TY - JOUR
T1 - Human endotrophin as a driver of malignant tumor growth
AU - Bu, Dawei
AU - Crewe, Clair
AU - Kusminski, Christine M.
AU - Gordillo, Ruth
AU - Ghaben, Alexandra L.
AU - Kim, Min
AU - Park, Jiyoung
AU - Deng, Hui
AU - Xiong, Wei
AU - Liu, Xiao Zheng
AU - Lønning, Per Eystein
AU - Halberg, Nils
AU - Rios, Adan
AU - Chang, Yujun
AU - Gonzalez, Anneliese
AU - Zhang, Ningyan
AU - An, Zhiqiang
AU - Scherer, Philipp E.
N1 - Publisher Copyright:
© 2019 American Society for Clinical Investigation.
PY - 2019
Y1 - 2019
N2 - We have previously reported that the carboxy-terminal proteolytic cleavage product of the COL6α3 chain that we refer to as "endotrophin" has potent effects on transformed mammary ductal epithelial cells in rodents. Endotrophin (ETP) is abundantly expressed in adipose tissue. It is a chemoattractant for macrophages, exerts effects on endothelial cells and through epithelialmesenchymal transition (EMT) enhances progression of tumor cells. In a recombinant form, human endotrophin exerts similar effects on human macrophages and endothelial cells as its rodent counterpart. It enhances EMT in human breast cancer cells and upon overexpression in tumor cells, the cells become chemoresistant. Here, we report the identification of endotrophin from human plasma. It is circulating at higher levels in breast cancer patients. We have developed neutralizing monoclonal antibodies against human endotrophin and provide evidence for the effectiveness of these antibodies to curb tumor growth and enhance chemosensitivity in a nude mouse model carrying human tumor cell lesions. Combined, the data validate endotrophin as a viable target for anti-tumor therapy for human breast cancer and opens the possibility for further use of these new reagents for anti-fibrotic approaches in liver, kidney, bone marrow and adipose tissue.
AB - We have previously reported that the carboxy-terminal proteolytic cleavage product of the COL6α3 chain that we refer to as "endotrophin" has potent effects on transformed mammary ductal epithelial cells in rodents. Endotrophin (ETP) is abundantly expressed in adipose tissue. It is a chemoattractant for macrophages, exerts effects on endothelial cells and through epithelialmesenchymal transition (EMT) enhances progression of tumor cells. In a recombinant form, human endotrophin exerts similar effects on human macrophages and endothelial cells as its rodent counterpart. It enhances EMT in human breast cancer cells and upon overexpression in tumor cells, the cells become chemoresistant. Here, we report the identification of endotrophin from human plasma. It is circulating at higher levels in breast cancer patients. We have developed neutralizing monoclonal antibodies against human endotrophin and provide evidence for the effectiveness of these antibodies to curb tumor growth and enhance chemosensitivity in a nude mouse model carrying human tumor cell lesions. Combined, the data validate endotrophin as a viable target for anti-tumor therapy for human breast cancer and opens the possibility for further use of these new reagents for anti-fibrotic approaches in liver, kidney, bone marrow and adipose tissue.
UR - http://www.scopus.com/inward/record.url?scp=85070658570&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.125094
DO - 10.1172/jci.insight.125094
M3 - Article
C2 - 30896449
AN - SCOPUS:85070658570
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 9
M1 - e125094
ER -