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. 2005 May;58(5):515-9.
doi: 10.1136/jcp.2004.018598.

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

T Byun  1 , M Karimi, J L Marsh, T Milovanovic, F Lin, R F Holcombe
Affiliations

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

T Byun et al. J Clin Pathol. 2005 May.

Abstract

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.

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Figures

Figure 1
Figure 1
In situ, antisense RNA hybridisation of Dkk3 in gastric and colonic normal and cancer tissue. A dark blue/purple colour indicates positive hybridisation. The insert in panel A shows a positive control with CaCo2 colon cancer cells, and that in panel C shows a negative control with HT-29 colon cancer cells. (A) Normal gastric tissue. Note the positive hybridisation with a stronger intensity of expression in deep gastric glands (arrows). Original magnification, ×10. (B) Gastric cancer tissue. Negative hybridisation was found in seven of nine samples tested. FAST red dye was used as a counterstain to reveal tissue architecture. Original magnification, ×40. (C) Normal colon tissue. Note the positive hybridisation with a stronger intensity of expression at the base of the crypts (arrows). Original magnification, ×10. (D) Colon cancer tissue. Positive hybridisation was found in four of 15 samples tested. Original magnification, ×10.
Figure 2
Figure 2
In situ hybridisation using an antisense FrzB RNA probe in gastric tissue samples. The purple colour indicates positive hybridisation. (A) Normal gastric tissue. Positive hybridisation was found in two of five samples tested. Original magnification, ×40. (B) Gastric cancer tissue. Negative hybridisation from the same patient as panel (A). Original magnification, ×40. Normal colon and colon cancer tissue exhibited no staining for FrzB (not shown).
Figure 3
Figure 3
In situ hybridisation using an antisense Wif1 RNA probe in colon tissue samples. The purple colour indicates positive hybridisation. The insert shows the negative sense probe control. (A) Normal colon tissue. Note the positive hybridisation with relatively stronger staining intensity at the base of the crypts (arrows). Original magnification, ×40. (B) Colon cancer tissue. Positive hybridisation. Original magnification, ×40. Normal gastric and gastric cancer tissue showed no staining for Wif1 (not shown).
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