<p>Dihydroartemisinin Prevents Progression and Metastasis of Head and Neck Squamous Cell Carcinoma by Inhibiting Polarization of Macrophages in Tumor Microenvironment</p>

Abstract

Background: Polarized M2 macrophages are an important type of tumor-associated macrophage (TAM), with roles in the growth, invasion, and migration of cancer cells in the tumor microenvironment. Dihydroartemisinin (DHA), a traditional Chinese medicine extract, has been shown to inhibit the progression and metastasis of head and neck squamous cell carcinoma (HNSCC); however, the effect of DHA on cancer prevention, and the associated mechanism, has not been investigated in the tumor microenvironment. Materials and Methods: First, human Thp-1 monocytes were induced and differentiated into M2 macrophages using phorbol 12-myristate 13-acetate (PMA), interleukin-6 (IL-6), and interleukin-4 (IL-4). Induction success was confirmed by cell morphology evaluation, flow cytometry, and quantitative real-time polymerase chain reaction (qRT-PCR). Then, DHA was applied to interfere with M2 macrophage polarization, and conditioned medium (CM), including conditioned medium from M2 macrophages (M2-CM) and conditioned medium from M2 macrophages with DHA (M2-DHA-CM), was obtained. CM was applied to Fadu or Cal-27 cells, and its effects on cancer invasion, migration, and angiogenesis were evaluated using transwell, wound-healing, and tube formation assays, respectively. Finally, Western blotting was used to evaluate the relationship between signal transducer and activator of transcription 3 (STAT3) signaling pathway activation and M2 macrophage polarization. Results: Human Thp-1 monocytes were successfully polarized into M2-like TAMs using PMA, IL-6, and IL-4. We found that M2-like TAMs promoted the invasion, migration, and angiogenesis of HNSCC cells; however, DHA significantly inhibited IL-4/IL-6-induced M2 macrophage polarization. Additionally, as DHA induced a decrease in the number of M2-like TAMs, M2-DHA-CM inhibited the induction of invasion, migration, and angiogenesis of Fadu and Cal-27 cells. Finally, DHA inhibited M2 macrophage polarization by blocking STAT3 pathway activation in macrophages. Conclusion: DHA inhibits the invasion, migration, and angiogenesis of HNSCC by preventing M2 macrophage polarization via blocking STAT3 phosphorylation.

The roles of extracellular vesicles in the development, microenvironment, anticancer drug resistance, and therapy of head and neck squamous cell carcinoma

“…As early as 2015, Chan et al reported that EXOs derived from NPC C666-1 cells could markedly enhance the tubulogenesis, migration and invasion of human umbilical vein endothelial cells [ 77 ]. Subsequently, Ferris et al demonstrated that EXOs containing interleukin- 10 (IL-10) and IL-6 secreted by HNSCC and IL-6-dependent inflammatory stimulation resulted in increased angiogenesis [ 78 , 79 ]. EVs derived from HPV (+) and HPV (-) HNSCC cell lines mainly carried urokinase plasminogen activator (uPA).…”

Characterization of a Tumor-Microenvironment-Relevant Gene Set Based on Tumor Severity in Colon Cancer and Evaluation of Its Potential for Dihydroartemisinin Targeting

“…Previous studies showed that DHA could inhibit COAD cell viability through regulating cell proliferation and apoptosis [15,42]. e data presented above, in addition to many studies in the literature, indicate that DHA is involved in regulating the TME of cancer [16,26]. However, there is no publicly available information about the role of DHA in the TME of COAD.…”

“…DHA has potential antitumor therapeutic effects across human cancers through inhibition of cancer cell proliferation, migration, and invasion capabilities. DHA was proposed to regulate the TME in head and neck cancer, breast cancer, and melanoma [ 16 , 25 , 26 ]. However, the effect of DHA in the TME of COAD has not been previously described.…”

“…The role of DHA in the TME has only been reported in few studies. DHA was proposed to prevent progression of head and neck cancer via regulating macrophages in TME [ 16 ]. However, whether DHA can influence cancer progression through regulating the TME in COAD is still not well characterized.…”

miR‐21‐regulated M2 polarization of macrophage is involved in arsenicosis‐induced hepatic fibrosis through the activation of hepatic stellate cells

“…It has been found out that the promoter of miR‐21 harbors multiple STAT3 binding sites and STAT3 activation is required for induction of miR‐21 transcription (Iliopoulos et al, 2010). And it is also found that STAT3 is activated during M2 polarization of macrophages (Chen et al, 2020). In our previous study, we found that arsenite induced increase of miR‐21 by the IL‐6/STAT3 pathway (Lu et al, 2015).…”