| Summary: | 博士 === 國立陽明大學 === 傳統醫藥研究所 === 104 === Infiltrated Macrophages in tumor tissues are important parts of the stromal compartment. Special microenvironment of tumor region can not only change the phenotypes and function of macrophages, but also closely related to the recruitment of macrophages. Once the tumor-associated macrophages (TAMs) were raised, tumor cell growth, angiogenesis, invasion and metastasis of normal tissues will be further involved. Therefore, this study reviews the correlation between tumor microenvironment and TAMs. TAMs polarized to M2 phenotype have been shown to play key roles in tumor progression in different cancer types including lung. MUC1 expression in various types of cancer was reported with poorer prognosis. Elevated MUC1 expression has been reported in inflammatory lung macrophages and associated with lung cancer development. In our study, we investigated the role of M2-polarized TAMs (M2-TAMs) in the generation of lung cancer stem cells (LCSCs) and developed a small-molecule agent modulating MUC1 expression in lung cancer cells which may subvert the microenvironment toward a favorable anti-tumor impact. We first found that MUC1 was overexpressed in lung cancer patients and which was associated with poor survival rates. In M2-TAMs and cancer cell co-culture experiment model simulating microenvironment impact, we found that the expression level of MUC1 along with cancer stemness genes significantly increased in lung cancer cells. Intriguingly, pterostilbene, a naturally occurring compound, dose-dependently suppressed self-renewal ability in M2-TAMs-cocultured lung cancer cells accompanied by downregulation of MUC1, NF-B, CD133, β-catenin and Sox2 expression. Moreover, we demonstrated MUC1-silenced M2-TAMs exhibited a significantly lower ability to promote the generation of LCSCs and a decreased level of NF-B, CD133 and Sox2. Collectively, it suggests that MUC1 may play an important role in TAMs-induced LCSC progression. Pterostilbene may have potential to be developed as a small-molecule modulating unfavorable effect of TAMs in lung cancer treatment.
Moreover, innate or acquired drug resistance and consequently, tumor relapse in lung cancer patients have been linked to the activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. Furthermore, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from the fruiting bodies of garcinia indica, possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory and anticancer activities, modulates the activities of lung cancer stem cells (LCSCs) and their associated aggressiveness. Here, we demonstrated the inhibitory effect of garcinol on LCSC phenotype of human NSCLC cells by using the analytical drug cytotoxicity or cell viability, flow-cytometric and functional assay approach. Garcinol significantly diminished the ability of NSCLC cell lines, H441 and A549, to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSCs viability in a dose-dependent manner. Consistent with these observations, Flow cytometric data showed that garcinol reduced putative LCSC pool, evidenced by the dose-dependent decreased proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In same assays, garcinol downregulated β-catenin, Dvl2, Axin2, and Cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/β-catenin signalling pathway. Take together, we demonstrated here that garcinol modulates the LCSC phenotype via regulation of the Wnt/β-catenin signaling and inactivation of STAT3, thus, presenting garcinol as a putative novel anti-LCSC therapeutic agent.
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