Torricelli Claudia, Fortino Vittoria, Capurro Elisa, Sacchi Giovanni, Ponzo Paola, Pacini Adriana, Muscettola Michela, Maioli Emanuela
Department of Physiology, University of Siena, via Aldo Moro, 53100 Siena, Italy.
Matrix Biol. 2006 Mar;25(2):104-11. doi: 10.1016/j.matbio.2005.09.006. Epub 2006 Feb 7.
In this paper the effect of N-terminal parathyroid hormone-related protein (PTHrp) and PTHrp-engaged pathways on MCF-7 breast cancer cell migration/invasivity and matrix metalloproteinases (MMPs) production were investigated. We found that: a) migration is not affected by PTHrp and Forskolin (FK)-activated PKA, while Phorbol Myristate Acetate (PMA)-activated PKC strongly stimulates MCF-7 cells motility. b) MMPs production was unaffected by PTHrp, but FK reduced membrane-type (MT)-1 MMP expression. Conversely, PMA induced a marked increase of MT1-MMP and MMP-9. c) Chemical activation of PKC is not sufficient, by itself, to confer invasive ability to MCF-7 cells, unless they were provided with additional factors, supplied by fibroblasts. d) Matrix invasion likely occurs through an activation cascade, involving at least three components: pro-MMP-9 and MT-1 MMP (supplied by PMA-stimulated MCF-7 cells) and pro MMP-2 (supplied by fibroblasts). e) The selective chemical inhibition of the adenylylciclase (AC)/PKA and phospholipase C (PLC)/PKC pathways confirmed that MCF-7 cells invasivity is not affected by exogenous PTHrp, which can only modulate their growth. However, the PTHrp responsibility in breast cancer invasion cannot be completely excluded. Indeed, fibroblasts are known to respond to PTHrp (which is a normal product of MCF-7 as well as other breast cancer cells) with enhanced release of MMP-2. On the basis of the documented requirement of fibroblast-derived MMP-2 for MCF-7 cell invasivity, a novel humoral fibroblast-breast cancer cell interaction, mediated by PTHrp, can be recognised.
本文研究了N端甲状旁腺激素相关蛋白（PTHrp）及其参与的信号通路对MCF-7乳腺癌细胞迁移/侵袭能力以及基质金属蛋白酶（MMPs）产生的影响。我们发现：a）PTHrp和福斯高林（FK）激活的蛋白激酶A（PKA）不影响细胞迁移，而佛波酯（PMA）激活的蛋白激酶C（PKC）强烈刺激MCF-7细胞的运动能力。b）PTHrp不影响MMPs的产生，但FK可降低膜型（MT）-1 MMP的表达。相反，PMA可显著增加MT1-MMP和MMP-9的表达。c）PKC的化学激活本身不足以赋予MCF-7细胞侵袭能力，除非它们获得由成纤维细胞提供的其他因子。d）基质侵袭可能通过一个激活级联反应发生，该反应至少涉及三个成分：前MMP-9和MT-1 MMP（由PMA刺激的MCF-7细胞提供）以及前MMP-2（由成纤维细胞提供）。e）腺苷酸环化酶（AC）/PKA和磷脂酶C（PLC）/PKC信号通路的选择性化学抑制证实，外源性PTHrp不影响MCF-7细胞的侵袭能力，其仅能调节细胞生长。然而，不能完全排除PTHrp在乳腺癌侵袭中的作用。事实上，已知成纤维细胞对PTHrp（这是MCF-7以及其他乳腺癌细胞的正常产物）的反应是增强MMP-2的释放。基于已证明的成纤维细胞来源的MMP-2对MCF-7细胞侵袭的必要性，可以识别一种由PTHrp介导的新型体液成纤维细胞-乳腺癌细胞相互作用。
