Oesophageal Adenocarcinoma is on the rise globally affecting more than 450,000 people worldwide (Pennathur, Gibson et al. 2013). Once diagnosed overall 5-year survival ranges from 15 % to 25 %, with the best outcomes being associated diagnosis in the early stages of cancer development (Pennathur, Gibson et al. 2013). Oesophageal Adenocarcinoma (OAC) arises from a pre malignant condition known as Barrett’s Oesophagus (BO). BO is associated with an increased risk of developing OAC compared to normal age matched controls.
Barrett’s oesophagus (BO) occurs when the normal squamous epithelium of the oesophagus is replaced by a metaplastic intestine-like epithelium containing goblet cells. The presence of goblet cells in the columnar epithelium is a diagnostic criterion of Barrett’s oesophagus in the US only (Illig, Klieser et al. 2013). There have been a number of changes to the definition of BO over the years. The most important of which is the post 1994 definition that includes columnar epithelium <3 cm in the definition of BO.
It has been demonstrated that the greater the length of columnar mucosa that is present in the oesophagus, the greater the chance of discovering intestinal-type metaplasia (IM) of the oesophagus. BO and IM all appear to be linked by reflux. Bile appears to drive intestinalisation and acid seems to promote the development of cardiac mucosa.
Barretts Oesophagus therefore is primarily the result of chronic Gastro-Oesophageal reflux disease also known as GORD (Lagergren, Bergström et al. 1999). GORD releases damaging agents in the reflux such as gastric acids, bile acids and pepsin. These agents damage and induce changes in the epithelium lining of the oesophagus (Grimm, Lazariotou et al. 2010, Baptissart, Vega et al. 2013). Chronic injury to the gastro-oesophageal junction by gastric and bile acids induces and promotes metaplastic changes of normal squamous oesophageal tissue to columnar epithelium (Illig, Klieser et al. 2013).
It is likely that wound healing in response to mucosal injury caused by bile salts may contribute to the development of BO. As the process of wound healing includes a number of phenotypic changes in a cell similar to the those acquired during the development of cancer known as the hallmarks of cancer (Hanahan and Weinberg, 2000). The development of a survival or repetitive competitive advantage in these cells may contribute to the development of malignancy. Concurrent inflammatory signals as a result of bile acid exposure may result in an increase in proliferation and mutagenesis. Repeated cycles of bile acid induced damage would naturally select for cells which have developed survival and reproductive advantages, which may allow for the transformation of normal squamous mucosa into columnar mucosa or intestinal metaplasia (Maley, 2007, Dvorakova et al., 2005).
GORD and Obesity
GORD and obesity represent one of the highest risk factors for the development of Oesophageal adenocarcinoma from Barretts Oesophagus (Allott, Lysaght et al. 2013) (Pennathur, Gibson et al. 2013).Upon the development of Barretts Oesophagus a progression to adenocarcinoma is noted in 16-59% of cases (Pennathur, Gibson et al. 2013).
Matrix metalloproteinase’s and their role in Oesophageal Adenocarcinoma
Tissue invasion and metastasis are largely recognised as one of the 6 hallmarks of cancer as outlined by Hanahan and Weinberg (Hanahan and Weinberg 2000). Invasive and metastatic capabilities are mediated mainly thorough extracellular proteases. Evidence is accumulating that Matrix Metalloproteinase’s (MMP’s) are likely to play a key role in invasion of the tumour cell through the degradation of the basement membrane.
MMPs are a family of highly homologous protein-degrading zinc dependent enzymes, which function as endopeptidases. These endopeptidases are therefore capable of degrading the basement membrane (Murray, Duncan et al. 1998, Coussens, Fingleton et al. 2002, Grimm, Lazariotou et al. 2010). The family has more than 25 members that can be divided into collagenases ,gelatinases,stromelysins, matrilysins and membrane type MMPs (Grimm, Lazariotou et al. 2010). MMPs are secreted as inactive precursors which are then activated by the cleavage of an N-terminal pro-peptide(Murray, Duncan et al. 1998).
Studies suggest that the gelatinases MMP-2 and MMP-9 are likely to have a role in Oesophageal cancer. Particularly, in the initial stages of tumour invasion as they are capable of degrading type IV collagen, Type IV collagen is a key component of the basement membrane. It facilitates local invasion of tumours and a microenvironment that facilitates growth and angiogenesis of tumours at primary and metastatic sites (Murray, Duncan et al. 1998, Tanioka, Yoshida et al. 2003, Herszenyi, Hritz et al. 2007, Allott, Lysaght et al. 2013). MMP-9 and MMP-2 are known to be up regulated 10 fold in oesophageal adenocarcinoma arising from visceral obesity(Allott, Lysaght et al. 2013). These have been shown to be implicated in a variety of others cancers e.g. pancreatic, rectal, squamous cell carcinoma, breast, renal and non-small cell lung carcinoma(Allott, Lysaght et al. 2013, Prasad, Chaurasiya et al. 2013).
MMP-9 expression is primarily isolated to the cytoplasm and the cytoplasmic membrane (invasive front) of the oesophageal epithelium in adenocarcinoma cells. A progressive increase in the expression of MMP-9 can be noted with increasing severity of oesophageal lesions (Tanioka, Yoshida et al. 2003, Herszenyi, Hritz et al. 2007). MMP-9 has been suggested as a marker for invasiveness. It represents an early angiogenic event in carcinogenesis whose expression correlates in tumour tissue with the depth of tumour invasion (Tanioka, Yoshida et al. 2003, Li, Ma et al. 2009). High MMP-9 expression in tumour tissue is considered a negative prognostic factor (Groblewska, Siewko et al. 2012).
MMP-2 expression has too been noted at the margins of infiltrating cells suggesting a role in invasion. Its expression is also higher in more advanced stages of cancer (Groblewska, Siewko et al. 2012). Knockout studies of MMP-2 and MMP-9 in mice have lead to a reduced incidence of metastasis following tumour cell implantation further suggesting there role in metastatic cancer (Allott, Lysaght et al. 2013).A greater understanding of these mechanisms may lead to the discovery of biomarkers to aid in the diagnosis process as there is an exact correlation between the stage of oesophageal carcinogenic sequence at which diagnosis is made and survival rates (Ong et al., 2010)
Inflammation, Barretts Oesophagus and Oesophageal Adenocarcinoma
Inflammation appears to be a key element in progression through the oesophageal carcinogenic sequence. Inflmmation may therefore be a useful target as a therapeutic option for BO. COX2 inhibitors held some promise in halting the progression of oesophageal malignancies. However, side effects involving cardio toxicity were observed which removed the potential for this therapeutic strategy (Bresalier et al., 2005).
The largest prospective intervention study ever carried out examining chemoprevention in patients with BO is being carried out in the UK. This study is known as the ASPECT study. Aspirin and esomeprazole, a proton pump inhibitor, are being used to target mortality and decrease the number of patients that progress from BO to OAC or high grade dysplasia. Biopsies will be obtained every 2 years from patients enrolled in this study, making it possible to characterise the expression of p16, p53 and ploidy changes. The protein expression levels of CDX2, COX2, PKCε and MCM2 will also be assessed followed each biopsy (Zagorowicz and Jankowski, 2007). Expression levels of the most important players in oesophageal adenocarcinogenesis can be assessed in each individual case following each routine biopsy. This will provide a valuable insight into the molecular mechanisms behind oesophageal adenocarcinogenesis.