Expression of Angiopoietin-like 4 Fibrinogen-Like Domain increases risk of brain metastases in women with breast cancer

Background Brain metastases challenge daily clinical practice, and the mechanisms by which cancer cells cross the blood-brain barrier remain largely undeciphered. Angiopoietin-like 4 (ANGPTL4) proteolytic fragments have controversial biological effects on endothelium permeability. Here, we studied the link between ANGPTL4 and the risk of brain metastasis in cancer patients. Methods From June 2014 to June 2015, serum samples from 86 cancer patients were prospectively collected, and ANGPTL4 concentrations were assessed. Using a murine model of brain metastases, we investigated the roles of nANGPTL4 and cANGPTL4 fragments in the occurrence of brain metastases. Results A positive ANGPTL4 serum concentration over 0.1ng/mL was associated with decreased overall-survival. Multivariate analyses found that only breast cancer brain metastases were significantly associated with elevated ANGPTL4 serum concentrations. 4T1 murine breast cancer cells were transfected with either nANGPTL4- or cANGPTL4-encoding cDNAs. Compared to mice injected with wild-type 4T1 cells, mice injected with nANGPTL4 cells had shorter median survival (p Conclusions This study opens the way for further translational research on the role of cANGPTL4 fragment in human breast cancer brain metastases.