Sexual dimorphism of liver metastasis by murine pancreatic neuroendocrine tumors is affected by expression of complement C5

• Published in: Oncotarget 2016-05, Vol.7 (21), p.30585-30596
• Main Authors: Contractor, Tanupriya, Kobayashi, Shinta, da Silva, Edaise, Clausen, Richard, Chan, Chang, Vosburgh, Evan, Tang, Laura H, Levine, Arnold J, Harris, Chris R
• Format: Article
• Language: English
• Subjects: Animals; Complement C5 - genetics; Complement C5 - metabolism; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Macrophages - metabolism; Male; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Research Paper; Sex Factors
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8874

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.