Integrin αvß6 mediates the immune escape through regulation of PD-L1 and serves as a novel marker for immunotherapy of colon carcinoma.

The immune escape of colon cancer and its role in the response to immunotherapies such as PD-1/PD-L1 checkpoint inhibitors have long been of great interest. The positive outcomes of immunotherapy are limited by the immunosuppressive nature of the tumor microenvironment. Integrin αvß6, which can regulate the progression of colon cancer, was recently reported to be involved in the immune suppression of colon cancer. In the present study, we explored the correlation between αvß6 and PD-L1 expression by immunohistochemistry of colon cancer tissues. Then, the regulation of PD-L1 signaling by αvß6 in colon cancer cells was demonstrated. We constructed an in vivo model and performed immunophenotyping experiments to analyze further the regulation of the immune response by αvß6. The role of αvß6 in the response to anti-PD-1 therapy in colon cancer was also verified. αvß6-positive tissues exhibited increased PD-L1 expression. Inhibition of αvß6 not only downregulated constitutive PD-L1 expression but also decreased IFN-γ-induced PD-L1 expression. In addition, αvß6-induced PD-L1 expression was suppressed by the ERK inhibitor PD98059, and knockdown of the ß6-ERK2 binding site had the equivalent effect. αvß6 decreased CD8+ T cell infiltration and granzyme B expression in CD8+ T cells in colon cancer patients. Furthermore, mice engrafted with αvß6-expressing colon cancer cells exhibited an unsatisfactory response to anti-PD-1 therapy, and anti-PD-1-induced increases in CD4+ and CD8+ T cell infiltration could be inhibited by αvß6. These results indicate that αvß6 mediates immune escape in colon cancer by upregulating PD-L1 through the ERK/MAPK pathway. Moreover, αvß6 could serve as a marker for the efficacy of anti-PD-1 therapy in colon cancer.

Development and validation of nomograms for predicting overall survival and cancer-specific survival in elderly patients with locally advanced gastric cancer: a population-based study.

OBJECTIVE: To evaluate the multiple factors influencing the survival of elderly patients with locally advanced gastric cancer (LAGC) and develop and validate the novel nomograms for predicting the survival. METHODS: The clinical features of patients treated between 2000 and 2018 were collected and collated from the Surveillance, Epidemiology, and End Results (SEER) database and three medical centres in China, and the patients were randomly divided into a training cohort (3494), internal validation cohort (1497) and external validation cohort (841). Univariate and multivariate analyses of the prognostic values were performed to identify independent prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS), and two nomogram models were developed. Harrell's concordance index (C-index) and calibration curves were employed to assess discrimination and calibration. Decision curve analysis (DCA) and receiver-operating characteristic (ROC) curves were utilized to investigate the clinical usefulness. RESULTS: In the SEER database, the 5-year OS of the patients was 31.08%, while the 5-year CSS of the patients was 44.09%. Furthermore, in the external validation set, the 5-year OS of the patients was 49.58%, and the 5-year CSS of these patients was 53.51%. After statistical analysis, nine independent prognostic factors of OS and CSS were identified, including age, race, tumour size, differentiation, TNM stage, gastrectomy type, lymph node metastasis (LNM), lymph node ratio (LNR) and chemotherapy. The C-index (approximately 0.7) and calibration curve (close to the optimal calibration line) indicated satisfactory discrimination and calibration of the nomogram. DCA and ROC curves showed that the developed nomogram was superior to TNM stage. CONCLUSION: The novel validated nomogram could accurately predict the prognosis of individual elderly patients with LAGC and guide the selection of clinical treatment measures.

Integrin αvß8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy.

