The essential role of fibroblasts in esophageal squamous cell carcinoma-induced angiogenesis

被引：114

作者：

Noma, Kazuhiro ^{[1
]}

Smalley, Keiran S. M. ^{[1
]}

Lioni, Mercedes ^{[1
]}

Naomoto, Yoshio ^{[2
,3
]}

Tanaka, Noriaki ^{[2
,3
]}

El-Deiry, Waflk ^{[4
]}

King, Alastair J. ^{[6
]}

Nakagawa, Hiroshi ^{[5
]}

Herlyn, Meenhard ^{[1
]}

机构：

[1] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

[2] Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci, Okayama, Japan

[3] Okayama Univ, Dept Transplant & Surg Oncol, Grad Sch Med Dent & Pharmaceut Sci, Okayama, Japan

[4] Univ Penn, Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA

[5] Univ Penn, Sch Med, Div Gastroenterol, Dept Med,Dept Genet,Abramson Canc Ctr, Philadelphia, PA 19104 USA

[6] GlaxoSmithKline Inc, Collegeville, PA USA

来源：

GASTROENTEROLOGY | 2008年 / 134卷 / 07期

关键词：

D O I：

10.1053/j.gastro.2008.02.061

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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)-beta 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-beta 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-beta in this process was shown by the complete inhibition of network formation following TGF-beta inhibitor treatment. Finally, we showed that ESCC-derived TGF-beta regulates angiogenesis through the release of VEGF from the fibroblasts and that the VEGF release was blocked following TGF-beta 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-beta signaling axis could be of therapeutic benefit in this deadly disease.

引用

页码：1981 / 1993

页数：13

共 30 条

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