University of Oulu

Zhang, H., Fredericks, T., Xiong, G., Qi, Y., Rychahou, P., Li, J., Pihlajaniemi, T., Xu, W., Xu, R. (2018) Membrane associated collagen XIII promotes cancer metastasis and enhances anoikis resistance. Breast Cancer Research, 20 (1), 116. doi:10.1186/s13058-018-1030-y

Membrane associated collagen XIII promotes cancer metastasis and enhances anoikis resistance

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Author: Zhang, Hui1,2; Fredericks, Tricia3; Xiong, Gaofeng2;
Organizations: 1Department of Laboratory Medicine, The First Hospital of Jilin University, Changchun
2UK Markey Cancer Center, University of Kentucky
3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky
4Department of Surgery, College of Medicine, University of Kentucky
5Center for Medical Genetics, School of Life Sciences, Central South University, Changsha
6Center for Cell-Matrix Research and Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine
7Department of Pharmacology and Nutritional Sciences, University of Kentucky
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.6 MB)
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Language: English
Published: Springer Nature, 2018
Publish Date: 2018-11-12


Background: Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse models show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. In the present study, we determined roles of collagen XIII in breast cancer progression and metastasis.

Methods: We analyzed the association of collagen XIII expression with breast cancer development and metastasis using published gene expression profiles generated from human breast cancer tissues. Utilizing gain- and loss- of function approaches and 3D culture assays, we investigated roles of collagen XIII in regulating invasive tumor growth. Using the tumorsphere/mammosphere formation assay and the detachment cell culture assay, we determined whether collagen XIII enhances cancer cell stemness and induces anoikis resistance. We also inhibited collagen XIII signaling with β1 integrin function-blocking antibody. Finally, using the lung colonization assay and the orthotopic mammary tumor model, we investigated roles of collagen XIII in regulating breast cancer colonization and metastasis. Cox proportional hazard (log-rank) test, two-sided Student’s t-test (two groups) and one-way ANOVA (three or more groups) analyses were used in this study.

Results: Collagen XIII expression is significantly higher in human breast cancer tissue compared with normal mammary gland. Increased collagen XIII mRNA levels in breast cancer tissue correlated with short distant recurrence free survival. We showed that collagen XIII expression promoted invasive tumor growth in 3D culture, enhanced cancer cell stemness, and induced anoikis resistance. Collagen XIII expression induced β1 integrin activation. Blocking β1 integrin activation significantly reduced collagen XIII-induced invasion and mammosphere formation. Importantly, silencing collagen XIII in MDA-MB-231 cells reduced lung colonization and metastasis.

Conclusions: Our results demonstrate a novel function of collagen XIII in promoting cancer metastasis, cell invasion, and anoikis resistance.

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Series: Breast cancer research
ISSN: 1465-5411
ISSN-E: 1465-542X
ISSN-L: 1465-5411
Volume: 20
Issue: 1
Article number: 116
DOI: 10.1186/s13058-018-1030-y
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3122 Cancers
Funding: This study was supported by start-up funding from Markey Cancer Center and funding support from NCI (1R01CA207772, 1R01CA215095 and 1R21CA209045 to R.X.), Markey Cancer Center CCSG pilot funding (P30 CA177558), and United States Department of Defense (W81XWH-15-1-0052 to R.X.). National Natural Science Foundation of China (81728013 to J.D.L), and the Centre of Excellence Grant 2012–2017 of the Academy of Finland (284605), the Sigrid Jusélius Foundation and the Finnish Cancer Foundation (to T.P.). National Natural Science Foundation of China (81672106 to W.X.).
Academy of Finland Grant Number: 284605
Detailed Information: 284605 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.