Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma

Alessandra Gentilini, Krista Rombouts, Sara Galastri, Alessandra Caligiuri, Eleonora Mingarelli, Tommaso Mello, Fabio Marra, Stefano Mantero, Massimo Roncalli, Pietro Invernizzi, Massimo Pinzani

Research output: Contribution to journalArticle

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Abstract

Backgrounds & Aims: Cholangiocarcinoma (CCA) is highly fatal because of early invasion, widespread metastasis, and lack of an effective therapy. Migration, invasion, and metastasis of CCA cells are modulated by signals received from stromal cells. The SDF-1-CXCR4 axis emerges as a pivotal regulator of migration and survival of different tumor cells. The aim of the present study was to characterize the interaction between CCA cells and human hepatic stellate cells (hHSC) focusing on the role of SDF-1. Methods: The intrahepatic CCA cell line HuCCT-1 and primary hHSC were used for this study. RNA expression was examined by RTQ-PCR and protein expression by Western blotting. Immunofluorescence microscopy and immunohistochemistry were also employed. Migration of CCA cells was assessed using modified Boyden chambers. Results: CXCR4 was clearly expressed in CCA cells of human CCA liver specimens. SDF-1 and hHSC conditioned medium (CM) promoted HuCCT-1 cell migration, which was abrogated by pre-incubation with AMD3100, a non-peptide antagonist of the CXCR4 receptor. In addition, HuCCT-1 cells silenced for CXCR4 did not migrate in presence of SDF-1. Both P-ERK and p-AKT were implicated in HuCCT-1 migration and showed a biphasic trend under stimulation of SDF-1. Finally, SDF-1 induced apoptotic rescue of HuCCT-1 cells by binding to CXCR4. Conclusions: Our study demonstrates that CCA cells migration and survival are modulated by the crosstalk between SDF-1, released by hHSC, and HuCCT-1 cells bearing CXCR4.

Original languageEnglish (US)
Pages (from-to)813-820
Number of pages8
JournalJournal of Hepatology
Volume57
Issue number4
DOIs
StatePublished - Oct 2012
Externally publishedYes

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Hepatic Stellate Cells
Cholangiocarcinoma
Cell Movement
CXCR4 Receptors
Neoplasm Metastasis
Stromal Cells
Conditioned Culture Medium
Fluorescence Microscopy
Cell Survival
Western Blotting
Immunohistochemistry
RNA
Cell Line
Polymerase Chain Reaction
Survival
Liver

Keywords

  • Cholangiocarcinoma
  • HuCCT-1 migration
  • HuCCT-1 survival
  • SDF-1/CXCR4 axis

ASJC Scopus subject areas

  • Hepatology

Cite this

Gentilini, A., Rombouts, K., Galastri, S., Caligiuri, A., Mingarelli, E., Mello, T., ... Pinzani, M. (2012). Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma. Journal of Hepatology, 57(4), 813-820. https://doi.org/10.1016/j.jhep.2012.06.012

Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma. / Gentilini, Alessandra; Rombouts, Krista; Galastri, Sara; Caligiuri, Alessandra; Mingarelli, Eleonora; Mello, Tommaso; Marra, Fabio; Mantero, Stefano; Roncalli, Massimo; Invernizzi, Pietro; Pinzani, Massimo.

In: Journal of Hepatology, Vol. 57, No. 4, 10.2012, p. 813-820.

Research output: Contribution to journalArticle

Gentilini, A, Rombouts, K, Galastri, S, Caligiuri, A, Mingarelli, E, Mello, T, Marra, F, Mantero, S, Roncalli, M, Invernizzi, P & Pinzani, M 2012, 'Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma', Journal of Hepatology, vol. 57, no. 4, pp. 813-820. https://doi.org/10.1016/j.jhep.2012.06.012
Gentilini, Alessandra ; Rombouts, Krista ; Galastri, Sara ; Caligiuri, Alessandra ; Mingarelli, Eleonora ; Mello, Tommaso ; Marra, Fabio ; Mantero, Stefano ; Roncalli, Massimo ; Invernizzi, Pietro ; Pinzani, Massimo. / Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma. In: Journal of Hepatology. 2012 ; Vol. 57, No. 4. pp. 813-820.
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abstract = "Backgrounds & Aims: Cholangiocarcinoma (CCA) is highly fatal because of early invasion, widespread metastasis, and lack of an effective therapy. Migration, invasion, and metastasis of CCA cells are modulated by signals received from stromal cells. The SDF-1-CXCR4 axis emerges as a pivotal regulator of migration and survival of different tumor cells. The aim of the present study was to characterize the interaction between CCA cells and human hepatic stellate cells (hHSC) focusing on the role of SDF-1. Methods: The intrahepatic CCA cell line HuCCT-1 and primary hHSC were used for this study. RNA expression was examined by RTQ-PCR and protein expression by Western blotting. Immunofluorescence microscopy and immunohistochemistry were also employed. Migration of CCA cells was assessed using modified Boyden chambers. Results: CXCR4 was clearly expressed in CCA cells of human CCA liver specimens. SDF-1 and hHSC conditioned medium (CM) promoted HuCCT-1 cell migration, which was abrogated by pre-incubation with AMD3100, a non-peptide antagonist of the CXCR4 receptor. In addition, HuCCT-1 cells silenced for CXCR4 did not migrate in presence of SDF-1. Both P-ERK and p-AKT were implicated in HuCCT-1 migration and showed a biphasic trend under stimulation of SDF-1. Finally, SDF-1 induced apoptotic rescue of HuCCT-1 cells by binding to CXCR4. Conclusions: Our study demonstrates that CCA cells migration and survival are modulated by the crosstalk between SDF-1, released by hHSC, and HuCCT-1 cells bearing CXCR4.",
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AU - Gentilini, Alessandra

