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Targeting the EGFR, VEGFR, and PDGFR on colon cancer cells and stromal cells is required for therapy

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Abstract

Immunohistochemical analysis of human colon cancers growing in the cecal walls of nude mice revealed that epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) were expressed by different tumor cells and tumor-associated endothelial cells, whereas platelet-derived growth factor receptor (PDGFR)β was expressed by tumor-associated endothelial cells and pericytes. We hypothesized that treatment of nude mice with AEE788 (an inhibitor of EGFR and VEGFR phosphorylation) and STI571 (an inhibitor of PDGFRβ phosphorylation) combined with irinotecan would overcome the intratumoral heterogeneity of these growth factors and efficiently inhibit colon cancer growth and metastasis. We implanted HT29 and KM12SM cells into the cecal walls of nude mice. Two weeks later, the mice were treated with oral vehicle solution; oral AEE788, oral STI571, or intraperitoneal injection of irinotecan as single agents; or the various combinations of these agents. We then assessed the mice for tumor growth and metastasis. Immunohistochemical analyses revealed that oral AEE788 suppressed proliferation and increased apoptosis of tumor cells and tumor-associated endothelial cells. Oral STI571 increased apoptosis of tumor-associated endothelial cells and pericytes. The combination of AEE788, STI571, and irinotecan produced the greatest inhibition of primary tumor growth and metastasis. Collectively, these data demonstrate that only targeting multiple tyrosine kinase receptors on colon cancer cells and tumor-associated stromal cells can overcome the effects of biologic heterogeneity for resistance to treatment and has the potential to improve therapeutic outcome for patients with this disease.

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Abbreviations

EGF:

Epidermal growth factor

HBSS:

Hanks’ balanced salt solution

MVD:

Microvessel density

PDGF:

Platelet-derived growth factor

TGF:

Transforming growth factor

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This work was supported in part by Cancer Center Support Core Grant CA16672 and SPORE in Prostate Cancer Grant CA902701 from the National Cancer Institute, National Institutes of Health. We thank Vickie J. Williams for editorial review and Lola Lopez for expert assistance with the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Cancer Biology, Unit 173, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Toshio Kuwai, Toru Nakamura, Takamitsu Sasaki, Yasuhiko Kitadai, Jang-Seong Kim, Robert R. Langley, Dominic Fan, Sun-Jin Kim & Isaiah J. Fidler

  2. Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Xuemei Wang & Kim-Anh Do

Authors
  1. Toshio Kuwai
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  2. Toru Nakamura
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  3. Takamitsu Sasaki
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  4. Yasuhiko Kitadai
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  11. Isaiah J. Fidler
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Correspondence to Isaiah J. Fidler.

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Kuwai, T., Nakamura, T., Sasaki, T. et al. Targeting the EGFR, VEGFR, and PDGFR on colon cancer cells and stromal cells is required for therapy. Clin Exp Metastasis 25, 477–489 (2008). https://doi.org/10.1007/s10585-008-9153-7

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  • DOI: https://doi.org/10.1007/s10585-008-9153-7

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