CRIP1 Reshapes the Gastric Cancer Microenvironment to Facilitate Development of Lymphatic Metastasis.

Lymphangiogenesis in tumors provides an auxiliary route for cancer cell invasion to drainage lymph nodes, facilitating the development of lymphatic metastasis (LM). However, the mechanisms governing tumor lymphangiogenesis and lymphatic permeability in gastric cancer (GC) remain largely unknown. Here, the unprecedented role and mechanism of cysteine-rich intestinal protein-1 (CRIP1) in mediating the development of GC LM is uncovered. A series of assays are performed to identify downstream targets of CRIP1, and rescue experiments are performed to confirm the effects of this regulatory axis on LM. CRIP1 overexpression facilitates LM in GC by promoting lymphangiogenesis and lymphatic vessel permeability. CRIP1 promotes phosphorylation of cAMP responsive element binding protein 1(CREB1), which then mediates vascular endothelial growth factor C (VEGFC) expression necessary for CRIP1-induced lymphangiogenesis and transcriptionally promotes C-C motif chemokine ligand 5 (CCL5) expression. CCL5 recruits macrophages to promote tumor necrosis factor alpha (TNF-α) secretion, eventually enhancing lymphatic permeability. The study highlights CRIP1 regulates the tumor microenvironment to promote lymphangiogenesis and LM in GC. Considering the current limited understanding of LM development in GC, these pathways provide potential targets for future therapeutics.

Circ_0049447 acts as a tumor suppressor in gastric cancer through reducing proliferation, migration, invasion, and epithelial-mesenchymal transition.

BACKGROUND: Although increasing abnormal expression of circular RNAs (circRNAs) has been revealed in various cancers, there were a small number of studies about circRNAs in gastric cancer (GC). Here, we explored the expression and function of a novel circRNA, circ_0049447, in GC. METHODS: A total of 80 GC tissues and non-tumorous tissues were collected from the First Affiliated Hospital of China Medical University. And all cells were cultured with 10% fetal bovine serum and incubated at 37°C and 5% CO2. The expression of circ_0049447 was quantified by real-time polymerase chain reaction. The biological function of circ_0049447 on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) was evaluated by cell counting kit-8 (CCK-8), colony formation assay, transwell migration and invasion assay, and Western blotting. Luciferase report assay was used to verify the direct binding between circ_0049447 and predicted microRNA (miRNA). Furthermore, a xenograft mouse model was used to validate the function of circ_0049447 in vivo. RESULTS: We demonstrated that circ_0049447 was downregulated in GC (P < 0.001). The area under the receiver operating characteristic curve reached 0.838, while sensitivity was 82.3% and specificity was 77.2%. CCK-8 and colony formation assay showed that overexpression of circ_0049447 could inhibit the proliferation (P < 0.05). Transwell migration and invasion assay showed upregulated circ_0049447 could impede migration in GC cells (P < 0.05). In addition, overexpression of circ_0049447 could impede GC cell EMT. Upregulation of miR-324-5p in GC specimens and direct binding between miR-324-5p with circ_0049447 proven by luciferase reporter assay indicated that circ_0049447 may inhibit GC by sponging certain miRNA. CONCLUSION: Circ_0049447 acts as a tumor suppressor in GC through reducing proliferation, migration, invasion, and EMT, and it is a promising biomarker for diagnosis.

The efficacy and safety of adding bevacizumab in neoadjuvant therapy for locally advanced rectal cancer patients: A systematic review and meta-analysis.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) are more likely to suffer local recurrence and distant metastases, contributing to worse prognoses. Considering the provided dramatic reduction of local recurrences, neoadjuvant CRT (nCRT) followed by curative resection with total mesorectal excision (TME) and adjuvant chemotherapy has been established as standard therapy for LARC patients. However, the efficacy of adding bevacizumab in neoadjuvant therapy, especially in induction therapy-containing nCRT for LARC patients remains uncertain. MATERIALS: PubMed, Embase, and Web of Science were searched to retrieve records on the application of bevacizumab in a neoadjuvant setting for LARC patients. The endpoints of interest were pCR and the rates of patients suffering Grade 3/4 bevacizumab-specific adverse events, namely bleeding, wound healing complications, and gastrointestinal perforation. RESULTS: 29 cohorts covering 1134 subjects were included in this systematic review. The pooled pCR rate for bevacizumab-relevant cohorts was 21% (95% confidence interval (95% CI), 17-25%; I2 = 61.8%), the pooled estimates of Grade 3/4 bleeding, Grade 3/4 wound healing complication, Grade 3/4 gastrointestinal perforation were 1% (95% CI, 0-3%; I2 = 0%), 2% (95% CI, 1-5%; I2 = 4.7%), and 2% (95% CI, 0-5%; I2 = 0%), respectively. CONCLUSION: The addition of bevacizumab in the nCRT, especially in the TNT, for LARC patients provides promising efficacy and acceptable safety. However, the results should be interpreted cautiously due to the small amount of relevant data and need further confirmation by future studies.

