Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo

The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vitro as well as its influence on macrophage polarization and associated cytokines in vivo. The results suggested that LDN supressed the proliferation, migration and invasion abilities and promote their apoptosis in Hela cells, whereas the opioid growth factor receptor (OGFr) silenced significantly reversed these effects in vitro. Knockdown the expression of OGFr, the inhibitory of LDN on EMT was weakened. LDN could inhibit cervical cancer progression in nude mice. In additon, LDN indirectly reduced the number of tumor-associated macrophages (TAMs), mainly M2 macrophages, and decreased expression of anti-inflammatory factor IL-10 in the serum of nude mice. These findings demonstrate that LDN could be a potential treatment for cervical cancer.     

Poly(I:C) stimulation is superior than Imiquimod to induce the antitumoral functional profile of tumor‐conditioned macrophages

Macrophage plasticity is the ability of mononuclear phagocytes to change phenotype, function, and genetic reprogramming upon encounter of specific local stimuli. In the tumor microenvironment, Tumor‐Associated Macrophages (TAMs) acquire an immune‐suppressive and tumor‐promoting phenotype. With the aim to re‐educate TAMs to antitumor effectors, in this study, we used two immunestimulatory compounds: the TLR7 agonist Imiquimod (IMQ) and the TLR3 agonist Poly(I:C). To better mimic in vitro the response of TAMs, we used Tumor‐Conditioned Macrophages (TC‐M?) differentiated in the presence of tumor cell supernatants. Our results show that TC‐M? respond differently from conventional M2‐polarized macrophages. Upon stimulation with IMQ, TC‐M? did not upregulate major histocompatibility complex (MHC II) molecules and unexpectedly expressed increased CD206. With both compounds, TC‐M? produced higher levels of inflammatory cytokines than M2 macrophages. IMQ and Poly(I:C) differed in the types of regulated genes and secreted mediators. Reflecting their signaling pathways, only IMQ significantly induced IL‐1β and IL‐6, while only Poly(I:C) stimulated CXCL10, and both upregulated CCL5. Of note, using a novel cytotoxicity assay, Poly(I:C), but not IMQ, was effective in triggering the cytotoxic activity of TC‐M? against cancer cells. Overall, the results demonstrate that Poly(I:C) stimulation of TC‐M? is superior than IMQ in terms of macrophage re‐education toward antitumor effectors.     

Hepatic leukemia-associated macrophages exhibit a pro-inflammatory phenotype in Notch1-induced acute T cell leukemia

Tumor-associated macrophages (TAMs) are well accepted and the pathological role of macrophages in hematopoietic malignancies have been proposed. Hepatomegaly is frequently observed in T cell acute lymphoblastic leukemia (T-ALL) patients with poor prognosis. However, the role of leukemia-associated macrophages (LAMs) in hepatic microenvironment remains unclear. Here, the characteristics of hepatic LAMs (H-LAMs) were studied in Notch1 induced T-ALL model. Increase in proportion and absolute counts of H-LAMs was detected with infiltration of inflammatory cells. Furthermore, H-LAMs exhibited a more M1-like phenotype distinct from that of TAMs in hepatocellular carcinoma and LAMs from BM or spleen in leukemia. Moreover, H-LAMs expressed increased level of cytokines in charge of recruiting inflammatory cells, which contributed to pro-inflammatory hepatic microenvironment.     

Macrophage coculture enhanced invasion of gastric cancer cells via TGF-β and BMP pathways

