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A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis
Karolinska Institute, Sweden; Shandong University, Peoples R China.
Karolinska Institute, Sweden; Sun Yat Sen University, Peoples R China.
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
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2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 16, 4769-4779 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor is at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAF) 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. Experimental Design: Multicolor-coded cancer cells and CAFs were coimplanted 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. Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor was 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 in 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. Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred 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. (C) 2017 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2017. Vol. 23, no 16, 4769-4779 p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-140968DOI: 10.1158/1078-0432.CCR-17-0101ISI: 000407614400027PubMedID: 28420724OAI: oai:DiVA.org:liu-140968DiVA: diva2:1142319
Note

Funding Agencies|European Research Council (ERC) advanced grant ANGIOFAT [250021]; Swedish Research Council [K2012-67X-21130-04-5, 2015-02410]; Swedish Cancer Foundation [140659]; Karolinska Institute Foundation [C166658073]; Karolinska Institute distinguished professor award [C166646352]; Torsten Soderbergs Foundation [M144/12]; Maud and Birger Gustavsson Foundation [C166655073]; NOVO Nordisk Foundation (BtN/AIR); Knut and Alice Wallenbergs Foundation [C166646483]; Swedish Cancer Society [15 0591]; Cancer Research Institute, New York; Fund for High Level University Construction of Medical Discipline, China [2016031638]

Available from: 2017-09-19 Created: 2017-09-19 Last updated: 2017-09-19

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