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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2209. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Roodman, G. D. Search for Related Content PubMed Articles by Roodman, G. D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Abe et al, page 2484 Osteoclasts and myeloma cells stick together G. David Roodman UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This article demonstrates the importance of osteoclast–myeloma cell interactions in both tumor growth and the bone destructive process in myeloma. In this issue, Abe and colleagues demonstrate that osteoclasts (OCs) support the growth of myeloma cells and that adhesive interactions between myeloma cells and OCs increase both the proliferation of myeloma cells and promote the survival of OCs. They further show that interleukin-6 (IL-6) and osteopontin (OPN), produced by OCs when they bind myeloma cells, are responsible for the enhanced growth of myeloma cells (Figure 1). However, in the presence of these adhesive interactions, blocking IL-6 and OPN with neutralizing antibodies only partially abrogates the growth-enhancing effects of OCs on myeloma cells, demonstrating the importance of these adhesive interactions. The authors further report that OCs support the growth of myeloma cells to a much greater extent than marrow stromal cells, even when additional OPN and IL-6 are added to the marrow stromal cells. Finally, they demonstrate that adhesive interactions between OCs and myeloma cells protect myeloma cells from the cytotoxic effects of doxorubicin. These studies further support the important role of the bone marrow microenvironment in the development of bone lesions and tumor growth in myeloma. Yaccoby and coworkers1 have shown that blocking osteoclastic bone resorption with bisphosphonates or osteoprotegerin results in decreased growth of myeloma cells. Recently, they have also reported that OCs support the growth of primary myeloma cells.2 Furthermore, the interplay between OCs, marrow stromal cells, and tumor cells results in a "vicious cycle" that increases both bone destruction and tumor growth. The finding by Abe et al that OCs appear to better support myeloma cell growth than the stromal cells may reflect the difference in the capacity of these cells to produce OPN. The fact that v3 integrin is involved in these interactions is not surprising sincev3 is expressed on OCs and binds OPN. The binding of myeloma cells to OCs results in enhanced OC production of OPN, which may in part explain the increased OC survival in these studies. Loss of cell adhesion decreases OC survival.3 Adhesive interactions via 41 integrin induce production of IL-6 and OPN by osteoclasts, which increase the growth and chemoresistance of myeloma cells. In addition, these interactions enhance osteoclast survival.   IL-6 has also been implicated as a mediator for marrow stromal cells as it supports the growth and survival of myeloma cells, and Nefedova and coworkers4 have previously reported that adhesive interactions between myeloma cells and marrow stromal cells make myeloma cells resistant to chemotherapeutic agents. This paper extends these previous findings of the important role the marrow microenvironment plays in myeloma and identifies the OC as a major player in the growth of myeloma cells. Mori et al5 have recently shown that interrupting adhesive interactions between myeloma cells and marrow stromal cells in a murine model of myeloma decreases tumor growth and bone destruction and may be an important therapeutic target for treating patients who have chemoresistant disease. References Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J. Myeloma interacts with the bone marrow micro-environment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol. 2002;116: 278-290.[CrossRef][Medline] [Order article via Infotrieve] Yaccoby S, Wezeman MJ, Henderson A, et al. Cancer and the microenvironment: myeloma-osteoclast interactions as a model. Cancer Res. 2004;64: 2016-2023.[Abstract/Free Full Text] Sakai H, Kobayashi Y, Sakai E, Shibata M, Kato Y. Cell adhesion is a prerequisite for osteoclast survival. Biochem Biophys Res Commun. 2000;270: 550-556.[CrossRef][Medline] [Order article via Infotrieve] Nefedova Y, Landowski TH, Dalton WS. Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia. 2003;17: 1175-1182.[CrossRef][Medline] [Order article via Infotrieve] Mori Y, Shimizu N, Dallas M, et al. Anti-(alpha)4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood. Prepublished on May 11, 2004, as DOI 10.1182/blood-2004-01-0236. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion Masahiro Abe, Kenji Hiura, Javier Wilde, Atsushi Shioyasono, Keiji Moriyama, Toshihiro Hashimoto, Shinsuke Kido, Takashi Oshima, Hironobu Shibata, Shuji Ozaki, Daisuke Inoue, and Toshio Matsumoto Blood 2004 104: 2484-2491. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Roodman, G. D. Search for Related Content PubMed Articles by Roodman, G. D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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