AU - Rombouts, Krista

AU - Galastri, Sara

AU - Caligiuri, Alessandra

AU - Mingarelli, Eleonora

AU - Mello, Tommaso

AU - Marra, Fabio

AU - Mantero, Stefano

AU - Roncalli, Massimo

AU - Invernizzi, Pietro

AU - Pinzani, Massimo

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N2 - Backgrounds & Aims: Cholangiocarcinoma (CCA) is highly fatal because of early invasion, widespread metastasis, and lack of an effective therapy. Migration, invasion, and metastasis of CCA cells are modulated by signals received from stromal cells. The SDF-1-CXCR4 axis emerges as a pivotal regulator of migration and survival of different tumor cells. The aim of the present study was to characterize the interaction between CCA cells and human hepatic stellate cells (hHSC) focusing on the role of SDF-1. Methods: The intrahepatic CCA cell line HuCCT-1 and primary hHSC were used for this study. RNA expression was examined by RTQ-PCR and protein expression by Western blotting. Immunofluorescence microscopy and immunohistochemistry were also employed. Migration of CCA cells was assessed using modified Boyden chambers. Results: CXCR4 was clearly expressed in CCA cells of human CCA liver specimens. SDF-1 and hHSC conditioned medium (CM) promoted HuCCT-1 cell migration, which was abrogated by pre-incubation with AMD3100, a non-peptide antagonist of the CXCR4 receptor. In addition, HuCCT-1 cells silenced for CXCR4 did not migrate in presence of SDF-1. Both P-ERK and p-AKT were implicated in HuCCT-1 migration and showed a biphasic trend under stimulation of SDF-1. Finally, SDF-1 induced apoptotic rescue of HuCCT-1 cells by binding to CXCR4. Conclusions: Our study demonstrates that CCA cells migration and survival are modulated by the crosstalk between SDF-1, released by hHSC, and HuCCT-1 cells bearing CXCR4.

AB - Backgrounds & Aims: Cholangiocarcinoma (CCA) is highly fatal because of early invasion, widespread metastasis, and lack of an effective therapy. Migration, invasion, and metastasis of CCA cells are modulated by signals received from stromal cells. The SDF-1-CXCR4 axis emerges as a pivotal regulator of migration and survival of different tumor cells. The aim of the present study was to characterize the interaction between CCA cells and human hepatic stellate cells (hHSC) focusing on the role of SDF-1. Methods: The intrahepatic CCA cell line HuCCT-1 and primary hHSC were used for this study. RNA expression was examined by RTQ-PCR and protein expression by Western blotting. Immunofluorescence microscopy and immunohistochemistry were also employed. Migration of CCA cells was assessed using modified Boyden chambers. Results: CXCR4 was clearly expressed in CCA cells of human CCA liver specimens. SDF-1 and hHSC conditioned medium (CM) promoted HuCCT-1 cell migration, which was abrogated by pre-incubation with AMD3100, a non-peptide antagonist of the CXCR4 receptor. In addition, HuCCT-1 cells silenced for CXCR4 did not migrate in presence of SDF-1. Both P-ERK and p-AKT were implicated in HuCCT-1 migration and showed a biphasic trend under stimulation of SDF-1. Finally, SDF-1 induced apoptotic rescue of HuCCT-1 cells by binding to CXCR4. Conclusions: Our study demonstrates that CCA cells migration and survival are modulated by the crosstalk between SDF-1, released by hHSC, and HuCCT-1 cells bearing CXCR4.

KW - Cholangiocarcinoma

KW - HuCCT-1 migration

KW - HuCCT-1 survival

KW - SDF-1/CXCR4 axis

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