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Cited by 115Cancer, Hypoxia, and MetabolismHedgehog Signaling Pathway StudiesCancer Cells and Metastasis

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

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Peiris-Pagès, Maria, Sotgia, Federica, Lisanti, Michael P.·2015·Oncotarget
DOI 10.18632/oncotarget.3828PMC PMC4484415
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Abstract

// Maria Peiris-Pagès 1,2 , Federica Sotgia 1,2 and Michael P. Lisanti 1,2 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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  • Alkylating agents, topoisomerase inhibitors, γ-irradiation, microtubule inhibitors and, to a lesser extent, vinca alkaloids have all been identified as senescence inducers in preclinical models.

    “Alkylating agents 27,95,96 (for example, cisplatin, cyclophosphamide and temozolomide), topoisomerase inhibitors 27,65,91,95 (such as doxorubicin, etoposide and camptothecin) and γ- irradiation 78 , but also microtubule inhibitors 27,97,98 (for example, paclitaxel) and, to a lesser extent, vinca alkaloids 78 (for example, vincristine), have all been identified as senescence inducers in preclinical”

    From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [96]

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Cited by

Sorted by citations

Authors
Peiris-Pagès, M., Sotgia, F., & Lisanti, M. P.
Affiliations
  • The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK
  • University of Manchester (GB)
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2015-04-14
Volume
6
Issue
13
Pages
10728-10745
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.3828
PMC
PMC4484415
OpenAlex
W1532133662
Cited by
115
References
6
Citations by year
2026: 4 · 2025: 9 · 2024: 8 · 2023: 8 · 2022: 14 · 2021: 16 · 2020: 14 · 2019: 8 · 2018: 11 · 2017: 6 · 2016: 11 · 2015: 5
FWCI
3.64
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
  • University of Manchester
  • European Commission
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
chemotherapy, cancer-associated fibroblasts, breast cancer, stromal fibroblasts, tumor microenvironment, glycolysis, autophagy, inflammation, second primary tumours, interferon signaling, antioxidant response, paracrine signaling, cancer stemness, immune cell recruitment
MeSH terms
Zinc Finger Protein GLI1, Antineoplastic Agents, Antioxidants, Autophagy, Breast Neoplasms, Dose-Response Relationship, Drug, Female, Fibroblasts, Glycolysis, Humans, Phenotype, Time Factors, Transcription Factors, Transfection, Neoplastic Stem Cells, Signal Transduction, Cytokines, Cellular Senescence, Oxidative Stress, Inflammation Mediators, Coculture Techniques, Paracrine Communication, Hedgehog Proteins, Tumor Microenvironment, MCF-7 Cells

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