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PC Cell-derived Growth Factor (Granulin Precursor) Expression and Action in Human Multiple Myeloma¹

Department of Pharmaceutical Sciences, School of Pharmacy [W. W., J. H., W. E. K., G. S.], and Program of Oncology, Marlene and Stewart Greenebaum Cancer Center [G. S.], University of Maryland, Baltimore, Maryland 21201

Purpose: Multiple myeloma (MM) is a clonal B-cell neoplasm. PC cell-derived growth factor (PCDGF) is a M_r 88,000 glycoprotein growth factor. Our objective was to investigate the expression, function, and signaling pathways of PCDGF in human MM.

Experimental Design: PCDGF expression, function, and signaling pathways in human MM were studies using two human MM cell lines: ARP-1 and RPMI 8226. In addition, PCDGF expression in MM patients was examined using 13 human bone marrow biopsy samples.

Results: PCDGF mRNA and protein expression was detected in human MM cell lines such as ARP-1 and RPMI 8226. PCDGF added exogenously stimulated cell growth and sustained cell survival of both ARP-1 and RPMI 8226 cells in a dose- and time-dependent fashion. Conversely, treatment with neutralizing anti-PCDGF antibody inhibited the growth of RPMI 8226 cells suggesting that PCDGF acts as an autocrine growth factor for MM cells. Studies of signal transduction pathways showed PCDGF stimulated mitogen-activated protein kinase and phosphatidylinositol 3'-kinase pathways but not the Janus-activated kinase-signal transducer and activator of transcription pathway. Immunohistochemical analysis of bone marrow smears obtained from MM patients indicated that PCDGF expression was associated with myeloma cells from MM patients and correlated with the presence of MM disease.

Conclusion: These data suggest that PCDGF is an autocrine growth factor in the cell growth and survival of human MM cells, and may be a potential candidate as a biomarker of MM cells.

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