Cancer of the endometrium is the most common malignant tumor of the female genital tract and it typically affects postmenopausal women [1, 2] The prognosis of endometrial cancer is generally good, since the age-adjusted 5-year overall survival is 82% . Although most patients are diagnosed at an early stage, i.e. disease confined to the uterus, still 20% of the cancers recur after primary treatment. Adjuvant treatment does not prolong the overall survival, maybe because of inadequate patient selection. Therefore, new prognostic markers are needed. Molecular markers in endometrial cancer are still rather poorly defined .
It has been commonly recognized that development of human neoplasia is accompanied by changes in the extracellular matrix (ECM) which is particularly important in regulating tumor dissemination . The glycosaminoglycan hyaluronic acid/hyaluronan (HA) is a ubiquitous component of the extracellular matrix (ECM).
Hyaluronan is an independent, unfavorable prognostic factor in another gynaecological malignancy, epithelial ovarian cancer , and a number of other malignancies [7, 8]. Hyaluronan and its receptor CD44 are both involved in the development and progression of endometrial cancer .
Hyaluronan can be produced in mammals by three hyaluronan synthase isoenzymes: HAS1, HAS2 and HAS3 . HAS mRNA levels often correspond to the rate of hyaluronan synthesis, and are known to influence the content of hyaluronan in transplanted tumors . Therefore, upregulation of HAS expression can contribute to the hyaluronan accumulation in tissues, and promote tumor growth and metastasis in experimental animals, in particular when coexpressed with hyaluronidase [12, 13].
The catabolism of hyaluronan is more complex process . Hyaluronan in the extracellular matrix can be partially fragmented by hyaluronidase activity or oxygen free radicals, and diffuse away through lymph. Alternatively, hyaluronan can be taken up by adjacent cells and be subject to lysosomal degradation in the tissue of origin . The rate of hyaluronan catabolism may therefore be contributed by the formation of oxygen free radicals, access to lymph, local uptake by cells, and hyaluronidases.
There are 6 hyaluronidases in the human genome, two of them (HYAL1 and HYAL2) are ubiquitous and characterized at protein level . HYAL1 and HYAL2 have been shown to inhibit tumor growth in vivo, and it has been suggested that these two genes have major roles in the microenvironment of tumor cells . Recent findings have suggested that depending on its concentration, HYAL1 can function either as a tumor promoter or as a suppressor .
The major transcript of HYAL3 is enzymatically inactive and appears to have only a supportive role in HYAL 1 expression . HYAL 3 knockout mice do not display any evidence of hyaluronan accumulation . Very little is known about HYAL4, but its expression is limited, and it might be a chondroitinase rather than hyaluronidase [16, 21]. The expression of the SPAM1 gene-encoded PH20 hyaluronidase is almost exclusively detected in testis and sperm, and shows activity in higher pH.
In an invasive bladder cancer cell line, blocking of HYAL1 expression decreases tumor growth, inhibits tumor infiltration and decreases microvessel density . Increased hyaluronidase expression has also been reported in prostate  and colon cancer, and in breast tumor metastases . In contrast, recent findings have shown that the expression of HYAL1 and HYAL2 genes is significantly decreased in lung and kidney cancer samples . Also experimental overexpression of HYAL1 in a rat colon carcinoma cell line inhibits tumor growth and generates necrotic tumors .
We have found that the median concentration of hyaluronan is increased in malignant ovarian tumors without hyaluronidase activation . In further studies we have shown that significantly decreased HYAL1 expression correlates with decreased hyaluronidase activity and elevated hyaluronan content of the tumors, while HAS expression was not as consistently associated to the accumulation of hyaluronan .
In this study we found that in the most common gynaecological malignancy, endometrial cancer, the accumulation of hyaluronan is also associated with decreased expression of hyaluronidase genes. Blocking the accumulation of hyaluronan might offer a new way of fighting against these diseases