Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers

Abstract

The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett’s esophagus (BE) is an ideal research model. Supervised clustering of gene expression profiles from microdissected stroma identified a gene signature that could distinguish between BE metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). EAC patients overexpressing any of the five genes (TMEPAI, JMY, TSP1, FAPα, and BCL6) identified from this stromal signature had a significantly poorer outcome. Gene ontology analysis identified a strong inflammatory component in BE disease progression, and key pathways included cytokine–cytokine receptor interactions and TGF-β. Increased protein levels of inflammatory-related genes significantly up-regulated in EAC compared with preinvasive stages were confirmed in the stroma of independent samples, and in vitro assays confirmed functional relevance of these genes. Gene set enrichment analysis of external datasets demonstrated that the stromal signature was also relevant in the preinvasive to invasive transition of the stomach, colon, and pancreas. These data implicate inflammatory pathways in the genesis of gastrointestinal tract cancers, which can affect prognosis.

Tumour–stroma crosstalk in the development of squamous cell carcinoma

“…Similar gene expression changes have been found in the stroma of other SCC correlating with prognosis (Roepman, de Koning et al 2006;Saadi, Shannon et al 2010). Type VII collagen has also recently been found to modulate the expression of an organic anion transporting polypeptide known as OATP1B8 in tumour cells.…”

Strategies to improve outcomes in esophageal adenocarcinoma

“…Suspicion must now fall on the esophageal microenvironment with the possibility that nonmutated stromal cells play a critical role in EAC development and progression, a theory that would be consistent with longterm acid and bile salt exposure leading to a proinflammatory milieu. This possibility is supported by the finding of a prognostic stromal signature identified by Saadi and colleagues in esophageal cancer patients that contained a predominance of inflammation-and TGF-b-related genes [51].…”

“…The agestandardized incidence rates of EAC are rising by just under 40% every 5 years in Western countries, and EAC has become the predominant type of esophageal cancer in these areas [3]. EAC arises in Barrett's esophagus (BE), a metaplasia of the distal esophagus in response to chronic inflammation due to acid and bile exposure [4,5]. The UK has the highest incidence of EAC globally, at up to 8.7 cases/100,000 of the population [6], with Caucasian males being the most commonly affected ethnic group [7].…”

Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis

“…As is well known, microarray data serve as a springboard and reference point for further studies on the molecular basis of colorectal transformation along the adenocarcinoma pathway; in this regard, Saadi et al (27) recently carried out a gene set enrichment analysis (GSEA) to demonstrate that genes of the stromal cellular compartment discriminate preinvasive from invasive disease and suggest outcome prediction in digestive tumors, including colorectal cancer. The authors identified several genes, including BCL6, and underlined that the upregulation of this protein shows a trend for significantly poorer outcome in esophageal adenocarcinoma.…”