Abstract
Activity of the endo-beta-glucuronidase heparanase, capable of cleaving heparan sulfate (HS), is most often elevated in many types of tumors, associating with increased tumor metastasis and decreased patients’ survival. Heparanase is therefore considered to be a valid drug target, and heparanase inhibitors are being evaluated clinically in cancer patients. Heparanase 2 (Hpa2) is a close homolog of heparanase that gained very little attention, likely because it lacks HS-degrading activity typical of heparanase. The role of Hpa2 in cancer was not examined in detail. In head and neck cancer, high levels of Hpa2 are associated with decreased tumor cell dissemination to regional lymph nodes and prolonged patients’ survival, suggesting that Hpa2 functions to attenuate tumor growth. Here, we examined the role of Hpa2 in normal thyroid tissue and in benign thyroid tumor, non-metastatic, and metastatic papillary thyroid carcinoma (PTC) utilizing immunostaining in correlation with clinicopathological parameters. Interestingly, we found that Hpa2 staining intensity does not significantly change in the transition from normal thyroid gland to benign, non-metastatic, or metastatic thyroid carcinoma. Remarkably, we observed that in some biopsies, Hpa2 is accumulating on the membrane (envelop) of the nucleus and termed this cellular localization NM (nuclear membrane). Notably, NM localization of Hpa2 occurred primarily in metastatic PTC and was associated with an increased number of positive (metastatic) lymph nodes collected at surgery. These results describe for the first time unrecognized localization of Hpa2 to the nuclear membrane, implying that in PTC, Hpa2 functions to promote tumor metastasis.
Highlights
Heparanase is an endo-beta-glucuronidase capable of cleaving heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs)
This, and other mechanisms utilized by heparanase to promote tumorigenesis [5,6,7,8,9], have turned this enzyme into a promising drug target and heparanase inhibitors are currently being evaluated in clinical trials as anti-cancer drugs [10, 11]
Given that Heparanase 2 (Hpa2) exhibits different expression patterns in various tissues and their respective carcinomas [20, 21], we examined the expression of Hpa2 in normal thyroid tissue and in benign, non-metastatic, and metastatic papillary thyroid carcinoma (PTC) in correlation with clinicopathological parameters
Summary
Heparanase is an endo-beta-glucuronidase capable of cleaving heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs). Heparanase 2 in Thyroid Carcinoma structural support and biochemical cues to various cell types. Cleavage of HS by heparanase results in remodeling of the ECM These structural and biochemical alterations are expected to exert a profound impact on cell behavior including, among others, cell differentiation, proliferation, migration and invasion. The latter is most often associated with increased metastatic capacity of tumor cells and augmented entry of inflammatory cells (i.e., T-cells, macrophages, NK-cells) to sites of inflammation [1,2,3]. In head and neck (H&N) cancer, heparanase expression is inversely correlated with patient status [12]. Cytoplasmic staining of heparanase inversely correlated with patient survival and predicted poor prognosis, whereas nuclear heparanase predicted a favorable outcome [12]
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