αvß8 integrin, a key activator of transforming growth factor ß (TGF-ß), inhibits anti-tumor immunity. We show that a potent blocking monoclonal antibody against αvß8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma, mammary cancer, colon cancer, and prostate cancer, especially when combined with other immunomodulators or radiotherapy. αvß8 is expressed at the highest levels in CD4+CD25+ T cells in tumors, and specific deletion of ß8 from T cells is as effective as ADWA-11 in suppressing tumor growth. ADWA-11 increases expression of a suite of genes in tumor-infiltrating CD8+ T cells normally inhibited by TGF-ß and involved in tumor cell killing, including granzyme B and interferon-γ. The in vitro cytotoxic effect of tumor CD8 T cells is inhibited by CD4+CD25+ cells, and this suppressive effect is blocked by ADWA-11. These findings solidify αvß8 integrin as a promising target for cancer immunotherapy.

Integrin αvß8 serves as a Novel Marker of Poor Prognosis in Colon Carcinoma and Regulates Cell Invasiveness through the Activation of TGF-ß1.

Integrin αvß8 expressed on tumor cells executes crucial regulatory functions during cell adhesion in the tumor microenvironment and supports the activation of TGF-ß1. This study aimed to investigate the expression of integrin αvß8 and its clinical significance in colon cancer, in addition to its influence on the invasion and migration of cancer cells. Our results showed that integrin αvß8 was an indicator of progression and poor prognosis in patients with colon cancer. Moreover, integrin αvß8 significantly promoted the invasion and migration of colon cancer cells by the activation of TGF-ß1 and upregulation of metalloproteinase-9. Furthermore, suppression of integrin αvß8 was found to inhibit the growth of colon cancer in vivo. Our results indicate that integrin αvß8 promotes tumor invasiveness and the migration of colon cancer through TGF-ß1 activation and is a potential prognostic biomarker. This study may provide clues to further understand the manner in which the tumor microenvironment mediates the development of colon cancer and develop strategies for novel therapeutic targets in the prevention and treatment of colon cancer.

Expression of Interleukin-6 and Integrin ανß6 in Colon Cancer: Association with Clinical Outcomes and Prognostic Implications.

As important factors in the tumor microenvironment, interleukin-6 (IL-6) and integrin ανß6 play significant roles in accumulating mutations that drive the progression and metastatic capacities of cancer. The aim of this study was to investigate the expression of IL-6 and integrin ανß6, their clinical significance, as well as their correlation in the colon cancer tissues of 145 cases using immunohistochemistry. Our results showed that IL-6 and integrin ανß6 are indicators of cancer progression and poor prognosis in patients with colon cancer. Moreover, their relationship may provide clues for further studies on how the tumor microenvironment mediates the development of colon cancer, as well as strategies for the identification of novel therapeutic targets in the prevention and treatment of colon cancer.

Integrin ß6 serves as an immunohistochemical marker for lymph node metastasis and promotes cell invasiveness in cholangiocarcinoma.

Cholangiocarcinoma is a devastating malignancy that is notoriously difficult to diagnose and is associated with a high mortality. Despite extensive efforts to improve the diagnosis and treatment of this neoplasm, limited progress has been made. Integrin ß6 is a subtype of integrin that is expressed exclusively on the surfaces of epithelial cells and is associated with a variety of tumors. In the present study, we investigated the expression and roles of integrin ß6 in cholangiocarcinoma. ß6 upregulation in cholangiocarcinoma was correlated with lymph node metastasis and distant metastasis. Moreover, integrin ß6 was identified as a biomarker for the diagnosis of cholangiocarcinoma and an indicator of lymph node metastasis. Integrin ß6 significantly promoted the proliferation, migration and invasion of cholangiocarcinoma cells. Furthermore, integrin ß6 increased Rac1-GTPase, resulting in the upregulation of metalloproteinase-9 (MMP9) and F-actin polymerization. Taken together, our results indicate that integrin ß6 promotes tumor invasiveness in a Rac1-dependent manner and is a potential biomarker for tumor metastasis. Integrin ß6 may help to improve the diagnostic accuracy, and targeting ß6 may be a novel strategy for the treatment of cholangiocarcinoma.

