Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor

Todd W. Bauer, Fan Fan, Wenbiao Liu, Marjorie Johnson, Nila U. Parikh, Graham C. Parry, Jennifer Callahan, Andrew P. Mazar, Gary E. Gallick, Lee M. Ellis, William G. Cance, Craig L. Slingluff, W. Roy Smythe, Courtney Townsend

Research output: Contribution to journalArticle

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Abstract

Objective: To determine whether insulinlike growth factor-I (IGF-I) and hepatocyte growth factor (HGF) cooperate to induce migration and invasion of human colorectal carcinoma (CRC) cells and whether the effects of IGF-I and/or HGF are mediated through activation of the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system, a central mediator of tumor-cell migration and invasion. Summary Background Data: CRC cells must invade through the basement membrane of the colon and migrate to form metastases. CRC cells are known to overexpress IGF-I receptor (IGF-IR), c-Met, and uPAR, 3 cell-surface receptors known to mediate cell migration and invasion. We hypothesized that IGF-IR and c-Met cooperate to induce migration and invasion in CRC cells and that this signaling is dependent on uPAR. Methods: KM12L4 human CRC cells were treated with IGF-I, HGF, or IGF-I + HGF in transwell migration and invasion chambers; cells that had migrated or invaded were counted. To determine the role of c-Met in IGF-I-induced migration and invasion, c-Met was inhibited by infection of cells with an adenovirus containing a c-Met ribozyme; transwell assays were then repeated. To determine the role of the uPA/uPAR system in IGF-I-induced CRC cell migration and invasion, transwell assays were repeated after pretreating cells with the uPA inhibitor amiloride or with neutralizing antibodies to uPA and uPAR. Results: IGF-I and HGF, alone or in combination, increased cell migration and invasion. The c-Met ribozyme inhibited IGF-I- and HGF-mediated migration and invasion, indicating that c-Met is essential for these processes. uPA and uPAR inhibition blocked IGF-I- and HGF-mediated migration and invasion, suggesting that uPAR is downstream of IGF/IGF-IR and HGF/c-Met in the signaling pathways that mediate cell migration and invasion. Conclusions: IGF-I and HGF cooperate to induce migration and invasion of CRC cells, and c-Met and uPA/uPAR are required for IGF-I-mediated migration and invasion. In our in vitro model of CRC migration and invasion, uPA and uPAR appear to be downstream of IGF-IR and c-Met and are required for migration and invasion. Elucidation of the pathways that contribute to tumor progression and metastasis should provide a foundation for the rational development and use of targeted therapies for CRC.

Original languageEnglish (US)
Pages (from-to)748-758
Number of pages11
JournalAnnals of Surgery
Volume241
Issue number5
DOIs
StatePublished - May 2005
Externally publishedYes

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Urokinase Plasminogen Activator Receptors
Fibrinogen
Hepatocyte Growth Factor
Intercellular Signaling Peptides and Proteins
Colon
Carcinoma
Colorectal Neoplasms
Cell Movement
IGF Type 1 Receptor
Catalytic RNA
Urokinase-Type Plasminogen Activator
Neoplasm Metastasis
Plasminogen Inactivators
Growth Factor Receptors
Amiloride
Plasminogen Activators
Cell Surface Receptors
Neutralizing Antibodies
Basement Membrane
Adenoviridae

ASJC Scopus subject areas

  • Surgery

Cite this

Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor. / Bauer, Todd W.; Fan, Fan; Liu, Wenbiao; Johnson, Marjorie; Parikh, Nila U.; Parry, Graham C.; Callahan, Jennifer; Mazar, Andrew P.; Gallick, Gary E.; Ellis, Lee M.; Cance, William G.; Slingluff, Craig L.; Smythe, W. Roy; Townsend, Courtney.

In: Annals of Surgery, Vol. 241, No. 5, 05.2005, p. 748-758.

