title: Proteomic identification of prognostic tumour biomarkers, using chemotherapy-induced cancer-associated fibroblasts.
abstract: Cancer cells grow in highly complex stromal microenvironments, which through metabolic remodelling, catabolism, autophagy and inflammation nurture them and are able to facilitate metastasis and resistance to therapy. However, these changes in the metabolic profile of stromal cancer-associated fibroblasts and their impact on cancer initiation, progression and metastasis are not well-known. This is the first study to provide a comprehensive proteomic portrait of the azathioprine and taxol-induced catabolic state on human stromal fibroblasts, which comprises changes in the expression of metabolic enzymes, myofibroblastic differentiation markers, antioxidants, proteins involved in autophagy, senescence, vesicle trafficking and protein degradation, and inducers of inflammation. Interestingly, many of these features are major contributors to the aging process. A catabolic stroma signature, generated with proteins found differentially up-regulated in taxol-treated fibroblasts, strikingly correlates with recurrence, metastasis and poor patient survival in several solid malignancies. We therefore suggest the inhibition of the catabolic state in healthy cells as a novel approach to improve current chemotherapy efficacies and possibly avoid future carcinogenic processes.
authors.affiliation: The Breast Cancer Now 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Peiris-Pagès
authors.affiliation: The Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Duncan L
authors.initials: DL
authors.lastname: Smith
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.|Semmelweis University 2nd Dept. of Pediatrics, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: The Breast Cancer Now 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.
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.affiliation: The Breast Cancer Now 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.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy; D001379:Azathioprine / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence; D018572:Disease-Free Survival; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D040901:Proteomics; D013312:Stress, Physiological; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D014408:Biomarkers, Tumor; D001379:Azathioprine; D017239:Paclitaxel
keywords: cancer survival; cancer-associated fibroblasts; catabolism; chemotherapy; markers; metabolism; quantitative proteomics; second primary tumours; tumour microenvironment