Exploring stromal-epithelial interactions in oesophageal cancer
Lead Research Organisation:
University of Southampton
Department Name: Cancer Sciences
Abstract
Cancer of the oesophagus (gullet) is becoming more common in the UK. Despite best current treatments the likelihood of cure is still very poor. The relationship between cells lining the oesophagus and the cells in the supporting layer beneath is fundamental to the development of oesophageal cancer. We make use of a specially developed model system to better understand this relationship with the aim of identifying new molecules as targets for cancer prevention and treatment. Our research uses human cells taken from biopsies of the oesophagus to grow a model oesophagus in the laboratory. Using this system we can determine the interaction between different cell types and the relative contribution that they make to cancer progression. Our overall aim is to understand the differences between cells in the supporting layer of the oesophagus at different stages of cancer growth and use these differences to design new ways of detecting and treating oesophageal cancer before it spreads.
Technical Summary
Objectives: This proposal describes an innovative programme of work to establish the importance of stromal-epithelial interactions in human oesophageal cancer.
Background: Carcinoma of the oesophagus is the 6th leading cause of cancer death with a 5-year survival of less than 15%. It is the most rapidly increasing cancer in the UK and in December 2008 the Chief Medical Officer for England called for increased research into its causes. Adenocarcinoma of the oesophagus is associated with the finding of a pre-malignant columnar metaplasia in the distal oesophagus - Barrett‘s oesophagus (BE). Recent evidence demonstrates that gene changes in the oesophageal stroma can be independent of changes in the epithelium, and are important in Barrett‘s carcinogenesis.
Methods: This project makes use of a novel organotypic model of the oesophagus that allows molecular genetic manipulation of both the epithelial and stromal cellular components in a physiological ex-vivo setting. We will use human tissue from endoscopic biopsies and oesophageal resections, taking both a candidate gene and genome wide approach with three research aims:
1. To build on our preliminary data to establish the role of periostin in oesophageal carcinoma invasion.
2. To define the contribution of other stromal signals to the maintenance and progression of oesophageal carcinoma.
3. To analyse the molecular events required for fibroblast activation in the oesophagus.
Outcomes: This project will lead to the discovery of novel diagnostic and prognostic biomarkers, and the potential for the rational development of new interventions and therapies.
Background: Carcinoma of the oesophagus is the 6th leading cause of cancer death with a 5-year survival of less than 15%. It is the most rapidly increasing cancer in the UK and in December 2008 the Chief Medical Officer for England called for increased research into its causes. Adenocarcinoma of the oesophagus is associated with the finding of a pre-malignant columnar metaplasia in the distal oesophagus - Barrett‘s oesophagus (BE). Recent evidence demonstrates that gene changes in the oesophageal stroma can be independent of changes in the epithelium, and are important in Barrett‘s carcinogenesis.
Methods: This project makes use of a novel organotypic model of the oesophagus that allows molecular genetic manipulation of both the epithelial and stromal cellular components in a physiological ex-vivo setting. We will use human tissue from endoscopic biopsies and oesophageal resections, taking both a candidate gene and genome wide approach with three research aims:
1. To build on our preliminary data to establish the role of periostin in oesophageal carcinoma invasion.
2. To define the contribution of other stromal signals to the maintenance and progression of oesophageal carcinoma.
3. To analyse the molecular events required for fibroblast activation in the oesophagus.
Outcomes: This project will lead to the discovery of novel diagnostic and prognostic biomarkers, and the potential for the rational development of new interventions and therapies.