Role of heparanase in odontogenic tumors

硫酸乙酰肝素蛋白多糖(HSPG)是重要的细胞外基质分子，在细胞与细胞、细胞与基质的相互作用中发挥重要作用。大多数生物学功能是由大量的生物活性分子隔离在硫酸乙酰肝素糖链上所赋予的。肝素酶是一种选择性降解HSPG的特异性内切糖苷酶。乙酰肝素酶降解HSPG可导致在发育和病理过程中发挥重要细胞功能的生物活性分子的释放，细胞外基质和基底膜完整性的严重降低。HSPG在牙胚中普遍表达，在中间层细胞和牙乳头细胞中表达最强，而乙酰肝素酶的免疫表达仅限于生长的颈曲区域。所有被研究的牙源性肿瘤对乙酰肝素酶的免疫反应强于牙胚。成釉细胞瘤和腺瘤样牙源性肿瘤。HSPG和乙酰肝素酶主要定位于肿瘤上皮，在成熟的纤维间质中未见明显染色，而在造釉细胞纤维瘤中表达，上皮细胞和间充质细胞均呈阳性反应。在成釉细胞癌中，HSPG的定位转移到间质组织，并伴有乙酰肝素酶的强上皮染色。因此，我们认为：1)乙酰肝素酶分子免疫定位增强可能是牙源性组织肿瘤生长的重要因素；2)肝素酶在正常牙源性组织中的主要作用可能是局部调节HSPG和HS结合的生物活性分子；3)肝素酶在正常牙胚和牙源性良性肿瘤中的功能在一定程度上也受到局部的严格调控；4)HSPG定位的改变和肿瘤细胞肝素酶免疫表达的增加，可能代表了成釉细胞瘤向成釉细胞癌的恶性进展。

Heparan sulphate proteoglycan (HSPG) are important extracellular matrix molecules that play critical roles in cell-cell and cell-matrix interactions. Most of the biological functions are conferred by the multitude of bioactive molecules sequestered on heparan sulphate sugar chains. Heparanase is a specific endoglycosidase enzyme that selectively degrades HSPG. The degradation of HSPG by heparanase can cause the release of bioactive molecules for important cellular functions in developmental and pathological processes and also the profound decrease in extracellular matrix and basement membrane integrity.HSPG were ubiquitously detected in the tooth germ with strongest intensities in the stratum intermedium cells and the dental papilla cells whereas heparanase immunoexpression was quite limited to the growing cervical loop areas. All odontogenic tumors studied, showed stronger immunoreaction to heparanase than in the tooth germ. In ameloblastoma and adenomatoid odontogenic tumor. HSPG and heparanase were localized primarily in the neoplastic epithelium without significant staining in the mature fibrous stroma while in ameloblastic fibroma; both epithelial and mesenchymal cells were reactive. In the case of ameloblastic carcinoma, the localization of HSPG shifted to the stromal tissues accompanied by strong epithelial staining to heparanase. From the results, we suggest that: 1) increased immunolocalization of heparanase molecules may be a responsible factor for the neoplastic growth of odontogenic tissues, 2) the main function of heparanase in the normal odontogenic tissue may be local modulation of HSPG and HS bound bioactive molecules, 3) the function of heparanase is locally and tightly regulated in normal tooth germ and also to some extent in benign odontogenic tumors, 4) change in localization of HSPG and increased immunoexpression of heparanase in neoplastic cells, may represent the malignant progression of ameloblastoma to ameloblastic carcinoma.