Abstract
Cancer cells are known to contain high levels of the heat shock protein 70 kDa (Hsp70), which mediates increased cell proliferation, escape from programmed cell death, enhanced invasion, and metastasis. A part of Hsp70 molecules may release from cancer cells and affect the behavior of adjacent stromal cells. To explore the effects of Hsp70 on the status of monocytes/macrophages in the tumor locale, we incubated human carcinoma cells of three distinct lines with normal and reduced content of Hsp70 with THP1 monocytes. Using two methods, we showed that the cells with knock-down of Hsp70 released a lower amount of protein in the extracellular medium. Three cycles of the co-cultivation of cancer and monocytic cells led to the secretion of several cytokines typical of the tumor microenvironment (TME) and to pro-cancer activation of the monocytes/macrophages as established by elevation of F4/80 and arginase-1 markers. Unexpectedly, the efficacy of epithelial–mesenchymal transition and resistance of carcinoma cells to anticancer drugs after incubation with monocytic cells were more pronounced in cells with lower Hsp70, e.g., releasing less Hsp70 into the extracellular milieu. These data suggest that Hsp70 released from tumor cells into the TME is able, together with the development of an anti-cancer immune response, to limit the conversion of a considerable part of monocytic cells to the pro-tumor phenotype.
Highlights
Tumor cells possess several attributes that are necessary to activate the immune response: They often carry mutant or improperly processed proteins that can trigger adaptive antitumor immunity, and inflammation often develops around the tumor area [1]
The aim of this study was to understand how the macrophage phenotype changes as it moves through new populations of tumor cells with high or low extracellular heat shock protein 70 kDa (Hsp70), how the cytokine profile of the tumor microenvironment (TME) varies, and how tumor cells react to these actions
These cells were designated as A431scr and A431shHsp70, A549scr and A549shHsp70, and DLD1scr and DLD1shHsp70
Summary
Tumor cells possess several attributes that are necessary to activate the immune response: They often carry mutant or improperly processed proteins that can trigger adaptive antitumor immunity, and inflammation often develops around the tumor area [1]. The pro-inflammatory cytokine, IL-1β, provokes the epithelial–mesenchymal transition (EMT) of tumor cells due to activation of the IL-1β/interleukin 1 receptor type 1 (IL-1RI)/β-catenin signaling pathway [7] and recruits additional immune cells to the tumor site [6]. IL-6, through its receptor IL-6R and Janus signaling pathway, activates STAT3, and this action leads to increased tumor cell proliferation, acquisition of resistance to anticancer drugs, EMT induction, and, elevated metastasis [12,13]. Another factor that regulates the TME is TNF-α, a pleotropic cytokine that plays a key role in the regulation of apoptosis, tumor angiogenesis, inflammation, and immunity [14]. CCL2 recruits MDSCs to tumors [18]
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