The M2 phenotype of tumor-associated macrophages (TAM) inhibits the anti-tumor inflammation, increases angiogenesis and promotes tumor progression. The transcription factor Nuclear Factor (erythroid-derived 2)-Like 2 (Nrf2) not only modulates the angiogenesis but also plays the anti-inflammatory role through inhibiting pro-inflammatory cytokines expression; however, the role of Nrf2 in the cancer cell and macrophages interaction is not clear. Hepatocellular carcinoma cells (Hep G2 and Huh 7) and pancreatic cancer cells (SUIT2 and Panc-1) were co-cultured with monocytes cells (THP-1) or peripheral blood monocytes derived macrophages, then the phenotype changes of macrophages and epithelial-mesenchymal transition of cancer cells were detected. Also, the role of Nrf2 in cancer cells and macrophages interaction were investigated. In this study, we found that cancer cells could induce an M2-like macrophage characterized by up-regulation of CD163 and Arg1, and down-regulation of IL-1b and IL-6 through Nrf2 activation. Also, Nrf2 activation of macrophages promoted VEGF expression. The Nrf2 activation of macrophages correlated with the reactive oxygen species induced by cancer cells derived lactate. Cancer cells educated macrophages could activate Nrf2 of the cancer cells, in turn, to increase cancer cells epithelial-mesenchymal transition (EMT) through paracrine VEGF. These findings suggested that Nrf2 played the important role in the cancer cells and macrophages interaction. Macrophage Nrf2 activation by cancer cell-derived lactate skews macrophages polarization towards an M2-like phenotype and educated macrophages activate Nrf2 of the cancer cells to promote EMT of cancer cells. This study provides a new understanding of the role of Nrf2 in the cancer cell and TAM interaction and suggests a potential therapeutic target.

Background: Light emitting‐diodes (LED) have various effects on living organisms and recent studies have shown the efficacy of visible light irradiation from LED for anticancer therapies. However, the mechanism of LED's effects on cancer cells remains unclear. The aim of the present study was to investigate the effects of LED on colon cancer cell lines and the role of photoreceptor Opsin 3 (Opn3) on LED irradiation in vitro.Methods: Human colon cancer cells (HT‐29 or HCT‐116) were seeded onto laboratory dishes and irradiated with 465‐nm LED at 30 mW/cm² for 30 minutes. Cell Counting Kit‐8 was used to measure cell viability, and apoptosis and caspase 3/8 expression were evaluated by AnnexinV/PI and reverse transcription‐polymerase chain reaction (RT‐PCR), respectively. Autophagy and expression of LC‐3 and beclin‐1 were also evaluated by autophagy assays, RT‐PCR and Western blotting. We further tested Opn3 knockdown by Opn3 siRNA and the G_i/o G‐protein inhibitor NF023 in these assays.Results: Viability of HT‐29 and HCT‐116 cells was lower in 465‐nm LED‐irradiated cultures than in control cultures. LC‐3 and beclin‐1 expressions were significantly higher in LED‐irradiated cultures, and autophagosomes were detected in irradiated cells. The reductive effect of cancer cell viability following blue LED irradiation was reversed by Opn3 knockdown or NF023 treatment. Furthermore, increased LC‐3 and beclin‐1 expression that resulted from blue LED irradiation was suppressed by Opn3 knockdown or NF023 treatment.Conclusion: Blue LED irradiation suppressed the growth of colon cancer cells and Opn3 may play an important role as a photoreceptor.

Background: Frailty is an important consideration for older patients undergoing surgery. We aimed to investigate whether frailty could be a prognostic factor in patients with pancreatic ductal adenocarcinoma who underwent pancreatic resection. Methods: One hundred and twenty patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma were enrolled. Frailty was defined as a clinical frailty scale score ≥4. Patients were divided into frailty (n = 29) and non-frailty (n=91) groups, and clinicopathological factors were compared between the two groups. Results: The frailty group showed an older age, lower serum albumin concentration, lower prognostic nutritional index, larger tumor diameter, and higher rate of lymph node metastasis than the non-frailty group (p < 0.05). Neutrophil–lymphocyte ratio and modified Glasgow prognostic score tended to be higher in the frailty group. Cancer-specific and disease-free survival rates were significantly poor in the frailty group (p < 0.05). With a multivariate analysis, frailty was an independent prognostic factor of cancer-specific survival. Conclusions: Frailty can predict the prognosis of patients with pancreatic ductal adenocarcinoma who undergo pancreatic resection.

Cancer‐associated fibroblasts (CAF), derived from stroma of cancer tissues, interact with cancer cells and play an important role in cancer initiation, growth, and metastasis. Nab‐paclitaxel (nab‐PTX) is a 130 nm albumin‐binding paclitaxel and recommended for many types of cancer chemotherapy. The nab‐PTX stromal‐disrupting effect during pancreatic cancer treatment has been reported. The aim of the present study was to determine the role of nab‐PTX in cancer cells and CAF interaction. Cancer cells (MIA PaCa‐2 and Panc‐1) were cocultured with CAF or treated with CAF conditioned medium, after which their migration and invasion ability, epithelial‐mesenchymal transition (EMT)‐related marker expression and C‐X‐C motif chemokine 10 (CXCL10) expression and secretion were detected. Nab‐PTX treatment was carried out during the coculture system or during preparation of CAF conditioned medium. Then cancer cell migration and invasion ability, EMT‐related marker expression, CXCL10 expression and secretion, and interleukin‐6 (IL‐6) expression and secretion by CAF were checked After coculture with CAF, migration and invasion ability of cancer cells increased. CAF also downregulated E‐cadherin and upregulated N‐cadherin and vimentin expression in cancer cells. During coculture or stimulation with cancer cell‐cultured medium, CAF significantly increased IL‐6 expression and secretion. However, nab‐PTX in the coculture system canceled CAF‐induced migration and invasion promotion and EMT‐related gene changes. Moreover, nab‐PTX increased CXCL10 expression of cancer cells which blocked CAF IL‐6 expression and secretion. Nab‐PTX treatment could increase CXCL10 expression of cancer cells which blocks CAF cancer cell migration and invasion‐promoting effect by inhibiting IL‐6 expression.

Https://doi.org/10.18632/oncotarget.27881 Kazunori Tokuda, Yuji Morine, Katsuki Miyazaki, Shinichiro Yamada, Yu Saito, Masaaki Nishi, Takuya Tokunaga, Tetsuya Ikemoto, Satoru Imura, Mitsuo Shimada

Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance, which limits its clinical significance for treating patients with HCC. Recent evidence suggests that epidermal growth factor receptor (EGFR) activation can trigger Lenvatinib-resistance; and is considered an important therapeutic target in HCC. Curcumin, one of the most studied naturally occurring botanicals with robust anti-cancer activity, is also reported to be a potent tyrosine kinase inhibitor. In this study, we hypothesized that the anti-EGFR potential of Curcumin might help overcome Lenvatinib resistance in HCC. We established two Lenvatinib-resistant cells and discovered that a combination of Curcumin and Lenvatinib exhibited a synergistic anti-tumor efficacy in the resistant HCC cell lines. In line with previous reports, Lenvatinib-resistant cell lines revealed significant activation of the EGFR, and genomewide transcriptomic profiling analysis identified that the PI3K-AKT pathway was associated with Lenvatinib resistance. The combination treatment with Curcumin and Lenvatinib dramatically suppressed gene and protein expression of the EGFR-PI3K-AKT pathway, suggesting Curcumin overcomes Lenvatinib resistance via inhibition of EGFR. We further validated these findings in tumor spheroids derived from resistant cell lines. In conclusion, we, for the first time, report that Curcumin reverses Lenvatinib resistance in HCC, and that their combination has clinical application potential for adjunctive treatment in HCC.