EMAIL THIS PAGE TO A FRIEND

Molecular cancer

Inhibition of oesophageal squamous cell carcinoma progression by in vivo targeting of hyaluronan synthesis.


PMID 21429221

Abstract

Oesophageal cancer is a highly aggressive tumour entity with at present poor prognosis. Therefore, novel treatment options are urgently needed. Hyaluronan (HA) is a polysaccharide present in the matrix of human oesophageal squamous cell carcinoma (ESCC). Importantly, in vitro ESCC cells critically depend on HA synthesis to maintain the proliferative phenotype. The aim of the present study is (1) to study HA-synthase (HAS) expression and regulation in human ESCC, and (2) to translate the in vitro results into a mouse xenograft model of human ESCC to study the effects of systemic versus tumour targeted HAS inhibition on proliferation and distribution of tumour-bound and stromal hyaluronan. mRNA expression was investigated in human ESCC biopsies by semiquantitative real-time RT PCR. Furthermore, human ESCC were xenografted into NMRI nu/nu mice. The effects on tumour progression and morphology of 4-methylumbelliferone (4-MU), an inhibitor of HA-synthesis, and of lentiviral knock down of HA-synthase 3 (HAS3), the main HAS isoform in the human ESCC tissues and the human ESCC cell line used in this study, were determined. Tumour progression was monitored by calliper measurements and by flat-panel detector volume computed tomography (fpVCT). HA content, cellular composition and proliferation (Ki67) were determined histologically. mRNA of HAS isoform 3 (HAS3) was upregulated in human ESCC biopsies and HAS3 mRNA was positively correlated to expression of the epidermal growth factor (EGF) receptor. EGF was also proven to be a strong inductor of HAS3 mRNA expression in vitro. During the course of seven weeks, 4-MU inhibited progression of xenograft tumours. Interestingly, remodelling of the tumour into a more differentiated phenotype and inhibition of cell proliferation were observed. Lentiviral knockdown of HAS3 in human ESCC cells prior to xenografting mimicked all effects of 4-MU treatment suggesting that hyaluronan produced by ESCC is accountable for major changes in tumour environment in vivo. Systemic inhibition of HA-synthesis and knockdown of tumour cell HAS3 cause decreased ESCC progression accompanied by tumour stroma remodelling and may therefore be used in novel approaches to ESCC therapy.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

R5886 RPMI-1640 Medium, HEPES Modification, With 25 mM HEPES, without L-glutamine., liquid, sterile-filtered, suitable for cell culture
R7388 RPMI-1640 Medium, Modified, with 20 mM HEPES and L-glutamine, without sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
51536C RPMI-1640 Medium, with 2.05 mM L-glutamine, with 25mM HEPES, liquid, sterile-filtered, suitable for cell culture
R7638 RPMI-1640 Medium, Dutch Modification, with sodium bicarbonate and 20mM HEPES, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
R1145 RPMI-1640 Medium, 10 ×, Without L-glutamine, folic acid and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
R7513 RPMI-1640 Medium, Modified, with sodium bicarbonate, without methionine, cystine and L-glutamine, liquid, sterile-filtered, suitable for cell culture
R7509 RPMI-1640 Medium, Modified, with sodium bicarbonate, without L-glutamine and phenol red, liquid, sterile-filtered, suitable for cell culture
R7755 RPMI-1640 Medium, AutoMod, without L-glutamine and sodium bicarbonate, powder, suitable for cell culture
R4130 RPMI-1640 Medium, HEPES Modification, with L-glutamine and 25mM HEPES, without sodium bicarbonate, powder, suitable for cell culture
R1383 RPMI-1640 Medium, With L-glutamine, without glucose and sodium bicarbonate, powder, suitable for cell culture
R8755 RPMI-1640 Medium, Modified, with L-glutamine, without phenol red and sodium bicarbonate, powder, suitable for cell culture
R6504 RPMI-1640 Medium, With L-glutamine, without sodium bicarbonate, powder, suitable for cell culture
R8005 RPMI-1640 Medium, Hybri-Max, Modified, with L-glutamine, 4500 mg/L glucose and 15mM HEPES, without sodium bicarbonate, powder, suitable for hybridoma
R1780 RPMI-1640 Medium, With L-glutamine and sodium bicarbonate. Without arginine, leucine, lysine, and phenol red, liquid, sterile-filtered, suitable for cell culture, designed for isotope labeling for cell culture applications
R2405 RPMI-1640 Medium, AQmedia, With L-alanyl-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture