Human endotrophin as a driver of malignant tumor growth
Dawei Bu, Clair Crewe, Christine M. Kusminski, Ruth Gordillo, Alexandra L. Ghaben, Min Kim, Jiyoung Park, Hui Deng, Wei Xiong, Xiao-Zheng Liu, Per Eystein Lønning, Nils Halberg, Adan Rios, Yujun Chang, Anneliese Gonzalez, Ningyan Zhang, Zhiqiang An, Philipp E. Scherer
Dawei Bu, Clair Crewe, Christine M. Kusminski, Ruth Gordillo, Alexandra L. Ghaben, Min Kim, Jiyoung Park, Hui Deng, Wei Xiong, Xiao-Zheng Liu, Per Eystein Lønning, Nils Halberg, Adan Rios, Yujun Chang, Anneliese Gonzalez, Ningyan Zhang, Zhiqiang An, Philipp E. Scherer
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Research Article Endocrinology Oncology

Human endotrophin as a driver of malignant tumor growth

Abstract

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 epithelial-mesenchymal 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.

Authors

Dawei Bu, Clair Crewe, Christine M. Kusminski, Ruth Gordillo, Alexandra L. Ghaben, Min Kim, Jiyoung Park, Hui Deng, Wei Xiong, Xiao-Zheng Liu, Per Eystein Lønning, Nils Halberg, Adan Rios, Yujun Chang, Anneliese Gonzalez, Ningyan Zhang, Zhiqiang An, Philipp E. Scherer

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Figure 5

Antibody effects on ETP-MCF-7 cells in vivo.

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Antibody effects on ETP-MCF-7 cells in vivo. (A) ETP transfected MCF-7 c...
(A) ETP transfected MCF-7 cells (2 × 106 cells) were implanted into nude mice. An estradiol pellet (0.72 mg) was implanted into nude mice. Then (i) 20 mg/kg ETPmAb4, (ii) 10 mg/kg ETPmAb4 with 10 mg/kg control IgG, (iii) 5 mg/kg ETPmAb4 with 15 mg/kg control IgG, (iv) 2 mg/kg ETPmAb4 with 18 mg//kg control IgG, and (v) 20 mg/kg control IgG (twice a week) were injected after 10-days implantation for 5-weeks. Tumor volume was determined by caliper measurement. Data was represented as mean ± SEM (n = 5/group), and ***P < 0.0001 by 2-way ANOVA with Sidak’s correction for multiple comparisons. Representative tumors shown. (B) Left: Total RNA was prepared from tumor tissues from ETP transfected MCF-7, ETPmAb4 treatment mice. The EMT markers genes Twist, Snail, Cdh2, and Cdh1 were determined by qRT-PCR, then normalized to GAPDH. Mean ± SEM, n = 3. Right: E-CAD immunofluorescence staining for tumor tissues from ETP transfected MCF-7 and ETPmAb4 treatment tumor. Scale bars: 50μm. (C) Left: MCF-7 and ETP transfected MCF-7 cells (2 × 106 cells) were implanted into nude mice. An estradiol pellet (0.72 mg) was implanted into nude mice. Then 20 mg/kg of antibody ETPmAb4 (twice a week), and 2.5 mg/kg of cisplatin (once a week) were injected after 10-days implantation for 6-weeks. Tumor volume was determined by caliper measurement. Right: Representative tumors shown. Data was represented as mean ± SEM (n = 5/group), and ***P < 0.0001 by 2-way ANOVA with Sidak’s correction for multiple comparisons.