The Addition of EGFR Inhibitors in Neoadjuvant Therapy for KRAS-Wild Type Locally Advanced Rectal Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) are at higher risk of local and distant recurrence and are thus more vulnerable to metastatic diseases. Neoadjuvant chemoradiotherapy (nCRT) and subsequent curative resection with total mesorectal excision (TME) followed by adjuvant chemotherapy have been recommended by the National Comprehensive Cancer Network (NCCN) guidelines as standard of care for LARC patients. However, the efficacy of the addition of epidermal growth factor receptor (EGFR) inhibitors in kirsten rat sarcoma viral oncogene (KRAS)-wild type LARC patients remains uncertain. MATERIALS: PubMed, Embase, and Web of Science were searched to retrieve records on the application of EGFR inhibitors in a neoadjuvant setting for LARC patients. pCR was used as surrogate endpoint to perform data synthesis in a single-arm setting. RESULTS: Ten cohorts covering 540 subjects were eligible in this systematic review. The pooled pCR rate for EGFR inhibitors was 15% (95% confidence interval (95% CI), 11-20%; I2 = 55.2%); the pooled estimates of Grade 3/4 diarrhea, Grade 3/4 hand-foot syndrome, Grade 3/4 acneiform rash were 17% (95% CI, 4-34%; I2 = 93.3%), 2% (95% CI, 0-5%; I2 = 13.7%), and 15% (95% CI, 9-22%; I2 = 65.4%), respectively. CONCLUSION: The addition of EGFR inhibitors in the nCRT for KRAS-wild type LARC patients provides comparable efficacy and acceptable safety. However, the results should be interpreted cautiously due to the small amount of relevant data and need further confirmation by more future studies.

Aspirin and Its Potential Preventive Role in Cancer: An Umbrella Review.

Background: Aspirin is one of the most commonly prescribed drugs worldwide and has been reported to possess anti-cancer properties in addition to antipyretic and analgesic effects. This umbrella review summarizes systematic reviews and meta-analyses that investigate the association between aspirin and cancer risk, aiming to help clinical and public health decision-makers interpret the results of these studies when re-positioning aspirin. Methods: An umbrella review of systematic reviews and meta-analyses. Results: The associations that reached statistical significance (17 in total) indicated potential preventive effects of aspirin on certain cancers or precancerous lesions. We found that no association was supported by strong evidence. Only one association (aspirin and overall cancer risk) was supported by highly suggestive evidence. The evidence supporting the association between aspirin and the risk of breast cancer, non-cardia gastric cancer, or prostate cancer was considered to be highly suggestive. The remaining 23 associations were supported by weak (13) or not suggestive evidence (10). Conclusions: The association between aspirin and a reduced risk of esophageal squamous cell carcinoma is supported by strong evidence, researchers and policy makers should pay more attention to the potential merit of repositioning aspirin to prevent esophageal squamous cell carcinoma.

Conversion Surgery for Stage IV Gastric Cancer.

The prognosis of stage IV gastric cancer (GC) is poor, with palliative chemotherapy remaining the main therapeutic option. Studies increasingly indicate that patients with unresectable stage IV GC, who undergo gastrectomy with radical intention after responding to several regimens of combined chemotherapy, can achieve good survival outcomes. Thus, surgery aiming at radical resection for unresectable stage IV GC after combined chemotherapy has received increasing attention in recent years. This novel therapeutic strategy was defined as conversion surgery in patients with unresectable stage IV GC and it can associate with significant improved survival when R0 resection can be achieved. Despite the recent advances in conversion surgery for patients with unresectable stage IV GC, selection criteria for combination chemotherapy regimens, indications for conversion surgery, optimal timing to surgery, and postoperative chemotherapy all remain controversial. This article reviews the current state of conversion surgery for unresectable stage IV GC.