Integrinß6-targeted immunoliposomes mediate tumor-specific drug delivery and enhance therapeutic efficacy in colon carcinoma.

PURPOSE: Adjuvant chemotherapy is one of the significant treatments for colon cancer in clinic. However, it does not achieve the desired therapeutic efficacy, largely due to chemotherapeutic resistance. Integrinß6 (ITGB6) is expressed in malignant colonic epithelia, but not in normal epithelia, and is associated with the progression, metastasis, and chemotherapeutic resistance of colon cancer. Accordingly, it is necessary to design therapeutic approaches for efficient and targeted drug delivery into ITGB6-positive cancer cells to improve chemotherapeutic efficacy in colon cancer. EXPERIMENTAL DESIGN: PEGylated liposomes were employed to design ITGB6-targeted immunoliposomes, which have ITGB6 monoclonal antibodies (mAbs) conjugated. We evaluated the ITGB6-targeted immunoliposomes internalization into colon cancer cells and examined 5-fluorouracil (5-FU)-induced cellular apoptosis produced by ITGB6-targeted immunoliposomes+5-FU. In addition, the biodistribution and antitumor efficiency of ITGB6-targeted immunoliposomes were observed in vivo. RESULTS: ITGB6-targeted immunoliposomes enhanced cellular internalization in ITGB6-positive colon cancer cells compared with liposomes. Furthermore, the ITGB6-targeted immunoliposome internalization was dependent on the ITGB6 expression level on cellular surface. ITGB6-targeted immunoliposomes decreased the 5-FU IC50 more than 90% in HT-29 and SW480ß6 cells relative to liposomes. Moreover, when loaded with 5-FU, ITGB6-targeted immunoliposomes produced an approximately 1.5-fold higher 5-FU-induced cellular apoptosis rate than liposomes. In vivo, the therapeutic activity of ITGB6-targeted immunoliposomes+5-FU was significantly superior, resulting in 25% to 35% reduction of tumor weight compared with 5-FU or liposomes+5-FU. CONCLUSIONS: ITGB6-targeted immunoliposomes provide a highly efficient approach for targeted drug delivery in colon cancer and thus offer the potential of a novel and promising anticancer strategy for clinical therapy.

Epieriocalyxin A Induces Cell Apoptosis Through JNK and ERK1/2 Signaling Pathways in Colon Cancer Cells.

Colorectal cancer is one of the most commonly diagnosed cancers in the world. Currently, drug resistance of cancer cell to chemotherapy is a major cause for cancer recurrence and death of the patients; therefore, new therapeutic strategy is required to improve the care of colorectal cancer patients. The Chinese herb, Isodon eriocalyx, has been used a therapeutic for a long time in China. In this study, we showed that Epieriocalyxin A (EpiA), a diterpenoid isolated from I. eriocalyx, suppressed Caco-2 colon cancer cell growth. EpiA induced annexin V flipping in cell membrane and DNA fragment. We also showed that EpiA induced the generation of ROS in cells, as well as damage of the mitochondrial membrane. Western blot results showed that both JNK and ERK1/2 activation was decreased after EpiA treatment in a dose-dependent manner. EpiA increased the expression of caspase 3 and Bax, and decreased Bcl2 expression. Our results suggest that EpiA is a novel compound that induces colon cancer apoptosis. EpiA could be a potential drug for colon cancer therapy in the future.

Interleukin-8 promotes cell migration through integrin αvß6 upregulation in colorectal cancer.

