Life, death ant the role of IGF-I in human multiple myeloma

Abstract: Multiple myeloma (MM) is a clonal expansion of malignant cells with a plasmablast- plasma cell morphology in the bone marrow. It is a fatal disease with a median survival of 2-3 years after start of conventional therapy. The aim of the thesis was to study the regulation of growth and survival of MM cell lines and primary, cells to identify potential targets for therapy. The results of the thesis show that MM cells express IGF-I (insulin-like growth factor-I) receptors and IGF-I. Furthermore, IGF-I was shown to stimulate growth and survival of MM cells. When IGF-IR signaling is inhibited by anti-IGF-IR antibodies in MM cells they are growth inhibited and may also undergo apoptosis. The somatostatin analogue octreotide has been demonstrated to interfere with the action of IGF-I. The results of the thesis show that MM cells express sst2, sst3 and sst5 which bind octreotide with a moderate or high affinity. Moreover, octreotide inhibits the growth of all investigated MM clones. In a few cases growth inhibition was also accompanied by the induction of apoptosis.Resistance to apoptosis may be important for cell survival and drug resistance in MM clones. Studies in the thesis demonstrated that interferon (IFN)-α and IFN-γ augment the sensitivity to Fas-induced apoptosis in MM cells independently of their growth inhibitory effect. The sensitivity to apoptosis was also increased by inhibition of IGF-IR signaling. Incubation of MM cells with anti-IGF-IR antibodies increased the sensitivity of the cells to apoptosis induced by Fas ligation and the glucocorticoid dexamethasone. It can be concluded that the IGF-IR may be a potential target for therapy in MM. Furthermore, increasing the sensitivity of MM cells to apoptosis by treatment with IFNs or drugs that interfere with the action of IGF-I may increase the sensitivity of the tumor cells to cytotoxic drugs.