Hyper-activation of multiple cell signaling pathways, including Akt, IRS-1, JAK/ STAT3, NF-kB, Wnt and MAPK, contribute to myeloma cell survival and/or proliferation, and myeloma tumor vascularization. We discovered the novel expression of two cell surface receptors that are able to activate these cell signals but were not previously known to be expressed by hematopoietic cells or to be involved in hematological malignancies. We analyzed bone marrow (BM) and peripheral blood (PB) mononuclear cells (MCs) from multiple myeloma (MM) patients and normal donors for the expression of new surface receptors by flow cytometry. We found that the malignant cells from myeloma patients (N = 10) and the MM cell lines RPMI 8226 and U266 express the receptor protein tyrosine phosphatase b/z (RPTPb/z). RPTPb/z contributes to the growth of solid tumors, including glioblastoma, neuroblastoma and melanoma by aberrant accumulation of b-catenin, leading to activation of Wnt, NF-kB and Akt-mediated cell signals. We interfered with RPTPb/z stimulation by its ligand, pleiotrophin (PTN), using specific anti-PTN antibody and showed significant inhibition of MM proliferation in vitro by MTT assay. Importantly, when this antibody was administered to MM tumor-bearing mice in vivo a significant decrease in tumor volume was detected. We have also discovered that peripheral blood monocytes from MM patients (N = 9) and normal donors (N = 7), and a monocytic cell line (THP-1), display untranslocated anaplastic lymphoma kinase (ALK) on the cell surface. Dysregulated ALK expression on a variety of solid tumors is associated with tumor growth, vascularization and metastasis. ALK+ monocytes and THP-1 cells, but not ALK− peripheral B or T lymphocytes or the ALK− monocytic cell line U937, respond to ALK stimulation by modulating hematopoietic genes and inducing the expression of endothelial genes as well as exhibiting changes in morphology typical of early vascular endothelial cells (

Chen et al, 2004, Blood 104: 1472
). ALK cross-linking leads to activation of the signaling intermediates IRS-1, PI3′K/Akt, STAT3 and MAPK, that are known to play key roles in angiogenesis. Thus RPTPb/z and ALK, or their downstream signal mediators, could be important new molecular targets for anti-myeloma (RPTPb/z) or anti-angiogenic (ALK) therapy. We are defining the signaling pathway(s) leading from RPTPb/z stimulation to MM cellular proliferation and survival, and from ALK to tumor vascularization via monocytic transdifferentiation. These studies provide potential new targets that should lead to new therapeutic strategies for treating MM.

Topics:
angiogenesis, monocytes, multiple myeloma, myeloma cells, neoplasms, minimally conscious state, proto-oncogene proteins c-akt, antibodies, irs1 protein, human, mitogen-activated protein kinases

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2005, The American Society of Hematology
2005
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