Oncotarget

Priority Research Papers:

Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells

Maria Peiris-Pagès, Federica Sotgia, Michael P. Lisanti _

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Oncotarget. 2015; 6:10728-10745. https://doi.org/10.18632/oncotarget.3828

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Abstract

Maria Peiris-Pagès1,2, Federica Sotgia1,2 and Michael P. Lisanti1,2

1 The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK

2 The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK

Correspondence to:

Federica Sotgia, email:

Michael Lisanti, email:

Keywords: chemotherapy, metabolism, second primary tumours, tumour microenvironment

Received: January 10, 2015 Accepted: March 26, 2015 Published: April 14, 2015

Abstract

Cancer cells recruit normal cells such as fibroblasts to establish reactive microenvironments. Via metabolic stress, catabolism and inflammation, these cancer-associated fibroblasts set up a synergistic relationship with tumour cells, that contributes to their malignancy and resistance to therapy. Given that chemotherapy is a systemic treatment, the possibility that healthy cell damage affects the metastatic risk or the prospect of developing a second malignancy becomes relevant. Here, we demonstrate that standard chemotherapies phenotypically and metabolically transform stromal fibroblasts into cancer-associated fibroblasts, leading to the emergence of a highly glycolytic, autophagic and pro-inflammatory microenvironment. This catabolic microenvironment, in turn, activates stemness (Sonic hedgehog/GLI signalling), antioxidant response and interferon-mediated signalling, in adjacent breast cancer cells. Thus, we propose a model by which chemotherapy-induced catabolism in healthy fibroblasts constitutes a source of energy-rich nutrients and inflammatory cytokines that would activate stemness in adjacent epithelial cells, possibly triggering new tumorigenic processes. In this context, immune cell recruitment would be also stimulated to further support malignancy.


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