M Polette

High level of MT‐MMP expression is associated with invasiveness of cervical cancer cells

MMP‐2 (gelatinase A) has been associated with the invasive potential of many cancer cells both in vitro and in vivo. It is now becoming clear that the activation of this enzyme might be a key step in tumor invasion. This activation process has been shown to be a membrane‐associated pathway inducible by various agents such as collagen type I, concanavalin A or TGF‐β, but its physiological regulation is still largely unresolved. MT‐MMP was recently discovered and described as a potential gelatinase‐A activator. In the present study, we investigated the expression of MT‐MMP (membrane‐type metalloproteinase) in cervical cancer cells both in vitro and in vivo. Comparing several in vitro‐transformed cervical cell lines, previously shown to display different invasive potentials, our results showed that the ability of cells to overexpress MT‐MMP mRNA following ConA induction correlated with their ability to activate gelatinase A and with a highly invasive behavior. Moreover, using immunohistochemistry and in situ hybridization, we found a higher level of MT‐MMP expression in invasive cervical carcinoma and lymphnode metastases compared to its expression in non‐invasive CIN III lesions. Our in vivo observations also clearly demonstrated a cooperation between stromal and tumor cells for the production of MT‐MMP. Taken together, our results clearly correlated high level MT‐MMP expression with invasiveness, and thus suggested that MT‐MMP might play a crucial role in cervical tumor invasion.

Role of Matrix, Fibroblasts and Type Iv Collagenases in Tumor Progression and Invasion

We have studied the role of the extracellular matrix and host cells in tumor progression and tumor invasion. Our results emphasize the importance of tumoral cell-host cell interactions during this process. Addition of human fibroblasts and/or basement membrane components to human mammary adenocarcinoma cells, when injected into athymic nude mice, results in an increase of take and growth rate of the tumors. Peritumoral extracellular matrix is remodeled through multiple mechanisms: overproduction of matrix components by fibroblasts, enhanced fibroblasts proliferation, modulation of interstitial collagenase production by fibroblasts and retraction of the matrix by tumoral cells. The degradation of basement membranes during the metastatic process is often associated with the secretion of proteolytic enzymes. The 72 kDa type IV collagenase, a metalloproteinase, can be produced by some tumoral cells. However, it appears also to be secreted by peritumoral stromal fibroblasts under the influence of tumoral cells. We have demonstrated the existence of a binding site for this enzyme on the membrane of mammary tumoral cells. These results suggest a cooperation between tumor cells and fibroblasts during basement membrane destruction.

Fhit regulates invasion of lung tumor cells

In many types of cancers, the fragile histidine triad (Fhit) gene is frequently targeted by genomic alterations leading to a decrease or loss of gene and protein expression. Fhit has been described as a tumor suppressor gene because of its ability to induce apoptosis and to inhibit proliferation of tumor cells. Moreover, several studies have shown a correlation between the lack of Fhit expression and tumor aggressiveness, thus suggesting that Fhit could be involved in tumor progression. In this study, we explored the potential role of Fhit during tumor cell invasion. We first showed that a low Fhit expression is associated with in vivo and in vitro invasiveness of tumor cells. Then, we showed that Fhit overexpression in Fhit-negative highly invasive NCI-H1299 cells by transfection of Fhit cDNA and Fhit inhibition in Fhit-positive poorly invasive HBE4-E6/E7 cells by transfection of Fhit small interfering RNA induce, respectively, a decrease and an increase in migratory/invasive capacities. These changes in cell behavior were associated with a reorganization of tight and adherens junction molecules and a regulation of matrix metalloproteinase and vimentin expression. These results show that Fhit controls the invasive phenotype of lung tumor cells by regulating the expression of genes associated with epithelial–mesenchymal transition.

Clinical Aspects of Matrix Metalloproteinases

Tumor metastasis is ultimately responsible for most cancer deaths. Tumor invasion and metastasis represent a multistep process including basement membrane disruption, stromal infiltration, angiogenesis, intravasation and extravasation and invasion of target organs by tumor cells. All these events require degradation and remodeling of the extracellular matrix (ECM) by various proteolytic enzymes. Among these enzymes, matrix metalloproteinases (MMPs) play a key role at various levels. These enzymes are associated with degradation of a broad spectrum of ECM components. MMPs are also implicated in the remodeling the ECM by creating and maintaining a microenvironment that facilitates angiogenesis and growth of tumors. Thus, in the last years, the exploration of MMPs expression has led to a large bunch of studies on their biological activities and their clinical implications.