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Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours
  1. Xianyong Gui1,
  2. Ziran Meng1,
  3. Yarrow J McConnell2,
  4. Shuhong Liu1,
  5. Vincent G Falck1,
  6. Lloyd A Mack2,
  7. Walley J Temple2
  1. 1Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada
  2. 2Division of Surgical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada
  1. Correspondence to Dr Xianyong Gui, Department of Pathology, Foothills Medical Centre, Main Building, 11th Floor, 1403 29 St NW, Calgary, Alberta, Canada T2N 2T9; xsean.gui{at}cls.ab.ca

Abstract

Background Tumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven by Notch-Hes1 pathway, while secretory lineage is driven by Wnt-Math1 pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3 for goblet cells, Gfi1-Sox9 for Paneth cells and Ngn3-Pdx1/Beta2/Pax4 for enteroendocrine cells).

Methods The expressions of various signalling proteins in different appendiceal tumours were detected by immunohistochemistry on tumour tissue microarray.

Results CCT showed reduced Hes1/Elf3 and Sox9/Klf4 coupled with elevated Math1, in keeping with endocrine phenotype. As compared with CCT, GCC showed higher Klf4 and similar Ngn3/Pax4, indicative of a shift of differentiation towards goblet cells as well as endocrine cells. GCC displayed a Notch signalling similar to adenocarcinoma. Mucinous tumours showed lower Elf3 than normal appendiceal epithelium and higher Math1/Gfi1/Klf4, suggestive of a differentiation towards less enterocytes but more goblet cells. NMA showed Notch signalling similar to other glandular tumours, but lower Klf4. However, some seemingly paradoxical changes were also observed, probably suggesting gene mutations and/or our incomplete understanding of the intestinal cell differentiation.

Conclusions Wnt/secretory lineage protein and Notch/absorptive lineage protein expression profiles are generally associated with the tumour cell differentiation and morphological diversity of common appendiceal tumours.

  • APPENDIX
  • NEOPLASMS
  • CARCINOID

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