Regulation of Osteosclerosis by Inoculated Cd133⁺ PC3 Cells in Bone‐marrow Microenvironmental Niches

Abstract

Bone 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 PC3 CD133+ 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 PC3 CD133+ 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.

Recent Advances of Osterix Transcription Factor in Osteoblast Differentiation and Bone Formation

“…It was reported that galectin-3, a tumor-secreted sugar-binding protein, regulates the expression of Osx, thereby remodeling bone in the bone microenvironment niche ( Nakajima et al, 2014 ). Opn released from cancer stem cells acts as a stimulator of osteogenesis by regulating Osx ( Kim et al, 2019 ). In addition, expressions of two cytokines, interleukin-8 (IL-8) and parathyroid hormone-related protein (PTHrP), that cause bone destruction by inducing osteoclast differentiation and activation, were increased by Osx over-expression.…”

State-of-the-art therapeutic strategies for targeting cancer stem cells in prostate cancer

“…Survival of PCSCs could promote tumor initiation, migration, and relapse, and induce therapy resistance ( 10 , 11 ). In addition, PCSC plasticity is anticipated to play a pivotal role in bone metastases of prostate cancer ( 12 ). PCSCs can be identified with cell surface markers expressed, and studies suggest that CD44 harbors them to exhibit tumor invasive properties ( 13 , 14 ).…”

Signaling Pathways and Targeted Therapies for Stem Cells in Prostate Cancer

“…5−7 In fact, the plasticity of PCSCs essentially plays a bigger part in bone metastases of PCa. 8,9 Furthermore, not all CSCs are the same in their morphology, capabilities, or characteristics, as CSCs are heterogeneous. As tumor spheroids develop, CSCs reprogram themselves to become increasingly heterogeneous, making it difficult to target then.…”

“…PCSCs are distinguished from PCa cells by their ability to differentiate uncontrollably, self-renewability, stemness, and quiescence. On the other hand, cancer stem cells (CSCs) divide symmetrically to produce a clone of two CSCs or asymmetrically to produce one CSC and another differentiated form that becomes part of the tumor. , Although evidence suggests the origin of CSCs, its ability to initiate tumors, or the degree to which CSCs can influence tumorigenesis is uncertain, and studies have shown that CSCs are involved in tumor relapse, migration, and resistance toward therapy. − In fact, the plasticity of PCSCs essentially plays a bigger part in bone metastases of PCa. , …”