Epithelial hyaluronic acid and CD44v6 are mutually involved in invasion of colorectal adenocarcinomas and linked to patient prognosis

Abstract

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.

Anti-CSC Effects in Human Esophageal Squamous Cell Carcinomas and Eca109/9706 Cells Induced by Nanoliposomal Quercetin Alone or Combined with CD 133 Antiserum

“…CD44 glycoprotein was found not only located at the surface, but also revealed in intercellular/extracellular adhesion matrix in multifocal and diffuse pattern (Knudson, 2003). The cell surface CD44, as the hyaluronan receptor as well as the E-selectin ligand, interacts with the matrix CD44 or the CD44 variant isoforms, such as CD44v6/CD44v3, are capable of facilitating cancer growth and metastasis, and higher CD44 expression is also correlated with poor prognosis in cancer cases (Thomas et al 2008;Kobel et al, 2004). Combined CD133/ CD44 expressions is a prognostic indicator of disease-free survival in patients with colorectal cancer (Galizia et al, 2012).…”

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

“…The final score was calculated by multiplying these two variables. A score of 0-5 was considered negative (IGF2 not overexpressed), and a score of 6 was considered positive (overexpression of IGF2) in accordance with Kobel et al 33 Discrepant score results for duplicate cores, when present, were consolidated as the higher interpretable score. 34 …”

“…Tissue cores with 450 interpretable tumor cells were scored on the basis of the percentage of positive tumor cells staining above background intensity in a membranous and/or cytoplasmic pattern according to published methodology. 33 In tumor cells, the staining intensity was designated as either non-existent (0), weak (1), moderate (2) or strong (3). The number of cells was scored as either no cells stained (0), o10% (1), 10-50% (2), 50-80% (3) or 480% (4).…”

Valor clínico-biológico de la concentración citosólica de ácido hialurónico en adenocarcinomas pulmonares CD44v6 positivos

“…También se considera una útil variable complementaria a la clasificación TNM, si bien no alcanza a ser factor pronóstico independiente tras análisis multivariante 22 . Los resultados anteriores parecen resaltar la importancia de la concentración citosólica de ácido hialuró-nico en los adenocarcinomas CD44v6, de tal modo que los altos valores en el índice AHc/CD44v6 se asocian con una mayor proliferación e indiferenciación celular, lo cual, unido a las mayores concentraciones de proteína oncogénica erbB2, sugiere un subgrupo de tumores con un posible diferente comportamiento como ha sido demostrado recientemente en otros tumores 31 . Sin embargo, dada el reducido número de enfermos estudiados, creemos que son necesarios más estudios para poder confirmar nuestros hallazgos.…”