Cancer cells may escape from host immune responses through active suppression of the immune response, but the detailed mechanisms in colorectal cancer remain to be elucidated. In this study, 108 colorectal tumor samples and their peritumoral tissues were collected for immunohistochemistry of infiltrating lymphocytes. Th1 and Tregs cells were determined by the positive expression of T-bet and FOXP3 proteins, respectively. The Tr1 cells were identified by CD49b and LAG-3 protein expression. IL-17-positive cells were identified by IL-17 expression. Results showed that the percentage of T-bet-positive cells was significantly decreased, while the percentages of IL-17-, FOXP3-, CD49b-, and LAG-3-positive cells were significantly increased in tumor tissues compared to that in peritumoral tissues. The ratio of IL-17-, FOXP3-, CD49b-, and LAG3-positive cells to T-bet-positive cells was significantly higher in tumor tissues than in peritumoral tissues. The percentage of infiltrating IL-17-positive cells in tumor tissues was negatively associated with lymph metastasis, invasion, and TNM stage. The percentage of CD49b- and LAG-3-positive cells was positively associated with differentiation, lymph metastasis, invasion, TNM, and Duke stage of colorectal cancer. The percentage of positive Th17 and Tr1 cells is a marker for poor prognosis in patients with CRC. In conclusion, decreased composition of regulative Th1 cells and increased composition of FOXP(+) Tregs-, CD49b(+)/LAG-3(+) Tr1-, and IL-17-positive cells in tumor tissues may be associated with the progression of colorectal cancer. The high percentage of IL-17- and Tr1-positive cells in tumor tissues is a predictive marker for poor prognosis of colorectal cancer.
This study aims to investigate the expression and significance of glucose-6-phosphate dehydrogenase (G6PD) in human gastric cancer progression and prognosis. Using immunohistochemistry and real-time RT-PCR assay, we identified abnormally elevated expression of G6PD in gastric cancer tissues compared to paired normal stomach mucosa tissues in 24 patients (p < 0.05). In order to investigate the correlations between G6PD and the clinicopathological features of gastric cancer, the expression of G6PD in 167 patients with gastric cancer were detected by immunohistochemistry, and the results showed that overexpression of G6PD was associated with the size of tumor (p = 0.039), depth of invasion (p = 0.039), lymph node metastasis (p = 0.044), distant metastasis (p = 0.003), TNM stage (p = 0.030), and survival rate (p = 0.010). Further, Cox multivariates analysis indicated that G6PD expression level was an independent prognostic factor for patients after radical resection (p = 0.013). In conclusion, overexpression of G6PD is closely related to progression of gastric cancer, and might be regarded as an independent predictor of poor prognosis for gastric cancer.
The tumor microenvironment (TME) is a hypoxic, acidic, and immune/inflammatory cell–enriched milieu that plays crucial roles in tumor development, growth, progression, and therapy resistance. Targeting TME is an attractive strategy for the treatment of solid tumors. Conventional cancer chemotherapies are mostly designed to directly kill cancer cells, and the effectiveness is always compromised by their penetration and accessibility to cancer cells. Small-molecule inhibitors, which exhibit good penetration and accessibility, are widely studied, and many of them have been successfully applied in clinics for cancer treatment. As TME is more penetrable and accessible than tumor cells, a lot of efforts have recently been made to generate small-molecule inhibitors that specifically target TME or the components of TME or develop special drug-delivery systems that release the cytotoxic drugs specifically in TME. In this review, we briefly summarize the recent advances of small-molecule inhibitors that target TME for the tumor treatment.
Autophagy-related gene-5 (ATG-5) is one of the key regulators of autophagic cell death. It has been widely regarded as a protective molecular mechanism for tumor cells during the course of chemotherapy. In the present study, we investigated the expression pattern of ATG-5 and multidrug resistance-associated protein-1 (MRP-1) in 135 gastric cancers (GC) patients who were treated with epirubicin, cisplatin and 5-FU adjuvant chemotherapy (ECF) following surgical resection and explored their potential clinical significance. We found that both ATG-5 (77.78%) and MRP-1 (79.26%) were highly expressed in GC patients. ATG-5 expression was significantly associated with depth of wall invasion, TNM stages and distant metastasis of GC (P<0.05), whereas MRP-1 expression was significantly linked with tumor size, depth of wall invasion, lymph node metastasis, TNM stages and differentiation status (P<0.05). ATG-5 expression was positively correlated with MRP-1 (rp = 0.616, P<0.01). Increased expression of ATG-5 and MPR-1 was significantly correlated with poor overall survival (OS; P<0.01) and disease free survival (DFS; P<0.01) of our GC cohort. Furthermore, we demonstrated that ATG-5 was involved in drug resistant of GC cells, which was mainly through regulating autophagy. Our data suggest that upregulated expression of ATG-5, an important molecular feature of protective autophagy, is associated with chemoresistance in GC. Expression of ATG-5 and MRP-1 may be independent prognostic markers for GC treatment.
