Targeting the bone marrow microenvironment in hematologic malignancies.
Unicellular drug-resistant models have been critical in elucidating intrinsic drug-resistant mechanisms; however, these models do not consider resistance mechanisms that may be elicited by extrinsic influences such as the tumor microenvironment. We propose that specific niches within the tumor microenvironment may provide a sanctuary for subpopulations of tumor cells to evade or circumvent drug-induced death and that this may represent a form of de novo drug resistance. We have found that elements of the bone marrow microenvironment, including extracellular matrices and normal stromal elements, protect malignant cells, including leukemia and myeloma cells, from drug-induced cell death. This extrinsic form of drug resistance may allow cells to survive initial drug treatment and thereby acquire a more complex, intrinsic drug-resistant phenotype. Focusing on this form of de novo drug resistance may ultimately prevent the emergence of acquired drug resistance and enhance drug therapy for hematologic malignancies.
Dalton
William S
WS
H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
Hazlehurst
Lori
L
Shain
Kenneth
K
Landowski
Terry
T
Alsina
Melissa
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans
D000970:Antineoplastic Agents