Dr. Dalton and his colleagues have found that elements of the bone marrow microenvironment, including extracellular matrices and normal stromal elements, protect hematologic malignant cells from drug-induced cell death. They proposed that environmentally mediated drug resistance (EMDR) protects tumor cells from stress and cell death by two mechanisms: 1) a paracrine mechanism due to soluble cytokine factors produced as a result of the tumor cell:environment interaction; and 2) a physical contact mechanism they have termed 'cell adhesion'mediated drug resistance" (CAM-DR). Their initial studies comparing genotypic and phenotypic profiles of drug resistance indicate that EMDR is less complex than acquired drug resistance. Focusing on EMDR may ultimately prevent the emergence of acquired drug resistance and enhance drug therapy for hematologic malignancies.
Dr. Dalton and his colleagues have examined the signal transduction pathways associated with tumor cells and the microenvironment with the idea that a thorough understanding of these pathways will lead to new therapeutic targets. They reported that adhesion to fibronectin of myeloma cell lines causes a reversible G1 arrest, which correlated with increased levels of p27kip1. Myeloma is characterized as a slow-growing malignancy, and the bone marrow microenvironment may participate in regulating the growth of the disease. They also showed that adhesion-mediated increases in p27kip1 levels contribute to the CAM-DR phenotype, as reducing p27kip1 levels with antisense techniques partially reversed the phenotype.
Similarly, Dr. Dalton and his colleagues, in collaboration with Dr. Gabrilovich of the Immunology Program, investigated the role of Notch family proteins in hematologic tumor cell line growth and response to chemotherapeutic drugs. Interaction with bone marrow stroma activated Notch signaling in tumor cells. However, activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis. This protection was associated with up-regulation of p21WAF/Cip and inhibition of cell growth. Overexpression of Notch-1 in Notch-1'negative U266 myeloma cells up-regulated p21 and resulted in protection from drug-induced apoptosis. This was the first report demonstrating that Notch-1 signaling may be a primary mechanism mediating the bone marrow stromal influence on hematologic malignant cell growth and survival.