Abstract
Syndecans are transmembrane heparan sulfate proteoglycans controlling cell adhesion, migration, and proliferation. We previously showed that syndecan-2 is involved in the control of apoptosis in cultured osteosarcoma cells. These data led us to the hypothesis that syndecan-2 may play a role in the apoptotic signaling in bone tumors. We immunohistochemically analyzed tissue sections from biopsies from 21 patients with well-characterized osteosarcoma. These tissues expressed low levels of syndecan-2 compared with osteoblasts and osteocytes in normal bone. Cultured human osteosarcoma cells also produced lower mRNA levels of syndecan-2 than normal osteoblastic cells. Moreover, the presence of syndecan-2 correlated with spontaneous apoptosis in osteosarcoma tissues as assessed by detection of DNA fragmentation in situ. Overexpression of syndecan-2 resulted in decreased number of migrating and invading U2OS osteosarcoma cells in Matrigel. In addition, overexpression of syndecan-2 sensitized human osteosarcoma cells to chemotherapy-induced apoptosis, increasing the response to methotrexate, doxorubicin, and cisplatin. Consistently, knockdown of the proteoglycan using stable transfection with a plasmid coding small interfering RNA resulted in inhibition of chemotherapy-induced apoptosis. Analysis of syndecan-2 expression both in biopsies and in corresponding postchemotherapy-resected tumors, as well as in cells treated with methotrexate or doxorubicin, showed that the cytotoxic action of chemotherapy can be associated with an increase in syndecan-2. These results provide support for a tumor-suppressor function for syndecan-2 and suggest that dysregulation of apoptosis may be related to abnormal syndecan-2 expression or induction in osteosarcoma. Moreover, our data identify syndecan-2 as a new factor mediating the antioncogenic effect of chemotherapeutic drugs.
Highlights
Osteosarcoma is the most common primary bone cancer occurring mainly in children [1, 2]
We show that syndecan-2 expression is low in bone tumors and this correlates with spontaneous apoptosis
Consistent with these observations, osteosarcoma cells expressed from 3- to 20-fold less syndecan-2 than normal human osteoblastic cells as measured by quantitative real-time PCR (qRT-PCR) (Fig. 1C)
Summary
Osteosarcoma is the most common primary bone cancer occurring mainly in children [1, 2]. Doi:10.1158/0008-5472.CAN-06-4164 osteosarcoma remains below 66% because a significant portion of patients respond poorly to chemotherapeutic protocols and because of frequent metastases occurring in lung and brain [2, 3]. Dysregulation of apoptotic processes are believed to contribute to metastatic potential and to drug resistance [4, 5]. Such dysregulation may represent a potent source of new therapeutic targets, the molecular mechanisms that control osteosarcoma cell fate are largely unknown
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