Endometriosis

The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver.

The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting Natural killer cell tumoricidal activity

Tumor microenvironment (TME) is a complex environment containing tumor cells, tumor-associated macrophages (TAMs), interstitial cells, and non-cellular components. Epithelial–mesenchymal transition (EMT), as a major actor in cancer tumorigenicity and metastasis, was involved in the interaction between TAMs and tumor cells. However, the potential mechanisms of EMT and how EMT-programmed tumor cells affect M2-like TAMs still need further exploration. An integrated analysis of nine CRC miRNA expression datasets was performed. Functional assays, including the EdU, clone formation, wound healing, and transwell assays, were used to determine the anticancer role of miR-195-5p in human CRC progression. Furthermore, RNA immunoprecipitation, RNA decay, and dual-luciferase reporter assays were used to determine the mechanism of miR-195-p CRC progression. Then co-culture, migration, and ELISA assays were applied to determine the role of miR-195-5p in macrophage recruitment and alternative polarization. Xenograft mouse models were used to determine the role of miR-195-5p in CRC tumorigenicity and TAM polarization in vivo. An integrated analysis confirmed that miR-195-5p was significantly downregulated in CRC tissues, and patients with a low level of miR-195-5p had significantly shortened overall survival as revealed by the TCGA-COAD dataset. Altered miR-195-5p in colon cancer cells led to distinct changes of proliferation, migration, invasion, and EMT. Mechanistically, miR-195-5p regulated NOTCH2 expression in a post-transcriptional manner by directly binding to 3′-UTR of the Notch2 mRNA. Subsequently, miR-195-5p/NOTCH2 suppressed GATA3-mediated IL-4 secretion in CRC cells and ultimately inhibited M2-like TAM polarization. miR-195-5p may play a vital role in regulating NOTCH2-mediated tumor cell EMT, thereby affecting IL-4-related M2-like TAM polarization in CRC.

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miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization

Calprotectin (S100A8/S100A9), a heterodimeric EF-hand Ca2+ binding protein, are abundant in cytosol of neutrophils and are involved in inflammatory processes and several cancerous pathogens. The purpose of the present systematic review is to evaluate the pro- and anti-tumorigenic functions of calprotectin and its relation to inflammation. We conducted a review of studies published in the Medline (1966–2018), Scopus (2004–2018), ClinicalTrials.gov (2008–2018) and Google Scholar (2004–2018) databases, combined with studies found in the reference lists of the included studies. Elevated levels of S100A8/S100A9 were detected in inflammation, neoplastic tumor cells and various human cancers. Recent data have explained that many cancers arise from sites of infection, chronic irritation, and inflammation. The inflammatory microenvironment which largely includes calprotectin, has an essential role on high producing of inflammatory factors and then on neoplastic process and metastasis. Scientists have shown different outcomes in inflammation, malignancy and apoptosis whether the source of the aforementioned protein is extracellular or intracellular. These findings are offering new insights that anti-inflammatory therapeutic agents and anti-tumorigenic functions of calprotectin can lead to control cancer development.

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Calprotectin (S100A8/S100A9): a key protein between inflammation and cancer.

In endometriosis, the endometrial lining of the uterus that is shed during menstruation becomes established as explants in the peritoneum, ovaries, and other sites. They develop a rich blood supply that promotes and sustains their growth. This study examined the hypothesis that agents inhibiting angiogenesis would prevent the growth of these explants. An attempt was made to specifically counter vascular endothelial cell growth factor A (VEGF-A), which is found at elevated levels in the peritoneal fluid of women with endometriosis. The blood vessels supplying human endometriotic lesions were found on immunohistochemical study to be mainly free of pericytes, as are vessels sensitive to angiogenic antagonists, and were in fact responsive to VEGF-A. In samples from 8 women, the proportion of such vessels was significantly higher in ectopic than in eutopic endometrium. When human endometrial tissue was implanted into nude mice, both soluble truncated receptor (flt-1) and a purified antibody to human VECF-A significantly inhibited growth of the implants. Pericyte-free vessels, which supplied the endometrial explants, were disrupted in lesions from mice treated with soluble fit-1. The findings were validated by studies in a rat sponge model, in which the increase in blood flow stimulated by growth factor was nearly completely eliminated by low-dose soluble FLT-1. These findings suggest that anti-VEGF-A agents might be able to disrupt the vascular supply of endometriotic lesions. The investigators believe that such antiangiogenic agents are likely to be effective in the clinical treatment of endometriosis.

