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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number102
JournalMolecular Cancer
Volume13
Issue number1
DOIs
Publication statusPublished - 2014 May 5

Fingerprint

Homeobox Genes
Communication
Interleukin-6
Neoplasms
Vascular Endothelial Growth Factor A
Colorectal Neoplasms
Heterografts
Bevacizumab
Cytokines
Tumor Microenvironment
Survival
Angiogenesis Inducing Agents
Coculture Techniques
Neutralizing Antibodies
Disease-Free Survival
In Situ Hybridization
Cultured Cells
Carcinogenesis
Endothelial Cells
Fibroblasts

Keywords

  • Aangiogenesis
  • Bevacizumab
  • Biomarker
  • Colorectal cancer

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology
  • Medicine(all)

Cite this

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication. / Hoshino, Yoshinori; Hayashida, Tetsu; Hirata, Akira; Takahashi, Hidena; Chiba, Naokazu; Ohmura, Mitsuyo; Wakui, Masatoshi; Jinno, Hiromitsu; Hasegawa, Hirotoshi; Maheswaran, Shyamala; Suematsu, Makoto; Kitagawa, Yuukou.

In: Molecular Cancer, Vol. 13, No. 1, 102, 05.05.2014.

Research output: Contribution to journalArticle

Hoshino, Y, Hayashida, T, Hirata, A, Takahashi, H, Chiba, N, Ohmura, M, Wakui, M, Jinno, H, Hasegawa, H, Maheswaran, S, Suematsu, M & Kitagawa, Y 2014, 'Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication', Molecular Cancer, vol. 13, no. 1, 102. https://doi.org/10.1186/1476-4598-13-102
Hoshino, Yoshinori ; Hayashida, Tetsu ; Hirata, Akira ; Takahashi, Hidena ; Chiba, Naokazu ; Ohmura, Mitsuyo ; Wakui, Masatoshi ; Jinno, Hiromitsu ; Hasegawa, Hirotoshi ; Maheswaran, Shyamala ; Suematsu, Makoto ; Kitagawa, Yuukou. / Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication. In: Molecular Cancer. 2014 ; Vol. 13, No. 1.
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AU - Hayashida, Tetsu

AU - Hirata, Akira

AU - Takahashi, Hidena

AU - Chiba, Naokazu

AU - Ohmura, Mitsuyo

AU - Wakui, Masatoshi

AU - Jinno, Hiromitsu

AU - Hasegawa, Hirotoshi

AU - Maheswaran, Shyamala

AU - Suematsu, Makoto

AU - Kitagawa, Yuukou

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N2 - 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.

AB - 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.

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KW - Bevacizumab

KW - Biomarker

KW - Colorectal cancer

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