The cancer cell oxygen sensor PHD2 promotes metastasis via activation of cancer-associated fibroblasts
Articolo
Data di Pubblicazione:
2015
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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
Animals; Cell Line, Tumor; Female; Fibroblasts; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Immunoblotting; Immunohistochemistry; Male; Mice; Models, Biological; Neoplasm Metastasis; Neoplasms; Reverse Transcriptase Polymerase Chain Reaction
Elenco autori:
Kuchnio A.; Moens S.; Bruning U.; Kuchnio K.; Cruys B.; Thienpont B.; Broux M.; Ungureanu A.A.; de Oliveira R.L.; Bruyere F.; Cuervo H.; Manderveld A.; Carton A.; Hernandez-Fernaud J.R.; Zanivan S.; Bartic C.; Foidart J.M.; Noel A.; Vinckier S.; Lambrechts D.; Dewerchin M.; Mazzone M.; Carmeliet P.
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