Colorectal cancer (CRC), which is notorious for high morbidity and mortality around the world, shows a predilection for metastasis to liver. Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, has been reported to promote CRC cell migration and is associated with poor prognosis of CRC. However, the underlying molecular mechanism of IL-8-mediated migration remains obscure. In this study, we first demonstrated the cross talk between IL-8 and integrin αvß6. We analyzed 139 human CRC samples, and found that the immunohistochemical expression of αvß6 was significantly correlated with expression of IL-8. Furthermore, IL-8 increased the migration through integrin αvß6 in human CRC cells, and both CXCR1 and CXCR2 were primarily involved during the process. IL-8 upregulated αvß6 expression in a dose-dependent manner through activation of ERK and Ets-1 signaling pathway. Taken together, our results indicated that IL-8 enhances the migration of CRC cells by increasing αvß6 integrin expression through the ERK/Ets-1 pathway. Targeting integrin αvß6 in IL-8 expressing tumors might be a potential therapeutic strategy for CRC patients.

ß6 integrin induces the expression of metalloproteinase-3 and metalloproteinase-9 in colon cancer cells via ERK-ETS1 pathway.

We previously reported that ß6 integrin played an important role in the progression of colon cancer. In this study, we demonstrated that ß6 integrin induced the expression of MMP-3/MMP-9 and the invasion of colon cancer cells. Moreover, that function was abolished by the inhibition of ERK/MAPK pathways or knockdown of ETS1, an important transcription factor of MMP genes. Here, we showed that ß6 induced phosphorylation of ETS1 via the ERK/MAPK pathways, through which the MMP-3/MMP-9 promoters were stimulated, thereby leading to the up-regulation of MMP-3/MMP-9, and subsequent the invasion of colon cancer cells.

Comparison of the BISAP scores for predicting the severity of acute pancreatitis in Chinese patients according to the latest Atlanta classification.

BACKGROUND: The bedside index of severity in acute pancreatitis (BISAP) is a new, convenient, prognostic multifactor scoring system. As there were no studies designed to validate this system according to the latest Atlanta classification in China and more data are needed before clinical application, we compared BISAP, the Acute Physiology and Chronic Health Evaluation (APACHE) II and Ranson scoring systems in predicting the severity, pancreatic necrosis and mortality of acute pancreatitis (AP) using the latest 2012 Atlanta classification in a tertiary care center in China. METHODS: The medical records of all patients with AP admitted to our hospitals between January 2010 and June 2013 were reviewed retrospectively. Severe AP was defined as the persistence of organ failure for more than 48 h. The capacity of the BISAP, APACHE II and Ranson's score system to predict severity, pancreatic necrosis and mortality was evaluated using linear-by-linear association. The predictive accuracy of the BISAP, APACHE II and Ranson's score was measured as the area under the receiver operating characteristic curve (AUC). RESULTS: Of 155 patients enrolled in the study, 16.7% were classified as having severe AP, and six (3.2%) died. There were statistically significant trends for increasing severity (P < 0.001), PNec (P < 0.001) and mortality (P < 0.001) with increasing BISAP. The AUC for severity predicted by BISAP was 0.793 (95% confidence interval [CI] 0.700-0.886), APACHE II 0.836 (95% CI 0.744-0.928) and by Ranson score was 0.903 (95% CI 0.814-0.992). The AUC for PNec predicted by BISAP was 0.834 (95% CI 0.739-0.929), APACHE II 0.801 (95% CI 0.691-0.910) and by Ranson score was 0.840 (95% CI 0.741-0.939). The AUC for mortality predicted by BISAP was 0.791 (95% CI 0.593-0.989), APACHE II 0.812 (95% CI 0.717-0.906) and by Ranson score was 0.904 (95% CI 0.829-0.979). CONCLUSIONS: BISAP score may be a valuable source for risk stratification and prognostic prediction in Chinese patients with AP. A prospective and multicenter validation study is required to confirm our results and further our recognition of BISAP scores in AP.

Protein expression of eIF4E and integrin αvß6 in colon cancer can predict clinical significance, reveal their correlation and imply possible mechanism of interaction.

