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Cancer Therapy: Preclinical

A zebrafish model discovers a novel mechanism of stromal fibroblast-mediated cancer metastasis

Cai Feng Liu, Yunjian Zhang, Sharon Lim, Kayoko Hosaka, Yunlong Yang, Tatiana Pavlova, Twana Alkasalias, Johan Hartman, Lasse Jensen, Xiao-Ming Xing, Xingsheng Wang, Yong-Tian Lu, Guo Hui Nie and Yihai Cao
Cai Feng Liu
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute
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Yunjian Zhang
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute
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Sharon Lim
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute
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Kayoko Hosaka
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute
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Yunlong Yang
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute
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Tatiana Pavlova
The Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet
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Twana Alkasalias
Microbiology, tumor and cell biology, karolinska institutet
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Johan Hartman
Dept of Oncology and Pathology, Karolinska Institute
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Lasse Jensen
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
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Xiao-Ming Xing
Department of pathology, The Affiliated Hospital of Qingdao University
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Xingsheng Wang
Department of Pathology and Department of Urology, the Affiliated Hospital of Qingdao University
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Yong-Tian Lu
Key Laboratory of International Collaborations, Shenzhen Second People's Hospital of Shenzhen
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Guo Hui Nie
Key Laboratory of International Collaborations, Shenzhen Second People's Hospital of Shenzhen
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Yihai Cao
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute
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  • For correspondence: yihai.cao@ki.se
DOI: 10.1158/1078-0432.CCR-17-0101
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Abstract

Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAFs) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes.  <p>Experimental design: Multi-color-coded cancer cells and CAFs were co-implanted into the transparent zebrafish body and metastasis at a single cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis.<br /><br />Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity.</p> Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred of cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development.

  • Received January 12, 2017.
  • Revision received April 14, 2017.
  • Accepted April 14, 2017.
  • Copyright ©2017, American Association for Cancer Research.
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Published OnlineFirst April 18, 2017
doi: 10.1158/1078-0432.CCR-17-0101

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A zebrafish model discovers a novel mechanism of stromal fibroblast-mediated cancer metastasis
Cai Feng Liu, Yunjian Zhang, Sharon Lim, Kayoko Hosaka, Yunlong Yang, Tatiana Pavlova, Twana Alkasalias, Johan Hartman, Lasse Jensen, Xiao-Ming Xing, Xingsheng Wang, Yong-Tian Lu, Guo Hui Nie and Yihai Cao
Clin Cancer Res April 18 2017 DOI: 10.1158/1078-0432.CCR-17-0101

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A zebrafish model discovers a novel mechanism of stromal fibroblast-mediated cancer metastasis
Cai Feng Liu, Yunjian Zhang, Sharon Lim, Kayoko Hosaka, Yunlong Yang, Tatiana Pavlova, Twana Alkasalias, Johan Hartman, Lasse Jensen, Xiao-Ming Xing, Xingsheng Wang, Yong-Tian Lu, Guo Hui Nie and Yihai Cao
Clin Cancer Res April 18 2017 DOI: 10.1158/1078-0432.CCR-17-0101
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Clinical Cancer Research
eISSN: 1557-3265
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