Figure: A 5TGM1 myeloma bearing mouse, in which the marrow has been replaced by tumor cells and there is a loss of trabecular bone.

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.

Projects:

• The effect of targeting both tumor cells and the host microenvironment using proteasome inhibitors
• The role of cells of the host bone marrow microenvironment in myeloma initiation and progression
• The role of host-derived MMPs in myeloma bone disease
• The role of novel receptors and ligands in myeloma bone disease

Research Techniques:

• Mouse models of myeloma (tail vein injection, subcutaneous injection, intra-tibial injection)
• Cell culture (myeloma cell lines, primary myeloma cells, osteoblast and osteoclast culture/assays)
• Molecular biology (gene expression, transfection)
• Biochemistry (western blotting, ELISA, multi-color flow cytometry)
• Immunohistochemistry (frozen, paraffin, plastic)
• Static and dynamic bone histomorphometry
• Imaging (micro-CT, GFP in vivo imaging, X-Ray)
  

Personnel:

• Jessica Fowler, graduate student
• Andreia Bates, graduate student
• Seint Lwin, research assistant II

Recent Publications:

• Edwards, C.M., Zhuang, J., Mundy, G.R. (2008) The pathogenesis of the bone disease of multiple myeloma. Bone (in press).
• Edwards, C.M., Edwards, J.R., Esparza, J., Oyajobi, B.O., McCluskey, B., Munoz, S., Grubbs, B., Mundy, G.R. (2007) 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; 2833-2842.
• Locklin, R.L., Federici, E., Espina, B., Hulley, P.A., Russell, R.G., Edwards, C.M. (2007) Selective targeting of DR-5 circumvents resistance of MG-63 osteosarcoma cells to TRAIL-induced apoptosis. Molecular Cancer Therapeutics 6; 3219-3228
• Roelofs, A.J., Edwards, C.M., Russell, R.G., Ebetino, F.H., Rogers, M.J., Hulley, P.A. (2007) Apomine enhances the anti-tumor effects of lovastatin on myeloma cells by downregulating 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Journal of Pharmacology and Experimental Therapeutics, 322; 228-235
• Locklin, R.M., Croucher, P.I., Russell, R.G.G., Edwards, C.M. (2007) Agonists of TRAIL death receptors induce myeloma cell apoptosis that is not prevented by cells of the bone marrow microenvironment. Leukemia.  21; 805-812.
• Edwards, C.M., Mueller, G., Perry, M., Russell, R.G.G., Van Camp, B., Guyon-Gellin, Y., Niesor, E., Bentzen, C., Vanderkerken, K., Croucher, P.I. (2007) APOMINE™, a mevalonate/isoprenoid pathway inhibitor, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma disease in vivo. International Journal of Cancer. 120; 1657-1663.
• Roelofs, A.J., Hulley, P.A., Russell, R.G.G., Ebetino, F.H., Shipman, C.M. (2006) Anti-Tumor Effects Of Risedronate, and Its Low Bone Affinity Phosphonocarboxylate Analogue NE10790, In Human Myeloma Cells In Vitro. International Journal of Cancer 119; 254-1261.
• Edwards, J.R., Sun, S.G., Shipman, C.M., Adamapoulos, I., Athanasou, N., Sabokbar, A. (2006) LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis. Arthritis and Rheumatism 54; 1451-1462..
• Holen, I. Shipman, C.M. (2005) The Role of Osteoprotegerin in Cancer. Clinical Science 110: 279-291.
• Shipman, C.M. Oyajobi, B.O., Mundy, G.R. (2005) Advances in the management of myeloma bone disease. Expert Opinion in Pharmacotherapy 6: 2781-2791
• Oyajobi, B.O., Shipman, C.M., Mundy, G.R. Recent Insights into Myeloma Bone Disease. IBMS BoneKEy 2005 10.1138/ibmske; 20050161.
• Shipman, C.M., Croucher, P.I. (2003) Osteoprotegerin is a soluble decoy receptor for TRAIL/Apo2L and can function as a paracrine survival factor for human myeloma cells. Cancer Research 63: 912-916
• Croucher, P.I., De Raeve, H., Perry, M.J., Hijzen, A., Shipman, C.M., Lippitt, J., Green, J., Van Marck, E., Van Camp, B., Vanderkerken, K. (2003) Zoledronic acid prevents the development of osteolytic bone lesions and increases survival in the 5T2MM murine model of multiple myeloma. Journal of Bone and Mineral Research. 18: 482-492.
• Croucher, P.I., Shipman, C.M., Van Camp, B., Vanderkerken, K. (2003) Bisphosphonates and osteoprotegerin as inhibitors of myeloma bone disease. Cancer, 97: 818-824
• Vanderkerken, K., De Leenheer, E., Shipman, C., Asosingh, K., Willwms, A., Van Camp, B., Croucher, P. (2003) Recombinant osteoprotegerin decreases tumour burden and increases survival in a murine model of multiple myeloma. Cancer Res, 63: 287 – 289.
• Croucher, P.I., Shipman, C.M., Lippitt, J.M., Asosingh, K., Hijzen, A., Brabbs, A.C., van Beek, E.J.R., Holen, I., Skerry, T.M., Dunstan, C.R., Russell, G.R., Van Camp, E., Vanderkerken, K. (2001) Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood, 98:3534-3540.
• Shipman, C.M., Croucher, P.I., Vanderkerken, K., (2001) Bisphosphonates and in vivo models of multiple myeloma, British Journal of Haematology, 113: 842 (letter)
• Jagdev, S.P., Coleman, R.E., Shipman, C.M., Rostami-H, A., Croucher, P.I. (2001) The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells; evidence for synergy with paclitaxel. British Journal of Cancer, 84; 1126-1134.
• Shipman, C.M., Vanderkerken, K., Rogers, M.J., Lippitt, J.M., Asosingh, K., Hughes, D.E., Van Camp, B., Russell, R.G.G., Croucher, P.I. (2000) The potent bisphosphonate ibandronate does not induce myeloma cell apoptosis in a murine model of established multiple myeloma. British Journal of Haematology, 111; 283-286
• Shipman, C.M., Rogers, M.J., Vanderkerken, K., Van Camp, B., Russell, R.G.G., Croucher,P.I. (2000) Bisphosphonates – Mechanisms of action in multiple myeloma. Acta Oncologica. 39; 829-835.
• Russell, R.G.G., Rogers, M.J., Frith, J.C., Luckman, S.P., Coxon, F.P., Benford, H.L. Croucher, P.I., Shipman, C., Fleisch, H.A. (1999) The pharmacology of bisphosphonates and new insights into their mechanism of action. Journal of Bone and Mineral Research. Suppl.2: 53 – 65.
• Shipman, C.M., Rogers, M.J., Apperley, J.F., Russell, R.G.G., Croucher, P.I.  (1998) Anti-tumour activity of bisphosphonates multiple myeloma. Leukaemia and Lymphoma, 32:129-138.
• Shipman, C.M., Croucher, P.I., Russell, R.G.G., Rogers, M.J. (1998) The bisphosphonate YM175 causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Research. 58:5294-5297.
• Shipman, C.M., Rogers, M.J., Apperley, J.F., Russell, R.G.G., Croucher, P.I. (1997) Bisphosphonates induce apoptosis in human myeloma cells; a novel anti-tumour activity. British Journal of Haematology, 98:665-672