This study aims to investigate the expression and significance of EphA2 and EphrinA-1 in human gastric adenocarcinoma progression and prognosis. The expression of EphA2 and EphrinA-1 was detected in the cell lines and tissues of gastric adenocarcinoma. Different expression levels of EphA2 and EphrinA-1 were found in two cell lines. The expression of EphA2 and EphrinA-1 was significantly higher in gastric adenocarcinoma tissues than in normal tissues. Statistical analysis showed a significant correlation of EphA2 expression with the depth of tumor invasion, tumor-node-metastasis (TNM) stages, and lymph node metastasis. EphrinA-1 over-expression was significantly correlated with TNM stages and lymph node metastasis, while EphA2 expression was found to be an independent prognostic factor of postoperative gastric adenocarcinoma. In conclusion, the increased expression of EphA2 and EphrinA-1 plays an important role in the progression of human gastric adenocarcinoma, in which elevated EphA2 expression is an independent factor that indicates poor prognosis in postoperative gastric adenocarcinoma.
In this study, we investigated ALDH1A3, Mcl1, and miR-125a/b expression in HT29 cells and the effect of miR-125a/b on ALDH1A3 and Mcl1 expression. Our results showed that low expression of miR-125a/b and high expression of ALDH1A3 and Mel1 were observed in both ALDH1-positive HT29 and HT29-taxol cells. Overexpression of miR-125a/b significantly inhibited ALDH1A3 and Mcl1 expression, reduced cell survival, and increased cell apoptosis in HT29-taxol cells. Injection of miR-125a/b expression vector inhibited tumor growth in xenograft HT29-taxol mouse model. The current study suggested that miR-125a/b expression plays a key role in chemoresistance through upregulating ALDH1A3 and Mcl1 gene expression.
Yes‐associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin‐producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy‐resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2‐induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2‐to‐YAP pathway that drives GC growth, progression and therapy‐resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy‐resistant GC.
<p class="abstract"><strong>Background:</strong> Malnutrition is common in patients with cancer, which adversely affects the survival and quality of life of cancer patients. However, there is no national data on the prevalence of malnutrition in Chinese cancer patients. This study aims to evaluate the prevalence of malnutrition and quality of life (QOL) of Chinese patients with local regional, recurrent or metastatic cancer, to address the prognostic value of nutritional status and QOL on the survival of cancer patients in China and to validate the patient-generated subjective global assessment (PG-SGA) questionnaire in Chinese cancer patients.</p><p class="abstract"><strong>Methods:</strong> This is an observational, multi-centered, and hospital-based prospective cohort study. We aimed to recruit 50,000 cancer patients (age 18 and above) over an 8-year period. Data collection will occur within 48 hr after patients are admitted to hospital, 30-days after hospital admission, and the follow-up will be conducted 1-8 years after enrolment. The primary outcome is overall survival, and secondary outcomes are length of hospital stay and hospital costs. Factors measured are demographic characteristics, tumor characteristics, anthropometry measurements, hematological measurement, body composition, PG-SGA scores, Karnofsky performance status scores, and QLQ C30 scores. This protocol was approved by local ethical committees of all the participant hospitals.</p><p class="abstract"><strong>Conclusions: </strong>This multi-centered, large-scale, long-time follow-up prospective study will help diagnose malnutrition in cancer patients in China, and identify the related risk factors associated with the negative outcomes. The anticipated results will highlight the need for a truly scientific appraisal of nutrition therapy, and help to improve outcomes among cancer patients in China.</p><p class="abstract"><strong>Trial Registration: </strong>The trial has been registered with the Chinese Clinical Trial Registry, ChiCTR1800020329. Registered on 19 December 2018.<strong></strong></p>
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