Tyrosine kinase receptor RON in human pancreatic cancer: Expression, function, and validation as a target

E. Ramsay Camp, Anthony Yang, Mike J. Gray, Fan Fan, Stanley R. Hamilton, Douglas B. Evans, Andrea T. Hooper, Daniel S. Pereira, Daniel J. Hicklin, Lee M. Ellis

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

BACKGROUND. Specific tyrosine kinase receptors such as c-MET mediate epithelial-mesenchymal (EMT) transition, leading to phenotypic alterations associated with increased cell motility. It was hypothesized that RON, a tyrosine kinase receptor related to c-MET, would be expressed in human pancreatic cancer cells, induce EMT, and would thus serve as a target for therapy in a preclinical model. METHODS. RON expression in human pancreatic cancer specimens was assessed by immunohistochemistry. In pancreatic cancer cell lines, RON expression was assessed by reverse-transcriptase polymerase chain reaction (PCR) and Western blot analysis. The human pancreatic cancer cell line L3.6p1, with high RON expression, was exposed to macrophage stimulating protein (MSP), the RON ligand, and assessed for cell migration, invasion, and changes associated with EMT. Western blot analysis and immunofluorescent staining were used to assess alterations in protein expression and cellular location, respectively. A RON monoclonal antibody (MoAb) was used to block ligand-induced activation of RON. RESULTS. Immunohistochemical staining revealed RON overexpression in 93% of human pancreatic cancer specimens relative to nonmalignant ductal tissue. RON mRNA and protein was expressed in 9 of 9 human pancreatic cancer cell lines. Treatment of L3.6p1 cells with MSP increased Erk phosphorylation, cell migration, and invasion (P < .001). RON activation led to a decrease in membrane-bound E-cadherin in association with nuclear translocation of β-catenin. RON MoAb inhibited downstream signaling as well as cell migration and invasion. In nude mice, RON MoAb inhibited subcutaneous and orthotopic tumor growth by about 60%. CONCLUSIONS. RON activation induced molecular and cellular alterations consistent with EMT. Inhibition of RON activation inhibited tumor growth in vivo. Novel antineoplastic therapies designed to inhibit RON activity may hinder mechanisms critical for pancreatic tumor progression.

Original languageEnglish (US)
Pages (from-to)1030-1039
Number of pages10
JournalCancer
Volume109
Issue number6
DOIs
StatePublished - Mar 15 2007
Externally publishedYes

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Receptor Protein-Tyrosine Kinases
Pancreatic Neoplasms
Cell Movement
Monoclonal Antibodies
rice bran saccharide
Cell Line
Western Blotting
Staining and Labeling
Ligands
Catenins
Neoplasms
Epithelial-Mesenchymal Transition
Cadherins
Growth
Reverse Transcriptase Polymerase Chain Reaction
Nude Mice
Antineoplastic Agents
Therapeutics

Keywords

  • Macrophage stimulating protein
  • Pancreatic cancer
  • RON
  • Tyrosine kinase receptor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Camp, E. R., Yang, A., Gray, M. J., Fan, F., Hamilton, S. R., Evans, D. B., ... Ellis, L. M. (2007). Tyrosine kinase receptor RON in human pancreatic cancer: Expression, function, and validation as a target. Cancer, 109(6), 1030-1039. https://doi.org/10.1002/cncr.22490

Tyrosine kinase receptor RON in human pancreatic cancer : Expression, function, and validation as a target. / Camp, E. Ramsay; Yang, Anthony; Gray, Mike J.; Fan, Fan; Hamilton, Stanley R.; Evans, Douglas B.; Hooper, Andrea T.; Pereira, Daniel S.; Hicklin, Daniel J.; Ellis, Lee M.

In: Cancer, Vol. 109, No. 6, 15.03.2007, p. 1030-1039.

Research output: Contribution to journalArticle

Camp, ER, Yang, A, Gray, MJ, Fan, F, Hamilton, SR, Evans, DB, Hooper, AT, Pereira, DS, Hicklin, DJ & Ellis, LM 2007, 'Tyrosine kinase receptor RON in human pancreatic cancer: Expression, function, and validation as a target', Cancer, vol. 109, no. 6, pp. 1030-1039. https://doi.org/10.1002/cncr.22490
Camp, E. Ramsay ; Yang, Anthony ; Gray, Mike J. ; Fan, Fan ; Hamilton, Stanley R. ; Evans, Douglas B. ; Hooper, Andrea T. ; Pereira, Daniel S. ; Hicklin, Daniel J. ; Ellis, Lee M. / Tyrosine kinase receptor RON in human pancreatic cancer : Expression, function, and validation as a target. In: Cancer. 2007 ; Vol. 109, No. 6. pp. 1030-1039.
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abstract = "BACKGROUND. Specific tyrosine kinase receptors such as c-MET mediate epithelial-mesenchymal (EMT) transition, leading to phenotypic alterations associated with increased cell motility. It was hypothesized that RON, a tyrosine kinase receptor related to c-MET, would be expressed in human pancreatic cancer cells, induce EMT, and would thus serve as a target for therapy in a preclinical model. METHODS. RON expression in human pancreatic cancer specimens was assessed by immunohistochemistry. In pancreatic cancer cell lines, RON expression was assessed by reverse-transcriptase polymerase chain reaction (PCR) and Western blot analysis. The human pancreatic cancer cell line L3.6p1, with high RON expression, was exposed to macrophage stimulating protein (MSP), the RON ligand, and assessed for cell migration, invasion, and changes associated with EMT. Western blot analysis and immunofluorescent staining were used to assess alterations in protein expression and cellular location, respectively. A RON monoclonal antibody (MoAb) was used to block ligand-induced activation of RON. RESULTS. Immunohistochemical staining revealed RON overexpression in 93{\%} of human pancreatic cancer specimens relative to nonmalignant ductal tissue. RON mRNA and protein was expressed in 9 of 9 human pancreatic cancer cell lines. Treatment of L3.6p1 cells with MSP increased Erk phosphorylation, cell migration, and invasion (P < .001). RON activation led to a decrease in membrane-bound E-cadherin in association with nuclear translocation of β-catenin. RON MoAb inhibited downstream signaling as well as cell migration and invasion. In nude mice, RON MoAb inhibited subcutaneous and orthotopic tumor growth by about 60{\%}. CONCLUSIONS. RON activation induced molecular and cellular alterations consistent with EMT. Inhibition of RON activation inhibited tumor growth in vivo. Novel antineoplastic therapies designed to inhibit RON activity may hinder mechanisms critical for pancreatic tumor progression.",
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AU - Yang, Anthony

