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The Role Of The Ras Oncogene In Multiple Myeloma Spread
By Anna M. Masellis, Cross Cancer Institute, Edmonton, Alberta
Multiple Myeloma (MM), an incurable cancer at present, is characterized by the accumulation of malignant plasma cells in the bone marrow (BM), high concentrations of monoclonal immunoglobulin, and lytic bone lesions. As for many tumors, the pathophysiology of myeloma includes the unregulated expansion of tumor cells concomitant with the spread of the tumor cells to multiple and distant sites throughout the body. That myeloma cells preferentially accumulate in the BM implies that this environment best supports the growth and maintenance of the myeloma clone. However, the mechanism underlying the movement of plasma cells from the BM microenvironment to the peripheral blood and the subsequent spread of plasma cells to distant skeletal and extraskeletal sites during disease progression, is not well understood.

The role of oncogenes in cancer progression has been widely investigated over the past decade. In particular, mutations in the Ras superfamily of GTPases contribute to cellular transformation and tumorigenesis. Mutations of N, K or H-Ras, resulting in constitutive accumulation of the GTP-bound form, have been associated with increased tumor cell proliferation as well as increased metastatic and invasive tumor cell behavior. While analysis of mutations in Ras remains a useful prognostic indicator, a further understanding of the mechanism by which mutations in Ras impact upon many distinct cellular behavior would enhance our understanding of the pathophysiology of many tumors. Ras mediates the transmission of signals from the extracellular environment to the cell nucleus. Critical to its function in signal transduction is the requirement for Ras co-distribution, with cell surface receptors and other signal transduction proteins, to discrete plasma membrane is an absolute requirement for the cellular transformation by Ras, and mutations which abolish Ras translocation to the plasma membrane likewise abolish it's tumorigenic properties.

We have previously identified the expression of RHAMM, the Receptor for Hyaluronan Mediated Motility, as a characteristic associated with malignant B cells expressed on ex-vivo MM cells but not on normal ex-vivo lymphocytes. RHAMM expression underlies the enhanced migratory behavior of myeloma plasma cells from extraskeletal sites, including peripheral blood. Paradoxically, bone marrow plasma are non-migratory despite expression of RHAMM. Migrating peripheral blood cells localize RHAMM to the plasma membrane, where it co-localizes specifically with Ras. In contrast, RHAMM is rapidly down-regulated from the cell surface of non-migrating bone marrow plasma cells, and no co-localization of Ras and RHAMM is observed.

A progress report is available for this grant.
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