The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications.
In this study we demonstrate that tumor necrosis factor alpha (TNFalpha) triggers only modest proliferation, as well as p44/p42 mitogen-activated protein kinase (MAPK) and NF-kappaB activation, in MM.1S multiple myeloma (MM) cells. TNFalpha also activates NF-kappaB and markedly upregulates (fivefold) secretion of interleukin-6 (IL-6), a myeloma growth and survival factor, in bone marrow stromal cells (BMSCs). TNFalpha in both a dose and time dependent fashion induced expression of CD11a (LFA-1), CD54 (intercellular adhesion molecule-1, ICAM-1), CD106 (vascular cell adhesion molecule-1, VCAM-1), CD49d (very late activating antigen-4, VLA-4), and/or MUC-1 on MM cell lines; as well as CD106 (VCAM-1) and CD54 (ICAM-1) expression on BMSCs. This resulted in increased (2-4-fold) per cent specific binding of MM cells to BMSCs, with related IL-6 secretion. Importantly, the proteasome inhibitor PS-341 abrogated TNFalpha-induced NF-kappaB activation, induction of ICAM-1 or VCAM-1, and increased adhesion of MM cells to BMSCs. Agents which act to inhibit TNFalpha may therefore abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment.
Hideshima
T
T
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA 02115, USA.
Chauhan
D
D
Schlossman
R
R
Richardson
P
P
Anderson
K C
KC
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D003546:Cysteine Endopeptidases; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D039441:Integrin alpha4; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D008954:Models, Biological; D018396:Mucin-1 / Q000096:biosynthesis / Q000235:genetics; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016328:NF-kappa B / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D015703:Antigens, CD; D001897:Boronic Acids; D015850:Interleukin-6; D016169:Lymphocyte Function-Associated Antigen-1; D018396:Mucin-1; D009097:Multienzyme Complexes; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4; D000069286:Bortezomib; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex