Activation of M2 macrophage autophagy by rapamycin increases the radiosensitivity of colorectal cancer xenografts.

BACKGROUND: Tumor-associated macrophages (TAMs) are intimately involved in cancer radiochemotherapy resistance. However, the mechanism by which macrophages affect radiosensitivity through autophagy remains unclear. The purpose of our study was to investigate how activating autophagy in type-II macrophages (M2) by using rapamycin (RAP) would affect the radiosensitivity of colorectal cancer (CRC) xenografts. MATERIALS AND METHODS: A nude mouse CRC model was established by injecting LoVo CRC cells. After tumor formation, supernatant from M2 cells (autophagy-unactivated), autophagy-activated M2 cells, or autophagy-downregulated M2 cells was injected peritumorally. All tumor-bearing mice were irradiated with 8-Gy X-rays twice, and the radiosensitivity of CRC xenografts was analyzed in each group. RESULTS: The mass, volume, and microvessel density (MVD) of tumors in the autophagy-unactivated M2 group significantly increased; however, supernatant from M2 cells that were autophagy-activated by rapamycin significantly decreased tumor weight, volume, and MVD compared with negative control. Combining bafilomycin A1 (BAF-A1) with RAP treatment restored the ability of the M2 supernatant to increase tumor mass, volume, and MVD. Immunohistochemical and Western blot results showed that compared with the negative control group, supernatant from M2 cells that were not activated by autophagy downregulated the expression of Livin and Survivin in tumor tissues; activation of M2 autophagy further downregulated the protein levels. CONCLUSIONS: Therefore, autophagy-activated M2 supernatant can downregulate the expression of the antiapoptotic genes Livin and Survivin in CRC xenografts, improving the radiosensitivity of CRC by inducing apoptosis in combination with radiotherapy and inhibiting the growth of transplanted tumors.

A pan-cancer analysis for the oncogenic role of cyclin-dependent kinase inhibitor 1B in human cancers.

BACKGROUND: Human health and life are threatened by cancer with high morbidity and mortality worldwide. In many experiments, CDKN1B level is associated with cancer risk, Nevertheless, no pan-cancer analysis has been conducted on CDKN1B in human cancers. METHODS: With the help of bioinformatics, a pan-cancer analysis was conducted on the expression levels of CDKN1B in cancer tissues and adjacent tissues from the TCGA, CPTAC and GEO databases. The CDKN1B expression levels in tumor patients was further validated using immunohistochemistry (IHC) and quantitative real-time PCR. RESULTS: In the study, we first investigated the cancer-related roles of CDKN1B's in 40 tumors with malignancy. The CDKN1B gene encodes the p27Kip1 protein, which can block the production cyclin-dependent kinase (CDK), which is obviously related to the function and survival of cancer cells and alters the prognosis of cancer patients. Furthermore, CDKN1B function requires both protein processing and RNA metabolism. Additionally, the elevated expression of the CDKN1B gene and protein was validated in several cancer tissues from the patients. CONCLUSIONS: These results showed that the levels of CDKN1B were considerably different in a number of cancer tissues, offering a potential future target for cancer therapy.

Dexamethasone-sparing regimen is an effective and safe alternative in overall antiemetic protection: A systematic review and meta-analysis.

OBJECTIVE: We performed a meta-analyisis to evaluate the efficacy of maintenance dexamethasone against acute or delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetic risk chemotherapy regimen. METHODS: PubMed, Embase, and Cochrane Library were searched for eligible studies. Data comparing maintenance dexamethasone with single-dose dexamethasone during the acute, delayed, and overall phase of CINV were extracted. Overall risk ratio (RR) was used to estimate the efficacy and adverse effects. RESULTS: Nine studies were included. In delayed phase, maintenance dexamethasone has similar efficacy to single-dose dexamethasone for no emetic episodes (RR, 1.06; 95% confidence interval [CI], 1.00-1.14), complete response (RR, 1.04; 95% CI, 0.98-1.11), complete control (RR, 1.07; 95% CI, 0.98-1.16), and total control (RR, 1.06; 95% CI, 0.91-1.23). In overall phase, maintenance dexamethasone has similar efficacy to single-dose dexamethasone for no emetic episodes (RR, 1.02; 95% CI, 0.94-1.11), complete response (RR, 1.02; 95% CI, 0.95 -1.09), complete control (RR, 1.03; 95% CI, 0.94-1.13), total control (RR, 1.05; 95% CI, 0.90-1.23), and no rescue medication (RR, 1.07; 95% CI, 0.97-1.19). Maintenance dexamethasone was only superior to single-dose dexamethasone for no rescue medication during delayed phase (RR, 1.10; 95% CI, 1.01-1.21, P = .034). The incidence of hiccup was observed higher in maintenance dexamethasone group (RR = 3.16, 95% CI, 1.12-8.92). CONCLUSION: The single-dose dexamethasone regimen offers high and similar overall control of symptoms as the maintenance dexamethasone regimen in this population. Multiple-day dexamethasone was suitable for patients who used rescue medication during the delayed phase.

Effects of autophagy regulation of tumor-associated macrophages on radiosensitivity of colorectal cancer cells.

Tumor­associated macrophages (TAMs), a major component of the tumor microenvironment, are crucial to the processes of tumor growth, infiltration and metastasis, and contribute to drug resistance. The importance of TAMs in radiation resistance of colorectal cancer remains unclear. To investigate the effects of autophagy regulation of TAMs on the radiosensitivity of colorectal cancer cells, the current study induced TAM formation from THP­1 monocyte cells. Sequential treatment of THP­1 cells with PMA for 72 h and human recombinant interleukin­4 for 24 h was used to stimulate THP­1 differentiation to TAMs. Expression of the cell surface markers CD68, CD204 and CD206, and changes to cell morphology were used to confirm successful differentiation. The TAMs were stimulated to promote or inhibit autophagy during co­culture with LoVo colorectal adenocarcinoma cells. The cells were irradiated, with subsequent measurement of LoVo colony formation and apoptosis. Additionally, the expression of p53, Bcl­2, survivin and Smac proteins was assessed by western blotting. Monodansylcadaverin staining was used to analyze the presence of autophagic vacuoles in TAM, and western blot analysis was used to assess the expression of Beclin­1, LC3B I and II, ATG­3, ­5 and ­7. The results demonstrated TAM autophagy to be markedly altered by rapamycin and bafilomycin A1 treatment. Following co­culture with TAMs, the colony formation rate and survival fraction of LoVo cells were significantly higher than those in the control group (P<0.05). It was further demonstrated that the regulation of autophagy in TAMs was able to inhibit the colony formation of LoVo colorectal cancer cells. Upregulation of TAM autophagy using rapamycin exhibited more effective inhibition of LoVo colony formation than autophagy downregulation. Notably, apoptosis was significantly increased in LoVo cells when co­cultured with TAMs only, or with rapamycin­mediated autophagy upregulated TAMs, compared with LoVo cells cultured alone (P<0.01). Expression of Bcl­2, survivin and p53 were reduced in LoVo cells co­cultured with TAMs, compared with the control group (P<0.05), whereas Smac expression was increased in the co­culture groups (P<0.01). It was demonstrated that rapamycin­mediated autophagy stimulation in TAMs led to reduced expression levels of survivin and Bcl­2, however, Smac expression was increased. The upregulation of autophagy in TAMs inhibited proliferation and induced apoptosis in colon cancer cells, and altered the expression of radiosensitivity­associated proteins. This data indicated that the radiosensitivity of colorectal cancer cells is associated with autophagy of TAM, and that stimulating TAM autophagy may increase the radiosensitivity of colorectal cancer cells.