Matrix Metalloproteinase‐9 in Tumor Cell Invasion

Abstract

Degradation of the extracellular matrix (ECM) is a critical feature of cancer cell invasion. Accumulating evidence suggests that proteolytic enzymes, including the matrix metalloproteinase (MMP) family, contribute to these multifactorial processes. Important features of these enzymes that exist in normal and neoplastic invasive processes are the induction of proteinase expression and the regulation of proteolytic activity. A common feature of the enzymes cited above is that they are produced as zymogens and require an activation step to become catalytically active. In addition, the expression of these enzymes requires stimuli that induce at the level of transcription whereas others are transcriptionally overexpressed. A correlation between proteolysis and malignant progression has been established. Specific inhibitors of serine and metalloproteinases have been used in in vitro and in vivo modelsI4 to demonstrate inhibition of tumor cell invasion and metastasis. The exact role of these specific proteinases in the mechanisms involved in the formation of metastatic lesions remains unclear.The interaction of tumor cells with the ECM and basement membrane occurs at multiple stages in the metastatic cascade. Benign adenoma and in situ carcinomas are characterized by a continuous basement membrane that separates the epithelium from the underlying stroma, whereas invasive carcinomas demonstrate zones of basement membrane loss around the invading tumor cells. Attention has been focused on proteolytic enzymes whose substrate specificities include ECM and basement membrane components. Some enzymes that have been implicated in the invasive processes of cancer cells include the MMPsS and urokinase-type plasminogen activator (uPA).~ Natural inhibitors of these enzymes have been identified and include the tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and TIMP-2)7-9 and plasminogen activator inhibitor types-1 and -2 (PAI-1 and PAI-2).1°Positive correlations between the expression of MMPs and uPA and the malignant phenotype have been demonstrated in vitro using numerous tumor and transformed cell liness4 These correlative studies have been supported by analyses using specific inhibitors. Inhibitors of MMPs or uPA have been shown to block tumor cell invasion across native or reconstituted basement membranes in v i t r~.~J *~'~ The ability of TIMP to prevent matrix degradation has been demonstrated in cell model systems. Inhibition of tumor cell invasion and metastasis in an in vivo animal model has been demonstrated using anti-uPA antibodiesZ or in vivo injections of TIMP.I3 A causal role for MMPs in cancer cell invasion was demonstrated using antisense TIMP RNA.14 These studies demonstrated that a reduction in TIMP levels resulted in a change of the cellular phenotype to one that was invasive in an in vitro model and metastatic in an in vivo model. These analyses implicate the MMPs in cancer cell invasion.The MMPs represent a family of structurally related enzymes that are grouped 324

Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma

“…The en-and is implicated in tissue destruction in various pathophysiological conditions including tumor invasion. 17 The enzyme hanced type IV collagenase activity in the tissue homogenate of HCC and the sera 9,10 was probably a mixture of MMP-2 and has a wide range of substrate specificity against interstitial fibrillar collagens (collagen types III and V) and against their MMP-9 activity. In monkey HCCs, elevated levels of MMP-2 mRNA were localized in the tumor inflammatory infiltrate.…”

Hypoxia induces epidermal keratinocyte matrix metalloproteinase‐9 secretion via the protein kinase C pathway

“…More invasive SCCs exhibit higher endogenous levels of MMP‐9 (Juarez et al, 1993). HT1080 cells produce both MMP‐2 and MMP‐9, yet specific antibodies directed against MMP‐9 inhibit HT1080 cell invasion (French et al, 1994). Similarly, neutralizing antibodies to MMP‐9 inhibit growth factor‐induced SCC12F migration (McCawley et al, 1998).…”

Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma

“…The enand is implicated in tissue destruction in various pathophysiological conditions including tumor invasion. 17 The enzyme hanced type IV collagenase activity in the tissue homogenate of HCC and the sera 9,10 was probably a mixture of MMP-2 and has a wide range of substrate specificity against interstitial fibrillar collagens (collagen types III and V) and against their MMP-9 activity. In monkey HCCs, elevated levels of MMP-2 mRNA were localized in the tumor inflammatory infiltrate.…”