Differentiation reprogramming in gastric intestinal metaplasia and dysplasia: role for SOX2 and CDX2

In this work we have assessed the expression profile of two transcription factors, SOX2 and CDX2 in intestinal metaplasia (IM) and dysplasia, two lesions that precede gastric cancer onset.  Our results provide a molecular basis to understand the heterogeneity of metaplastic lesions and favor the hypothesis that dysplasia arises from IM. These results have clinical implications since they advise a closer surveillance of patients presenting with IM.

Authors and Affiliations:

Vânia Camilo¹, Mónica Garrido², Pedro Valente², Sara Ricardo¹, Ana Luísa Amaral¹, Rita Barros¹, Paula Chaves³, Fátima Carneiro^1,2,4, Leonor David^1,2, Raquel Almeida^1,2,5

 ¹Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

²Faculty of Medicine of the University of Porto, Porto, Portugal

³Portuguese Oncology Institute Francisco Gentil, E.P.E., Lisbon, Portugal

⁴Pathology Department, Centro Hospitalar S. João, Porto, Portugal

⁵Biology Department, Faculty of Sciences of the University of Porto, Porto, Portugal

Abstract:

Aims: Intestinal metaplasia (IM), which results from de novo expression of CDX2, and dysplasia are precursor lesions of gastric cancer associated with increased risk for cancer development. Multiple evidence suggest a role for SOX2 transcription factor in gastric differentiation. In an attempt to establish SOX2 relationship with CDX2 and with the differentiation reprogramming that characterizes gastric carcinogenesis, we assessed their involvement in IM and dysplasia.

Methods and Results: Characterization of gastric (SOX2, MUC5AC, MUC6) and intestinal (CDX2 and MUC2) markers in normal gastric mucosa, in 55 foci of IM and in 26 foci of dysplasia, was performed by immunohistochemistry. SOX2 was expressed in the normal gastric mucosa, in the presumptive stem cell compartment, and was maintained in 7% of the complete (MUC5AC^-) and 85% of the incomplete (MUC5AC⁺) IM subtypes. 12% of the dysplastic lesions expressed SOX2 and the association with MUC5AC was lost. CDX2 was present in all IM and dysplastic lesions.

Conclusions: SOX2 associates with gastric differentiation in incomplete IM and is lost in the progression to dysplasia, whereas CDX2 is de novo acquired in IM and maintained in dysplasia. This suggests that the balance between gastric and intestinal differentiation programs impacts on the gastric carcinogenesis cascade progression.

Journal:  Histopathology

Link: http://onlinelibrary.wiley.com/doi/10.1111/his.12544/abstract;jsessionid=A69C9483F299B5BA5F00A41A814936FD.f04t02