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Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis

Oncogene volume 37, pages 3790–3805 (2018)Cite this article

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Abstract

Liver metastases remain a major cause of death from gastrointestinal tract cancers as well as from other malignancies such as breast and lung carcinomas and melanoma. Understanding the underlying biology is essential for the design of effective targeted therapies. We previously reported that collagen IV α1/α2 overexpression in non-metastatic lung carcinoma (M27colIV) cells increased their metastatic ability, specifically to the liver and documented high collagen IV levels in surgical resections of liver metastases from diverse tumor types. Here, we aimed to elucidate the functional relevance of collagen IV to metastatic outgrowth in the liver. Gene expression profiling revealed in M27colIVcells significant increases in the expression of chemokines CCL5 (5.7-fold) and CCL7 (2.6-fold) relative to wild-type cells, and this was validated by qPCR and western blotting. Similarly, in human colon carcinoma KM12C and KM12SM cells with divergent liver-colonizing potentials, CCL7 and CCL5 production correlated with type IV collagen expression and the metastatic phenotype. CCL7 silencing by short hairpin RNA (shRNA) reduced experimental liver metastasis in both cell types, whereas CCL5 silencing reduced metastasis of M27colIV cells, implicating these cytokines in metastatic expansion in the liver. Subsequent functional analyses implicated both MEK/ERK and PI3K signaling upstream of CCL7 upregulation and identified CCL7 (but not CCL5) as a critical migration/invasion factor, acting via the chemokine receptor CCR3. Chemokine CCL5 was identified as a regulator of the T-cell immune response in the liver. Loss of CCL7 in KM12SM cells was also associated with altered E-cadherin and reduced vimentin and Snail expression, implicating it in epithelial-to-mesenchymal transition in these cells. Moreover, in clinical specimens of colon cancer liver metastases analyzed by immunohistochemistry, CCL5 and CCL7 levels paralleled those of collagen IV. The results identify the chemokines CCL5 and CCL7 as type IV collagen-regulated genes that promote liver metastasis by distinct and complementary mechanisms.

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Acknowledgements

We thank Dr. Julia Burnier for the initial analysis of the microarray data, Ms. Anette Berglund for skillful technical assistance with immunohistochemistry, and the laboratory of Dr. Jean-Jacques Lebrun for help and advice. This work was supported mainly by grants MOP 80201 from the Canadian Institute for Health Research and a PSR-SIIRI-843 grant from the Québec Ministère de l'Économie, de l’Innovation et des Exportations (to P.B.) and also by grants from the Swedish Research Council and Västerbotten County Council (to H.N.). R.F.R. was supported by the Henry R. Shibata fellowship from the Cedars Cancer Institute. R.F.R. and G.V. were supported by MITACS internships.

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  1. These authors contributed equally: George Vaniotis, Roni F. Rayes.

Authors and Affiliations

  1. Department of Surgery, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada

    George Vaniotis, Roni F. Rayes, Shu Qi, Ni Wang, Stephanie Perrino, France Bourdeau & Pnina Brodt

  2. Medicine and Research Institute of the McGill University Health Center, Montreal, Quebec, Canada

    Simon Milette & Pnina Brodt

  3. Department of Surgery, Department of Surgical and Perioperative Sciences, Umea University, Umea, Sweden

    Hanna Nyström

  4. Department of Anatomy and Cell Biology, McGill University and Research Institute of the McGill University Health Center, Montreal, Quebec, Canada

    Yi He & Nathalie Lamarche-Vane

  5. Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada

    Yi He, Nathalie Lamarche-Vane & Pnina Brodt

  6. Department of Oncology, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada

    Pnina Brodt

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Vaniotis, G., Rayes, R.F., Qi, S. et al. Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis. Oncogene 37, 3790–3805 (2018). https://doi.org/10.1038/s41388-018-0242-z

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