The cancer cell oxygen sensor PHD2 promotes metastasis via activation of cancer-associated fibroblasts

Kuchnio, A. et al. (2015) The cancer cell oxygen sensor PHD2 promotes metastasis via activation of cancer-associated fibroblasts. Cell Reports, 12(6), pp. 992-1005. (doi: 10.1016/j.celrep.2015.07.010) (PMID:26235614)

Abstract

Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs). We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1) by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2) by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment) is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2’s therapeutic potential.

• Item Type: Articles
• Additional Information: Supporting fellowships were provided by FWO-Vlaanderen (A.K., U.B., A.A.U., R.L.O., F.B.), Vlaamse Liga tegen Kanker (A.K., S.M.), Marie Curie-IEF (U.B.), Agentschap voor Innovatie door Wetenschap en Technologie (B.C.), and Cancer Research UK (J.R.H.-F., S.Z.). Supporting grants were received from IUAP P7, Methusalem funding, GOA2006/11, FWO (grants G.0598.12, G.0692.09, G.0532.1, and G.0817.11), FWO Krediet aan navorsers (1.5.202.10.N), and ERC Advanced Research (EU-ERC269073) (P.C.). P.C. and M.M. are named as inventors on patent applications for subject matter related to the results described in this paper.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zanivan, Professor Sara
• Authors: Kuchnio, A., Moens, S., Bruning, U., Kuchnio, K., Cruys, B., Thienpont, B., Broux, M., Ungureanu, A. A., Leite de Oliveira, R., Francoise, B., Cuervo, H., Manderveld, A., Hernandez-Fernaud, J. R., Zanivan, S. R., Bartic, C., Foidart, J.-M., Noel, A., Vinckier, S., Lambrechts, D., Dewerchin, M., Mazzone, M., and Carmeliet, P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 30 July 2015
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Cell Reports 12(6):992-1005
• Publisher Policy: Reproduced under a Creative Commons License