BACKGROUND: Both eukaryotic translation initiation factor 4E (eIF4E) and integrin αvß6 play an important role in the development and progression of cancer. The aim of this study was to investigate the expression of eIF4E and Integrin αvß6, their clinical significance as well as the two proteins' correlation in colonic carcinoma tissues. RESULTS: The expression levels of eIF4E and integrin αvß6 were analyzed in colon cancerous and paraneoplastic tissues of 138 cases via tissue microarray (TMA)- immunohistochemistry. And their clinical significance as well as the two proteins' correlation was also investigated. The expression of eIF4E was significantly associated with clinical TNM stage (P = 0.009), while T stage (P = 0.011) and TNM stage (P = 0.012) were significantly associated with integrin αvß6 expression. Moderately weak correlation exists between the two proteins (r =0.299, P <0.001). The survival analysis by Kaplan-Meier and Cox regression model showed that protein expression of high eIF4E and positive integrin αvß6, as independent prognostic factors (RR = 2.417, P = 0.001 and RR = 2.393, P = 0.001), tended to have a significantly poorer 5-year survival rate (P = 0.013 and 0.025, respectively, the log-rank test). CONCLUSION: eIF4E and Integrin αvß6 were indicators of tumor's progression and poor prognosis of patients with colon cancer. And the potential signaling loop involving them may provide a helpful therapeutic target in prevention and treatment of colon cancer.

Diagnosis and treatment experience of rectal carcinoid (a report of 312 cases).

OBJECTIVE: To explore the diagnosis of rectal carcinoid tumors and to adopt the best method of treatment. PATIENTS AND METHODS: A group of 312 cases of pathologically confirmed rectal carcinoid were analyzed retrospectively. Data were obtained retrospectively from a database of all colorectal malignancies at Qilu Hospital from January 2004 to December 2012. 4072 colorectal malignant tumors and 312 rectal carcinoid tumors were diagnosed. Endoscopic resection was performed on 44 patients, while the other 248 underwent anus partial extended radical polypectomy. We evaluated the clinical manifestations, diagnosis, treatment and follow-ups regarding carcinoids and the relation between tumor diameter and the rate of recurrence or metastasis after surgery. RESULTS: There is no recurrence or metastasis after the transanal local resection in 284 cases with the tumor diameter less than 2 cm, 6 months to 7 years' follow-up. While, in 12 cases with the tumor diameter more than 2 cm radical surgery was performed, 8 cases had liver metastases at the time of the diagnosis of rectal carcinoid, 4 cases had no recurrence or metastasis after two and a half years' of follow ups, there is no recurrence or metastasis in 4 cases of multiple rectal carcinoids, whom all underwent radical surgery, follow ups continued for 2 years. CONCLUSION: Early diagnosis and treatment is important for rectal carcinoids, local resection is a simple, safe and effective treatment for carcinoids with a tumor diameter less than 2 cm.

The ß6-integrin-ERK/MAP kinase pathway contributes to chemo resistance in colon cancer.

5-Fluorouracil (5-FU) is the most widely used chemo drug for the treatment of colon cancer. However, a sub-population of colon cancer patients do not respond to 5-FU and this treatment does not provide survival benefit due to chemo resistance. The mechanisms involved in 5-FU resistance are not fully understood and multiple factors have been involved in the sensitivity of cancer cells to 5-FU. We previously reported that ß6-integrin plays an important role in invasion, metastasis and degradation of extracellular matrix of colon cancer. In this study, we investigated whether ß6-integrin is associated with chemo resistance in colon cancer. We found that over-expression of ß6-integrin protected SW480 and HT-29 colon cancer cells from 5-FU-induced growth inhibition and apoptosis, which were accompanied by changes in cytochrome C released from the mitochondria and activity of caspase-3 and caspase-9. Moreover, ß6-integrin resulted in up-regulation of Bcl-2 and down-regulation of Bax. We also found that ß6-integrin induced 5-FU resistance through the ERK/MAP kinase pathway and the ß6-ERK2 direct binding. The results indicate ß6-integrin might be a novel therapeutic target in colon cancer therapy.