Research output: Contribution to journalArticle

Bauer, TW, Fan, F, Liu, W, Johnson, M, Parikh, NU, Parry, GC, Callahan, J, Mazar, AP, Gallick, GE, Ellis, LM, Cance, WG, Slingluff, CL, Smythe, WR & Townsend, C 2005, 'Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor', Annals of Surgery, vol. 241, no. 5, pp. 748-758. https://doi.org/10.1097/01.sla.0000160699.59061.92
Bauer, Todd W. ; Fan, Fan ; Liu, Wenbiao ; Johnson, Marjorie ; Parikh, Nila U. ; Parry, Graham C. ; Callahan, Jennifer ; Mazar, Andrew P. ; Gallick, Gary E. ; Ellis, Lee M. ; Cance, William G. ; Slingluff, Craig L. ; Smythe, W. Roy ; Townsend, Courtney. / Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor. In: Annals of Surgery. 2005 ; Vol. 241, No. 5. pp. 748-758.
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title = "Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor",
abstract = "Objective: To determine whether insulinlike growth factor-I (IGF-I) and hepatocyte growth factor (HGF) cooperate to induce migration and invasion of human colorectal carcinoma (CRC) cells and whether the effects of IGF-I and/or HGF are mediated through activation of the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system, a central mediator of tumor-cell migration and invasion. Summary Background Data: CRC cells must invade through the basement membrane of the colon and migrate to form metastases. CRC cells are known to overexpress IGF-I receptor (IGF-IR), c-Met, and uPAR, 3 cell-surface receptors known to mediate cell migration and invasion. We hypothesized that IGF-IR and c-Met cooperate to induce migration and invasion in CRC cells and that this signaling is dependent on uPAR. Methods: KM12L4 human CRC cells were treated with IGF-I, HGF, or IGF-I + HGF in transwell migration and invasion chambers; cells that had migrated or invaded were counted. To determine the role of c-Met in IGF-I-induced migration and invasion, c-Met was inhibited by infection of cells with an adenovirus containing a c-Met ribozyme; transwell assays were then repeated. To determine the role of the uPA/uPAR system in IGF-I-induced CRC cell migration and invasion, transwell assays were repeated after pretreating cells with the uPA inhibitor amiloride or with neutralizing antibodies to uPA and uPAR. Results: IGF-I and HGF, alone or in combination, increased cell migration and invasion. The c-Met ribozyme inhibited IGF-I- and HGF-mediated migration and invasion, indicating that c-Met is essential for these processes. uPA and uPAR inhibition blocked IGF-I- and HGF-mediated migration and invasion, suggesting that uPAR is downstream of IGF/IGF-IR and HGF/c-Met in the signaling pathways that mediate cell migration and invasion. Conclusions: IGF-I and HGF cooperate to induce migration and invasion of CRC cells, and c-Met and uPA/uPAR are required for IGF-I-mediated migration and invasion. In our in vitro model of CRC migration and invasion, uPA and uPAR appear to be downstream of IGF-IR and c-Met and are required for migration and invasion. Elucidation of the pathways that contribute to tumor progression and metastasis should provide a foundation for the rational development and use of targeted therapies for CRC.",
author = "Bauer, {Todd W.} and Fan Fan and Wenbiao Liu and Marjorie Johnson and Parikh, {Nila U.} and Parry, {Graham C.} and Jennifer Callahan and Mazar, {Andrew P.} and Gallick, {Gary E.} and Ellis, {Lee M.} and Cance, {William G.} and Slingluff, {Craig L.} and Smythe, {W. Roy} and Courtney Townsend",
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TY - JOUR

T1 - Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor

AU - Bauer, Todd W.

AU - Fan, Fan

AU - Liu, Wenbiao

AU - Johnson, Marjorie

AU - Parikh, Nila U.

AU - Parry, Graham C.

AU - Callahan, Jennifer

AU - Mazar, Andrew P.

AU - Gallick, Gary E.

AU - Ellis, Lee M.

AU - Cance, William G.

AU - Slingluff, Craig L.

