Hedgehog pathway activity in the LADY prostate tumor model.
BACKGROUND
Robust 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.


RESULTS
We 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.


CONCLUSIONS
Our 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.
Gipp
Jerry
J
University of Wisconsin Medical School, Department of Surgery, Division of Urology, Clinical Sciences Center, Madison, WI 53792, USA. gipp@surgery.wisc.edu
Gu
Guangyu
G
Crylen
Curtis
C
Kasper
Susan
S
Bushman
Wade
W
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000727:Androgen-Binding Protein / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004847:Epithelial Cells / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D051542:Hepatocyte Nuclear Factor 3-beta / Q000096:biosynthesis / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000096:biosynthesis / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D064231:Nestin; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D000071676:Zinc Finger Protein GLI1
D000727:Androgen-Binding Protein; D000957:Antigens, Viral, Tumor; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D007381:Intermediate Filament Proteins; D051741:Kruppel-Like Transcription Factors; C577484:NES protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C497762:Notch1 protein, mouse; C092313:Npdc1 protein, mouse; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C465570:Shh protein, mouse; D000071676:Zinc Finger Protein GLI1; C514061:ihh protein, mouse; C027519:probasin; D051542:Hepatocyte Nuclear Factor 3-beta