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| Title: | Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model |
| Authors: | Chang, Han-Hsin
Chen, Bo-Yie
Wu, Chia-Yung
Tsao, Zih-Jay
Chen, Ying-Yu
Chang, Chin-Pao
Yang, Chi-Rei
Lin, David Pei-Cheng |
| Contributors: | 中山醫學大學 |
| Date: | 2011 |
| Issue Date: | 2015-07-14T08:14:51Z (UTC)
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| ISSN: | 1021-7770 |
| Abstract: | Background
Hedgehog signalling has been implicated in prostate tumorigenesis in human subjects and mouse models, but its effects on transforming normal basal/stem cells toward malignant cancer stem cells remain poorly understood.
Methods
We produced pCX-shh-IG mice that overexpress Hedgehog protein persistently in adult prostates, allowing for elucidation of the mechanism during prostate cancer initiation and progression. Various markers were used to characterize and confirm the transformation of normal prostate basal/stem cells into malignant cancer stem cells under the influence of Hedgehog overexpression.
Results
The pCX-shh-IG mice developed prostatic intraepithelial neoplasia (PIN) that led to invasive and metastatic prostate cancers within 90 days. The prostate cancer was initiated through activation of P63+ basal/stem cells along with simultaneous activation of Hedgehog signalling members, suggesting that P63+/Patch1+ and P63+/Smo+ cells may serve as cancer-initiating cells and progress into malignant prostate cancer stem cells (PCSCs). In the hyperplastic lesions and tumors, the progeny of PCSCs differentiated into cells of basal-intermediate and intermediate-luminal characteristics, whereas rare ChgA+ neuroendocrine differentiation was seen. Furthermore, in the metastatic loci within lymph nodes, kidneys, and lungs, the P63+ PCSCs formed prostate-like glandular structures, characteristic of the primitive structures during early prostate development. Besides, androgen receptor (AR) expression was detected heterogeneously during tumor progression. The existence of P63+/AR-, CK14+/AR- and CD44+/AR- progeny indicates direct procurement of AR- malignant cancer trait.
Conclusions
These data support a cancer stem cell scenario in which Hedgehog signalling plays important roles in transforming normal prostate basal/stem cells into PCSCs and in the progression of PCSCs into metastatic tumor cells.
Background
Adult prostate epithelial stem cells reside within the basal cell layer and possess high self-renewal capacity, leading to the generation of intermediate, luminal, and neuroendocrine cell lineages [1,2]. Normally, most of the adult prostate epithelial stem cells differentiate into intermediate cells without requirement of androgen receptor (AR) activity. The process is characterized by loss of P63 and gain of CK14 or CD44 expression [3-5]. Then, the intermediate cells undergo terminal differentiation as they form the luminal cells with CK8 expression and become dependent on AR activity for maintenance and fulfilling of their functions [3,4].
Like many other cancer stem cells, a hypothesis of prostate cancer stem cells (PCSCs) originated from normal stem cells has been proposed based on their highly tumorigenic trait and basal/stem cell-like properties of self-renew and differentiation [6-9]. The hypothesis has been supported by some recent studies indicating that androgen-refractory prostate cancer cells contain an apparent basal/stem cell-like signature [9-12], suggesting that these cancer cells may not be derived from the AR+ luminal cell population [9]. In other words, AR signalling may be entirely bypassed during the transformation of prostate stem cells into PCSCs [9]. Alternatively, AR signalling may remain active at early stages of transformation but become repressed as the cancer cells eventually progress into an AR-independent status [13]. The entire bypass pathway has attracted much attention recently, since the basal/stem cells in human prostates are AR(- or low) [14], likely to be the direct origin of androgen-independent cancer cells through tumorigenic transformation, although there has been no evidence so far to support this hypothesis.
Hedgehog (Hh) signalling plays a key role in stem cell plasticity and in many developmental, physiological, and pathogenetic processes [15]. Binding of the Hedgehog ligand to the Patched 1 (Patch1) receptor releases the Patch1-associated Smoothened (Smo) G-protein, which triggers a cascade of intracellular signalling activations that lead to the binding of downstream transcription factors, e.g., Gli1, Gli2 and Gli3 to their target sequences and then expression of target genes involved in the control of cell division or differentiation [16]. Aberrant Hh signalling activation has been implicated in prostate tumorigenesis in human subjects and mouse models [17-22]. Previously, we had confirmed that Hh signalling members are expressed in tumorigenic P63+ basal cells in human specimens and these cells are capable of differentiation into multiple lineages, suggesting that Hh signalling may promote primary prostatic cancer stem cells [20]. However, the tumorigenic activation of basal/stem cells and their progression toward a metastatic status under the influence of Hh signalling remain to be further elucidated. To further characterize the basal cells during tumorigenic activation, we established a mouse prostate cancer model in which prostate tumorigenesis was induced from a normal status through persistent Hh overexpression [21], taking advantage of using mouse models to elucidate tumor formation and evaluate candidate therapeutic agents [23,24].
In this study, we used the Hh overexpression mouse model to elucidate whether the PCSCs arise from P63+ basal/stem cells and to examine whether these cancer cells can maintain stem cell characteristics after metastasis. More importantly, we intended to elucidate whether P63+ basal/stem cells can be directly transformed into AR- cancer cells. We demonstrated that Hh overexpression initiated malignant transformation of P63+ basal/stem cells that subsequently differentiated into both AR+ and AR- progeny of the basal-intermediate and intermediate-luminal progeny, but rare ChgA+ neuroendocrine cells. The Hh-initiated P63+ basal/stem cells were characteristic of PCSCs, as they were able to form primitive prostate-like glandular structures in the metastatic loci. Besides, androgen receptor (AR) expression was detected heterogeneously in PCSCs when they were differentiated into intermediate and luminal cells, indicating that androgen were not necessary for these PCSCs (AR-). These data challenge the model of AR+ transition into androgen-independent PCSCs and suggest a potentially better treatment strategy by inhibition of Hedgehog signalling prior to androgen-deprivation therapy. |
| URI: | https://ir.csmu.edu.tw:8080/ir/handle/310902500/11238
http://dx.doi.org/10.1186/1423-0127-18-6 |
| Relation: | Journal of Biomedical Science 2011, 18:6 |
| Appears in Collections: | [School of Nutritional Science] Journal paper
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