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Expression and Activation of Signal Regulatory Protein on Astrocytomas

¹Departments of Immunology and ²Pathology, San Francisco VA Medical Center, San Francisco, California, and Divisions of ³Hematology/Oncology, ⁴Rheumatology, and ⁵Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, California

High-grade astrocytomas and glioblastomas are usually unresectable because they extensively invade surrounding brain tissue. Here, we report the expression and function of a receptor on many astrocytomas that may alter both the proliferative and invasive potential of these tumors. Signal regulatory protein (SIRP) 1 is an immunoglobulin superfamily transmembrane glycoprotein that is normally expressed in subsets of myeloid and neuronal cells. Transfection of many cell types with SIRP1, including glioblastomas, has been shown to inhibit their proliferation in response to a range of growth factors. Furthermore, the expression of a murine SIRP1 mutant has been shown to enhance cell adhesion and initial cell spreading but to inhibit cell extension and movement. The extracellular portion of SIRP1 binds CD47 (integrin-associated protein), although this interaction is not required for integrin-mediated activation of SIRP1. On phosphorylation, SIRP1 recruits the tyrosine phosphatases SHP-1 and SHP-2, which are important in its functions. Although SHP-1 is uniquely expressed on hematopoietic cells, SHP-2 is ubiquitously expressed, so that SIRP1 has the potential to function in many cell types, including astrocytomas. Because SIRP1 regulates cell functions that may contribute to the malignancy of these tumors, we examined the expression of SIRPs in astrocytoma cell lines by flow cytometry using a monoclonal antibody against all SIRPs. Screening of nine cell lines revealed clear cell surface expression of SIRPs on five cell lines, whereas Northern blotting for SIRP transcripts showed mRNA present in eight of nine cell lines. All nine cell lines expressed the ligand for SIRP1, CD47. To further examine the expression and function of SIRPs, we studied the SF126 and U373MG astrocytoma cell lines, both of which express SIRPs, in greater detail. SIRP transcripts in these cells are identical in sequence to SIRP1. The expressed deglycosylated protein is the same size as SIRP1, but in the astrocytoma cells, it is underglycosylated compared with SIRP1 produced in transfected Chinese hamster ovary cells. It is nonetheless still capable of binding soluble CD47. Moreover, SIRP1 in each of the two cell lines recruited SHP-2 on phosphorylation, and SIRP1 phosphorylation in cultured cells is CD47 dependent. Finally, examination of frozen sections from 10 primary brain tumor biopsies by immunohistochemistry revealed expression of SIRPs on seven of the specimens, some of which expressed high levels of SIRPs. Most of the tumors also expressed CD47. This is the first demonstration that astrocytomas can express SIRP. Given the known role of SIRP in regulating cell adhesion and responses to mitogenic growth factors, the expression of SIRP1 on astrocytomas may be of considerable importance in brain tumor biology, and it offers the potential of a new avenue for therapeutic intervention.

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