Sexual dimorphism of liver metastasis by murine pancreatic neuroendocrine tumors is affected by expression of complement C5
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Tanupriya Contractor1,*, Shinta Kobayashi2,*, Edaise da Silva3, Richard Clausen1, Chang Chan4, Evan Vosburgh1, Laura H. Tang3, Arnold J. Levine2,4, Chris R. Harris1,4,5
1Raymond and Beverly Sackler Foundation Laboratory, New Brunswick NJ
2Institute for Advanced Study, Princeton NJ
3Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York NY
4Rutgers University Cancer Institute of New Jersey and Department of Pediatrics, Robert Wood Johnson Medical School, New Brunswick NJ
5Department of Pediatrics, Robert Wood Johnson Medical School, New Brunswick NJ
*Co-first authors, the author contributed equally to this work
Chris R. Harris, e-mail: firstname.lastname@example.org
Keywords: neuroendocrine tumors, pancreatic, metastasis, complement C5, sexual dimorphism
Received: November 03, 2015 Accepted: March 31, 2016 Published: April 20, 2016
In a mouse model for neuroendocrine tumors of the pancreas (PanNETs), liver metastasis occurred at a higher frequency in males. Male mice also had higher serum and intratumoral levels of the innate immunity protein complement C5. In mice that lost the ability to express complement C5, there was a lower frequency of metastasis, and males no longer had a higher frequency of metastasis than females. Treatment with PMX53, a small molecule antagonist of C5aR1/CD88, the receptor for complement C5a, also reduced metastasis. Mice lacking a functional gene for complement C5 had smaller primary tumors, which were less invasive and lacked the CD68+ macrophages that have previously been associated with metastasis in this type of tumor. This is the first report of a gene that causes sexual dimorphism of metastasis in a mouse model. In the human disease, which also shows sexual dimorphism for metastasis, clinically advanced tumors expressed more complement C5 than less advanced tumors.
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