Regulation of CD44v6 expression in gastric carcinoma by the IL-6/STAT3 signaling pathway and its clinical significance.

As a cancer stem cell marker, CD44 variant 6 (CD44v6) has been implicated in carcinogenesis, tumor progression, and metastasis in a variety of human carcinomas. However, little is known about the expression of CD44v6 in Gastric Carcinoma (GC). Therefore we investigated CD44v6 expression in clinical specimen and further explore the underlying molecular mechanisms.In this study, we systemically investigated CD44v6 expression by immunohistochemistry in normal, premalignant gastric mucosa (low and high grade intraepithelial neoplasia), and GC at various stages. The correlation of CD44v6 expression with clinicopathological characteristics, and prognosis in GC was also analyzed. Next, we investigated cell proliferation, migration and invasion in GC cell lines. Furthermore, we explored a novel mechanism by which CD44V6 was upregulated in GC cell.The immunohistochemistry results showed that enhanced expression of CD44v6 was closely associated with tumor differentiation, lymph node metastasis, TNM stage and poor prognosis in GC patients. In gastric cancer cell lines, CD44v6 involved in cell proliferation, invasion and metastasis in Next, report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD44v6. RNA interference silencing of STAT3 resulted in decrease of CD44v6 levels. We also found that STAT3 inhibitor AG490 decrease expression of CD44v6 by blocking activation of STAT3, even in the presence of IL-6. Targeting STAT3-mediated CD44v6 up-regulation may represent a novel, effective treatment by eradicating the stomach tumor microenvironment.

High Infiltration of Polarized CD163+ Tumor-Associated Macrophages Correlates with Aberrant Expressions of CSCs Markers, and Predicts Prognosis in Patients with Recurrent Gastric Cancer.

Background: As the most predominant tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) are associated with poor outcome in multiple solid cancers and play important roles in cancer progression. Cancer stem cells (CSCs) may account for metastasis and recurrence after cancer therapy. However, the association between TAMs and CSCs is not clarified in gastric cancer (GC). The aim of the present study was to evaluate the effects of TAMs on CSCs in GC and find out the risk factors to predict recurrence and prognosis. Material and methods: This study included consecutive 236 patients with histologically confirmed primary GC. TAMs marker CD163 and CSCs-related proteins were detected by immunohistochemistry (IHC) in GC tissues and their prognostic values were all investigated. Results: High expression of CD163+ TAMs was found in patents with aggressive characteristics, especially for patents with recurrence. There existed a significant correlation between high expression of CD163 and CSCs-related markers in GC tissues. In patients with recurrence, high-expression of CD163 TAMs was an independent worse prognostic factor. Conclusion: High infiltration of TAMs was related to aggressive behavior, associated with aberrant expression of CSC markers, and an independent worse prognostic factor in GC. Targeting TAMs may be a potential treatment strategy for GC, including patients with recurrence.

Hypoxia-inducible factor-1 alpha Correlates with Tumor-Associated Macrophages Infiltration, Influences Survival of Gastric Cancer Patients.

Background: Hypoxia was a common feature for accelerating tumor metastasis by both inducting epithelial-mesenchymal transition (EMT) of tumor cells and polarization of tumor-associated macrophages (TAMs). The association and roles between hypoxia, EMT and TAMs in the biological behavior of gastric cancer (GC) for the time being recurrence is unclear. Material and methods: hypoixa by expression of hypoxia-inducible factor-1 alpha (HIF-1α), polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68 and CD163, and the expression of E-cadherin as EMT property had been evaluated in 236 patients consecutive with histologically confirmed GC. Clinical significance was assessed for all these patients. Results: High expression of HIF-1α was found in patients with aggressive features, especially for recurrent patients. High infiltration of TAMs and abnormal expression of EMT-marker were also related to aggressive characteristics and predicted poor prognosis in GC. Meanwwhile, there existed a significant correlation among expression of HIF-1α, infiltration of TAMs and EMT marker in GC tissues. Multivariate Cox analysis revealed that high expression of HIF-1α combined TAMs infiltration were independent prognostic factors for disease-specific survival rate. Conclusion: HIF-1α is an unfavorable indicator for prognosis, may promote tumor progression through the induction of EMT and establishment of a pro-tumor immunosuppressive microenvironment. Further investigation into the therapeutic effects of blocking hypoxia is possible a potential strategy for GC treatment.