ORIGINAL ARTICLE

Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis

T Byun¹, M Karimi¹, J L Marsh², T Milovanovic¹, F Lin³ and R F Holcombe¹

¹ Division of Hematology/Oncology, University of California, Irvine Medical Center, 101 The City Drive, Bld 23, Rm 244, Orange, CA 92868, USA
² Department of Developmental and Cell Biology, University of California
³ Department of Pathology, University of California

Correspondence to:
Correspondence to:
Dr R F Holcombe
MD, Division of Hematology/Oncology, University of California, Irvine Medical Center, 101 The City Drive, Bld 23, Rm 244, Orange, CA 92868, USA; rholcomb{at}uci.edu

Background: Wnt signalling dysregulation has been implicated in cancer, including colon and gastric cancer. Initiation of Wnt signalling is modulated by soluble Wnt antagonists (sWAs), including soluble frizzled related proteins, dickkopf (Dkk) proteins, and Wnt inhibitory factor-1 (Wif1).

Aims: To evaluate the role of sWAs in upper (gastric) and lower (colon) gastrointestinal tract tumorigenesis.

Methods: Dkk1–3, Wif1, and FrzB expression was evaluated by in situ RNA hybridisation on normal and malignant human gastric and colon tissues. Expression was graded semiquantitatively.

Results: Wif1, Dkk1, and Dkk2 were not expressed in normal gastric tissue. Dkk3 was expressed in some samples, with stronger expression in deep gastric glands. FrzB was expressed in several normal gastric samples, but not in matched tumour specimens. In contrast, Dkk1 and FrzB were not expressed in normal colon. Wif1 was expressed in most colon samples, with stronger expression at crypt bases. Dkk3 and Dkk2 expression was also concentrated at crypt bases. There were no differences between sWA expression in malignant colon and matched normal tissue.

Conclusions: sWA expression differed between upper and lower gastrointestinal tract. The loss of FrzB in gastric cancer suggests that it acts as a tumour suppressor. The graded expression of Dkk3 in gastric tissue, and Dkk2, Dkk3, and Wif1 in colon tissue, with increased expression in the deep gastric glands/colonic crypt bases, where gastrointestinal stem cells reside, suggests that sWAs may be crucial Wnt signalling regulators in these tissues, and may contribute to stem cell pool maintenance. sWAs are important components of the gastrointestinal proliferative regulatory network.

Abbreviations: Dkk, dickkopf; FrzB, Frisbee; Fz, frizzled; LRP, lipoprotein receptor related protein; sFRP, soluble frizzled related protein; sWA, soluble Wnt antagonist; Wif1, Wnt inhibitory factor-1

Keywords: Wnt signalling; cancer; colon; stomach; frizzled related proteins

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