The somatostatin analog octreotide inhibits growth of interleukin-6 (IL-6)-dependent and IL-6-independent human multiple myeloma cell lines.

Somatostatin and its analogs can inhibit growth in several cell types, in part by interfering with insulin-like growth factor-I (IGF-I) signaling. Our previous studies point to the importance of paracrine and autocrine IGF-I in the support of growth and survival of human multiple myeloma (MM) cell lines. In this report, we have investigated the potential role of a somatostatin analog, octreotide, in regulating growth and/or survival in MM. The results show that all MM cell lines express functional somatostatin receptors (sst). The MM cell lines express the subtypes sst2, sst3, and predominantly sst5 as determined by reverse-transcriptase polymerase chain reaction and fluorescence-activated cell sorter analysis. Octreotide inhibited the growth of both the interleukin-6 (IL-6)-dependent and the IL-6-independent MM cell lines. The effect is mainly cytostatic, resulting in 25% to 45% growth inhibition, and in three of eight of the MM cell lines a weak induction of apoptosis was recorded. Our results also show that octreotide may act as an inducer of apoptosis in primary B-B4(+) plasma cells isolated from bone marrow of MM patients. In conclusion, the results show a novel pathway for growth inhibition of MM cells: the activation of somatostatin receptor signaling.

Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines.

Human multiple myeloma (MM) represents a highly aneuploid tumor as shown by cytogenetic studies. This may partly explain the heterogeneity with regard to growth factor requirements demonstrated among MM cells. We have previously reported the expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR) mRNA in some MM cell lines. In this study we investigated the role of IGF-I as a growth and/or survival factor in three MM cell lines: LP-1, EJM, and Karpas 707. We report that all cell lines expressed IGF-I and IGF-IR mRNA and protein. LP-1 and Karpas 707, but not EJM, were stimulated to proliferation in a dose-dependent manner by exogenous IGF-I. An IGF-IR blocking antibody inhibited both the IGF-I-induced and spontaneous growth of LP-1, and Karpas 707, while the EJM cell line was unaffected by the addition of the antibody. In conclusion, our results show that IGF-I can act as a growth factor in human MM, and they suggest that an autocrine IGF-I loop may contribute to the growth and survival in some MM cell lines.

A novel human B-cell line (U-2904) bearing t(8;14) and t(14;18) translocations.

Sequential activation of bcl-2 and c-myc appears to be involved in the pathogenesis of rare de novo acute lymphoid leukemias bearing both t(8;14) and t(14;18). Acquisition of t(8;14) by follicular-lymphoma cells with t(14;18) has also been related to the clinical transformation into an overt acute lymphoid leukemia in rare cases reported, and a role for c-myc involvement in the progression of some follicular lymphomas with t(14;18) has been suggested by the detection of c-myc rearrangements in association with histologic transformation. However, c-myc abnormalities different from those observed in Burkitt's lymphoma have been reported in diffuse large-cell lymphomas with breakpoints in 8q24, and a t(8;14) molecularly different from the classical one has been found in follicular lymphomas without t(14;18). We report the preliminary characterization of the EBV-negative cell line U 2904 established from a transformed follicular lymphoma that carries both t(8;14) (q24;q32) and t(14;18) (q32;q21) translocations. U 2904 cells have a mature B-cell phenotype, grow in agarose and are tumorigenic in nude mice. Rearrangements of both c-myc and bcl-2 confirmed the involvement of both oncogenes in the translocations which lead to abundant c-myc and bcl-2 transcripts. Two JH rearrangements and one C alpha rearrangement were observed which did not co-migrate with either c-myc or bcl-2 rearrangements. This is the first report of a cell line bearing both t(8;14) and t(14;18) derived from a follicular lymphoma after documented transformation into a centroblastic lymphoma without leukemic features. U 2904 provides further evidence for the involvement of c-myc in the progression of follicular lymphomas.

Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus.

BACKGROUND: It has previously been observed that the insulin-producing cells of human pancreatic islets are more resistant to alloxan-, streptozotocin-, nitroprusside-, or cytokine-induced injury than those of mouse and rat islets. MATERIALS AND METHODS: Human pancreatic islets were obtained from heart-beating organ donors. The expression of the stress proteins heat shock protein 70 (hsp70) and heme oxygenase and the anti-apoptosis gene bcl-2 was determined in isolated rat, mouse, and human islets, either cultured in vitro or transplanted under the kidney capsule of nude mice, using immunoblot analysis. Rat and human islet sensitive hydrogen peroxide was assess by glucose oxidation measurements. Isolated islets were also analyzed for their catalase and superoxide dismutase activities, and the islet cell levels of reduced glutathione were determined in response to hydrogen peroxide and nitroprusside. Programmed cell death in human and rat islets in response to streptozotocin was evaluated using TUNEL staining. RESULTS: Cultured human islets expressed higher contents of hsp70 than mouse and rat islets at basal conditions. Also after 4 weeks under the kidney capsule of normoglycemic mice, the hsp70 levels were higher in human islets than in rat islets. The expression of another stress protein, heme oxygenase (HO), was strongly increased in cultured rat islets, but was not affected in human islets. Expression of the bcl-2 gene could not be detected in human islets. In spite of this, 0.5 mM streptozotocin induced apotosis in rat but not in human islet cells. Hydrogen peroxide (0.1 and 0.4 mM) decreased glucose oxidation rates in rat but not in human islets. The levels of reduced glutathione were moderately decreased in human and rat islet cells and sharply decreased in mouse islet cells in response to hydrogen peroxide. Moreover, the activities of catalase and superoxide dismutase (SOD) were markedly lower in mouse islets than in human islets. The activity of catalase was lower in rat islets than in human islets. CONCLUSION: Human islets differ clearly from mouse and rat islets in their increased expression of hsp70, catalase, and SOD, which may explain the increased resistance of human islets to beta cell toxins.

Cellular death in neuroblastoma: in situ correlation of apoptosis and bcl-2 expression.

Apoptosis is the selective physiologic deletion of cells that are no longer required. Over-expression of the bcl-2 proto-oncogene extends survival of neurons otherwise destined for apoptosis. The unique capacity of neuroblastoma (NB) to undergo spontaneous regression and the prognostic dichotomy of children with this malignancy led us to evaluate bcl-2 expression and apoptosis in NB. An in situ DNA nick-labeling technique to detect apoptotic cells, as well as immunohistochemistry and morphology, were utilized in a selection of NB tumor specimens and in the human fetal sympathetic nervous system. bcl-2 expression was present in all 28 NB tumors examined and in sympathetic ganglia of the human fetus. Measurement of overall bcl-2 expression and of extent of apoptosis correlated with favorable prognosis. In low-stage tumors, bcl-2 expression was most intense in poorly differentiated tumor cells adjacent to fibrovascular stroma. Cells distant from the stroma exhibited increasing degrees of chromaffin differentiation, with apoptosis most evident in bcl-2-negative neuroblasts adjacent to well-differentiated NB cells. The spatial distribution of bcl-2 expression, apoptosis and chromaffin differentiation in favorable-prognosis NB may provide insight into mechanisms of persistent tumor existence or regression.