Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts
Cancer-associated fibroblasts (CAFs) represent an important component of the tumour microenvironment and are implicated in disease progression. Two outstanding questions in cancer biology are how CAFs arise and how they might be targeted therapeutically. The calcium signal also has an important role...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/6/680 |
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| author | Francisco Sadras Teneale A. Stewart Mélanie Robitaille Amelia A. Peters Priyakshi Kalita-de Croft Patsy S. Soon Jodi M. Saunus Sunil R. Lakhani Sarah J. Roberts-Thomson Gregory R. Monteith |
| author_facet | Francisco Sadras Teneale A. Stewart Mélanie Robitaille Amelia A. Peters Priyakshi Kalita-de Croft Patsy S. Soon Jodi M. Saunus Sunil R. Lakhani Sarah J. Roberts-Thomson Gregory R. Monteith |
| author_sort | Francisco Sadras |
| collection | DOAJ |
| description | Cancer-associated fibroblasts (CAFs) represent an important component of the tumour microenvironment and are implicated in disease progression. Two outstanding questions in cancer biology are how CAFs arise and how they might be targeted therapeutically. The calcium signal also has an important role in tumorigenesis. To date, the role of calcium signalling pathways in the induction of the CAF phenotype remains unexplored. A CAF model was generated through exogenous transforming growth factor beta 1 (TGFβ1) stimulation of the normal human mammary fibroblast cell line, HMF3S (HMF3S-CAF), and changes in calcium signalling were investigated. Functional changes in HMF3S-CAF calcium signalling pathways were assessed using a fluorescent indicator, gene expression, gene-silencing and pharmacological approaches. HMF3S-CAF cells demonstrated functionally altered calcium influx pathways with reduced store-operated calcium entry. In support of a calcium signalling switch, two voltage-gated calcium channel (VGCC) family members, Ca<sub>V</sub>1.2 and Ca<sub>V</sub>3.2, were upregulated in HMF3S-CAFs and a subset of patient-derived breast CAFs. Both siRNA-mediated silencing and pharmacological inhibition of Ca<sub>V</sub>1.2 or Ca<sub>V</sub>3.2 significantly impaired CAF activation in HMF3S cells. Our findings show that VGCCs contribute to TGFβ1-mediated induction of HMF3S-CAF cells and both transcriptional interference and pharmacological antagonism of Ca<sub>V</sub>1.2 and Ca<sub>V</sub>3.2 inhibit CAF induction. This suggests a potential therapeutic role for targeting calcium signalling in breast CAFs. |
| first_indexed | 2024-03-10T10:21:35Z |
| format | Article |
| id | doaj.art-8345c56fb6594f5e944735b38dfda3a5 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T10:21:35Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-8345c56fb6594f5e944735b38dfda3a52023-11-22T00:23:18ZengMDPI AGBiomedicines2227-90592021-06-019668010.3390/biomedicines9060680Altered Calcium Influx Pathways in Cancer-Associated FibroblastsFrancisco Sadras0Teneale A. Stewart1Mélanie Robitaille2Amelia A. Peters3Priyakshi Kalita-de Croft4Patsy S. Soon5Jodi M. Saunus6Sunil R. Lakhani7Sarah J. Roberts-Thomson8Gregory R. Monteith9School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, AustraliaMater Research, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, AustraliaSchool of Pharmacy, The University of Queensland, Brisbane, QLD 4102, AustraliaSchool of Pharmacy, The University of Queensland, Brisbane, QLD 4102, AustraliaCentre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, QLD 4006, AustraliaSouth Western Sydney Clinical School, University of New South Wales, Liverpool, NSW 2170, AustraliaCentre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, QLD 4006, AustraliaCentre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, QLD 4006, AustraliaSchool of Pharmacy, The University of Queensland, Brisbane, QLD 4102, AustraliaSchool of Pharmacy, The University of Queensland, Brisbane, QLD 4102, AustraliaCancer-associated fibroblasts (CAFs) represent an important component of the tumour microenvironment and are implicated in disease progression. Two outstanding questions in cancer biology are how CAFs arise and how they might be targeted therapeutically. The calcium signal also has an important role in tumorigenesis. To date, the role of calcium signalling pathways in the induction of the CAF phenotype remains unexplored. A CAF model was generated through exogenous transforming growth factor beta 1 (TGFβ1) stimulation of the normal human mammary fibroblast cell line, HMF3S (HMF3S-CAF), and changes in calcium signalling were investigated. Functional changes in HMF3S-CAF calcium signalling pathways were assessed using a fluorescent indicator, gene expression, gene-silencing and pharmacological approaches. HMF3S-CAF cells demonstrated functionally altered calcium influx pathways with reduced store-operated calcium entry. In support of a calcium signalling switch, two voltage-gated calcium channel (VGCC) family members, Ca<sub>V</sub>1.2 and Ca<sub>V</sub>3.2, were upregulated in HMF3S-CAFs and a subset of patient-derived breast CAFs. Both siRNA-mediated silencing and pharmacological inhibition of Ca<sub>V</sub>1.2 or Ca<sub>V</sub>3.2 significantly impaired CAF activation in HMF3S cells. Our findings show that VGCCs contribute to TGFβ1-mediated induction of HMF3S-CAF cells and both transcriptional interference and pharmacological antagonism of Ca<sub>V</sub>1.2 and Ca<sub>V</sub>3.2 inhibit CAF induction. This suggests a potential therapeutic role for targeting calcium signalling in breast CAFs.https://www.mdpi.com/2227-9059/9/6/680breast cancercancer-associated fibroblastscalciumcalcium signallingvoltage-gated calcium channelsstore-operated calcium entry |
| spellingShingle | Francisco Sadras Teneale A. Stewart Mélanie Robitaille Amelia A. Peters Priyakshi Kalita-de Croft Patsy S. Soon Jodi M. Saunus Sunil R. Lakhani Sarah J. Roberts-Thomson Gregory R. Monteith Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts Biomedicines breast cancer cancer-associated fibroblasts calcium calcium signalling voltage-gated calcium channels store-operated calcium entry |
| title | Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts |
| title_full | Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts |
| title_fullStr | Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts |
| title_full_unstemmed | Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts |
| title_short | Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts |
| title_sort | altered calcium influx pathways in cancer associated fibroblasts |
| topic | breast cancer cancer-associated fibroblasts calcium calcium signalling voltage-gated calcium channels store-operated calcium entry |
| url | https://www.mdpi.com/2227-9059/9/6/680 |
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