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Nat Cell Biol. 2014 Jul;16(7):685-94. doi: 10.1038/ncb2977. Epub 2014 Jun 1.

Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH.

Author information

1
1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2].
2
1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Institut de Malalties Hemato-Oncològiques, Hospital Clínic de Barcelona-IDIBAPS and CIBER-EHD), 08036 Barcelona, Spain [3].
3
Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
4
1] Grup d'Oncogenesi i Antitumorals, Hospital de Sant Pau, 08026 Barcelona, Spain [2] Grup d'Oncogenesi i Antitumorals, Institute of Biomedical Research (IIB Sant Pau), Network Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08026 Barcelona, Spain.
5
1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Molecular Partners AG, 8952 Schlieren, Switzerland.
6
Institut de Malalties Hemato-Oncològiques, Hospital Clínic de Barcelona-IDIBAPS and CIBER-EHD), 08036 Barcelona, Spain.
7
Memorial Sloan-Kettering Cancer Center, 10065 New York, USA.
8
1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.

Abstract

The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS mutation influences where and when metastasis occurs, are unknown. We provide clinical and molecular evidence showing that different MAPK signalling pathways are implicated in this process. Whereas ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver, reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously established liver lesions. Downregulation of p38 MAPK signalling results in increased expression of the cytokine PTHLH, which contributes to colon cancer cell extravasation to the lung by inducing caspase-independent death in endothelial cells of the lung microvasculature. The concerted acquisition of metastatic traits in the colon cancer cells together with the sequential colonization of liver and lung highlights the importance of metastatic lesions as a platform for further dissemination.

PMID:
24880666
DOI:
10.1038/ncb2977
[Indexed for MEDLINE]

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