AU - Smythe, W. Roy

AU - Townsend, Courtney

PY - 2005/5

Y1 - 2005/5

N2 - Objective: To determine whether insulinlike growth factor-I (IGF-I) and hepatocyte growth factor (HGF) cooperate to induce migration and invasion of human colorectal carcinoma (CRC) cells and whether the effects of IGF-I and/or HGF are mediated through activation of the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system, a central mediator of tumor-cell migration and invasion. Summary Background Data: CRC cells must invade through the basement membrane of the colon and migrate to form metastases. CRC cells are known to overexpress IGF-I receptor (IGF-IR), c-Met, and uPAR, 3 cell-surface receptors known to mediate cell migration and invasion. We hypothesized that IGF-IR and c-Met cooperate to induce migration and invasion in CRC cells and that this signaling is dependent on uPAR. Methods: KM12L4 human CRC cells were treated with IGF-I, HGF, or IGF-I + HGF in transwell migration and invasion chambers; cells that had migrated or invaded were counted. To determine the role of c-Met in IGF-I-induced migration and invasion, c-Met was inhibited by infection of cells with an adenovirus containing a c-Met ribozyme; transwell assays were then repeated. To determine the role of the uPA/uPAR system in IGF-I-induced CRC cell migration and invasion, transwell assays were repeated after pretreating cells with the uPA inhibitor amiloride or with neutralizing antibodies to uPA and uPAR. Results: IGF-I and HGF, alone or in combination, increased cell migration and invasion. The c-Met ribozyme inhibited IGF-I- and HGF-mediated migration and invasion, indicating that c-Met is essential for these processes. uPA and uPAR inhibition blocked IGF-I- and HGF-mediated migration and invasion, suggesting that uPAR is downstream of IGF/IGF-IR and HGF/c-Met in the signaling pathways that mediate cell migration and invasion. Conclusions: IGF-I and HGF cooperate to induce migration and invasion of CRC cells, and c-Met and uPA/uPAR are required for IGF-I-mediated migration and invasion. In our in vitro model of CRC migration and invasion, uPA and uPAR appear to be downstream of IGF-IR and c-Met and are required for migration and invasion. Elucidation of the pathways that contribute to tumor progression and metastasis should provide a foundation for the rational development and use of targeted therapies for CRC.

AB - Objective: To determine whether insulinlike growth factor-I (IGF-I) and hepatocyte growth factor (HGF) cooperate to induce migration and invasion of human colorectal carcinoma (CRC) cells and whether the effects of IGF-I and/or HGF are mediated through activation of the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system, a central mediator of tumor-cell migration and invasion. Summary Background Data: CRC cells must invade through the basement membrane of the colon and migrate to form metastases. CRC cells are known to overexpress IGF-I receptor (IGF-IR), c-Met, and uPAR, 3 cell-surface receptors known to mediate cell migration and invasion. We hypothesized that IGF-IR and c-Met cooperate to induce migration and invasion in CRC cells and that this signaling is dependent on uPAR. Methods: KM12L4 human CRC cells were treated with IGF-I, HGF, or IGF-I + HGF in transwell migration and invasion chambers; cells that had migrated or invaded were counted. To determine the role of c-Met in IGF-I-induced migration and invasion, c-Met was inhibited by infection of cells with an adenovirus containing a c-Met ribozyme; transwell assays were then repeated. To determine the role of the uPA/uPAR system in IGF-I-induced CRC cell migration and invasion, transwell assays were repeated after pretreating cells with the uPA inhibitor amiloride or with neutralizing antibodies to uPA and uPAR. Results: IGF-I and HGF, alone or in combination, increased cell migration and invasion. The c-Met ribozyme inhibited IGF-I- and HGF-mediated migration and invasion, indicating that c-Met is essential for these processes. uPA and uPAR inhibition blocked IGF-I- and HGF-mediated migration and invasion, suggesting that uPAR is downstream of IGF/IGF-IR and HGF/c-Met in the signaling pathways that mediate cell migration and invasion. Conclusions: IGF-I and HGF cooperate to induce migration and invasion of CRC cells, and c-Met and uPA/uPAR are required for IGF-I-mediated migration and invasion. In our in vitro model of CRC migration and invasion, uPA and uPAR appear to be downstream of IGF-IR and c-Met and are required for migration and invasion. Elucidation of the pathways that contribute to tumor progression and metastasis should provide a foundation for the rational development and use of targeted therapies for CRC.

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U2 - 10.1097/01.sla.0000160699.59061.92

DO - 10.1097/01.sla.0000160699.59061.92

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SP - 748

EP - 758

JO - Annals of Surgery

JF - Annals of Surgery

SN - 0003-4932

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