Stromelysin in tumor progression and metastasis

Abstract

There are several characteristics of stromelysin that suggest that expression of this enzyme may play an important role in tumor invasion and metastasis; the stromelysin gene is expressed in response to stimulation by oncogenes and tumor promoters, and the protein product of this gene is a metalloproteinase capable of degrading multiple components of the extracellular matrix. Experimental evidence to support this hypothesis has been derived from several animal model systems, in which a positive correlation has been observed between stromelysin expression and tumor progression and metastasis. In addition, in vivo experiments in which the levels of TIMP, the tissue inhibitor of metalloproteinases, were altered also strongly suggest a causal role for metalloproteinases in tumor metastases. The expression of active stromelysin in tumor cells requires the fulfillment of several criteria, and this multistep process is reminiscent of the molecular events that are currently understood to contribute to tumor progression and carcinogenesis. Expression of stromelysin mRNA requires both a stimulus, a step which may correspond to the activation of an oncogene in multistep carcinogenesis, as well as the lifting of transcriptional repression, which may correspond to the loss of tumor suppressor function. Both positive and negative modulation of stromelysin transcription appear to utilize pathways that involve the protooncogenes c-fos and/or c-jun. The expression of active stromelysin enzyme also requires conversion of the proenzyme to an active form, and a proper balance between the expression of inhibitors and the levels of active enzyme. The multiple levels of stromelysin regulation support the concept of multistep carcinogenesis and may provide a tool for further understanding of the molecular nature of the events that lead to tumor progression, invasion, and metastasis.

Misregulation of Stromelysin-1 Expression in Mouse Mammary Tumor Cells Accompanies Acquisition of Stromelysin-1-dependent Invasive Properties

“…The association of carcinoma cells with SL1 in WAP-ras transgenic mouse tumors that are undifferentiated and metastasizing, but not with tumors of WAP-myc transgenic mice that are differentiated and nonmetastasizing, supported previous findings (8,9) that the level of SL1 expression may be correlated with malignant progression and, possibly, invasion. In addition, the same tumor regions that exhibited stromal invasion showed SL1-positive carcinoma cells, whereas in noninvasive areas, SL1 was found only in myoepithelial cells (41).…”

“…SL1 overexpression is frequently associated with tumor progression and invasion (8,9). Because we hypothesize that SL1 may cause formation of invasive tumors in mice transgenic for SL1, we examined the effect of SL1-antisense ODNs on invasion of Matrigel by tumor cells.…”

“…3 Studies performed with synthetic inhibitors of MMP activity and tissue inhibitors of metalloproteinases (TIMPs) have shown that suppression of MMP activity also suppresses tumor growth and metastasis (6,7). In many cases, the level of SL1 expression in tumors of the mammary gland and other tissues is positively correlated with the degree of malignancy (8,9). However, the only direct evidence for the nature of the MMPs involved was provided by the demonstration that function-blocking antibodies against gelatinase A and antisense inhibition of matrilysin expression decreased the invasiveness of tumor cells in a reconstituted basement membrane assay (10,11).…”

Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma

“…In another study of the association between FBLN2 expression and breast cancer progression, transfection of FBLN2 into breast cancer cell lines also reduced the cell migration and invasion abilities in vitro (Yi et al, 2007). MMP2, which is a potent gelatinase, cleaves the protein components of the ECM and is involved in the processes of tumor cell invasion and metastasis (McDonnell and Matrisian 1990;Libra et al, 2009). The decreased MMP2 activities in FBLN2S transfectants provide an explanation and evidence for the invasion suppression by FBLN2S.…”

In vitro invasion of small-cell lung cancer cell lines correlates with expression of epidermal growth factor receptor

“…Several reports have indicated the role of uPA in the invasive phenotype in both cell lines and in primary tumours. where it is predominantly located at the leading edges of the tumour (Markus et al, 1983;Skriver et al, 1984;Kohga et al, 1985;Sappino et al, 1987: Hollas et al, 1991Hoosein et al, 1991;Ossowski et al, 1991;Reith and Rucklidge, 1992 Matrisian, 1990;McDonnell et al, 1991: Salamonsen et al, 1991: Marcotte et al, 1992Okada et al, 1992;Sreenath et al, 1992;Liabakk et al, 1996). The knowledge of the complexity of this protease system has now been increased as TIMPs have been found.…”