Targeting the TumorMicroenvironment for Enhancing Chemotherapy in HematologicMalignancies

Abstract

Mounting evidence now suggests that dynamic interactions between the cancer cell and its local and systemic microenvironment play a critical role in tumor development and that all of the clinical properties of a tumor, including response to therapy, depend heavily on the tumor stroma. We have much less understanding of the biology and genetics of stroma-tumor interactions than we do of tumor cells. Despite recent advances in the treatment of cancer, cancer still remains incurable, largely because of the emergence of drug-resistant tumor cells. Hematologic malignancies arise from defects in normal hematopoiesis and are often associated with aberrant expression of growth and survival factors, such as TGF-□, VEGF, bFGF, IL-6, and BAFF. These growth factors have also been shown to be involved in dysregulated apoptosis. Once a hematopoietic cell becomes malignant, these growth factors can be produced by both the tumor cell as well as by cells surrounding the tumor. These surrounding cells, such as bone marrow stromal cells, together with the extracellular matrix, cytokines and growth factors, and blood vessels, comprise the tumor microenvironment. This microenvironment provides a safe haven for the tumor cells to grow, and, following chemotherapeutic treatment, contributes the emergence of minimal residual disease (MRD), where a small number of drug resistant tumor cells survive cytotoxic stress. These drug resistant tumor cells, which often exhibit upregulation of anti-apoptotic pathways, are typically the cause of relapse of hematologic diseases. Thus, targeting these tumor cells along with the tumor microenvironment in which the tumor cells reside is vital in overcoming the devastating effects associated with hematologic malignancies.