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Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells

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Abstract

CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.

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Acknowledgement

We would like to thank Dr. Martin Fernandez-Zapico, Paula Carlson, Christopher Kolbert, Sharon Delgado, Launice Melbourne, Humberto Martinez-Suarez, Dr. Alexandrine Randriamahefa, Michael Lin, and Linda Wellik for the technical assistance. This work was supported by the Lustgarten Foundation for Pancreatic Cancer Research, National Institute of Health RO1 grant DK52913 and DK56620, the Miles and Shirely Fitterman Funds for Mayo GIH Proteomics and Genomics Studies (R. Urrutia), RO1 Grant GM59763 (K.E. Hedin), RO1 grant 59388 (V. Shah) and Specialized Program of Research Excellence grant P50-CA102701 (D.D. Billadeau, K.E. Hedin, V. Shah and R. Urrutia) and the Mayo Clinic College of Medicine.

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Authors and Affiliations

  1. Gastroenterology Research Unit, Saint Mary’s Hospital, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Subrha Chatterjee, Vijay Shah & Raul Urrutia

  2. Oncology Research Department, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Daniel D. Billadeau

  3. Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Patricia Bramati & Karen Hedin

  4. Department of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Raghavakaimal Sreekumar

  5. Tumor Biology Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Daniel D. Billadeau, Raghavakaimal Sreekumar & Raul Urrutia

  6. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Raul Urrutia

  7. Gastroenterology Research Unit, Saint Mary’s Hospital, 2-445 Alfred Bldg, Rochester, MN, 55905, USA

    Raul Urrutia

Authors
  1. Daniel D. Billadeau
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  2. Subrha Chatterjee
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  3. Patricia Bramati
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  4. Raghavakaimal Sreekumar
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  5. Vijay Shah
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  6. Karen Hedin
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  7. Raul Urrutia
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Correspondence to Raul Urrutia.

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Billadeau, D.D., Chatterjee, S., Bramati, P. et al. Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells. J Gastrointest Canc 37, 110–119 (2006). https://doi.org/10.1007/s12029-007-0011-7

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  • DOI: https://doi.org/10.1007/s12029-007-0011-7

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