Claire M. Edwards, Ph.D.
Research Assistant Professor of Cancer Biology
Vanderbilt University Medical Center
1235 MRB IV
Nashville, TN 1235 37232-0575
The host bone marrow microenvironment in multiple myeloma
Research in our laboratory is focused upon the critical role of the bone marrow microenvironment in the growth and development of multiple myeloma, and the associated bone disease. Multiple myeloma is the second most common adult hematological malignancy. One of the major clinical features is the development of a unique osteolytic bone disease, characterized by progressive and devastating bone destruction. Myeloma cells are located close to sites of active bone resorption, and are ideally placed to interact with cells of the bone microenvironment, including osteoclasts and osteoblasts. The detailed molecular mechanisms underlying myeloma bone disease remain unknown, however, more recently, our understanding of the biology of myeloma bone disease has increased and it has become clear that whilst the osteoclast is the major destructive cell in myeloma bone disease, a major component of this bone disease is a lack of new bone formation, which is not restored by inhibitors of osteoclastic bone resorption. Our research is focused upon studying the host bone marrow microenvironment; identifying the complex molecular mechanisms which mediate both the growth and survival of myeloma cells within the bone marrow, and the development of myeloma bone disease. We use a combination of in vitro cellular and molecular approaches with a murine model of myeloma which enables us to investigate molecular mechanisms and identify potential therapeutic targets in vivo.
- Ayati, BP, Edwards, CM, Webb, GF, Wikswo, JP A mathematical model of bone remodeling dynamics for normal bone cell populations and myeloma bone disease. Biol Direct, 528, 2010.
- Fowler, JA, Mundy, GR, Lwin, ST, Lynch, CC, Edwards, CM A murine model of myeloma that allows genetic manipulation of the host microenvironment. Dis Model Mech, 2(11-12), 604-11, 2009.
- Edwards, CM, Lwin, ST, Fowler, JA, Oyajobi, BO, Zhuang, J, Bates, AL, Mundy, GR Myeloma cells exhibit an increase in proteasome activity and an enhanced response to proteasome inhibition in the bone marrow microenvironment in vivo. Am J Hematol, 84(5), 268-72, 2009.
- Edwards, CM, Mundy, GR Eph receptors and ephrin signaling pathways: a role in bone homeostasis. Int J Med Sci, 5(5), 263-72, 2008.
- Edwards, CM, Edwards, JR, Lwin, ST, Esparza, J, Oyajobi, BO, McCluskey, B, Munoz, S, Grubbs, B, Mundy, GR Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood, 111(5), 2833-42, 2008.
- Edwards, CM, Zhuang, J, Mundy, GR The pathogenesis of the bone disease of multiple myeloma. Bone, 42(6), 1007-13, 2008.
- Edwards, CM Wnt signaling: bone''s defense against myeloma. Blood, 112(2), 216-7, 2008.
- Locklin, RM, Croucher, PI, Russell, RG, Edwards, CM Agonists of TRAIL death receptors induce myeloma cell apoptosis that is not prevented by cells of the bone marrow microenvironment. Leukemia, 21(4), 805-12, 2007.
- Roelofs, AJ, Edwards, CM, Russell, RG, Ebetino, FH, Rogers, MJ, Hulley, PA Apomine enhances the antitumor effects of lovastatin on myeloma cells by down-regulating 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Pharmacol Exp Ther, 322(1), 228-35, 2007.
- Edwards, CM, Mueller, G, Roelofs, AJ, Chantry, A, Perry, M, Russell, RG, Van Camp, B, Guyon-Gellin, Y, Niesor, EJ, Bentzen, CL, Vanderkerken, K, Croucher, PI Apomine, an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo. Int J Cancer, 120(8), 1657-63, 2007.
- Locklin, RM, Federici, E, Espina, B, Hulley, PA, Russell, RG, Edwards, CM Selective targeting of death receptor 5 circumvents resistance of MG-63 osteosarcoma cells to TRAIL-induced apoptosis. Mol Cancer Ther, 6(12 Pt 1), 3219-28, 2007.
