Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression

Abstract

Loss of the coxsackie and adenovirus receptor (CAR) has previously been observed in gastric cancer. The role of CAR in gastric cancer pathobiology, however, is unclear. We therefore analysed CAR in 196 R 0 -resected gastric adenocarcinomas and noncancerous gastric mucosa samples using immunohistochemistry and immunofluorescence. Coxsackie and adenovirus receptor was found at the surface and foveolar epithelium of all non-neoplastic gastric mucosa samples (n ¼ 175), whereas only 56% of gastric cancer specimens showed CAR positivity (Po0.0001). Loss of CAR correlated significantly with decreased differentiation, increased infiltrative depths, presence of distant metastases, and was also associated with reduced carcinoma-specific survival. To clarify whether CAR impacts the tumorbiologic properties of gastric cancer, we subsequently determined the role of CAR in proliferation, migration, and invasion of gastric cancer cell lines by application of specific CAR siRNA or ectopic expression of a human full-length CAR cDNA. These experiments showed that RNAi-mediated CAR knock down resulted in increased proliferation, migration, and invasion of gastric cancer cell lines, whereas enforced ectopic CAR expression led to opposite effects. We conclude that the association of reduced presence of CAR in more severe disease states, together with our findings in gastric cancer cell lines, suggests that CAR functionally contributes to gastric cancer pathogenesis, showing features of a tumour suppressor.

A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus

“…22 --24 However, tumor cells often show reduced CAR expression following tumor progression. 18,21,25,26 Decreased CAR expression has also been shown in tumor tissues after repeated injection of Ad-p53. 27,28 It is therefore necessary to assess the CAR expression level of target tumor tissues before and after Ad5-based cancer gene therapy and oncolytic virotherapy.…”

Loss of Coxsackie and adenovirus receptor downregulates α-catenin expression

“…In several human carcinomas, particularly in more advanced stages, a reduced CAR presence was found, partially associated with loss of tumour differentiation, increased infiltration, and poor prognosis (Sachs et al, 2002;Matsumoto et al, 2005;Korn et al, 2006;Buscarini et al, 2007;Okegawa et al, 2007;Anders et al, 2009). On the basis of data from studies in cell lines, it has been speculated that loss of CAR promotes the proliferation, migration, and invasion of cancer cells (Okegawa et al, 2000(Okegawa et al, , 2001Runnebaum, 2003, 2004;Huang et al, 2005;Wang et al, 2005).…”

The Contribution of Ig-Superfamily and MARVEL D Tight Junction Proteins to Cancer Pathobiology

“…In contrast, others have labeled CAR as a potential tumor suppressor, in studies where its downregulation has been associated with increased proliferation (41)(42)(43), invasive phenotypes (44,45) and hypoxic conditions; which themselves downregulate the transcription of CAR (46). In gastric cancer cells CAR gene silencing has been shown to induce increased proliferation as well as migration and invasion, with the reverse occurring under CAR overexpression conditions (43).…”

“…In gastric cancer cells CAR gene silencing has been shown to induce increased proliferation as well as migration and invasion, with the reverse occurring under CAR overexpression conditions (43). Similarly, bladder carcinomas and those of the head and neck have displayed stepwise reductions in CAR expression in parallel with increasing tumor grade (41,44,45).…”