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Tumor microenvironment (TME) is the cellular environment in which tumor exists, and it contributes to tumor formation and progression. The TME is composed of tumor cells, stromal cells, cytokines, and chemotactic factors of which fibroblasts are the main cellular components. In our present study, we found that colorectal cancer (CRC) cells expressing integrin αvβ6 clearly could induce morphological changes in inactive fibroblasts and increased the expression of activated fibroblast markers such as α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Those activated fibroblasts in the TME are called cancer-associated fibroblasts (CAFs). In order to investigate the mechanism by which CRC cells expressing integrin αvβ6 activated CAFs, a series of assays have been carried out in the follow-up. We found that CRC cells could secrete inactive transforming growth factor β (TGF-β); however, integrin αvβ6 activated TGF-β, which subsequently activated fibroblasts. This process was disrupted by knockdown of integrin αvβ6. In contrast, activated fibroblasts could promote CRC cell invasion. In particular, the strengthening effect on expression of integrin αvβ6 in colon cancer cells was obvious. Additionally, we found that CAFs could secrete stromal cell-derived factor-1 (SDF-1) and promote CRC cell metastasis in distant organs via the SDF-1/C–X–C chemokine receptor type 4 (CXCR4) axis. Taken together, we assumed that CRC cells and CAFs activated one another and worked together to promote cancer progression, with integrin αvβ6 playing a role in the bi-directional regulation of these cells. Hence, integrin αvβ6 may serve as a therapeutic target for the future CRC treatment.

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.

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 β6 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 β6 in cholangiocarcinoma. β6 upregulation in cholangiocarcinoma was correlated with lymph node metastasis and distant metastasis. Moreover, integrin β6 was identified as a biomarker for the diagnosis of cholangiocarcinoma and an indicator of lymph node metastasis. Integrin β6 significantly promoted the proliferation, migration and invasion of cholangiocarcinoma cells. Furthermore, integrin β6 increased Rac1-GTPase, resulting in the upregulation of metalloproteinase-9 (MMP9) and F-actin polymerization. Taken together, our results indicate that integrin β6 promotes tumor invasiveness in a Rac1-dependent manner and is a potential biomarker for tumor metastasis. Integrin β6 may help to improve the diagnostic accuracy and targeting β6 may be a novel strategy for the treatment of cholangiocarcinoma.

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. Integrinβ6 (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 SW480β6 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. Clin Cancer Res; 21(5); 1183–95. ©2014 AACR.