Expression of angiopoietin-like 4 fibrinogen-like domain (cANGPTL4) increases risk of brain metastases in women with breast cancer
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Tu Dao1,2,3,9,*, Guillaume Gapihan1,*, Christophe Leboeuf1, Diaddin Hamdan1, Jean-Paul Feugeas4,10, Hanene Boudabous5, Laurent Zelek5,6, Catherine Miquel1,7, Thuan Tran2,3, Catherine Monnot8, Stéphane Germain8, Anne Janin1,7,# and Guilhem Bousquet1,5,6,#
1 Université Paris Diderot, Inserm, UMR_S942, Paris, France
2 Medical Oncology Department, National Cancer Hospital, Ha Noi, Vietnam
3 Ha Noi Medical University, Oncology Department, Ha Noi, Vietnam
4 INSERM, U722-Paris, Paris, France
5 Oncology Department, Hôpital Avicenne, APHP, Bobigny, France
6 Université Paris 13, Villetaneuse, Paris, France
7 Pathology Department, Hôpital St Louis, APHP, Paris, France
8 Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France
9 Cancer Research and Clinical Trial Center, National Cancer Hospital, Ha Noi, Vietnam
10 Université de Franche Comté, Besançon, France
* These authors contributed equally to this work
# These authors are co-senior authors
Keywords: cANGPTL4; brain metastases; breast cancer; blood-brain barrier; vascular permeability
Received: November 27, 2019 Accepted: March 19, 2020 Published: May 05, 2020
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.
Materials and Methods: From June 2015 to June 2016, serum samples from 113 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, the two cleaved fragments of ANGPTL4, in the occurrence of brain metastases.
Results: An ANGPTL4 serum concentration over 0.1 ng/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 < 0.05), while mice injected with cANGPTL4 had longer survival (p < 0.01). On tissue sections, compared to wild-type mice, mice injected with nANGPTL4 cells had significantly larger surface areas of lung metastases (p < 0.01), and mice injected with cANGPTL4 had significantly larger surface areas of brain metastases (p < 0.01).
Conclusions: In this study, we showed that a higher expression of Angiopoietin-like 4 Fibrinogen-Like Domain (cANGPTL4) was associated with an increased risk of brain metastases in women with breast cancer.
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