EMT Molecular Signatures of Pancreatic Neuroendocrine Neoplasms

Abstract

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA and synaptophysin and the proliferation marker Ki-67 are used. These parameters, however, are qualitative and lack the capacity to fully define the tumour phenotype. Molecules of epithelial–mesenchymal transition (EMT) are potential candidates for improved tumour characterisation. Using qRT-PCR, we measured mRNA levels of 27 tumour markers, including 25 EMT-associated markers, in tumour tissue and matched non-tumour tissues for 13 patients with pancreatic NENs. Tissue from patients with three different grades of tumour had distinctly different mRNA profiles. Of the 25 EMT-associated markers analysed, 17 were higher in G3 tissue relative to matched non-tumour tissue, including CD14, CD24, CD31, CD44, CD45, CD56, CK6, CK7, CK13, CK20, NSE, CDX2, CgA, DAXX, PCNA, laminin and Ki-67. The differences in levels of seven EMT-associated markers, Ki-67, DAXX, CD24, CD44, vimentin, laminin and PDX1 plus CgA and NSE (neuroendocrine markers) enabled a distinct molecular signature for each tumour grade to be generated. EMT molecules differentially expressed in three tumour grades have potential for use in tumour stratification and prognostication and as therapeutic targets for treatment of neuroendocrine cancers, following validation with additional samples.

The Clinical Impact of Death Domain-Associated Protein and Holliday Junction Recognition Protein Expression in Cancer: Unmasking the Driving Forces of Neoplasia

“…The contribution of DAXX in pancreatic neuroendocrine tumors (PanNETs) is undoubtedly among the most extensively studied. While it has been the subject of a considerable number of studies, no contradictory results have been reported, with researchers agreeing on the overall tumor-promoting role of DAXX loss in pancreas tumorigenesis [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69].…”

“…In contrast, G3 samples exhibited higher DAXX mRNA expression in tumor tissues relative to non-tumorous ones. Additionally, DAXX IHC staining was absent in non-tumor, G1 and G2 tumor tissues, while strong nuclear staining was observed in less than 25% of cells in G3 tumor tissues [56]. DAXX mutation was identified in 13 out of 51 cases (25%) of 51 neuroendocrine liver metastases specimens, and the presence of DAXX mutation was associated with shorter hepatic progression-free survival (PFS) [57].…”