Antiangiogenic Agents Are Effective Inhibitors of Endometriosis

CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) plays an important role in tumor progression and a number of studies have suggested that it is an indicator of tumor prognosis. This current meta-analysis systematically reevaluated the predictive potential of CD147/EMMPRIN in various cancers. We searched PubMed and Embase databases to screen the literature. Fixed-effect and random-effect meta-analytical techniques were used to correlate CD147 expression with outcome measures. A total of 53 studies that included 68 datasets were eligible for inclusion in the final analysis. We found a significant association between CD147/EMMPRIN overexpression and adverse tumor outcomes, such as overall survival, disease-specific survival, progression-free survival, metastasis-free survival or recurrence-free survival, irrespective of the model analysis. In addition, CD147/EMMPRIN overexpression predicted a high risk for chemotherapy drugs resistance. CD147/EMMPRIN is a central player in tumor progression and predicts a poor prognosis, including in patients who have received chemo-radiotherapy. Our results provide the evidence that CD147/EMMPRIN could be a potential therapeutic target for cancers.

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CD147/EMMPRIN overexpression and prognosis in cancer: A systematic review and meta-analysis.

Background/Objective 
Vascular endothelial growth factor (VEGF) is the most important promotor of angiogenesis. Some studies indicate that anti-angiogenic agents that interfere with VEGF and its receptor (VEGFR), i.e., anti-VEGF/VEGFR agents, may be applied to treat endometriosis. This meta-analysis investigated the efficacy of anti-VEGF/VEGFR agents in animal models of endometriosis.


Methods 
A systematic literature search was performed for animal studies published in English or Chinese from January 1995 to June 2016, which evaluated the effect of anti-VEGF/VEGFR agents on endometriosis. The databases were: PubMed, Web of Science, BIOSIS, Embase, and CNKI. The quality of included studies was assessed using the SYRCLE tool. The random-effect models were used to combine the results of selected studies. Heterogeneity was assessed using H2statistic and I2 statistic. Subgroup analyses were performed to determine the source of heterogeneity in endometriosis scores and follicle numbers.


Results 
We identified 13 studies that used anti-VEGF/VEGFR agents in various animal models. The meta-analysis showed that anti-VEGF/VEGFR agents were associated with smaller size (standardized mean difference (SMD) –0.96, 95% CI –1.31 to –0.62; P < 0.0001) and weight (SMD –1.70, 95% CI –2.75 to –0.65; P = 0.002) of endometriosis lesions, relative to the untreated controls, as well as a lower incidence rate of endometriosis (risk ratio 0.26, 95% CI 0.07 to 0.93; P = 0.038) and endometriosis score (SMD –1.17, 95% CI –1.65 to –0.69; P < 0.0001); the number of follicles were similar (SMD –0.78, 95% CI –1.65 to 0.09; P = 0.08).


Conclusions 
Anti-VEGF/VEGFR agents appeared to inhibit the growth of endometriosis, with no effect on ovarian function. Anti-angiogenic therapy may be a novel strategy in treating endometriosis.

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Efficacy of Anti-VEGF/VEGFR Agents on Animal Models of Endometriosis: A Systematic Review and Meta-Analysis.

Background/aims This study is aimed at identification of miR-195-5p/MMP14 expression in cervical cancer (CC) and their roles on cell proliferation and invasion profile of CC cells through TNF signaling pathway in CC. Methods Microarray analysis, gene set enrichment analysis (GSEA) and DAVID were used to analyze differentially expressed miRNAs, mRNAs and signaling pathways. MiR-195-5p and MMP14 expression levels in CC cell were determined by qRT-PCR. Western blot was employed to measure MMP14 and TNF signaling pathway-relating protein level. Luciferase reporter system was used to confirm the targeting relationship between MMP14 and miR-195-5p. Cell proliferation and invasion was respectively deeded by CCK8, transwell. In vivo experiment was carried out to study the impact of MMP14 and miR-195-5p on CC development in mice. Results The microarray analysis and the results of qRT-PCR determined that miR-195-5p was under-expressed and MMP14 was over-expressed in CC cells. GSEA and DAVID analysis showed that TNF signaling pathway was regulated by miR-195-5p/MMP14 and activated in cervical carcinoma cells. The miR-195-5p and MMP14 have a negative regulation relation. In vivo experiment found that down-regulated MMP14 and up-regulated miR-195-5p suppressed the tumor development. Conclusion Our results suggest that MMP14 is a direct target of miR-195-5p, and down-regulated MMP14 and up-regulated miR-195-5p suppressed proliferation and invasion of CC cells by inhibiting TNF signaling pathway.

