期刊
CANCER RESEARCH
卷 75, 期 2, 页码 306-315出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-2819
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资金
- Swedish Research Council
- Swedish Cancer Foundation
- Karolinska Institute Foundation
- Karolinska Institute distinguished professor award
- Torsten Soderbergs foundation
- European Research Council (ERC) advanced grant ANGIOFAT [250021]
- NOVO Nordisk Foundation
- Novo Nordisk Fonden [NNF14OC0012835, NNF13OC0005609] Funding Source: researchfish
Cancer metastasis can occur at early stages of tumor development due to facilitative alterations in the tumor microenvironment. Although imaging techniques have considerably improved our understanding of metastasis, early events remain challenging to study due to the small numbers of malignant cells involved that are often undetectable. Using a novel zebrafish model to investigate this process, we discovered that tumor-associated macrophages (TAM) acted to facilitate metastasis by binding tumor cells and mediating their intravasation. Mechanistic investigations revealed that IL6 and TNF alpha promoted the ability of macrophages to mediate this step. M2 macro-phages were particularly potent when induced by IL4, IL10, and TGF beta. In contrast, IFN gamma-lipopolysaccharide-induced M1 macrophages lacked the capability to function in the same way in the model. Confirming these observations, we found that human TAM isolated from primary breast, lung, colorectal, and endometrial cancers exhibited a similar capability in invasion and metastasis. Taken together, our work shows how zebrafish can be used to study how host contributions can facilitate metastasis at its earliest stages, and they reveal a new macrophage-dependent mechanism of metastasis with possible prognostic implications. (C) 2014 AACR.
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