- Edwards, JR, Sun, SG, Locklin, R, Shipman, CM, Adamopoulos, IE, Athanasou, NA, Sabokbar, A LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis. Arthritis Rheum, 54(5), 1451-62, 2006.
- Holen, I, Shipman, CM Role of osteoprotegerin (OPG) in cancer. Clin Sci (Lond), 110(3), 279-91, 2006.
- Roelofs, AJ, Hulley, PA, Meijer, A, Ebetino, FH, Russell, RG, Shipman, CM Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S-phase arrest, in human myeloma cells. Int J Cancer, 119(6), 1254-61, 2006.
- Shipman, CM, Oyajobi, BO, Mundy, GR Advances in the management of myeloma bone disease. Expert Opin Pharmacother, 6(16), 2781-91, 2005.
- Croucher, PI, Shipman, CM, Van Camp, B, Vanderkerken, K Bisphosphonates and osteoprotegerin as inhibitors of myeloma bone disease. Cancer, 97(3 Suppl), 818-24, 2003.
- Shipman, CM, Croucher, PI Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells. Cancer Res, 63(5), 912-6, 2003.
- Vanderkerken, K, De Leenheer, E, Shipman, C, Asosingh, K, Willems, A, Van Camp, B, Croucher, P Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma. Cancer Res, 63(2), 287-9, 2003.
- Croucher, PI, De Hendrik, R, Perry, MJ, Hijzen, A, Shipman, CM, Lippitt, J, Green, J, Van Marck, E, Van Camp, B, Vanderkerken, K Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res, 18(3), 482-92, 2003.
- Shipman, CM, Croucher, PI, Vanderkerken, K. "Bisphosphonates and in vivo models of multiple myeloma." British Journal of Haematology, 113842, 2001.
- Russell, G, Mueller, G, Shipman, C, Croucher, P Clinical disorders of bone resorption. Novartis Found Symp, 232251-67; discussion 267-71, 2001.
- Croucher, PI, Shipman, CM, Lippitt, J, Perry, M, Asosingh, K, Hijzen, A, Brabbs, AC, van Beek, EJ, Holen, I, Skerry, TM, Dunstan, CR, Russell, GR, Van Camp, B, Vanderkerken, K Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood, 98(13), 3534-40, 2001.
- Jagdev, SP, Coleman, RE, Shipman, CM, Rostami-H, A, Croucher, PI The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer, 84(8), 1126-34, 2001.
- Shipman, CM, Rogers, MJ, Vanderkerken, K, Van Camp, B, Graham, R, Russell, G, Croucher, PI Bisphosphonates--mechanisms of action in multiple myeloma. Acta Oncol, 39(7), 829-35, 2000.
- Shipman, CM, Vanderkerken, K, Rogers, MJ, Lippitt, JM, Asosingh, K, Hughes, DE, Van Camp, B, Russell, RG, Croucher, PI The potent bisphosphonate ibandronate does not induce myeloma cell apoptosis in a murine model of established multiple myeloma. Br J Haematol, 111(1), 283-6, 2000.
- Russell, RG, Rogers, MJ, Frith, JC, Luckman, SP, Coxon, FP, Benford, HL, Croucher, PI, Shipman, C, Fleisch, HA The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res, 14 Suppl 253-65, 1999.
- Shipman, CM, Rogers, MJ, Apperley, JF, Graham, R, Russell, G, Croucher, PI Anti-tumour activity of bisphosphonates in human myeloma cells. Leuk Lymphoma, 32(1-2), 129-38, 1998.
- Shipman, CM, Croucher, PI, Russell, RG, Helfrich, MH, Rogers, MJ The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Res, 58(23), 5294-7, 1998.
- Shipman, CM, Rogers, MJ, Apperley, JF, Russell, RG, Croucher, PI Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol, 98(3), 665-72, 1997.