The role of microenvironment and immunity in drug response in leukemia

Abstract

Leukemia is a cancer of the white blood cells, with over 54,000 new cases per year diagnosed worldwide and a 5-year survival rate below 60%. This highlights a need for research into the mechanisms behind its etiology and causes of therapy failure. The bone marrow microenvironment, in which adult stem cells are maintained in healthy individuals, has been implicated as a source of chemoresistance and disease relapse. Here the various ways that the microenvironment can contribute to the resistance and persistence of leukemia are discussed. The targeting of the microenvironment by leukemia cells to create an environment more suitable for cancer progression is described. The role of soluble factors, drug transporters, microvesicles, as well as the importance of direct cell-cell contact, in addition to the effects of inflammation and immune surveillance in microenvironment-mediated drug resistance are discussed. An overview of the clinical potential of translating research findings to patients is also provided. Understanding of and further research into the role of the bone marrow microenvironment in leukemia progression and relapse are crucial towards developing more effective treatments and reduction in patient morbidity. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

The Regulation of Pathways of Inflammation and Resolution in Immune Cells and Cancer Stem Cells by Selenium

“…Moreover, because TKIs do not target LSCs, there is a significant gap in our ability to specifically target LSCs to treat CML (Bhatia et al, 2003; Copland et al, 2006; Graham et al, 2002; Jorgensen, Allan, Jordanides, Mountford & Holyoake, 2007). Much like the HSCs that are maintained in specific niches in the bone marrow, CSCs also maintain quiescence with self-renewal capabilities (Bakker, Qattan, Mutti, Demonacos & Krstic-Demonacos, 2016). LSCs are perhaps the best studied CSCs.…”

“…LSCs are sensitive to intrinsic and extrinsic factors that include components generated by immune cells within the bone marrow or other tissue microenvironment (Bakker, Qattan, Mutti, Demonacos & Krstic-Demonacos, 2016; Konopleva & Jordan, 2011; Tabe & Konopleva, 2014). As introduced in section 1, the extrinsic pathway of LSC control involves monocytes and macrophages that can be reprogrammed with selenium to promote eicosanoid class switching to produce bioactive CyPGs, which are endowed with anti-proliferative activity (Finch, et al, 2017; Gandhi, et al, 2014; Gandhi, et al, 2011).…”

Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

“…Drug resistance and cancer progression are mediated by several factors including communication between the bone marrow microenvironment and leukaemia cells in a two-way exchange of regulation [29, 30]. Different modes of communication are involved such as soluble factors and direct cell-cell contact [31–33].…”

“…Different modes of communication are involved such as soluble factors and direct cell-cell contact [31–33]. Furthermore, inflammation, oxidative stress and different types of cell death have been implicated in determining leukaemic cell fate, depending on the drugs used and exposure to the microenvironment [10, 29, 34, 35]. However, better understanding of the role of the bone marrow microenvironment in leukaemia is important, given its impact on clinical outcomes.…”

Microenvironment and its role in acquire drug resistance of leukemia treatment

“…When leukemic cells grow, they disrupt normal hematopoietic progenitor cell (HPC) bone marrow niches and create abnormal microenvironments. Also, niches have been linked to the development of drug resistance [7,8].…”