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Several in vitro and in vivo models have revealed the key role of CXCR4/CXCL12 axis in tumor-stroma interactions. Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4-expressing cancer cells. This specific prosurvival influence of stromal cells on tumor cells is thought to protect them from cytotoxic chemotherapy and is postulated as a possible explanation for the minimal residual disease in hematological and solid cancers. Therefore, CXCR4/CXCL12 signaling is an attractive therapeutic target in cancer, as proven in preclinical leukemia mouse models, where CXCR4 inhibition sensitized cancer cells to conventional chemotherapy. This study investigates whether inhibition of CXCR4 with the specific inhibitor AMD3100 sensitizes human prostate cancer cells to docetaxel. We showed that both mouse and human stromal cell lines have a protective effect on PC3-luc cells by promoting their survival after chemotherapy. Furthermore, we demonstrated that AMD3100 sensitizes PC3-luc cells to docetaxel. In a subcutaneous xenograft mouse model of human prostate carcinoma, we showed that a combination of docetaxel and AMD3100 exerts increased antitumor effect compared with docetaxel alone. We concluded that CXCR4 inhibition chemosensitizes prostate cancer cells, both in vitro and in vivo. To explore the relevance of these findings, we analyzed CXCR4 expression levels in human prostate cancer samples. We found that cancer cells present in bone metastatic lesions express higher CXCR4 levels relative to the cells present in primary tumors and lymph node metastatic lesions. These findings underscore the potential of CXCR4 inhibitors as chemosensitizing agents.

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BackgroundMalnutrition, low muscle strength and muscle mass are highly prevalent in older hospitalized patients and associated with adverse outcomes. Malnutrition may be a risk factor for developing low muscle mass. We aimed to investigate the association between the risk of malnutrition and 1) muscle strength and muscle mass at admission and 2) the change of muscle strength and muscle mass during hospitalization in older patients.MethodsThe EMPOWER study included 378 patients aged seventy years or older who were acutely or electively admitted to four different wards of an academic teaching hospital in Amsterdam. Patients were grouped into low risk of malnutrition and high risk of malnutrition based on the Short Nutritional Assessment Questionnaire (SNAQ) score and were assessed for hand grip strength and muscle mass using hand held dynamometry respectively bioelectrical impedance analysis (BIA) within 48 h after admission and at day seven, or earlier at the day of discharge. Muscle mass was expressed as skeletal muscle mass, appendicular lean mass, fat free mass and the skeletal muscle index.ResultsThe mean age of the patients was 79.7 years (SD 6.39), 48.9% were female. At admission, being at high risk of malnutrition was significantly associated with lower muscle mass (Odds Ratio, 95% CI, 0.90, 0.85–0.96), but not with muscle strength. Muscle strength and muscle mass did not change significantly during hospitalization in both groups.ConclusionIn older hospitalized patients, a high risk of malnutrition is associated with lower muscle mass at admission, but not with muscle strength nor with change of either muscle strength or muscle mass during hospitalization.