhibition of non-specific antibody binding, sections were incubated for 90 min at room temperature with primary antibody (5E4; diluted 1:50).…”

“…Overexpression of MMP-10 has been demonstrated in several human tumors of epithelial origin including lung, head and neck, oesophageal and oral squamous cell carcinoma and squamous and basal cell carcinomas of the skin [9][10][11][12][13] . Unlike several other MMPs which are localised predominantly in tumor stroma 13,14 , tumor cells themselves appear to express MMP-10 6,9,13,15 .…”

“…Unlike several other MMPs which are localised predominantly in tumor stroma 13,14 , tumor cells themselves appear to express MMP-10 6,9,13,15 . The expression profile of MMP-10 in several tumor types and localization of MMP-10 predominantly to tumor cells coupled with a broad substrate specificity strongly supports MMP-10 as a valid target for therapeutic intervention [7][8][9][11][12][13] .…”

Matrix metalloproteinase-10 is a critical effector of protein kinase Cι-Par6α-mediated lung cancer

“…Unlike most other MMP species, MMP-10 is expressed primarily in NSCLC tumor cells not the surrounding stromal elements (Cho et al, 2004;Gill et al, 2004), a pattern of expression similar to that of PKCi in NSCLC tumors (Regala et al, 2005b). Immunohistochemical analysis demonstrated coexpression of high levels of PKCi and MMP-10 in primary NSCLC tumor cells (Figure 6d).…”