Abstract
BackgroundRobust Hedgehog (Hh) signaling has been implicated as a common feature of human prostate cancer and an important stimulus of tumor growth. The role of Hh signaling has been studied in several xenograft tumor models, however, the role of Hh in tumor development in a transgenic prostate cancer model has never been examined.ResultsWe analyzed expression of Hh pathway components and conserved Hh target genes along with progenitor cell markers and selected markers of epithelial differentiation during tumor development in the LADY transgenic mouse model. Tumor development was associated with a selective increase in Ihh expression. In contrast Shh expression was decreased. Expression of the Hh target Patched (Ptc) was significantly decreased while Gli1 expression was not significantly altered. A survey of other relevant genes revealed significant increases in expression of Notch-1 and Nestin together with decreased expression of HNF3a/FoxA1, NPDC-1 and probasin.ConclusionOur study shows no evidence for a generalized increase in Hh signaling during tumor development in the LADY mouse. It does reveal a selective increase in Ihh expression that is associated with increased expression of progenitor cell markers and decreased expression of terminal differentiation markers. These data suggest that Ihh expression may be a feature of a progenitor cell population that is involved in tumor development.
Highlights
Robust Hedgehog (Hh) signaling has been implicated as a common feature of human prostate cancer and an important stimulus of tumor growth
When mice were sacrificed at 16 weeks, there was noted to be massive enlargement of the coagulating gland (CG) of the LADY mice as compared to the controls and histologic examination confirmed the presence of diffuse hyperplasia, stromal reaction and in situ carcinoma as previously described (Fig. 1)
To examine expression of the Hh pathway genes during tumor development, we examined gene expression in the CG at six and 16 weeks, time points corresponding to an early post-pubertal stage and to the adult stage of fully developed in situ carcinoma, respectively
Summary
Robust Hedgehog (Hh) signaling has been implicated as a common feature of human prostate cancer and an important stimulus of tumor growth. Binding of Hh ligand to the Ptc receptor on the target cell initiates an intracellular signal transduction cascade that activates expression of Hh target genes through the activity of a family of Gli transcription factors [1]. Previous studies have identified Shh as an important regulator of prostate development [2,3,4,5,6,7]. Shh is expressed exclusively in the epithelium of the developing prostate. Ihh is expressed in the prostate epithelium. It is expressed at relatively lower levels in the developing prostate but in a distinctive pattern and, in contrast to Shh, its expression is maintained undi-
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