AU - Gray, Mike J.

AU - Fan, Fan

AU - Hamilton, Stanley R.

AU - Evans, Douglas B.

AU - Hooper, Andrea T.

AU - Pereira, Daniel S.

AU - Hicklin, Daniel J.

AU - Ellis, Lee M.

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N2 - BACKGROUND. Specific tyrosine kinase receptors such as c-MET mediate epithelial-mesenchymal (EMT) transition, leading to phenotypic alterations associated with increased cell motility. It was hypothesized that RON, a tyrosine kinase receptor related to c-MET, would be expressed in human pancreatic cancer cells, induce EMT, and would thus serve as a target for therapy in a preclinical model. METHODS. RON expression in human pancreatic cancer specimens was assessed by immunohistochemistry. In pancreatic cancer cell lines, RON expression was assessed by reverse-transcriptase polymerase chain reaction (PCR) and Western blot analysis. The human pancreatic cancer cell line L3.6p1, with high RON expression, was exposed to macrophage stimulating protein (MSP), the RON ligand, and assessed for cell migration, invasion, and changes associated with EMT. Western blot analysis and immunofluorescent staining were used to assess alterations in protein expression and cellular location, respectively. A RON monoclonal antibody (MoAb) was used to block ligand-induced activation of RON. RESULTS. Immunohistochemical staining revealed RON overexpression in 93% of human pancreatic cancer specimens relative to nonmalignant ductal tissue. RON mRNA and protein was expressed in 9 of 9 human pancreatic cancer cell lines. Treatment of L3.6p1 cells with MSP increased Erk phosphorylation, cell migration, and invasion (P < .001). RON activation led to a decrease in membrane-bound E-cadherin in association with nuclear translocation of β-catenin. RON MoAb inhibited downstream signaling as well as cell migration and invasion. In nude mice, RON MoAb inhibited subcutaneous and orthotopic tumor growth by about 60%. CONCLUSIONS. RON activation induced molecular and cellular alterations consistent with EMT. Inhibition of RON activation inhibited tumor growth in vivo. Novel antineoplastic therapies designed to inhibit RON activity may hinder mechanisms critical for pancreatic tumor progression.

AB - BACKGROUND. Specific tyrosine kinase receptors such as c-MET mediate epithelial-mesenchymal (EMT) transition, leading to phenotypic alterations associated with increased cell motility. It was hypothesized that RON, a tyrosine kinase receptor related to c-MET, would be expressed in human pancreatic cancer cells, induce EMT, and would thus serve as a target for therapy in a preclinical model. METHODS. RON expression in human pancreatic cancer specimens was assessed by immunohistochemistry. In pancreatic cancer cell lines, RON expression was assessed by reverse-transcriptase polymerase chain reaction (PCR) and Western blot analysis. The human pancreatic cancer cell line L3.6p1, with high RON expression, was exposed to macrophage stimulating protein (MSP), the RON ligand, and assessed for cell migration, invasion, and changes associated with EMT. Western blot analysis and immunofluorescent staining were used to assess alterations in protein expression and cellular location, respectively. A RON monoclonal antibody (MoAb) was used to block ligand-induced activation of RON. RESULTS. Immunohistochemical staining revealed RON overexpression in 93% of human pancreatic cancer specimens relative to nonmalignant ductal tissue. RON mRNA and protein was expressed in 9 of 9 human pancreatic cancer cell lines. Treatment of L3.6p1 cells with MSP increased Erk phosphorylation, cell migration, and invasion (P < .001). RON activation led to a decrease in membrane-bound E-cadherin in association with nuclear translocation of β-catenin. RON MoAb inhibited downstream signaling as well as cell migration and invasion. In nude mice, RON MoAb inhibited subcutaneous and orthotopic tumor growth by about 60%. CONCLUSIONS. RON activation induced molecular and cellular alterations consistent with EMT. Inhibition of RON activation inhibited tumor growth in vivo. Novel antineoplastic therapies designed to inhibit RON activity may hinder mechanisms critical for pancreatic tumor progression.

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