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

Cinzia Martinengo, Teresa Poggio, Matteo Menotti, Maria Stella Scalzo, Cristina Mastini, Chiara Ambrogio, Elisa Pellegrino, Ludovica Riera, Roberto Piva, Domenico Ribatti, Fabio Pastorino, Patrizia Perri, Mirco Ponzoni, Qi Wang, Claudia Voena, Roberto Chiarle

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22 Citations (Scopus)

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 speci fic therapeutic target in ALK-rearranged ALCL and NSCLC.

Original languageEnglish
Pages (from-to)6094-6106
Number of pages13
JournalCancer Research
Volume74
Issue number21
DOIs
Publication statusPublished - Nov 1 2014

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Anaplastic Large-Cell Lymphoma
Neoplasm Metastasis
Non-Small Cell Lung Carcinoma
Growth
Neoplasms
anaplastic lymphoma kinase
Hypoxia
CCAAT-Enhancer-Binding Proteins
T-Cell Lymphoma
Heterografts
Anti-Idiotypic Antibodies
Up-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Martinengo, C., Poggio, T., Menotti, M., Scalzo, M. S., Mastini, C., Ambrogio, C., ... Chiarle, R. (2014). ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis. Cancer Research, 74(21), 6094-6106. https://doi.org/10.1158/0008-5472.CAN-14-0268

ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis. / Martinengo, Cinzia; Poggio, Teresa; Menotti, Matteo; Scalzo, Maria Stella; Mastini, Cristina; Ambrogio, Chiara; Pellegrino, Elisa; Riera, Ludovica; Piva, Roberto; Ribatti, Domenico; Pastorino, Fabio; Perri, Patrizia; Ponzoni, Mirco; Wang, Qi; Voena, Claudia; Chiarle, Roberto.

In: Cancer Research, Vol. 74, No. 21, 01.11.2014, p. 6094-6106.

Research output: Contribution to journalArticle

Martinengo, C, Poggio, T, Menotti, M, Scalzo, MS, Mastini, C, Ambrogio, C, Pellegrino, E, Riera, L, Piva, R, Ribatti, D, Pastorino, F, Perri, P, Ponzoni, M, Wang, Q, Voena, C & Chiarle, R 2014, 'ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis', Cancer Research, vol. 74, no. 21, pp. 6094-6106. https://doi.org/10.1158/0008-5472.CAN-14-0268
Martinengo C, Poggio T, Menotti M, Scalzo MS, Mastini C, Ambrogio C et al. ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis. Cancer Research. 2014 Nov 1;74(21):6094-6106. https://doi.org/10.1158/0008-5472.CAN-14-0268
Martinengo, Cinzia ; Poggio, Teresa ; Menotti, Matteo ; Scalzo, Maria Stella ; Mastini, Cristina ; Ambrogio, Chiara ; Pellegrino, Elisa ; Riera, Ludovica ; Piva, Roberto ; Ribatti, Domenico ; Pastorino, Fabio ; Perri, Patrizia ; Ponzoni, Mirco ; Wang, Qi ; Voena, Claudia ; Chiarle, Roberto. / ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis. In: Cancer Research. 2014 ; Vol. 74, No. 21. pp. 6094-6106.
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AU - Ambrogio, Chiara

AU - Pellegrino, Elisa

AU - Riera, Ludovica

AU - Piva, Roberto

AU - Ribatti, Domenico

AU - Pastorino, Fabio

AU - Perri, Patrizia

AU - Ponzoni, Mirco

AU - Wang, Qi

AU - Voena, Claudia

AU - Chiarle, Roberto

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