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 M. Townsend

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51 Scopus citations

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 1 2005

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ASJC Scopus subject areas

  • Surgery

Cite this

Bauer, T. W., Fan, F., Liu, W., Johnson, M., Parikh, N. U., Parry, G. C., Callahan, J., Mazar, A. P., Gallick, G. E., Ellis, L. M., Cance, W. G., Slingluff, C. L., Smythe, W. R., & Townsend, C. M. (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, 241(5), 748-758. https://doi.org/10.1097/01.sla.0000160699.59061.92