Cancer-associated fibroblasts (CAFs) have recently been implicated in tumor growth and metastasis in gastric cancer. Cancer stem cells (CSCs) have been proposed to have an important role in cancer progression. The aim of this study was to clarify the effect of CAFs on CSCs characteristics in gastric carcinoma. Scirrhous gastric cancer cell lines, OCUM-12 and OCUM-2MD3, and non-scirrhous gastric cancer cell lines, MKN-45 and MKN-74, were used. OCUM-12=side population (SP) cells and OCUM-2MD3=SP cells were sorted by flow cytometry as CSC-rich cells from the parent cells. CaF-37 was established from the tumoral gastric specimens as CAFs. Flow cytometric analysis of SP fraction, spheroid colony assay, and RT-PCR analysis of CSC markers were performed to identify CSCs properties. Effect of CAFs on the tumorigenicity by OCUM-12=SP cells was examined using nude mice. CAF CM significantly increased the percentages of the SP fraction of OCUM-12=SP and OCUM-2MD3=SP cells, but not that of MKN-45=SP and MKN-74=SP cells. Taken together, CM from CaF-37 significantly increased the number of spheroid colonies and the expression level of CSC markers of OCUM-12=SP and OCUM-2MD3=SP cells. These stimulatingactivities by CM were significantly decreased by TGFb inhibitors, but not FGFR and cMet inhibitor. Tumorigenicity by subcutaneous coinoculation of OCUM-12=SP cells with CAFs was significantly high in comparison with that by OCUM-12=SP cells alone. Phospho-Smad2 expression level was significantly increased by co-inoculation with CAFs. These findings suggested that CAFs might regulate the stemness of CSCs in scirrhous gastric cancer by TGFb signaling.

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Purpose It has been reported that lysyl oxidase (LOX) is a hypoxia-responsive factor and is associated with the malignant progression of carcinoma. The aim of this study was to clarify the relationship between the epithelialmesenchymal transition (EMT) and LOX in gastric cancer cells under hypoxia. Methods Two gastric cancer cell lines, OCUM-2MD3 and OCUM-12, were used in an in vitro study. The effect of LOX small interfering RNA (siRNA) on the EMT and motility of gastric cancer cells under hypoxic condition was analyzed by reverse transcription PCR, Western blot, a wound-healing assay, and an invasion assay. Correlations between LOX expression and the clinicopathological features of 544 patients with gastric carcinoma were examined immunohistochemically.Results Hypoxic conditions increased the number of polygonal or spindle-shaped cells resulting from EMT in gastric cancer cells. The EMT of cancer cells induced by hypoxia was inhibited by treatment with LOX siRNA. The number of migrating and invading gastric cancer cells in hypoxia was significantly decreased by LOX knockdown. LOX siRNA significantly increased the E-cadherin level and decreased the vimentin level of gastric cancer cells. LOX expression was significantly associated with invasion depth, tumor differentiation, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal metastasis. Multivariable analysis revealed that LOX was an independent parameter for overall survival. Conclusion LOX affects the EMT of gastric cancer cells in hypoxic conditions. LOX expression is a useful prognostic factor for patients with gastric cancer.

Background:Triple-negative breast cancer (TNBC) patients testing positive for androgen receptor (AR) expression are thought to be chemotherapy resistant, similar to other hormone receptor-positive breast cancers; however, this has not been substantially validated in the clinic. In this study, we investigated the association between chemotherapy sensitivity and AR expression in patients treated with neoadjuvant chemotherapy (NAC) using standardised chemotherapy criteria and regimens.Methods:A total of 177 patients with resectable early-stage breast cancer were treated with NAC. Oestrogen receptor, progesterone receptor, HER2, Ki67 and AR status were assessed immunohistochemically.Results:Sixty-one patients were diagnosed with TNBC; AR expression was identified in 23 (37.7%), which was significantly less common than that found in non-TNBC patients (103 of 116; 88.8% P<0.001). The rate of pathological complete response after NAC was significantly lower (P=0.001), and disease recurrence was more common (P=0.008) in patients with AR-positive compared with those with AR-negative TNBC. In TNBC cases, as expected, the non-recurrence period in cases that were negative for AR expression was significantly extended (P=0.006, log-rank).Conclusions:Androgen receptor expressions may be useful as biomarkers to predict treatment responses to NAC in TNBC. Moreover, induction of a change in subtype to the AR-negative phenotype was observed after NAC.

Background: Triple-negative breast cancer (TNBC) has a poor prognosis because of frequent recurrence. Androgen receptor (AR) is involved in the pathogenesis of breast cancer, but its role is not clearly defined. The aim of this study was to explore the expression of AR and its relationship with clinicopathologic features in TNBC. Methods: This study investigated 1036 cases of sporadic invasive breast carcinoma. Immunohistochemical assays were performed to determine the expression of AR in 190 TNBC samples. The relationships between AR expression and clinicopathologic data and prognosis were analyzed. Results: In 190 TNBC cases, the prognosis of AR-positive patients was significantly better (p = 0.019, log-rank) than AR-negative patients, and in multivariate analysis, AR expression was an independent indicator of good prognosis (p = 0.039, hazard ratio = 0.36). In patients with disease relapse, AR positivity was significantly correlated with better prognosis (p = 0.034, log-rank). Conclusions: AR expression may be useful as a subclassification marker for prognosis in TNBC.