Abstract
ABSTRACTBone is the most common site of prostate cancer (PC) metastasis. Studies suggest that cancer stem cells (CSCs) are associated with stemness characteristics, providing some support for the concept that CSCs act as osteosclerotic precursors in bone microenvironmental niches. Here, we asked whether ectopic overexpression of CD133 maintains stability of CSCs in human PC cell lines and induces the changes of molecular features in the bone microenvironment. Ectopic overexpression of CD133 in PC3 or DU145 cells led to increased expression of ALDHA1, OCT4, and NANOG, enhanced colony‐forming ability, and increased ALDH activity. In addition, micro‐CT imaging, confocal microscopy, and H&E staining of mouse tissue confirmed that CD133 overexpression in PC3 and DU145 led to marked osteolytic bone tumor. However, expression of osteoblastic markers such as collagen type I, bone sialoprotein, and osteocalcin (OC) at the tumor margin of CD133‐overexpressing PC3 tumors in mouse tibiae was higher than that of CD133‐overexpressing DU145 tumors with osteosclerotic molecular features. In addition, expression of osteopontin (OPN) mRNA/protein by CD133‐overexpressing PC3 cells was higher than that by DU145 cells. Especially, conditioned medium (CM) from PC3CD133+ cells increased osterix (OSX) activity in bone marrow stromal cells (BMSCs), resulting in increased expression of OC mRNA/protein resulted in increased staining of mineralized matrix by Alizarin red. However, CM from OPN silenced PC3CD133+ cells led to a reduction of OC mRNA and protein expression through OSX activity resulted in reduced amount of mineralized matrix. In conclusion, these findings suggest that CD133 plays a functional role in regulating CSC characteristics in PCs and modulates their abilities in which induce the osteosclerosis of BMSCs. In addition, OPN from CSCs acts as a niche component that promotes osteosclerosis by supporting osteoblastic differentiation of BMSCs. © 2019 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
About 90% patients with advanced prostate cancer (PC) have incurable bone metastases, with a mean survival of 1 year.[1,2] Bone metastasis results in significant complications, including bone pain, impaired mobility, pathological fracture, spinal cord compression, and symptomatic hypercalcemia.[3,4] In particular, the osteosclerotic nature of most bone metastases related to PC means that there is a marked increase in osteoblastic activity.[5]
The hypothesis that tumors depend on a small fraction of cells, called cancer stem cells (CSCs), for long‐term survival is based on data demonstrating that subsets of human leukemic cells transferred tumor‐initiating activity to SCID mice.[8]. Recent studies show that PC stem‐like cells originating from a primary tumor have a high potential for invasion and possess self‐ renewal and clonogenic properties.[9]. These cells can be identified by expression of stem cell markers such as aldehyde dehydrogenase 1 (ALDH1), CD133, c‐Met, and prostate stem cell antigen.[10]. It is considered that CSCs are typically dormant and that their later regrowth triggers metastasis
We used murine models, in which PC cells would be inoculated in tibial bone marrow for establishment of interaction with bone marrow stromal cells (BMSCs) and metastatic PCs.[11]. It will show that CSC‐like cells affect the destination of pre‐osteoblasts and pre‐osteoclasts, which are significantly enriched for a mesenchymal and hematopoietic stem cell phenotype in the bone marrow.[12]. CSCs in the bone marrow were maintained over time, a phenomenon not caused by effects on proliferation, homing, or cell survival in the circulation
Summary
About 90% patients with advanced prostate cancer (PC) have incurable bone metastases, with a mean survival of 1 year.[1,2] Bone metastasis results in significant complications, including bone pain, impaired mobility, pathological fracture, spinal cord compression, and symptomatic hypercalcemia.[3,4] In particular, the osteosclerotic nature of most bone metastases related to PC means that there is a marked increase in osteoblastic activity.[5].
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