- 作者: Han-Hsin Chang; Bo-Yie Chen; Chia-Yung Wu; Zih-Jay Tsao; Ying-Yu Chen; Chin-Pao Chang; Chi-Rei Yang; David Pei-Cheng Lin
- 作者服務機構: School of Nutrition, Chung Shan Medical University, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
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. - 中文關鍵字: --
- 英文關鍵字: --