Tumor-associated macrophage derived IL-6 enriches cancer stem cell population and promotes breast tumor progression via Stat-3 pathway

Abstract

Background Cancer stem cells (CSCs) play crucial role in tumor progression, drug resistance and relapse in various cancers. CSC niche is comprised of various stromal cell types including Tumor-associated macrophages (TAMs). Extrinsic ques derived from these cells help in maintenance of CSC phenotype. TAMs have versatile roles in tumor progression however their function in enrichment of CSC is poorly explored. Methods Mouse macrophages (RAW264.7) cells were activated by interaction with conditioned media (CM) of murine breast cancer cells (4T1) into TAMs and the effect of activated macrophage (TAM) derived factors was examined on enrichment of cancer stem cells (CSCs) and tumor growth using in vitro and in vivo models. Results In this study, we report that macrophages upon interaction with breast cancer cells activate tumor promoting function and exhibit differential expression of various proteins as shown by secretome analysis using proteomics studies. Based on secretome data, we found that Interleukin-6 (IL-6) is one of the up-regulated genes expressed in activated macrophages. Further, we confirm that TAMs produce high levels of IL-6 and breast cancer cell derived factors induce IL-6 production in activated macrophages via p38-MAPK pathway. Furthermore, we demonstrate that tumor activated macrophages induce enrichment of CSCs and expression of CSC specific transcription factors such as Sox-2, Oct-3/4 and Nanog in breast cancer cells. We further prove that TAM derived IL-6 plays a key role in TAM mediated CSC enrichment through activation of Signal transducer and activator of transcription 3 (STAT-3) signaling. TAM derived IL-6 influences breast cancer cell migration and angiogenesis. Moreover, our in vivo findings indicated that TAM derived IL-6 induces CSC population and resulting tumor growth in breast cancer. Conclusion These finding provide evidence that TAM derived IL-6 plays a major role in CSC enrichment and tumor progression in breast cancer and IL-6 and its regulated signalling network may act as potential therapeutic target for management of breast cancer.

Irradiated Mammary Spheroids Elucidate Mechanisms of Macrophage-Mediated Breast Cancer Recurrence

“…Taken together, this data suggests that interactions between tissue damaged from RT and M2 and M1 macrophages causes secretion of IL-6 that in turn recruits 4T1 cells ( Figure 4C ). Myeloid-derived IL-6 has been reported in 4T1 progression and metastasis 33,34 . However, this is the first report of IL-6 driving 4T1 invasiveness post-RT in the context of recurrence.…”

The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme

“…These results further differentiate, from a molecular point of view, the two GBM subgroups, assigning a specific IL6-NANOG signature to the KDM5C High . Since IL6 overexpression is induced by hypoxia [ 65 ], and as IL6 may strongly induce NANOG expression and promote proliferation and stemness in other tumors [ 66 , 67 , 68 ], the co-expression of IL6-NANOG likely represents a hypoxia-induced module, which appears as a distinctive feature of the KDM5C High GBM phenotype. Nevertheless, our results further emphasize TREM2 as a GBM biomarker, as recently reported [ 69 ].…”

HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer

“…In this study, high expression of IL6 was identified in HSPB1-overexpressing group, and the inhibited expression of IL6 caused by HSPB1 knockdown could be rescued by IKβ-α knockdown. IL6 could be secreted from various cells in cancer tissues, including myeloid cells, cancer-associated fibroblasts, and cancer cells (45–47). Our results revealed that HSPB1 overexpression promoted the secretion of IL6, whereas HSPB1 knockdown led to decreased IL6 secretion in breast cancer cells.…”