Seftor Richard E B, Seftor Elisabeth A, Kirschmann Dawn A, Hendrix Mary J C
Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa 52242-1109, USA.
Mol Cancer Ther. 2002 Nov;1(13):1173-9.
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.
层粘连蛋白5（Ln-5）γ2链与基质金属蛋白酶（MMPs）中的MMP-2以及膜型1（MT1）-MMP协同作用，在三维基质上培养时，高侵袭性黑色素瘤细胞进行血管生成拟态需要这些蛋白。此外，MMP-2和MT1-MMP蛋白水解产生Ln-5γ2链促迁移片段，对于经侵袭性肿瘤细胞预处理的基质诱导低侵袭性肿瘤细胞的血管生成拟态是必要的。这些观察结果表明，专门针对侵袭性肿瘤细胞的治疗方案可能没有考虑到在侵袭性肿瘤被清除或破坏后仍然存在的细胞外微环境变化，这可能导致肿瘤复发或持续存在。作为解决这一问题的潜在治疗方法，本文的研究测量了在三维培养中向侵袭性转移性黑色素瘤细胞添加抑制MMP活性的化学修饰四环素（CMT-3；COL-3）的分子效应。COL-3抑制侵袭性细胞中的血管生成拟态以及血管生成拟态相关基因的表达，也抑制接种到经侵袭性细胞预处理基质上的低侵袭性细胞的血管生成拟态诱导。此外，分子分析表明，COL-3不仅抑制经侵袭性细胞预处理基质中Ln-5γ2链促迁移片段的产生，还抑制经侵袭性细胞预处理基质诱导低侵袭性细胞中Ln-5γ2链基因的表达。这些结果表明，COL-3（以及相关的化学修饰四环素）可能有助于靶向侵袭性肿瘤微环境中的分子线索，并有可能与其他专门靶向并杀死侵袭性肿瘤细胞的疗法联合使用。
