Köbel Martin, Weichert Wilko, Crüwell Katharina, Schmitt Wolfgang D, Lautenschläger Christine, Hauptmann Steffen
Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Magdeburger Strasse 14, 06097 Halle, Germany.
Virchows Arch. 2004 Nov;445(5):456-64. doi: 10.1007/s00428-004-1095-0. Epub 2004 Sep 16.
Desmoplastic stroma of colorectal adenocarcinomas contains a variety of extracellular matrix molecules, including hyaluronic acid (HA). Overexpression of the HA receptor CD44 and, in particular, its splicing variant CD44v6 has been described as a prognostic factor for patients with colorectal adenocarcinomas in some studies, but converse reports also exist. Our hypothesis is that these divergent results may be related to the fact that the function of CD44v6 depends on the HA content of cell-surrounding matrix. Therefore, we studied the expression of HA and CD44v6 in tissue samples of 145 patients suffering from colorectal adenocarcinomas using immunohistochemistry. Expression of HA was separately evaluated in tumor epithelium and stroma. We additionally examined the influence of HA on invasion and adhesion of colorectal adenocarcinoma cells in vitro. The results show that epithelial HA expression was not correlated with tumor stage but with lymph-node or distant metastasis. Patients with tumors expressing epithelial HA had a decreased overall survival ( P=0.017) as well as tumors with coexpression of epithelial HA and CD44v6 ( P=0.011). The latter issue remained an independent prognostic factor in multivariate analysis (relative risk 5.06; 95% confidence interval, 1.18-21.57; P=0.028). HA exclusively stimulated in vitro invasion of CD44v6-expressing cells. This stimulation was partly reversed by an anti-CD44v6 antibody. Our findings suggest that the adverse prognostic effect of CD44v6 in colorectal adenocarcinoma might be restricted to those tumors that have pericellular HA.
结直肠癌的促纤维增生性基质包含多种细胞外基质分子，包括透明质酸（HA）。在一些研究中，HA受体CD44的过表达，尤其是其剪接变体CD44v6，已被描述为结直肠癌患者的一个预后因素，但也有相反的报道。我们的假设是，这些不同的结果可能与CD44v6的功能取决于细胞周围基质的HA含量这一事实有关。因此，我们使用免疫组织化学研究了145例结直肠癌患者组织样本中HA和CD44v6的表达。在肿瘤上皮和基质中分别评估HA的表达。我们还在体外研究了HA对结直肠癌细胞侵袭和黏附的影响。结果显示，上皮HA表达与肿瘤分期无关，但与淋巴结转移或远处转移有关。表达上皮HA的肿瘤患者的总生存率降低（P = 0.017），上皮HA和CD44v6共表达的肿瘤患者也是如此（P = 0.011）。在多变量分析中，后一个问题仍然是一个独立的预后因素（相对风险5.06；95%置信区间，1.18 - 21.57；P = 0.028）。HA专门刺激表达CD44v6的细胞的体外侵袭。这种刺激被抗CD44v6抗体部分逆转。我们的研究结果表明，CD44v6在结直肠癌中的不良预后作用可能仅限于那些细胞周围有HA的肿瘤。