Prognostic Biomarkers for Gastric Cancer: An Umbrella Review of the Evidence.

Introduction: Biomarkers are biological molecules entirely or partially participating in cancerous processes that function as measurable indicators of abnormal changes in the human body microenvironment. Aiming to provide an overview of associations between prognostic biomarkers and gastric cancer (GC), we performed this umbrella review analyzing currently available meta-analyses and grading the evidence depending on the credibility of their associations. Methods: A systematic literature search was conducted by two independent investigators of the PubMed, Embase, Web of Science, and Cochrane Databases to identify meta-analyses investigating associations between prognostic biomarkers and GC. The strength of evidence for prognostic biomarkers for GC were categorized into four grades: strong, highly suggestive, suggestive, and weak. Results: Among 120 associations between prognostic biomarkers and GC survival outcomes, only one association, namely the association between platelet count and GC OS, was supported by strong evidence. Associations between FITC, CEA, NLR, foxp3+ Treg lymphocytes (both 1- and 3-year OS), CA 19-9, or VEGF and GC OS were supported by highly suggestive evidence. Four associations were considered suggestive and the remaining 108 associations were supported by weak or not suggestive evidence. Discussion: The association between platelet count and GC OS was supported by strong evidence. Associations between FITC, CEA, NLR, foxp3+ Treg lymphocytes (both 1- and 3-year OS), CA 19-9, or VEGF and GC OS were supported by highly suggestive evidence, however, the results should be interpreted cautiously due to inadequate methodological quality as deemed by AMSTAR 2.0.

The Potential Effect of Metformin on Cancer: An Umbrella Review.

Background: Metformin has been reported to possess anti-cancer properties in addition to glucose-lowering activity and numerous systematic reviews and meta-analyses have studied the association between metformin use and cancer incidence or survival outcomes. We performed an umbrella review to assess the robustness of these associations to facilitate proper interpretation of these results to inform clinical and policy decisions. Methods: We searched PubMed and Embase systematic reviews and meta-analyses investigating the effect of metformin use on cancer incidence or survival outcomes published from inception to September 2, 2018. We estimated the summary effect size, the 95% CI, and the 95% prediction interval, heterogeneity, evidence of small-study effects, and evidence of excess significance bias. Results: We included 21 systematic reviews and meta-analyses covering 11 major anatomical sites and 33 associations. There was strong evidence for the association between metformin use and decreased pancreatic cancer incidence. The association between metformin use and improved colorectal cancer overall survival (OS) was supported by highly suggestive evidence. Seven associations (all cancer incidence, all cancer OS, breast cancer OS, colorectal cancer incidence, liver cancer incidence, lung cancer OS, and pancreatic cancer OS) presented only suggestive evidence. The remaining 24 associations were supported by weak or not-suggestive evidence. Conclusions: Associations between metformin use and pancreatic cancer incidence or colorectal cancer OS are supported by strong or highly suggestive evidence, respectively. However, these results should be interpreted with caution due to the poor methodological quality of the systematic reviews and meta-analyses.

Statin use and its potential therapeutic role in esophageal cancer: a systematic review and meta-analysis.

Purpose: Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductases, are designed to treat lipid disorders, especially hypercholesterolemia. Apart from their role in preventing heart diseases in patients with high cholesterol, recent evidence suggests that statins have anti-tumor properties. However, studies assessing the association between statin use and esophageal cancer survival outcomes have provided controversial results. Methods: We conducted a systematic review and meta-analysis focusing on studies evaluating associations between statin use and survival outcomes for esophageal cancer patients. Results: A total of five cohort studies comprising 24,576 patients were included. Statin use associated with improved overall survival (OS: HR 0.84, 95% CI, 0.75-0.94) and disease-free survival (DFS: HR 0.84, 95% CI, 0.75-0.96) of esophageal cancer patients. The improved survival outcomes were consistent in the esophageal adenocarcinoma subgroup and the esophageal squamous cell cancer subgroup. Conclusion: A potential therapeutic role of statins in esophageal cancer has been demonstrated in our study, however, the results should be interpreted cautiously and need further confirmation by future studies.

The long noncoding RNA CTA-941F9.9 is frequently downregulated and may serve as a biomarker for carcinogenesis in colorectal cancer.

