Signaling pathways involved in multiple myeloma-bone marrow stromal cell interaction

Project funded by THE NATIONAL UNIVERSITY RESEARCH COUNCIL,
Ministry of Education and Research, Romania
(contract no. 395, 01-10-2007).

Project manager

Mihaela Zlei, PhD, Biologist at the St. Spiridon Hospital, Laboratory of Immunology and Genetics, Iasi, Romania. Bd. Independentei nr.1 Iasi, code 700111, Romania,
e-mail mihaelazlei@hotmail.com

Summary

Multiple myeloma (MM) remains an incurable malignancy with medullary localization and the documented occurrence of multi-drug resistance phenotypes reoriented the scientific interest toward the study of bone marrow (BM) microenvironment. BM stromal cells (BMSCs), together with other normal components of the microenvironment, have a major role in mm pathogeny, mediating anti-apoptotic and proliferative effects on mm cells and cytokines. In previous studies, carried out in collaboration with a German group from the Department of Hematology, University of Freiburg, we established an experimental model for the in vitro study of interactions between mm cells and BMSCs. Using this co-culture system we identified particular cytokine patterns. Consequently, we further intend, as a major objective of the current project proposal, to identify common signaling pathways activated inside the microenvironment and to evaluate their potential as molecular therapy target.

Specific objectives

1. To identify key signaling pathways involved in MM cell survival and proliferation within a co-culture system with BMSCs (2008). Despite intensive studies in this field, presently there are substantial gaps in the knowledge of common signaling pathways activated in MM cells within the BM milieu. In prior studies we described BM-microenvironment specific cytokine profiles. Identifying of the common pathways activated by these cytokines remains a priority for designing efficient therapy strategies with impact on the management of MM patients.
2. To evaluate the impact of hypoxia on the BMSCs-mediated MM cell growth effects and on the activation of key signaling pathways in MM cells (2009). The role of hypoxia in tumor progression as a potential key element of tumor microenvironment in various types of cancer has been well documented. This objective involves comparative studies of co-cultures under either normoxia or hypoxia and envisions the validation of an improved in vitro culture system for the study of MM within the BM microenvironment.
3. To evaluate the effect of specific inhibitors of the identified signaling pathways (see objectives 1 and 2) and to define their impact on BMSC-mediated protection of MM cells (2010). Following the fulfillment of objectives 1 and 2 we expect to be able to select particular components of the pathways activated after MM cell-BMSC interaction. And the range of their specific inhibitors to be used. This last objective will create an opportunity for validation of key elements of myelomageneous microenvironment as therapy targets for combating the survival, proliferation and migration in hypoxia culture conditions.

Project development

The project is designed to begin in January 2008. During 2007 our group developed the BMSCs and MM cell collection and reviewed the recent literature in order to identify specific indications for optimizing the methodology and the panel of reagents. In order to fulfill the first objective, i.e. to identify key signaling pathways involved in MM cell survival and proliferation within a co-culture system with BMSCs, we will exploit previously acquired data describing cytokine and chemokine profiles specific to intercellular interactions within the BM microenvironment in MM. These factors activate common signaling pathways, although their starting points are distinct.