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Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis.

ABSTRACT: Bone is the most common site of prostate cancer metastasis. Once prostate cancer cells metastasize to bone, the mortality rate of prostate cancer patients increases significantly. Furthermore, bone metastases produce multiple skeletal complications, including bone pain that impairs the patients' quality of life. Effective therapies for bone metastatic disease are underdeveloped with most current therapies being primarily palliative with modest survival benefit. Although the exact mechanisms through which prostate cancer metastasizes to bone are unclear, growing evidence suggests that the bone marrow microenvironment, particularly its hematopoietic activity, is a significant mediator of prostate cancer bone tropism. Moreover, the bone microenvironment may regulate metastatic prostate cancer cells between dormant and proliferative states. In this review, we discuss (1) how prostate cancer cells interact with the bone microenvironment to establish bone metastases and (2) current and future potential treatments for prostate cancer patients with bone metastases.

SUBMITTER: Park SH

PROVIDER: S-EPMC5807175 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis.

Park Sun H SH Keller Evan T ET Shiozawa Yusuke Y

Calcified tissue international 20171101 2

Bone is the most common site of prostate cancer metastasis. Once prostate cancer cells metastasize to bone, the mortality rate of prostate cancer patients increases significantly. Furthermore, bone metastases produce multiple skeletal complications, including bone pain that impairs the patients' quality of life. Effective therapies for bone metastatic disease are underdeveloped with most current therapies being primarily palliative with modest survival benefit. Although the exact mechanisms thro ...[more]

PMID: 29094177

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Project description:BackgroundThe molecular characteristics of prostate cancer (PCa) cells and the immunosuppressive bone tumor microenvironment (TME) contribute to the limitations of immune checkpoint therapy (ICT). Identifying subgroups of patients with PCa for ICT remains a challenge. Herein, we report that basic helix-loop-helix family member e22 (BHLHE22) is upregulated in bone metastatic PCa and drives an immunosuppressive bone TME.MethodsIn this study, the function of BHLHE22 in PCa bone metastases was clarified. We performed immunohistochemical (IHC) staining of primary and bone metastatic PCa samples, and assessed the ability to promote bone metastasis in vivo and in vitro. Then, the role of BHLHE22 in bone TME was determined by immunofluorescence (IF), flow cytometry, and bioinformatic analyses. RNA sequencing, cytokine array, western blotting, IF, IHC, and flow cytometry were used to identify the key mediators. Subsequently, the role of BHLHE22 in gene regulation was confirmed using luciferase reporter, chromatin immunoprecipitation assay, DNA pulldown, co-immunoprecipitation, and animal experiments. Xenograft bone metastasis mouse models were used to assess whether the strategy of immunosuppressive neutrophils and monocytes neutralization by targeting protein arginine methyltransferase 5 (PRMT5)/colony stimulating factor 2 (CSF2) could improve the efficacy of ICT. Animals were randomly assigned to treatment or control groups. Moreover, we performed IHC and correlation analyses to identify whether BHLHE22 could act as a potential biomarker for ICT combination therapies in bone metastatic PCa.ResultsTumorous BHLHE22 mediates the high expression of CSF2, resulting in the infiltration of immunosuppressive neutrophils and monocytes and a prolonged immunocompromised T-cell status. Mechanistically, BHLHE22 binds to the CSF2 promoter and recruits PRMT5, forming a transcriptional complex. PRMT5 epigenetically activates CSF2 expression. In a tumor-bearing mouse model, ICT resistance of Bhlhe22+ tumors could be overcome by inhibition of Csf2 and Prmt5.ConclusionsThese results reveal the immunosuppressive mechanism of tumorous BHLHE22 and provide a potential ICT combination therapy for patients with BHLHE22+ PCa.

Project description:BackgroundBone metastasis is the leading cause of death in patients with prostate cancer (PCa) and currently has no effective treatment. Disseminated tumor cells in bone marrow often obtain new characteristics to cause therapy resistance and tumor recurrence. Thus, understanding the status of disseminated prostate cancer cells in bone marrow is crucial for developing a new treatment.MethodsWe analyzed the transcriptome of disseminated tumor cells from a single cell RNA-sequencing data of PCa bone metastases. We built a bone metastasis model through caudal artery injection of tumor cells, and sorted the tumor hybrid cells by flow cytometry. We performed multi-omics analysis, including transcriptomic, proteomic and phosphoproteomic analysis, to compare the difference between the tumor hybrid cells and parental cells. In vivo experiments were performed to analyze the tumor growth rate, metastatic and tumorigenic potential, drug and radiation sensitivity in hybrid cells. Single cell RNA-sequencing and CyTOF were performed to analyze the impact of hybrid cells on tumor microenvironment.ResultsHere, we identified a unique cluster of cancer cells in PCa bone metastases, which expressed myeloid cell markers and showed a significant change in pathways related to immune regulation and tumor progression. We found that cell fusion between disseminated tumor cells and bone marrow cells can be source of these myeloid-like tumor cells. Multi-omics showed the pathways related to cell adhesion and proliferation, such as focal adhesion, tight junction, DNA replication, and cell cycle, were most significantly changed in these hybrid cells. In vivo experiment showed hybrid cells had a significantly increased proliferative rate, and metastatic potential. Single cell RNA-sequencing and CyTOF showed tumor-associated neutrophils/monocytes/macrophages were highly enriched in hybrid cells-induced tumor microenvironment with a higher immunosuppressive capacity. Otherwise, the hybrid cells showed an enhanced EMT phenotype with higher tumorigenicity, and were resistant to docetaxel and ferroptosis, but sensitive to radiotherapy.ConclusionTaken together, our data demonstrate that spontaneous cell fusion in bone marrow can generate myeloid-like tumor hybrid cells that promote the progression of bone metastasis, and these unique population of disseminated tumor cells can provide a potential therapeutic target for PCa bone metastasis.

Dataset Information

Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis.

Publications

Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis.

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