Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy
Autor: | James L. Thorne, Melina C. Teske, Robyn V. Broad, Andrew M. Hanby, Laura M. Wastall, Stacey J. Jones, Thomas A. Hughes |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Myxovirus Resistance Proteins
Cancer Research medicine.medical_treatment Apoptosis Triple Negative Breast Neoplasms Article 03 medical and health sciences Paracrine signalling Breast cancer 0302 clinical medicine Cancer-Associated Fibroblasts Interferon Antineoplastic Combined Chemotherapy Protocols Paracrine Communication Biomarkers Tumor Tumor Cells Cultured Humans Medicine Clonogenic assay skin and connective tissue diseases Cell Proliferation Chemotherapy biology business.industry Interferon-beta Fibroblasts Prognosis medicine.disease Coculture Techniques Gene Expression Regulation Neoplastic Cancer therapeutic resistance Oncology 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Immunohistochemistry Female Antibody Transcriptome business medicine.drug |
Zdroj: | British Journal of Cancer |
ISSN: | 0007-0920 |
Popis: | Background Triple negative breast cancers (TNBC) have poor prognoses despite aggressive treatment with cytotoxic chemotherapy. Cancer-associated fibroblasts (CAFs) are prominent in tumour stroma. Our hypothesis was that CAFs modulate chemotherapy sensitivity. Methods TNBC cells and breast fibroblasts were cultured; survival after chemotherapeutics was assessed using luciferase or clonogenic assays. Signalling was investigated using transcriptomics, reporters, recombinant proteins and blocking antibodies. Clinical relevance was investigated using immunohistochemistry. Results Breast CAFs dose-dependently protected TNBC cell lines MDA-MB-231 and MDA-MB-157, but not MDA-MB-468s, from chemotherapy. CAF-induced protection was associated with interferon (IFN) activation. CAFs were induced to express IFNβ1 by chemotherapy and TNBC co-culture, leading to paracrine activation in cancer cells. Recombinant IFNs were sufficient to protect MDA-MB-231 and MDA-MB-157 but not MDA-MB-468 cells. In TNBC patients, IFNβ1 expression in CAFs correlated with cancer cell expression of MX1, a marker of activated IFN signalling. High expression of IFNβ1 (CAFs) or MX1 (tumour cells) correlated with reduced survival after chemotherapy, especially in claudin-low tumours (which MDA-MB-231 and MDA-MB-157 cells represent). Antibodies that block IFN receptors reduced CAF-dependent chemoprotection. Conclusions CAF-induced activation of IFN signalling in claudin-low TNBCs results in chemoresistance. Inhibition of this pathway represents a novel method to improve breast cancer outcomes. |
Databáze: | OpenAIRE |
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