Chemotherapy disrupts bone marrow stromal cell function [electronic resource] /

by Clutter, Suzanne Davis.

Chemotherapy Disrupts Bone Marrow Stromal Cell Function Suzanne Davis Clutter Advisor: Laura F. Gibson, Ph.D. Associate Professor Department of Pediatrics A variety of bone marrow microenvironment derived signals influence steady state hematopoiesis as well as hematopoietic recovery following bone marrow transplantation. Bone marrow stromal cells found in this unique anatomical niche influence hematopoiesis, in part, through production of soluble cytokines and chemokines. Developmental signals are also initiated by physical interaction of hematopoietic progenitor cells with stromal cells which are mediated by binding of their integrins to receptors on the stromal cell surface. Finally, the extracellular matrix, including may components produced by stromal cells, provides structure as well as a scaffold on which hematopoietic growth factors can be concentrated and stabilized in the marrow. Efficient hematopoietic recovery following transplantation of stem or immature progenitor cells requires sustained function of these components of the bone marrow during dose escalated chemotherapy. In the current study we investigated the effects of the chemotherapeutic agent etoposide (VP-16) on bone marrow stromal cell function. We have previously demonstrated that stromal cells chronically exposed to VP-16 display diminished extra-cellular levels of SDF-1 resulting in disrupted support of pro-B cell chemotaxis. We have also determined that bone marrow stromal cell MMP-2 protein is diminished following exposure to VP-16. Regulation of MMP-2 is required for release of SDF-1 from stromal cell surfaces and ultimately required for optimal support of chemotaxis. Additionally, VP-16 treatment results in alterations of pathways that regulate protein translation, consistent with diminished translation of MMP-2 protein in treated stromal cells. We also determined that following acute VP-16 exposure, MMP-2 activation was transiently increased. Increased MMP-2 activity resulted in activation of TGF-?, which resulted in diminished stromal cell support of pro-B cell adhesion and survival. Collectively, these data contribute to our understanding of the global impact of chemotherapy on the bone marrow microenvironment.