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ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells

Intracellular pH (pHi) regulation is a challenge for the exocrine pancreas, where the luminal secretion of bicarbonate-rich fluid is accompanied by interstitial flows of acid. This acid–base transport requires a plethora of ion transporters, including bicarbonate transporters and the Na(+)/H(+) exch...

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Autores principales: Di Molfetta, Daria, Cannone, Stefania, Greco, Maria Raffaella, Caroppo, Rosa, Piccapane, Francesca, Carvalho, Tiago Miguel Amaral, Altamura, Concetta, Saltarella, Ilaria, Tavares Valente, Diana, Desaphy, Jean Francois, Reshkin, Stephan J., Cardone, Rosa Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341693/
https://www.ncbi.nlm.nih.gov/pubmed/37445810
http://dx.doi.org/10.3390/ijms241310632
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author Di Molfetta, Daria
Cannone, Stefania
Greco, Maria Raffaella
Caroppo, Rosa
Piccapane, Francesca
Carvalho, Tiago Miguel Amaral
Altamura, Concetta
Saltarella, Ilaria
Tavares Valente, Diana
Desaphy, Jean Francois
Reshkin, Stephan J.
Cardone, Rosa Angela
author_facet Di Molfetta, Daria
Cannone, Stefania
Greco, Maria Raffaella
Caroppo, Rosa
Piccapane, Francesca
Carvalho, Tiago Miguel Amaral
Altamura, Concetta
Saltarella, Ilaria
Tavares Valente, Diana
Desaphy, Jean Francois
Reshkin, Stephan J.
Cardone, Rosa Angela
author_sort Di Molfetta, Daria
collection PubMed
description Intracellular pH (pHi) regulation is a challenge for the exocrine pancreas, where the luminal secretion of bicarbonate-rich fluid is accompanied by interstitial flows of acid. This acid–base transport requires a plethora of ion transporters, including bicarbonate transporters and the Na(+)/H(+) exchanger isoform 1 (NHE1), which are dysregulated in Pancreatic Ductal Adenocarcinoma (PDAC). PDAC progression is favored by a Collagen-I rich extracellular matrix (ECM) which exacerbates the physiological interstitial acidosis. In organotypic cultures of normal human pancreatic cells (HPDE), parenchymal cancer cells (CPCs) and cancer stem cells (CSCs) growing on matrices reproducing ECM changes during progression, we studied resting pHi, the pHi response to fluxes of NaHCO(3) and acidosis and the role of NHE1 in pHi regulation. Our findings show that: (i) on the physiological ECM, HPDE cells have the most alkaline pHi, followed by CSCs and CPCs, while a Collagen I-rich ECM reverses the acid–base balance in cancer cells compared to normal cells; (ii) both resting pHi and pHi recovery from an acid load are reduced by extracellular NaHCO(3), especially in HPDE cells on a normal ECM; (iii) cancer cell NHE1 activity is less affected by NaHCO(3). We conclude that ECM composition and the fluctuations of pHe cooperate to predispose pHi homeostasis towards the presence of NaHCO(3) gradients similar to that expected in the tumor.
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spelling pubmed-103416932023-07-14 ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells Di Molfetta, Daria Cannone, Stefania Greco, Maria Raffaella Caroppo, Rosa Piccapane, Francesca Carvalho, Tiago Miguel Amaral Altamura, Concetta Saltarella, Ilaria Tavares Valente, Diana Desaphy, Jean Francois Reshkin, Stephan J. Cardone, Rosa Angela Int J Mol Sci Article Intracellular pH (pHi) regulation is a challenge for the exocrine pancreas, where the luminal secretion of bicarbonate-rich fluid is accompanied by interstitial flows of acid. This acid–base transport requires a plethora of ion transporters, including bicarbonate transporters and the Na(+)/H(+) exchanger isoform 1 (NHE1), which are dysregulated in Pancreatic Ductal Adenocarcinoma (PDAC). PDAC progression is favored by a Collagen-I rich extracellular matrix (ECM) which exacerbates the physiological interstitial acidosis. In organotypic cultures of normal human pancreatic cells (HPDE), parenchymal cancer cells (CPCs) and cancer stem cells (CSCs) growing on matrices reproducing ECM changes during progression, we studied resting pHi, the pHi response to fluxes of NaHCO(3) and acidosis and the role of NHE1 in pHi regulation. Our findings show that: (i) on the physiological ECM, HPDE cells have the most alkaline pHi, followed by CSCs and CPCs, while a Collagen I-rich ECM reverses the acid–base balance in cancer cells compared to normal cells; (ii) both resting pHi and pHi recovery from an acid load are reduced by extracellular NaHCO(3), especially in HPDE cells on a normal ECM; (iii) cancer cell NHE1 activity is less affected by NaHCO(3). We conclude that ECM composition and the fluctuations of pHe cooperate to predispose pHi homeostasis towards the presence of NaHCO(3) gradients similar to that expected in the tumor. MDPI 2023-06-25 /pmc/articles/PMC10341693/ /pubmed/37445810 http://dx.doi.org/10.3390/ijms241310632 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Di Molfetta, Daria
Cannone, Stefania
Greco, Maria Raffaella
Caroppo, Rosa
Piccapane, Francesca
Carvalho, Tiago Miguel Amaral
Altamura, Concetta
Saltarella, Ilaria
Tavares Valente, Diana
Desaphy, Jean Francois
Reshkin, Stephan J.
Cardone, Rosa Angela
ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells
title ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells
title_full ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells
title_fullStr ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells
title_full_unstemmed ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells
title_short ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells
title_sort ecm composition differentially regulates intracellular and extracellular ph in normal and cancer pancreatic duct epithelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341693/
https://www.ncbi.nlm.nih.gov/pubmed/37445810
http://dx.doi.org/10.3390/ijms241310632
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