Thomas R. Cox, Sep 2015
I’m pleased to announce that our recent paper on Cancer-Associated-Fibroblasts (CAFs) in cancer has just been published in the Journal EMBO Reports titled “Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis.“
In this paper we show that chronic hypoxia (lack of oxygen) within primary tumours leads to a deactivation of cancer associated fibroblasts.
Fibroblasts are found in most tissues in the body and are important in controlling many normal tissue functions. They are primarily responsible for producing the extracellular matrix (ECM) that makes up tissues, and supports normal cell growth and function. In cancer they become hyper-activated and their altered behaviour is thought to be critical in promoting tumour progression. We show that both hypoxia and the loss of a molecule called Prolyl Hydroxylase Domain-containing protein 2 (PHD2) reverses the activation of fibroblasts and stops them carrying out tumour-promoting activities. This opens up new avenues for treating cancer patients which may help improve cancer therapy in the clinic.
Cancer-associated fibroblasts (CAFs) interact with tumour cells and promote growth and metastasis. Here, we show that CAF activation is reversible: chronic hypoxia deactivates CAFs, resulting in the loss of contractile force, reduced remodelling of the surrounding extracellular matrix and, ultimately, impaired CAF-mediated cancer cell invasion. Hypoxia inhibits prolyl hydroxylase domain protein 2 (PHD2), leading to hypoxia-inducible factor (HIF)-1α stabilisation, reduced expression of αSMA and periostin, and reduced myosin II activity. Loss of PHD2 in CAFs phenocopies the effects of hypoxia, which can be prevented by simultaneous depletion of HIF-1α. Treatment with the PHD inhibitor DMOG in an orthotopic breast cancer model significantly decreases spontaneous metastases to the lungs and liver, associated with decreased tumour stiffness and fibroblast activation. PHD2 depletion in CAFs co-injected with tumour cells similarly prevents CAF-induced metastasis to lungs and liver. Our data argue that reversion of CAFs towards a less active state is possible and could have important clinical implications.
Madsen CD, Pedersen JT, Venning FA, Singh LB, Moeendarbary E, Charras G, Cox TR, Sahai E, Erler JT. Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis. EMBO Reports 2015 Aug 31. pii: e201540107 | doi: 10.15252/embr.201540107
We acknowledge the support of FEBS long‐term Fellowship for funding CDM and the Wellcome Trust‐MIT Postdoctoral Fellowship for funding EM. This work was further supported by Cancer Research UK grant CRUK_A5317, the Francis Crick Institute (CDM and ES), the Novo Nordisk Foundation, Denmark, with a Hallas Møller Stipend (CDM and JTE), the Danish Cancer Society (R117‐A7294‐B2731)(JTP), the Danish Council for Independent Research YDUN grant (1084181001) (FVA) and the Innovation Fund Denmark (1311‐00010B) (TRC).