Abstract
Resistance to anticancer therapeutics greatly affects the phenotypic and functional properties of tumor cells, but how chemoresistance contributes to the tumorigenic activities of cancer stem-like cells remains unclear. In this study, we found that a characteristic of cancer stem-like cells from chemoresistant tumors (CSC-R) is the ability to produce a variety of proinflammatory cytokines and to generate M2-like immunoregulatory myeloid cells from CD14(+) monocytes. Furthermore, we identified the IFN-regulated transcription factor IRF5 as a CSC-R-specific factor critical for promoting M-CSF production and generating tumorigenic myeloid cells. Importantly, myeloid cells primed with IRF5(+) CSC-R facilitate the tumorigenic and stem cell activities of bulk tumors. Importantly, the activation of IRF5/M-CSF pathways in tumor cells were correlated with the number of tumor-associated CSF1 receptor(+) M2 macrophages in patients with non-small lung cancer. Collectively, our findings show how chemoresistance affects the properties of CSCs in their niche microenvironments.
Highlights
Resistance to anticancer modalities poses serious obstacles that must be addressed to improve the clinical prognosis for patients with cancer
cancer stem cells (CSC) derived from chemoresistant variants (CSC-R) were refractory to cytotoxic therapies compared with CSCs from untreated tumor cells (CSC-N)
We found that mRNA levels of various cytokines and chemokines, such as IL-1b, IL-6, IL-8, IL-12p40, TNF-a, M-CSF, and CCL2 were produced in cells from chemoresistant tumors (CSC-R) subsets at higher amounts compared with the bulk tumor cell counterparts, bulk chemoresistant cells could produce proinflammatory mediators at higher levels than CSC-N or treatment-na€ve bulk tumor cells (Fig. 2A and Supplementary Fig. S2A)
Summary
Resistance to anticancer modalities poses serious obstacles that must be addressed to improve the clinical prognosis for patients with cancer. Recent studies have revealed that multiple mechanisms enable the development of resistance to anticancer therapies through genetic alterations and environmental modifications such as vascular and immunologic remodeling within tumor tissues [1,2,3,4]. Accumulating evidence has established that rare populations termed cancer stem cells (CSC) are indispensable as a main source of tumorigenicity and anticancer drug resistance [5]. It remains largely unclear whether chemoresistance further modifies the phenotypic and functional manifestations of CSCs, previous studies have revealed that the low sensitivity to cytotoxic therapies of CSCs derives mainly from cellular quiescence and multidrug transporter activity [6].
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