CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy.

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

Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease

OBJECTIVE: We studied the reciprocal effect of pregnancy and von Hippel-Lindau (VHL) disease by analyzing the influence of pregnancy on VHL disease- related lesions and VHL disease on pregnancy outcome. METHODS: Medical charts and imaging reports from the VHL disease expertise centers in the Netherlands were used to retrospectively assess lesion progression score before and after pregnancy and to obtain data on pregnancy outcome and VHL disease-related lesions. The Friedman test was used for analysis (p </= 0.05). Twenty-nine patients were studied (48 pregnancies, 49 newborns). RESULTS: The progression score of cerebellar hemangioblastomas significantly changed between the single MRI scan before and the 2 scans after pregnancy (p = 0.049) (n = 12). Fetal mortality rate was 2% (n = 1) caused by maternal pheochromocytoma. Maternal VHL disease-related complications occurred in 17% (n = 8) of all pregnancies. In 4 patients, a life-threatening situation emerged: hydrocephalus due to cerebellar hemangioblastoma (n = 2) and pheochromocytoma (n = 2). CONCLUSIONS: Pregnancy in patients with VHL disease induces cerebellar hemangioblastoma progression and causes a high VHL disease-related pregnancy complication rate. We recommend intensified surveillance of patients with VHL disease, especially of cerebellar hemangioblastomas during preconception care and pregnancy