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Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication

Authors: Yoshinori Hoshino, Tetsu Hayashida, Akira Hirata, Hidena Takahashi, Naokazu Chiba, Mitsuyo Ohmura, Masatoshi Wakui, Hiromitsu Jinno, Hirotoshi Hasegawa, Shyamala Maheswaran, Makoto Suematsu, Yuko Kitagawa

Published in: Molecular Cancer | Issue 1/2014

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Abstract

Background

Homeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis.

Methods

We examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens.

Results

HOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system.

Conclusions

HOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment.
Appendix
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Metadata
Title
Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication
Authors
Yoshinori Hoshino
Tetsu Hayashida
Akira Hirata
Hidena Takahashi
Naokazu Chiba
Mitsuyo Ohmura
Masatoshi Wakui
Hiromitsu Jinno
Hirotoshi Hasegawa
Shyamala Maheswaran
Makoto Suematsu
Yuko Kitagawa
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-102

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