Heparanase 2 Attenuates Head and Neck Tumor Vascularity and Growth
| Autor: | Miriam Gross-Cohen, Sari Feld, Ilana Doweck, Uri Barash, Neta Ilan, Peleg Hasson, Israel Vlodavsky, Gil Arvatz, Inna Naroditsky, Gera Neufeld |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology medicine.medical_specialty Stromal cell Angiogenesis Lysyl oxidase Mice SCID Biology Real-Time Polymerase Chain Reaction Article Metastasis Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Mice Inbred NOD Cell Line Tumor medicine Animals Humans Heparanase Cell Proliferation Glucuronidase Neovascularization Pathologic Squamous Cell Carcinoma of Head and Neck Cell growth Cancer Heparan sulfate medicine.disease 030104 developmental biology Oncology chemistry Head and Neck Neoplasms 030220 oncology & carcinogenesis Carcinoma Squamous Cell Cancer research Heterografts |
| Zdroj: | Cancer Research. 76:2791-2801 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-15-1975 |
| Popis: | The endoglycosidase heparanase specifically cleaves the heparan sulfate (HS) side chains on proteoglycans, an activity that has been implicated strongly in tumor metastasis and angiogenesis. Heparanase-2 (Hpa2) is a close homolog of heparanase that lacks intrinsic HS-degrading activity but retains the capacity to bind HS with high affinity. In head and neck cancer patients, Hpa2 expression was markedly elevated, correlating with prolonged time to disease recurrence and inversely correlating with tumor cell dissemination to regional lymph nodes, suggesting that Hpa2 functions as a tumor suppressor. The molecular mechanism associated with favorable prognosis following Hpa2 induction is unclear. Here we provide evidence that Hpa2 overexpression in head and neck cancer cells markedly reduces tumor growth. Restrained tumor growth was associated with a prominent decrease in tumor vascularity (blood and lymph vessels), likely due to reduced Id1 expression, a transcription factor highly implicated in VEGF-A and VEGF-C gene regulation. We also noted that tumors produced by Hpa2-overexpressing cells are abundantly decorated with stromal cells and collagen deposition, correlating with a marked increase in lysyl oxidase expression. Notably, heparanase enzymatic activity was unimpaired in cells overexpressing Hpa2, suggesting that reduced tumor growth is not caused by heparanase regulation. Moreover, growth of tumor xenografts by Hpa2-overexpressing cells was unaffected by administration of a mAb that targets the heparin-binding domain of Hpa2, implying that Hpa2 function does not rely on heparanase or heparan sulfate. Cancer Res; 76(9); 2791–801. ©2016 AACR. |
| Databáze: | OpenAIRE |
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