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The Effects of miR-195-5p/MMP14 on Proliferation and Invasion of Cervical Carcinoma Cells Through TNF Signaling Pathway Based on Bioinformatics Analysis of Microarray Profiling.

Background Activation of NLPR3 inflammasome is associated with the development and progression of some types of malignant tumors, but its role in endometrial cancer is unclear. This study aimed to investigate the expression and function of NLRP3 inflammasome in endometrial cancer. Materials and methods The expression levels of NLRP3, its inflammasome components and estrogen receptor β in endometrial cancer and paired non-tumor tissues were detected. The effects of NLPR3 silencing or overexpression on the proliferation, migration, and invasion of Ishikawa and HEC-1A cells were determined. The impact of NLPR3 silencing on the growth of implanted tumors was determined in vivo. The effects of estrogen on NLPR3 inflammasome activation and Ishikawa cell proliferation were determined. Results The upregulation of NLRP3, ASC, caspase-1, and IL-1β was associated with the progression of endometrial cancer and poor survival. NLPR3 silencing inhibited the proliferation, migration, and invasion of endometrial cancer cells while NLPR3 overexpression had opposite effects. NLPR3 silencing reduced IL-1β and caspase-1 expression and the growth of implanted endometrial tumors, accompanied by decreased pro-IL-1β maturation. Estrogen enhanced NLPR3, ERβ, pro-IL-1β, IL-1β expression, and endometrial cancer cell proliferation, which were mitigated by treatment with ERβ inhibitor but not ERα inhibitor. Conclusion Our results suggest that estrogen acts through ERβ to enhance the activation of NLPR3 inflammasome and promote the progression of endometrial cancer. NLPR3 inflammasome may be a new therapeutic target for endometrial cancer.

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NLRP3 inflammasome activation by estrogen promotes the progression of human endometrial cancer.

// Teng Hua 1, * , Shuangge Liu 1, * , Xiaoyan Xin 1, * , Zhishan Jin 1 , Qibin Liu 2 , Shuqi Chi 1 , Xiaoxiao Wang 1 , Hongbo Wang 1 1 Department of Gynaecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China 2 Department of Surgery, Wuhan Pulmonary Hospital, Wuhan 430000, PR China * These authors have contributed equally to this work Correspondence to: Hongbo Wang, email: hb_wang1969@sina.com Keywords: cancer, L1 cell adhesion molecule, prognosis, meta-analysis Received: August 29, 2016      Accepted: October 24, 2016      Published: November 09, 2016 ABSTRACT The L1 cell adhesion molecule (L1CAM) extensively participates in nervous system development and the malignant progression of human tumours. The prognostic value of L1CAM for the survival of patients with solid tumours remains controversial. The present meta-analysis was thus performed to highlight the relationship between L1CAM expression and prognosis in cancer patients. Relevant publications were identified after searching several widely used databases, including PubMed, EMBASE and the ISI Web of Science. A fixed-effect or random-effect meta-analytical model was employed to correlate L1CAM expression with different outcome measures in both entire tumours and stratified subgroups. 37 studies in total with 8552 patients were eligible for the final analysis. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) suggested that high L1CAM expression had an unfavourable impact on overall survival (HR=2.06, 95%CI 1.65-2.57, P<0.001), disease-specific survival (HR=2.45, 95%CI 1.48-4.05, P<0.001), disease-free survival (HR=2.42, 95%CI 1.4-4.19, P=0.002) and progression-free survival/recurrence-free survival (HR=2.07, 95%CI 1.41-3.05, P<0.001). Subgroup analysis revealed a similar correlation in most tumour types. Overall, L1CAM might be an effective poor prognostic factor for patients with various tumour types.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=13236&path%5B%5D=43010

Teng Hua

Papers

CD147/EMMPRIN overexpression and prognosis in cancer: A systematic review and meta-analysis.

Efficacy of Anti-VEGF/VEGFR Agents on Animal Models of Endometriosis: A Systematic Review and Meta-Analysis.

The Effects of miR-195-5p/MMP14 on Proliferation and Invasion of Cervical Carcinoma Cells Through TNF Signaling Pathway Based on Bioinformatics Analysis of Microarray Profiling.

NLRP3 inflammasome activation by estrogen promotes the progression of human endometrial cancer.

Prognostic significance of L1 cell adhesion molecule in cancer patients: A systematic review and meta-analysis.