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

doi:10.1038/ncb2977

. 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

Jelena Urosevic¹, Xabier Garcia-Albéniz², Evarist Planet³, Sebastián Real³, María Virtudes Céspedes⁴, Marc Guiu³, Esther Fernandez³, Anna Bellmunt³, Sylwia Gawrzak³, Milica Pavlovic³, Ramon Mangues⁴, Ignacio Dolado⁵, Francisco M Barriga³, Cristina Nadal⁶, Nancy Kemeny⁷, Eduard Batlle⁸, Angel R Nebreda⁸, Roger R Gomis⁸

Affiliations

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.

PMID: 24880666
DOI: 10.1038/ncb2977

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

Jelena Urosevic et al. Nat Cell Biol. 2014 Jul.

. 2014 Jul;16(7):685-94.

doi: 10.1038/ncb2977. Epub 2014 Jun 1.

Authors

Affiliations

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.

PMID: 24880666
DOI: 10.1038/ncb2977

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.

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Comment in

Integration of microenvironmental and stress signaling antagonizes colorectal cancer progression.
Linde N, Sosa MS, Aguirre-Ghiso JA. Linde N, et al. EMBO J. 2014 Aug 18;33(16):1737-9. doi: 10.15252/embj.201489364. Epub 2014 Jul 14. EMBO J. 2014. PMID: 25024435 Free PMC article.
MAPK signaling control of colon cancer metastasis.
Urosevic J, Nebreda AR, Gomis RR. Urosevic J, et al. Cell Cycle. 2014;13(17):2641-2. doi: 10.4161/15384101.2014.946374. Cell Cycle. 2014. PMID: 25486343 Free PMC article. No abstract available.

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[1] Cancer Res. 1986 Apr;46(4 Pt 2):1928-33 - PubMed

[2] Cancer Res. 1986 Apr;46(4 Pt 2):1928-33 - PubMed

[3] Cell Mol Life Sci. 2011 Jan;68(1):1-13 - PubMed

[4] Cell Mol Life Sci. 2011 Jan;68(1):1-13 - PubMed

[5] J Exp Med. 2000 Aug 21;192(4):571-80 - PubMed

[6] J Exp Med. 2000 Aug 21;192(4):571-80 - PubMed

[7] Nat Rev Cancer. 2003 Jun;3(6):453-8 - PubMed

[8] Nat Rev Cancer. 2003 Jun;3(6):453-8 - PubMed

[9] Nature. 2010 Apr 15;464(7291):999-1005 - PubMed

[10] Nature. 2010 Apr 15;464(7291):999-1005 - PubMed

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

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

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