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.
Digital Object Identifier (DOI)
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.).
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Zhang, Hui; Fredericks, Tricia; Xiong, Gaofeng; Qi, Yifei; Rychahou, Piotr G.; Li, Jia-Da; Pihlajaniemi, Taina; Xu, Wei; and Xu, Ren, "Membrane Associated Collagen XIII Promotes Cancer Metastasis and Enhances Anoikis Resistance" (2018). Markey Cancer Center Faculty Publications. 130.
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