Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The laminin 5 (Ln-5) gamma2 chain and matrix metalloproteinases (MMPs) MMP-2 and membrane type 1 (MT1)-MMP act cooperatively and are required for highly aggressive melanoma cells to engage in vasculogenic mimicry when cultured on a three-dimensional matrix. Furthermore, generation of Ln-5 gamma2 chain promigratory fragments by MMP-2 and MT1-MMP proteolysis is necessary for an aggressive tumor cell-preconditioned matrix to induce vasculogenic mimicry in poorly aggressive tumor cells. These observations suggest that treatment regimes that specifically target aggressive tumor cells may fail to take into account changes in the extracellular microenvironment that persist after removal or destruction of an aggressive tumor and could result in a recurrence or continuance of the tumor. As a potential therapeutic approach to address this concern, the work presented here measured the molecular consequences of adding a chemically modified tetracycline (CMT-3; COL-3) that inhibits MMP activity to aggressive metastatic melanoma cells in three-dimensional culture. COL-3 inhibited vasculogenic mimicry and the expression of vasculogenic mimicry-associated genes in aggressive cells, as well as the induction of vasculogenic mimicry in poorly aggressive cells seeded onto an aggressive cell-preconditioned matrix. Furthermore, molecular analysis revealed that COL-3 not only inhibited the generation of Ln-5 gamma2 chain promigratory fragments in the aggressive cell-preconditioned matrix but also inhibited the induction of Ln-5 gamma2 chain gene expression in poorly aggressive cells by the aggressive cell-preconditioned matrix. These results suggest that COL-3 (and related chemically modified tetracyclines) may be useful in targeting molecular cues in the microenvironment of aggressive tumors and could potentially be used in a combinatorial manner with other therapies that specifically target and kill aggressive tumor cells.
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PMID:Targeting the tumor microenvironment with chemically modified tetracyclines: inhibition of laminin 5 gamma2 chain promigratory fragments and vasculogenic mimicry. 1247 98

A necessity for development and tumor progression is a blood supply formed by vasculogenic and/or angiogenic events, involving the cooperative interactions of cells with their microenvironment. Based on the recent characterization of vasculogenic mimicry by aggressive melanoma cells, particularly their ability to express VE (vascular endothelial)-cadherin, TIE-1, and EphA2, current studies have focused on the molecular signals deposited by these cells as they remodel their microenvironment. The experimental approach utilizes unique three-dimensional collagen matrices preconditioned by metastatic melanoma cells, which contain laminin 5 gamma2 chain-enriched tracks with promigratory cleavage fragments produced by cooperative interactions with specific matrix metalloproteinases (MMPs). The results demonstrate that the collagen matrices preconditioned by the metastatic cells induce poorly aggressive melanoma cells to express, for the first time, key angiogenic/vasculogenic/matrix-remodeling genes. Treatment of aggressive melanoma cells with an MMP inhibitor resulted in the inhibition of vasculogenic mimicry-associated genes in these tumor cells and abrogation of the inductive effects of the preconditioned matrix on poorly aggressive melanoma cells. These observations illustrate the remarkable influence of the microenvironment on the phenotype of melanoma cells and may provide new perspectives on tumor cell plasticity and unique treatment strategies.
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PMID:Remodeling of the microenvironment by aggressive melanoma tumor cells. 1281 47