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Cancer Res. 2014 Nov 1;74(21):6094-106. doi: 10.1158/0008-5472.CAN-14-0268. Epub 2014 Sep 5.

ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis.

Author information

1
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
2
Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
3
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
4
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy. National Cancer Institute "Giovanni Paolo II," Bari, Italy.
5
Experimental Therapy Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
6
Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts.
7
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy. claudia.voena@unito.it roberto.chiarle@childrens.harvard.edu.
8
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy. Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts. claudia.voena@unito.it roberto.chiarle@childrens.harvard.edu.

Abstract

Rearrangements involving the anaplastic lymphoma kinase (ALK) gene are defining events in several tumors, including anaplastic large-cell lymphoma (ALCL) and non-small cell lung carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared with other types of T-cell lymphoma or EGFR- and K-RAS-mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC, we found that under hypoxic conditions, ALK directly regulated the abundance of hypoxia-inducible factors (HIF), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF1α and HIF2α in hypoxic conditions required ALK activity and its downstream signaling proteins STAT3 and C/EBPβ. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF2α, but not HIF1α, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF1α and HIF2α. In conclusion, we uncovered an ALK-specific regulation of the hypoxia response across different ALK(+) tumor types and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC.

PMID:
25193384
DOI:
10.1158/0008-5472.CAN-14-0268
[Indexed for MEDLINE]
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