Hedgehog signaling in urogenital regeneration and neoplasia
Abstract/Contents
- Abstract
- The Hedgehog (Hh) signaling pathway functions in embryonic development to control cell growth, cell fate and pattern many aspects of the vertebrate body plan. The role of the pathway in adult tissue homeostasis, regeneration and cancer, however, is still emerging, especially in the context of epithelial/stromal interactions. Previous work on the adult bladder demonstrated the importance of stromal Hh pathway response in mediating homeostatic response to injury by eliciting production of stromal factors that act on the epithelium; in this dissertation I investigate the role of epithelial/stromal interactions involving the Hh pathway in prostate regeneration and bladder cancer. In the adult prostate, Hh pathway response occurs in a subset of stromal cells. Prostate regeneration involves the formation of new prostate branches, and I showed that stromal cells at the tips of nascent buds lacked Hh pathway response. Decreased pathway activity in stromal cells leads to increased branching, and this correlates with increased secretion of hepatocyte growth factor (Hgf), which acts on the epithelium to induce prostate branching. In regions that are not budding, stromal Hh pathway response down-regulates expression of Hgf. Hence, the spatial organization of stromal Hh pathway response in combination with the negative regulation of secreted hepatocyte growth factor (Hgf) levels by Hh pathway activity, together modulate branching morphogenesis during prostate regeneration. I also examined the role of Hh pathway activity in development of invasive urothelial carcinoma and find, despite its initial presence in the cancer cell of origin, that Sonic hedgehog (Shh) expression is lost during progression. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression. This cancer-protective effect is associated with Shh-induced stromal expression of BMP signals, which stimulate urothelial differentiation, and progression is reduced by pharmacological activation of BMP pathway activity. Taken together, the results of this dissertation highlight the importance, in regeneration and cancer, of epithelial/stromal interactions in which the Hh pathway is a key mediator. In both models examined, Hh ligand produced by the epithelium stiumates pathway response in the stroma, which regulates the secretion of factors that act on the epithelium. In a broader context, this work provides a conceptual framework for understanding epithelial/stromal interactions involving Hh signaling in other organ systems, a more detailed understanding of which will enable better therapeutic strategies for the treatment of disease.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Lim, Yeok Loo Agnes | |
|---|---|---|
| Associated with | Stanford University, Department of Developmental Biology. | |
| Primary advisor | Beachy, Philip Arden | |
| Thesis advisor | Beachy, Philip Arden | |
| Thesis advisor | Clarke, Michael F | |
| Thesis advisor | Krasnow, Mark, 1956- | |
| Thesis advisor | Talbot, William | |
| Advisor | Clarke, Michael F | |
| Advisor | Krasnow, Mark, 1956- | |
| Advisor | Talbot, William |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Yeok Loo Agnes Lim. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Yeok Loo Agnes Lim
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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