The Essential Role of Fibroblasts in Esophageal Squamous Cell Carcinoma-Induced Angiogenesis

Kazuhiro Noma, Keiran S M Smalley, Mercedes Lioni, Yoshio Naomoto, Noriaki Tanaka, Wafik El-Deiry, Alastair J. King, Hiroshi Nakagawa, Meenhard Herlyn

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Esophageal squamous cell carcinoma (ESCC) is known to be a highly angiogenic tumor. Here, we investigated the role of the stromal fibroblasts in the ESCC-induced angiogenic response using a novel 3-dimensional model. Methods: A novel assay was developed where cocultures of ESCC and esophageal fibroblasts induced human microvascular endothelial cell (HMVEC) vascular network formation in a 3-dimensional collagen gel. Biochemical studies showed that the ESCC-induced activation of the fibroblasts was required to induce vascular network formation via a transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF)-dependent pathway. Results: Conditioned media from a panel of 4 ESCC lines transdifferentiated normal esophageal fibroblasts into myofibroblasts via TGF-β signaling. The presence of fibroblasts was essential for efficient HMVEC network formation, and the addition of ESCC cells to these cultures greatly enhanced the angiogenic process. The role of TGF-β in this process was shown by the complete inhibition of network formation following TGF-β inhibitor treatment. Finally, we showed that ESCC-derived TGF-β regulates angiogenesis through the release of VEGF from the fibroblasts and that the VEGF release was blocked following TGF-β inhibition. Conclusions: This study shows the essential role of fibroblasts in the ESCC angiogenic-induced response and suggests that the pharmacologic targeting of the TGF-β signaling axis could be of therapeutic benefit in this deadly disease.

Original languageEnglish
Pages (from-to)1981-1993
Number of pages13
JournalGastroenterology
Volume134
Issue number7
DOIs
Publication statusPublished - Jun 2008
Externally publishedYes

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Transforming Growth Factors
Fibroblasts
Vascular Endothelial Growth Factor A
Endothelial Cells
Growth Inhibitors
Myofibroblasts
Esophageal Squamous Cell Carcinoma
Conditioned Culture Medium
Coculture Techniques
Blood Vessels
Collagen
Cell Culture Techniques
Gels
Cell Line
Neoplasms

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Noma, K., Smalley, K. S. M., Lioni, M., Naomoto, Y., Tanaka, N., El-Deiry, W., ... Herlyn, M. (2008). The Essential Role of Fibroblasts in Esophageal Squamous Cell Carcinoma-Induced Angiogenesis. Gastroenterology, 134(7), 1981-1993. https://doi.org/10.1053/j.gastro.2008.02.061

The Essential Role of Fibroblasts in Esophageal Squamous Cell Carcinoma-Induced Angiogenesis. / Noma, Kazuhiro; Smalley, Keiran S M; Lioni, Mercedes; Naomoto, Yoshio; Tanaka, Noriaki; El-Deiry, Wafik; King, Alastair J.; Nakagawa, Hiroshi; Herlyn, Meenhard.

In: Gastroenterology, Vol. 134, No. 7, 06.2008, p. 1981-1993.

Research output: Contribution to journalArticle

Noma, K, Smalley, KSM, Lioni, M, Naomoto, Y, Tanaka, N, El-Deiry, W, King, AJ, Nakagawa, H & Herlyn, M 2008, 'The Essential Role of Fibroblasts in Esophageal Squamous Cell Carcinoma-Induced Angiogenesis', Gastroenterology, vol. 134, no. 7, pp. 1981-1993. https://doi.org/10.1053/j.gastro.2008.02.061
Noma, Kazuhiro ; Smalley, Keiran S M ; Lioni, Mercedes ; Naomoto, Yoshio ; Tanaka, Noriaki ; El-Deiry, Wafik ; King, Alastair J. ; Nakagawa, Hiroshi ; Herlyn, Meenhard. / The Essential Role of Fibroblasts in Esophageal Squamous Cell Carcinoma-Induced Angiogenesis. In: Gastroenterology. 2008 ; Vol. 134, No. 7. pp. 1981-1993.
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