Abstract

Objective. Transforming growth factor β (TGF-β) superfamily plays an important role in regulating gastric cancer progression. As previously demonstrated, tumor-associated macrophages (TAMs) promoted the invasion of gastric cancer cells in Matrigel. However, the role of TGF-β superfamily signaling between TAMs and gastric cancer remains unclear. Material and methods. Three-dimensional dynamic migration imaging system was used to detect gastric cancer invasion rate cocultured with macrophages in Matrigel before or after TGF-β receptor 1 or bone morphogenic protein (BMP) receptor 1A and 1B inhibition; real-time RT-PCR was used to quantitatively investigate gene expression (TGF-β1, TGF-β2, BMP4, and BMP7, ADAM9, MMP9, TIMP3, VEGF-A, and VEGF-C). Results. TGF-β1, TGF-β2, BMP4, and BMP7 expressions were increased significantly in macrophages grown with cancer cells as compared to macrophages grown alone. The invasion rate and invasion-related genes expressions of both AGS and Hs-746T gastric cancer cell lines were upregulated by macrophages, although the expression profile was different. Invasion rate and invasion-related genes' expressions of AGS cells cocultured with macrophages were downregulated significantly after TGF-βR1 and BMPR1 inhibition. Conclusions. Macrophages associated with tumor might promote gastric cancer cells invasion though enhancing TGF-β/BMPs signal pathway. Inhibiting TGF-β/BMPs signal between TAMs and gastric cancer cells might provide a new therapeutic method of gastric cancer.     

Tumor-derived microparticles in tumor immunology and immunotherapy

Microvesicles or microparticles, a type of cytoplasm membrane-derived extracellular vesicles, can be released by cancer cells or normal cell types. Alteration of F-actin cytoskeleton by various signals may lead to the cytoplasm membrane encapsulating cellular contents to form microparticles, which contain various messenger molecules, including enzymes, RNAs and even DNA fragments, and are released to extracellular space. The release of microparticles by tumor cells (T-MPs) is a very common event in tumor microenvironments. As a result, T-MPs not only influence tumor cell biology but also profoundly forge tumor immunology. Moreover, T-MPs can act as a natural vehicle that delivers therapeutic drugs to tumor cells and immune cells, thus, remodeling tumor microenvironments and resetting antitumor immune responses, thus, conferring T-MPs a potential role in tumor immunotherapies and tumor vaccines. In this review, we focus on the double-edged sword role of T-MPs in tumor immunology, specifically in TAMs and DCs, and emphasize the application of drug-packaging T-MPs in cancer patients. We aim to provide a new angle to understand immuno-oncology and new strategies for cancer immunotherapy.     

TAMs、MC与食管癌临床病理及血管生成的关系

目的 观察肿瘤相关巨噬细胞(TAMs)、肥大细胞(MC)与食管鳞癌临床病理特征的关系及对微血管生成的影响.方法 应用免疫组织化学S-P法测定食管鳞癌组织和正常食管黏膜中TAMs、MC和微血管的数量及分布(MCD).结果 在正常黏膜和食管鳞癌中,TAMs的计数分别为42.60±6.68和48.33±8.66,MC分别为10.65±3.66和16.68±2.84,MVD分别为26.32 ±2.02和38.18 ±5.14(P<0.05);淋巴结转移组和无淋巴结转移组TAMs分别为37.01±3.98和35.11±2.42,MVD分别为38.72 ±2.80和36.76 ±2.01,MC分别为17.00±2.48和15.60±2.03(P<0.05);浸润至及肌层以外者与肌层以内者,TAMs计数分别为46.36±3.63和43.78±4.47,MVD分别为36.89±3.05和38.67±2.82,MC分别为14.94±4.86和17.67±3.72(P<0.05).TAMB、MC、微血管和性别、大体类型及分化程度之间差异无统计学意义(P>0.05).结论 食管鳞癌中的TAMs、MC数量与淋巴结转移及浸润深度相关,与肿瘤的分化程度、性别及大体类型无关;且与微血管生成有关,非特异性抗炎治疗对食管鳞癌的治疗可能有意义.     

TAMs的生物学特性及其在恶性肿瘤诊疗中的作用

0引言 巨噬细胞以未成熟的单核细胞从骨髓释放,经血循环,通过细胞因子招募进入组织并分化成为成熟的巨噬细胞.位于恶性肿瘤组织中的巨噬细胞被称为肿瘤相关巨噬细胞(Tumor-associated macrophages,TAMs),是肿瘤基质的重要组分,近来许多研究表明其可诱导免疫抑制,加速肿瘤细胞生长和播散、促进肿瘤血管的发生和稳定,与肿瘤的发生、发展密切相关.