Simian Marina, Molinolo Alfredo, Lanari Claudia
Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
Am J Pathol. 2006 Jan;168(1):270-9. doi: 10.2353/ajpath.2006.050012.
Proteolytic activity and remodeling of the extracellular matrix are important players in tumor progression. However, to date the role of the extracellular matrix in tumor regression remains unresolved. To address this, we used a progesterone-dependent in vivo mouse mammary tumor line, C4-HD, which regresses in response to hormone therapy. Within the first 72 hours of treatment, massive apoptosis was accompanied by changes in the staining patterns of laminin and collagens I, III, and IV. We thus hypothesized that an increase in matrix metalloproteinase (MMP) activity could be involved in this process. This indeed was the case as the activities of MMP-2, -9, and -3 increased in regressing tumors, coinciding with the peak of apoptosis. Moreover, cell-cell interactions were disrupted during early hours of regression with E-cadherin levels reduced and fragmentation products detected during regression. Analysis of beta-catenin revealed that although total levels within the tissue did not change, this molecule switched from being involved in cell-cell adhesion in the growing tumor to being expressed in the reactive stroma during regression. Our data provide a novel role for proteolytic activity in tumor regression and question the underlying principle for using MMP inhibitors in cancer treatment.
蛋白水解活性和细胞外基质重塑是肿瘤进展中的重要因素。然而，迄今为止，细胞外基质在肿瘤消退中的作用仍未明确。为了解决这个问题，我们使用了一种依赖孕酮的体内小鼠乳腺肿瘤模型C4-HD，该模型在激素治疗后会消退。在治疗的前72小时内，大量细胞凋亡伴随着层粘连蛋白以及I、III和IV型胶原蛋白染色模式的变化。因此，我们推测基质金属蛋白酶（MMP）活性的增加可能参与了这一过程。实际情况确实如此，在消退的肿瘤中，MMP-2、-9和-3的活性增加，与细胞凋亡的峰值一致。此外，在消退的早期阶段，细胞间相互作用被破坏，E-钙黏蛋白水平降低，且在消退过程中检测到其裂解产物。对β-连环蛋白的分析表明，尽管组织内的总水平没有变化，但该分子在生长中的肿瘤中参与细胞间黏附，而在消退过程中则在反应性基质中表达。我们的数据揭示了蛋白水解活性在肿瘤消退中的新作用，并对癌症治疗中使用MMP抑制剂的潜在原则提出了质疑。
