To evaluate the validity of CHAC1 for predicting the prognosis of kidney renal clear cell carcinoma (KIRC) and to explore its therapeutic potential for KIRC, we conducted several bioinformatic analyses using the sequencing data and clinical information derived from online databases. We found CHAC1 is down‐regulated in KIRC samples when compared with normal samples but up‐regulated in KIRC samples with relatively higher malignancy and later stages. Univariate cox analysis and multivariate cox regression analysis were conducted and the results revealed up‐regulated CHAC1 is an independent risk factor for poor prognosis of KIRC. Further, the nomogram model based on the result of multivariate cox regression analysis was constructed and effectively predicted patients' 1‐year, 3‐year and 5‐year survival respectively. The correlation analyses showed CHAC1 is associated with the immune pathway markers of memory B cell, natural killer cell and type1 T helper cell as well as the checkpoint genes like ADORA2A, CD200, CD44, CD70, HHLA2, NRP1, PDCD1LG2 and TNFRSF18. Furthermore, experiments in vitro indicated CHAC1 could induce cell death in KIRC cell lines but had limited influence on cell migration and cell invasion. In conclusion, CHAC1 is found a valid indicator for poor prognosis of kidney renal clear cell carcinoma.

Purpose: To investigate the efficacy and mechanisms of Notch signaling inhibition as an adjuvant to docetaxel in castration-resistant prostate cancer (CRPC) using a γ-secretase inhibitor (GSI), PF-03084014. Experimental Design: The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and docetaxel-resistant CRPC cell lines in vitro and in murine models. Both soft tissue and bone sites were evaluated in vivo. Impacts on cell proliferation, apoptosis, cancer stem cells, and angiogenesis were evaluated. Results: The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and docetaxel-resistant CRPC tumor growth in soft tissue and bone greater than either agent alone. Antitumor activity was associated with PF-03084014–induced inhibition of Notch pathway signaling; decreased survival signals (cyclin E; MEK/ERK, PI3K/AKT, EGFR and NF-κB pathway; BCL-2, BCL-XL); increased apoptotic signals (BAK, BAX; cleaved caspase-3); reduced microvessel density; reduced epithelial–mesenchymal transition; and reduced cancer stem–like cells in the tumor. Conclusions: These results reveal that PF-03084014 enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC. Clin Cancer Res; 21(20); 4619–29. ©2015 AACR. See related commentary by Zhang and Armstrong, p. 4505

AJA publishes new findings in basic and clinical (including modern, traditional and epidemiological) research on Andrology.

Although the potential roles of endothelial cells in the microvascules of prostate cancer during angiogenesis have been documented, their direct impacts on the prostate cancer metastasis remain unclear. We found that the CD31-positive and CD34-positive endothelial cells are increased in prostate cancer compared with the normal tissues and that these endothelial cells were decreased upon castration, gradually recovered with time, and increased after prostate cancer progressed into the castration-resistant stage, suggesting a potential linkage of these endothelial cells with androgen deprivation therapy. The in vitro invasion assays showed that the coculture of endothelial cells with prostate cancer cells significantly enhanced the invasion ability of the prostate cancer cells. Mechanism dissection found that coculture of prostate cancer cells with endothelial cells led to increased interleukin (IL)-6 secretion from endothelial cells, which may result in downregulation of androgen receptor (AR) signaling in prostate cancer cells and then the activation of TGF-β/matrix metalloproteinase-9 (MMP-9) signaling. The consequences of the IL-6→AR→TGFβ→MMP-9 signaling pathway might then trigger the increased invasion of prostate cancer cells. Blocking the IL-6→AR→TGFβ→MMP-9 signaling pathway either by IL-6 antibody, AR-siRNA, or TGF-β1 inhibitor all interrupted the ability of endothelial cells to influence prostate cancer invasion. These results, for the first time, revealed the important roles of endothelial cells within the prostate cancer microenvironment to promote the prostate cancer metastasis and provide new potential targets of IL-6→AR→TGFβ→MMP-9 signals to battle the prostate cancer metastasis. Mol Cancer Ther; 12(6); 1026–37. ©2013 AACR.