Modification of the primary tumor microenvironment by transforming growth factor α-epidermal growth factor receptor signaling promotes metastasis in an orthotopic colon cancer model

Takamitsu Sasaki, Toru Nakamura, Robert B Rebhun, Hua Cheng, Katherine Stemke Hale, Rachel Z. Tsan, Isaiah J. Fidler, Robert R. Langley

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31 Scopus citations


The transforming growth factor α (TGFα)/epidermal growth factor receptor (EGFR) signaling pathway appears to play a critical role in colon cancer progression, but the cellular and molecular mechanisms that contribute to metastasis remain unknown. KM12C colon cancer cell clones expressing high (C9) or negligible (C10) levels of TGFα were implanted into the cecal walls of nude mice. C9 tumors formed autocrine and paracrine EGFR networks, whereas C10 tumors were unable to signal through EGFR. The tumor microenvironment of C9, but not C10, contained cells enriched in vascular endothelial growth factor (VEGF) A, interleukin-8, and matrix metalloproteinases-2 and -9 and had a high vascular surface area. C9 tumors recruited a macrophage population that co-expressed F4/80 and lymphatic vessel endothelial hyaluronic acid receptor and produced VEGFC. The mean lymphatic density of C9 tumors was threefold higher than that of C10 tumors. C9, but not C10, tumor cells metastasized to regional lymph nodes in all mice and to the liver in 5 of 10 mice. Forced expression of TGFα in C10 tumor cells led to the generation of autocrine and paracrine EGFR signaling, macrophage recruitment, enhanced blood and lymphatic vascular surface areas, and increased lymphatic metastasis. Collectively , these data show that activation of TGFα-EGFR signaling in colon cancer cells creates a microenvironment that is conducive for metastasis, providing a rationale for efforts to inhibit EGFR signaling in TGFα-positive colon cancers.

Original languageEnglish (US)
Pages (from-to)205-216
Number of pages12
JournalAmerican Journal of Pathology
Issue number1
StatePublished - Jul 2008
Externally publishedYes


ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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