BACKGROUND: Long noncoding RNAs (lncRNAs) participate in the carcinogenesis of many different cancers. This study aimed to detect expression of lncRNA CTA-941F9.9 in colorectal cancer tissues compared with matched nontumorous adjacent tissues (NATs). Moreover, we investigated whether this molecule is able to influence carcinogenesis in colorectal cancer (CRC). METHODS: Colorectal cancer tissues and NATs from two cohorts of patients were examined. Quantitative PCR was performed to quantify levels of CTA-941F9.9 expression in these samples. The association between CTA-941F9.9 expression and clinicopathological features, including receiver operating characteristic (ROC) curves, was also analyzed to evaluate the diagnostic value of CTA-941F9.9 in CRC. Potential effects of lncRNA CTA-941F9.9 on CRC cells were assessed via autophagy, transwell assay, CCK8 assays, and flow cytometry. RESULTS: Our experimental results showed lncRNA CTA-941F9.9 to be significantly downregulated in CRC tissues in both cohorts, with areas under the ROC curve (AUC) of 0.802 and 0.876. However, no significant correlations between CTA-941F9.9 expression levels and clinicopathological characteristics or patient outcomes were observed. We also found that CTA-941F9.9 promotes autophagy in CRC cell lines but no significant function of CTA-941F9.9 in regulating cancer cell proliferation or migration. CONCLUSIONS: LncRNA CTA-941F9.9 is frequently downregulated in CRC compared with NATs and might play an important role in CRC carcinogenesis.

Racial/ethnic disparities in the adjuvant chemotherapy of locally advanced colon cancer patients.

BACKGROUND: Most race/ethnicity-oriented investigations focus on Caucasian Americans (whites) and African Americans (blacks), leaving Asians, Hispanic white (Hispanics), and other minorities less well studied. Adjuvant chemotherapy (CT) after curative resection is critical to patients with locally advanced colon cancer (LACC). We studied the racial disparities in the adjuvant CT of LACC to aid in selecting optimal treatments for people from different races/ethnicities in this era of precision medicine. METHODS: Patients with American Joint Committee on Cancer (AJCC) stage II or III colon cancer (CC) (together termed as LACC) were included based on Surveillance, Epidemiology, and End Results cancer registry-Medicare linked databases. The log-rank test and Cox multivariate regression analysis were performed to investigate the racial/ethnic disparities in cohorts divided according to the regimen of adjuvant CT. RESULTS: In the LACC patients who did not receive adjuvant CT, Asian patients had better survival than other groups (all, P <0.05). For the fluoropyrimidine cohort, the survival of Asian patients was better than that of whites, blacks, and other minorities (all, P <0.05). For the fluoropyrimidine with oxaliplatin cohort, other minorities had superior survival to other groups (all, P <0.05). Similar findings were demonstrated for patients with AJCC stage II and III CC, and the observed better survival persisted after adjustments in the Cox models. CONCLUSIONS: Among LACC patients not receiving adjuvant CT, Asians achieved better survival than other races/ethnicities. Superior survival was also observed for Asians in the fluoropyrimidine cohort and for other minorities in the fluoropyrimidine with oxaliplatin cohort for AJCC stage III CC.

The efficacy of adding targeted agents to neoadjuvant therapy for locally advanced rectal cancer patients: a meta-analysis.

Patients with locally advanced rectal cancer (LARC) are at tremendous risk of metastatic diseases. To improve the prognoses of LARC patients, the efficacy of adding targeted agents to neoadjuvant therapy has been investigated by many researchers but remains controversial. A literature search of relevant databases was conducted through December 2016, 804 studies were identified and 32 investigations were ultimately included. A total of 1196 patients from 31 cohorts of 29 studies were eligible for quantitative synthesis in this single-arm setting meta-analysis. As pathologic complete response (pCR) shows promise as a prognosis indicator, we focused on pCR rates to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. In our study, we revealed pooled estimates of pCR of 27% (95%CI, 21-34%) and 14% (95%CI, 9-21%) for bevacizumab-relevant cohorts and cetuximab-relevant cohorts, respectively. The safety of adding targeted agents to neoadjuvant therapy was also evaluated by pooling the data of Grade 3/4 toxicity. In conclusion, our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides appreciable pCR for LARC patients. Meanwhile, the efficacy of cetuximab remains inconclusive, RCTs with larger scale and better study design that stress more on mutational status are needed.