IL-6 promotes growth and epithelial-mesenchymal transition of CD133+ cells of non-small cell lung cancer

Abstract

We examined IL-6 effects on growth, epithelial-mesenchymal transition (EMT) process, and metastatic ability of CD133+ and CD133– cell subpopulations isolated from three non-small cell lung cancer (NSCLC) cell lines: A549, H157, and H1299. We developed IL-6 knocked-down and scramble (sc) control cells of A549 and H157 cell lines by lentiviral infection system, isolated CD133+ and CD133– sub-populations, and investigated the IL-6 role in self-renewal/growth of these cells. IL-6 showed either an inhibitory or lack of effect in modulating growth of CD133– cells depending on intracellular IL-6 levels, but there was higher self-renewal ability of IL-6 expressing CD133+ cells than IL-6 knocked down cells, confirming the promoter role of IL-6 in CD133+ cells growth. We then examined tumor growth of xenografts developed from CD133+ cells of A549IL-6si vs. A549sc cell lines. Consistently, there was retarded growth of tumors developed from A549IL-6si, CD133+ cells compared to tumors originating from A549sc, CD133+ cells. The effect of IL-6 in promoting CD133+ self-renewal was due to hedgehog (Hhg) and Erk signaling pathway activation and higher Bcl-2/Bcl-xL expression. We also investigated whether IL-6 regulates the EMT process of CD133− and CD133+ cells differently. Expression of the EMT/metastasis-associated molecules in IL-6 expressing cells was higher than in IL-6 knocked down cells. Together, we demonstrated dual roles of IL-6 in regulating growth of CD133– and CD133+ subpopulations of lung cancer cells and significant regulation of IL-6 on EMT/metastasis increase in CD133+ cells, not in CD133– cells.

Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway

“…In this study, we confirmed the promotion of TAMs on EMT, and further found COX-2 in TAMs had a significant regulatory function on EMT in breast cancer cells. It has been proved that COX-2/PGE 2 and IL-6 could induce EMT in human cancers, which strongly suggest that inducing the secretion of pro-metastatic cytokines from macrophages is closely involved in the pro-tumor effect of COX-2 in TAMs 43-45.…”

IL-6 Secreted from Cancer-Associated Fibroblasts Mediates Chemoresistance in NSCLC by Increasing Epithelial-Mesenchymal Transition Signaling

“…, stromal IL-6 expression was significantly correlated with the EMT status of cancer cells and with prognosis in patients, indicating that stromal IL-6 secreted from CAFs enhanced EMT signaling and induced resistance against chemotherapy or CD133 expressing NSCLC cells which are correlated with CSC like cells 37. Thus, understanding the impact of IL-6 pathways in dictating cellular responses may provide further insight into the regulation of tumor progression and enriching CSC like cells, and may help to tailor appropriate adjuvant therapy for NSCLC.…”

A novel anticancer agent SNG1153 inhibits growth of lung cancer stem/progenitor cells

“…CD133 has been identified as a stem-like cell marker and used to enrich H460 lung cancer stem cells [1, 41, 42]. We examined the population of cells with CD133 positive phenotype in tumorsphere cells derived from H460 cells and found that CD133 positive cell population was 15-fold higher in H460 tumorsphere compared to H460 adherent cells (Figure 2C, 2D).…”