Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis

Shilpa Choudhary, Poornima Hegde, James R. Pruitt, Thais M. Sielecki, Dharamainder Choudhary, Kristen Scarpato, David Degraff, Carol C. Pilbeam, John A. Taylor

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Macrophage migratory inhibitory factor (MIF) is a proinflammatory cytokine shown to promote tumorigenesis. Using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model of bladder cancer, we previously showed that MIF knockout mice display decreased angiogenesis and invasion compared with wild-type. This study examines the role of MIF in bladder cancer via use of oral inhibitors of MIF. In vitro, high-grade bladder cancer cells were treated with recombinant human MIF +/- (rhMIF+/-) inhibitor. Measurements included cell counts, proliferation by 3H-thymidine incorporation (TdR), extracellular signal-regulated kinase (ERK) phosphorylation by western blot analysis, messenger RNA (mRNA) expression by quantitative PCR and protein secretion by enzyme-linked immunosorbent assay. Treatment with rhMIF increased ERK phosphorylation, cell counts, TdR and mRNA expression and protein secretion of vascular endothelial growth factor, which were blocked by specific inhibitors of ERK and MIF. In vivo, 3-month-old male C57Bl/6 mice were given BBN for 22 and 16 weeks in study 1 and study 2, respectively. Mice (n = 8-10 per group) were gavaged with vehicle or doses of MIF inhibitors daily from weeks 16-22 in both studies. Average bladder weights, reflecting tumor mass, tumor stage/ burden, mitotic rate and proliferation indices, and microvessel densities were reduced in inhibitor groups versus controls. In summary, MIF promotes bladder cancer via increasing cell proliferation and angiogenesis and oral inhibitors of MIF may prove useful in treatment of this disease.

Original languageEnglish (US)
Pages (from-to)2891-2899
Number of pages9
JournalCarcinogenesis
Volume34
Issue number12
DOIs
StatePublished - Dec 1 2013

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Urinary Bladder Neoplasms
Extracellular Signal-Regulated MAP Kinases
Macrophages
Tumor Burden
Thymidine
Butylhydroxybutylnitrosamine
Cell Count
Phosphorylation
Cell Proliferation
Messenger RNA
Angiogenesis Inhibitors
Microvessels
Knockout Mice
Vascular Endothelial Growth Factor A
Carcinogenesis
Urinary Bladder
Proteins
Western Blotting
Enzyme-Linked Immunosorbent Assay
Cytokines

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Choudhary, S., Hegde, P., Pruitt, J. R., Sielecki, T. M., Choudhary, D., Scarpato, K., ... Taylor, J. A. (2013). Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis. Carcinogenesis, 34(12), 2891-2899. https://doi.org/10.1093/carcin/bgt239
Choudhary, Shilpa ; Hegde, Poornima ; Pruitt, James R. ; Sielecki, Thais M. ; Choudhary, Dharamainder ; Scarpato, Kristen ; Degraff, David ; Pilbeam, Carol C. ; Taylor, John A. / Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis. In: Carcinogenesis. 2013 ; Vol. 34, No. 12. pp. 2891-2899.
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abstract = "Macrophage migratory inhibitory factor (MIF) is a proinflammatory cytokine shown to promote tumorigenesis. Using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model of bladder cancer, we previously showed that MIF knockout mice display decreased angiogenesis and invasion compared with wild-type. This study examines the role of MIF in bladder cancer via use of oral inhibitors of MIF. In vitro, high-grade bladder cancer cells were treated with recombinant human MIF +/- (rhMIF+/-) inhibitor. Measurements included cell counts, proliferation by 3H-thymidine incorporation (TdR), extracellular signal-regulated kinase (ERK) phosphorylation by western blot analysis, messenger RNA (mRNA) expression by quantitative PCR and protein secretion by enzyme-linked immunosorbent assay. Treatment with rhMIF increased ERK phosphorylation, cell counts, TdR and mRNA expression and protein secretion of vascular endothelial growth factor, which were blocked by specific inhibitors of ERK and MIF. In vivo, 3-month-old male C57Bl/6 mice were given BBN for 22 and 16 weeks in study 1 and study 2, respectively. Mice (n = 8-10 per group) were gavaged with vehicle or doses of MIF inhibitors daily from weeks 16-22 in both studies. Average bladder weights, reflecting tumor mass, tumor stage/ burden, mitotic rate and proliferation indices, and microvessel densities were reduced in inhibitor groups versus controls. In summary, MIF promotes bladder cancer via increasing cell proliferation and angiogenesis and oral inhibitors of MIF may prove useful in treatment of this disease.",
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Choudhary, S, Hegde, P, Pruitt, JR, Sielecki, TM, Choudhary, D, Scarpato, K, Degraff, D, Pilbeam, CC & Taylor, JA 2013, 'Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis', Carcinogenesis, vol. 34, no. 12, pp. 2891-2899. https://doi.org/10.1093/carcin/bgt239

Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis. / Choudhary, Shilpa; Hegde, Poornima; Pruitt, James R.; Sielecki, Thais M.; Choudhary, Dharamainder; Scarpato, Kristen; Degraff, David; Pilbeam, Carol C.; Taylor, John A.

In: Carcinogenesis, Vol. 34, No. 12, 01.12.2013, p. 2891-2899.

Research output: Contribution to journalArticle

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T1 - Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis

AU - Choudhary, Shilpa

AU - Hegde, Poornima

AU - Pruitt, James R.

AU - Sielecki, Thais M.

AU - Choudhary, Dharamainder

AU - Scarpato, Kristen

AU - Degraff, David

AU - Pilbeam, Carol C.

AU - Taylor, John A.

PY - 2013/12/1

Y1 - 2013/12/1

N2 - Macrophage migratory inhibitory factor (MIF) is a proinflammatory cytokine shown to promote tumorigenesis. Using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model of bladder cancer, we previously showed that MIF knockout mice display decreased angiogenesis and invasion compared with wild-type. This study examines the role of MIF in bladder cancer via use of oral inhibitors of MIF. In vitro, high-grade bladder cancer cells were treated with recombinant human MIF +/- (rhMIF+/-) inhibitor. Measurements included cell counts, proliferation by 3H-thymidine incorporation (TdR), extracellular signal-regulated kinase (ERK) phosphorylation by western blot analysis, messenger RNA (mRNA) expression by quantitative PCR and protein secretion by enzyme-linked immunosorbent assay. Treatment with rhMIF increased ERK phosphorylation, cell counts, TdR and mRNA expression and protein secretion of vascular endothelial growth factor, which were blocked by specific inhibitors of ERK and MIF. In vivo, 3-month-old male C57Bl/6 mice were given BBN for 22 and 16 weeks in study 1 and study 2, respectively. Mice (n = 8-10 per group) were gavaged with vehicle or doses of MIF inhibitors daily from weeks 16-22 in both studies. Average bladder weights, reflecting tumor mass, tumor stage/ burden, mitotic rate and proliferation indices, and microvessel densities were reduced in inhibitor groups versus controls. In summary, MIF promotes bladder cancer via increasing cell proliferation and angiogenesis and oral inhibitors of MIF may prove useful in treatment of this disease.

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