David L, Dulong V, Coquerel B, Le Cerf D, Cazin L, Lamacz M, Vannier J-P
Groupe de Recherche sur le Micro-Environnement et le Renouvellement Cellulaire Intégré (M.E.R.C.I., UPRES EA 3829), Faculté de Médecine Pharmacie, Université de ROUEN, Rouen, France.
Cell Prolif. 2008 Apr;41(2):348-64. doi: 10.1111/j.1365-2184.2008.00515.x.
Beyond to control of cell migration, differentiation and proliferation, the extracellular matrix (ECM) also contributes to invasiveness of human cancers. As the roles of hyaluronan (HA) and collagens in this process are still controversial, we have investigated their involvement in cancer pathogenesis.
With this aim in view, we developed a three-dimensional matrix, as reticulate HA hydrogel alone or coated with different collagens, in which cells could invade and grow.
We show that cancer cells, which were non-invasive in a single HA hydrogel, acquired this capacity in the concomitant presence of type I or III collagens. Both types of ECM compound, HA and collagens, possess the capacity to stimulate production of metalloprotease-2, recognized otherwise as a factor for poor cancer prognosis. HA-provoked cellular invasiveness resulted from CD44-mediated increase in cytosolic [Ca2+] and its subsequent hydrolysis due to ADAM (a disintegrin and metalloprotease) proteolytic activity. Interestingly, this mechanism seemed to be absent in non-invasive cancer cell lines.
Furthermore, using basic fibroblast growth factor and stromal cell-derived factor-1alpha, we also show that this three-dimensional reticulate matrix may be considered as a valuable model to study chemokinetic and chemotactic potentials of factors present in tumour stroma.
细胞外基质（ECM）除了控制细胞迁移、分化和增殖外，还对人类癌症的侵袭性有影响。由于透明质酸（HA）和胶原蛋白在此过程中的作用仍存在争议，我们研究了它们在癌症发病机制中的参与情况。
出于这一目的，我们开发了一种三维基质，即单独的网状HA水凝胶或涂有不同胶原蛋白的水凝胶，细胞可在其中侵袭和生长。
我们发现，在单一HA水凝胶中无侵袭性的癌细胞，在同时存在I型或III型胶原蛋白时获得了这种能力。两种ECM成分，HA和胶原蛋白，都具有刺激金属蛋白酶-2产生的能力，而金属蛋白酶-2被认为是癌症预后不良的一个因素。HA引发的细胞侵袭性是由CD44介导的胞质[Ca2+]增加及其随后由于ADAM（一种去整合素和金属蛋白酶）的蛋白水解活性而水解所致。有趣的是，这种机制在非侵袭性癌细胞系中似乎不存在。
此外，使用碱性成纤维细胞生长因子和基质细胞衍生因子-1α，我们还表明这种三维网状基质可被视为研究肿瘤基质中存在的因子的化学动力学和趋化潜力的有价值模型。
