Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells.
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.
The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.|The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.
Maria
M
Peiris-Pagès
The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.|The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.
Federica
F
Sotgia
The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK.|The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK.
Michael P
MP
Lisanti
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D059016:Tumor Microenvironment; D000071676:Zinc Finger Protein GLI1
D000970:Antineoplastic Agents; D000975:Antioxidants; D016207:Cytokines; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D018836:Inflammation Mediators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
chemotherapy; metabolism; second primary tumours; tumour microenvironment