IGF-II is a major proliferative/anti-apoptotic cytokine and a therapeutic target in multiple myeloma, other hematologic neoplasias and solid tumors. Free

2418

We have shown (Oncogene 2002;21:5673, PNAS 2002;99:14374; Blood 2002;100s) that inhibition of insulin-like growth factor-1 receptor (IGF-1R) kinase activity suppresses proliferation, survival and drug resistance of tumor cells from multiple myeloma (MM), other hematologic malignancies and solid tumors and that serum insulin-like growth factors (IGFs) are sufficient to stimulate IGF-1R kinase activity. So far, studies of ligands for IGF-1R have focused on IGF-I (mainly due to its prominent role in childhood growth). We hypothesized that IGF-II is also a critical regulator of tumor cell proliferation/survival and we used specific neutralizing antibodies (Ab) against IGF-I or IGF-II to selectively abrogate their respective contributions to the biologic activities of serum (fetal bovine, healthy donor or MM patient sera) on tumor cells. We found that anti-IGF-II Ab significantly suppressed proliferation/survival of primary tumor cells and cell lines of MM (including cells resistant to conventional or novel drugs), and cell lines from solid tumors (e.g. breast, prostate, lung, colon, thyroid, ovarian, renal Ca, retinoblastoma, sarcoma), leukemias and lymphomas. IGF-II neutralization generally had more pronounced effect than anti-IGF-I Ab. Combined neutralization of both cytokines had effect comparable to IGF-1R inhibition. ELISA assays showed higher levels of IGF-II than IGF-I in sera of 20 MM patients (795±153 vs 181±74 ng/mL respectively, p<0.05). IGF-1R does not exhibit kinase activity in absence of ligand(s) binding, thus a major part of biologic effects of IGF-1R signaling in tumor cells may be triggered by IGF-II. We then studied the gene expression and proteomic profiles of IGF-II stimulation and, conversely, IGF-II inhibition of tumor cells. We found that physiological levels of IGF-II stimulate pleiotropic proliferative/anti-apoptotic pathways, including activation of key growth/survival pathways (e.g. PI-3K/Akt, Ras/Raf/MAPK, IKK-α/NF-κB); increased expression of inhibitors of apoptosis (e.g. FLIP, XIAP, cIAP-2); neutralization of pro-apoptotic Forkhead transcription factors; increased proteasome and telomerase activity; and enhanced proliferative response of tumor cells to other growth factors (e.g. MM or PrCa cells to IL-6). Anti-IGF-II Ab also partially inhibited the protective effect of serum against Dex, chemotherapeutics or PS-341; and suppressed VEGF production by tumor cells (e.g. MM, prostate or thyroid Ca) or BMSCs. Our studies show that IGF-II plays major role in tumor cell proliferation/survival and that IGF-I levels in cancer patients are not the sole determinant of the activity of IGFs/IGF-1R pathway, therefore comprehensive suppression of biological activity of both IGF-I and IGF-II is needed to abrogate their pleiotropic effects in conferring resistance against diverse anti-cancer drugs