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Visceral obesity stimulates anaphase bridge formation and spindle assembly checkpoint dysregulation in radioresistant oesophageal adenocarcinoma

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An Erratum to this article was published on 20 November 2015

Abstract

Purpose

Oesophageal adenocarcinoma is an exemplar model of obesity-associated cancer. Locally advanced disease is treated with neoadjuvant chemoradiotherapy, and survival rates are highest in patients demonstrating a pathological response following neoadjuvant therapy. Given that 55 % of oesophageal adenocarcinoma patients are obese, uncovering the effect of adipose tissue on radioresponse is clinically relevant. This study investigates if adipose tissue activates genomic instability events in radioresponsive (OE33P) and radioresistant (OE33R) oesophageal cancer cell lines and tumour samples.

Methods

OE33R and OE33P were cultured with adipose-conditioned media derived from oesophageal adenocarcinoma patients (n = 10). Anaphase bridges, a marker of genomic instability, were enumerated in both cell lines following treatment with adipose media, and normalised to cell number. Genomic instability is regulated by the spindle assembly complex. Expression of two spindle assembly complex genes (MAD2L2, BUB1B) was assessed using qPCR, and validated in patient tumour specimens from viscerally obese (n = 46) and nonobese patients (n = 41).

Results

Adipose-conditioned media increased anaphase bridging in OE33R (p < 0.0001), with a threefold increase in OE33R compared to OE33P (p < 0.01). Levels of anaphase bridges in OE33R cells correlated with visceral obesity status as measured by waist circumference (R = 0.709, p = 0.03) and visceral fat area (R = 0.794, p = 0.006). Adipose tissue altered expression of MAD2L2 in vitro. In vivo, MAD2L2 expression was higher in viscerally obese oesophageal adenocarcinoma patients compared with nonobese patients (p < 0.05).

Conclusions

Anaphase bridge levels are influenced by obesity and radiosensitivity status in oesophageal adenocarcinoma. Furthermore, visceral adipose-conditioned media stimulates dysregulation of the spindle assembly complex in oesophageal adenocarcinoma patients.

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Acknowledgments

We would like to thank the members of the oesophageal surgical team at St. James’s hospital. We would also like to thank all the patients who gave their consent for sample procurement. This work was supported by funding from the Health Research Board (HPF/2011/59).

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Authors and Affiliations

  1. Department of Surgery, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland

    A. M. Mongan, N. Lynam-Lennon, R. Casey, G. Pidgeon, J. V. Reynolds & J. O’Sullivan

  2. Cancer Biology & Therapeutics Lab, School of Biological, Biomedical & Environmental Sciences, University of Hull, Cottingham road, Hull, HU6 76X, UK

    S. Maher

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  1. A. M. Mongan
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Correspondence to J. O’Sullivan.

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Mongan, A.M., Lynam-Lennon, N., Casey, R. et al. Visceral obesity stimulates anaphase bridge formation and spindle assembly checkpoint dysregulation in radioresistant oesophageal adenocarcinoma. Clin Transl Oncol 18, 632–640 (2016). https://doi.org/10.1007/s12094-015-1411-y

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