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Gastroesophageal Carcinogenesis Manuel Pera

 The mission of the Gastroesophageal Cancer Program is to advance our knowledge of the pathogenesis, prevention, prognosis and treatment of gastroesophageal malignancies to reduce the incidence, increase survival and improve the quality of life of individuals affected by these tumours.

The program has two investigative themes:

• Barrett’s oesophagus and oesophageal adenocarcinoma: mechanisms of carcinogenesis and tumour biology. In the past couple of years, an increase in the incidence of oesophageal adenocarcinoma and gastroesophageal adenocarcinoma has been seen in Western nations. Barrett's oesophagus, defined as the substitution of the squamous epithelia of the distal oesophagus by columnar epithelia due to gastroesophageal reflux, constitutes the precursor lesion to oesophageal adenocarcinoma. Dr. Manuel Pera has a long-standing interest in understanding the pathogenesis of Barrett’s oesophagus and its malignant transformation process to oesophageal adenocarcinoma.

In 1989 Dr. Manuel Pera and his group described for the first time (Cancer Res 49:6803,1989) inducing areas of columnar metaplasia and adenocarcinomas in the oesophagus of rats after the development of a chronic reflux of duodenal content by means of an oesophagojejunal anastomosis and administration of the carcinogen 2,6-DMNM. In this first study, it was demonstrated that biliopancreatic reflux, which is very prevalent in Barrett’s oesophagus patients, acted in the animal model as a promoting mechanism of oesophageal carcinogenesis when the number of tumours increased and at the same time produced a hystopathological change that made way for the development of carcinomas with glandular differentiations. Later studies with the same animal model demonstrated that chronic reflux (> 20 weeks) of biliopancreatic secretions towards the oesophagus per se, without concomitant administration of the carcinogen is sufficient to induce the development of areas of glandular metaplasia and adenocarcinomas (Carcinogenesis 21:1587, 2000).

Our group offered the hypothesis then that when acted upon by components of duodenal reflux, the keratinocytes of the basal layer of the squamous epithelium of the oesophagus would have the potential to undergo a transdifferentiation process towards acquiring a columnar phenotype. This data support the hypothesis on the origin of Barrett’s oesophagus in humans from cells of the oesophagus itself. Recently we have demonstrated that the oesophageal keratinocytes in rats with chronic reflux action express the Cdx2 transcription factor that is a determiner for the apparition of an intestinal phenotype, both in the stomach (intestinal metaplasia) and in the oesophagus (Barrett’s metaplasia) (J Gastrointest Surg 11:869, 2007). Likewise, Cdx2 regulates the transcription of other markers of intestinal differentiation, such as Muc2 and, in this sense, we have observed the expression of Muc2 in those areas of squamous epithelium with columnar differentiation.

In line with the translational research component, Dr. Pera’s laboratory is primarily interested in characterising the phenotypic changes that occur in the squamous epithelium of the proximal oesophagus exposed to a mixed reflux of bile and acid, and its evolution towards the development of cardiac epithelium and intestinal metaplasia with goblet cells in a clinical model of Barrett’s oesophagus developed after a subtotal oesophagectomy and reconstruction with an oesophagogastrostomy. It is also crucial to determine whether the squamous epithelium of patients with Barrett’s oesophagus is more prone to undergoing a process of transdifferentiation toward the acquisition of a columnar phenotype. More. 

• Angiogenesis and gastric cancer Despite new adjuvant therapies, surgical resection still remains the only potentially curative treatment for gastric cancer. Identification of prognostic and predictive factors that reflect the biology of gastric cancer (tumour spread and metastasis) is important for refining our assessment of prognoses and the selection of patients who may benefit from adjuvant systemic therapy. Angiogenesis, the formation of new blood vessels that develop from pre-existing blood vessels, is a fundamental process in tumour growth and metastasis, and the vascular endothelial growth factor (VEGF) has been identified as the most potent and specific promoter of tumour angiogenesis, as it is secreted by almost all solid cancers. Dr. Manuel Pera’s research group has determined the value of tumour microvessel density and the expression of p53 and VEGF as prognostic markers in patients with gastric cancer who have been operated on for a cure. They have demonstrated that p53 expression and VEGF expression are independent prognostic factors for both disease-free survival and overall survival, and that p53 status may also influence the response to chemotherapy (Br J Cancer 90:206, 2004). His research work continues to focus on investigating the potential value of serum angiogenic factors as more objective prognostic markers in gastric cancer patients.