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

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 2008 Apr 29

PMID 18439605

Citations 75

Authors

Kazuhiro Noma

Keiran S M Smalley

Mercedes Lioni

Yoshio Naomoto

Noriaki Tanaka

Wafik El-Deiry

Alastair J King

Hiroshi Nakagawa

Meenhard Herlyn

Affiliations

Soon will be listed here.

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)-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.

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References

Sappino A, Skalli O, Jackson B, Schurch W, Gabbiani G . Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int J Cancer. 1988; 41(5):707-12. DOI: 10.1002/ijc.2910410512. View

Levy L, Hill C . Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 2005; 17(1-2):41-58. DOI: 10.1016/j.cytogfr.2005.09.009. View

Tanaka S, Mori M, Mafune K, Ohno S, Sugimachi K . A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable oesophageal carcinoma. Br J Cancer. 2000; 82(9):1557-60. PMC: 2363384. DOI: 10.1054/bjoc.1999.1178. View

Souza R, Vellucci V, Meltzer S, Reiss M . Loss of transforming growth factor-beta type II receptor gene expression in primary human esophageal cancer. Lab Invest. 1996; 75(2):263-72. View

Nakagawa T, Lan H, Zhu H, Kang D, Schreiner G, Johnson R . Differential regulation of VEGF by TGF-beta and hypoxia in rat proximal tubular cells. Am J Physiol Renal Physiol. 2004; 287(4):F658-64. DOI: 10.1152/ajprenal.00040.2004. View

Tsukamoto H, Mishima Y, Hayashibe K, Sasase A . Alpha-smooth muscle actin expression in tumor and stromal cells of benign and malignant human pigment cell tumors. J Invest Dermatol. 1992; 98(1):116-20. DOI: 10.1111/1523-1747.ep12496020. View

de Wever O, Mareel M . Role of tissue stroma in cancer cell invasion. J Pathol. 2003; 200(4):429-47. DOI: 10.1002/path.1398. View

Ito T, Ishii G, Chiba H, Ochiai A . The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene. 2007; 26(51):7194-203. DOI: 10.1038/sj.onc.1210535. View

Velazquez O, Snyder R, Liu Z, Fairman R, Herlyn M . Fibroblast-dependent differentiation of human microvascular endothelial cells into capillary-like 3-dimensional networks. FASEB J. 2002; 16(10):1316-8. DOI: 10.1096/fj.01-1011fje. View

10.

Elenbaas B, Weinberg R . Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res. 2001; 264(1):169-84. DOI: 10.1006/excr.2000.5133. View

11.

Orimo A, Gupta P, Sgroi D, Arenzana-Seisdedos F, Delaunay T, Naeem R . Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005; 121(3):335-48. DOI: 10.1016/j.cell.2005.02.034. View

12.

Direkze N, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D . Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 2004; 64(23):8492-5. DOI: 10.1158/0008-5472.CAN-04-1708. View

13.

Nakayama H, Enzan H, Miyazaki E, Naruse K, Kiyoku H, Hiroi M . The role of myofibroblasts at the tumor border of invasive colorectal adenocarcinomas. Jpn J Clin Oncol. 1998; 28(10):615-20. DOI: 10.1093/jjco/28.10.615. View

14.

Fukai Y, Fukuchi M, Masuda N, Osawa H, Kato H, Nakajima T . Reduced expression of transforming growth factor-beta receptors is an unfavorable prognostic factor in human esophageal squamous cell carcinoma. Int J Cancer. 2003; 104(2):161-6. DOI: 10.1002/ijc.10929. View

15.

de Wever O, Nguyen Q, Van Hoorde L, Bracke M, Bruyneel E, Gespach C . Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J. 2004; 18(9):1016-8. DOI: 10.1096/fj.03-1110fje. View

16.

Dvorak H . Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986; 315(26):1650-9. DOI: 10.1056/NEJM198612253152606. View

17.

Kalluri R, Zeisberg M . Fibroblasts in cancer. Nat Rev Cancer. 2006; 6(5):392-401. DOI: 10.1038/nrc1877. View

18.

Andl C, Mizushima T, Nakagawa H, Oyama K, Harada H, Chruma K . Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo. J Biol Chem. 2002; 278(3):1824-30. DOI: 10.1074/jbc.M209148200. View

19.

Jain R . Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005; 307(5706):58-62. DOI: 10.1126/science.1104819. View

20.

Orimo A, Weinberg R . Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle. 2006; 5(15):1597-601. DOI: 10.4161/cc.5.15.3112. View