Expression patterns of hyaluronan, hyaluronan synthases and hyaluronidases indicate a role for hyaluronan in the progression of endometrial cancer

Abstract

Objective. The extracellular glycosaminoglycan hyaluronan (HA) and its degradative enzymes, hyaluronidases (Hyal), play important roles in tumor metastasis and angiogenesis. HA promotes tumor cell adhesion and migration, while its cleaved fragments stimulate angiogenesis. The aims of this study were to assess the levels of HA and how it might be regulated in endometrial cancer. Methods. Endometrial carcinomas were grouped according to histologic grade (Grade 1–3). HA histochemistry utilized a biotinylated HA binding peptide ( n = 15), while HA synthase (HAS) immunohistochemistry utilized an antibody recognizing HAS1, HAS2 HAS3 ( n = 24). Real-time RT-PCR was used to determine the mRNA expression of Hyal 1, Hyal 2 ( n = 13) and Hyal 3 ( n = 11) in endometrial carcinomas. Results. HA, its synthases and degradative enzymes were identified in endometrial carcinomas of all histologic grades. HA was predominantly localized to tumor-associated stroma. Semiquantitative analysis revealed increased HA levels with tumor grade, however, this increase only attained significance in Grade 2 carcinomas ( P < 0.05). HA staining intensity scores were significantly associated with the presence of myometrial invasion ( P < 0.05). Alternatively, HAS was predominantly localized in tumor epithelial cells, and its levels did not vary with tumor grade. Expression of Hyal 3 and Hyal 2 mRNA were >1000−fold and >30−fold greater respectively than that of Hyal 1 mRNA, the major Hyal expressed in other cancers. No Hyal type varied with tumor grade. Conclusion. This is the first study to demonstrate the cellular localization of HA and its synthases and that Hyal 3 mRNA is predominant in endometrial cancer. The results suggest a role for elevated HA in endometrial cancer progression.