Tumor- and Osteoblast-Derived Periostin in Prostate Cancer bone Metastases.
Ontology highlight
ABSTRACT:
SUBMITTER: Sun CY
PROVIDER: S-EPMC8787093 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.
| S-EPMC8121836 | biostudies-literature
Project description:The most common metastatic lesions of prostate cancer are in bone and can be classified into three distinct pathology subtypes: lytic, blastic, and an indeterminate mixture of both. We investigated a cohort of decalcified formalin-fixed and paraffin-embedded (FFPE) patient specimens from the bone that contained metastatic prostate cancer with lytic or blastic features. These tissue sections were utilized for immunohistochemistry (IHC) staining, isolation of RNA for gene expression, and Digital Spatial Profiling (DSP) of changes in both the tumor and microenvironment. A diverse set of unique immune cell populations and signaling pathways to both lytic and blastic types of prostate cancer metastases were present. In blastic lesions immune cells were enriched for pSTAT3 and components of the JAK-STAT pathway. In lytic-type lesions, immune cells were enriched for pAKT activity and components of the PI3K-AKT pathway. Enrichment for immune checkpoints including PD-L1, B7-H4, OX40L, and IDO-1 were identified in blastic prostate cancer, providing new therapeutic targets for patients with bone metastases. Biopsies could guide selection of patients into appropriate therapeutic interventions based on protein levels and RNA expression of desired targets in metastatic disease. Molecular pathology has been an excellent complement to the diagnosis, treatment, and management of primary tumors and could be successfully extended to patients with metastatic lesions.
| S-EPMC6839115 | biostudies-literature
Project description:Cross-talk between tumor cells and their microenvironment is critical for malignant progression. Cross-talk mediators, including soluble factors and direct cell contact, have been identified, but roles for the interaction of physical forces between tumor cells and the bone microenvironment have not been described. Here, we report preclinical evidence that tumor-generated pressure acts to modify the bone microenvironment to promote the growth of prostate cancer bone metastases. Tumors growing in mouse tibiae increased intraosseous pressure. Application of pressure to osteocytes, the main mechanotransducing cells in bone, induced prostate cancer growth and invasion. Mechanistic investigations revealed that this process was mediated in part by upregulation of CCL5 and matrix metalloproteinases in osteocytes. Our results defined the critical contribution of physical forces to tumor cell growth in the tumor microenvironment, and they identified osteocytes as a critical mediator in the bone metastatic niche.
| S-EPMC4452392 | biostudies-literature
Project description:Sphingosine 1-phosphate (S1P) plays important roles in cell proliferation, differentiation or survival mainly through its surface G-protein-coupled receptors S1P1-5. Bone represents the major site of metastasis for prostate cancer (CaP) cells, which rely on bone-derived factors to support their proliferation and resistance to therapeutics. In the present work we have found that conditioned medium (CM) from the MC3T3 osteoblastic cell line or primary murine and human osteoblast-like cells, as well as co-culture with MC3T3 stimulate proliferation of CaP lines in S1P-dependent manner. In addition, osteoblastic-derived S1P induces resistance of CaP cells to therapeutics including chemotherapy and radiotherapy. When S1P release from osteoblastic cells is decreased (inhibition of SphK1, knock-down of SphK1 or the S1P transporter, Spns2 by siRNA) or secreted S1P neutralized with anti-S1P antibody, the proliferative and survival effects of osteoblasts on CaP cells are abolished. Because of the paracrine nature of the signaling, we studied the role of the S1P receptors expressed on CaP cells in the communication with S1P secreted by osteoblasts. Strategies aimed at down-regulating S1P1, S1P2 or S1P3 (siRNA, antagonists), established the exclusive role of the S1P/S1P1 signaling between osteoblasts and CaP cells. Bone metastases from CaP are associated with osteoblastic differentiation resulting in abnormal bone formation. We show that the autocrine S1P/S1P3 signaling is central during differentiation to mature osteoblasts by regulating Runx2 level, a key transcription factor involved in osteoblastic maturation. Importantly, differentiated osteoblasts exhibited enhanced secretion of S1P and further stimulated CaP cell proliferation in a S1P-dependent manner. By establishing the dual role of osteoblast-borne S1P on both osteoblastic differentiation and CaP cell proliferation and survival, we uncover the importance of S1P in the bone metastatic microenvironment, which may open a novel area of study for the treatment of CaP bone metastasis by targeting S1P.
| S-EPMC5528572 | biostudies-other
Project description:Osteoblast-derived VEGF is important for bone development and postnatal bone homeostasis. Previous studies have demonstrated that VEGF affects bone repair and regeneration; however, the cellular mechanisms by which it works are not fully understood. In this study, we investigated the functions of osteoblast-derived VEGF in healing of a bone defect. The results indicate that osteoblast-derived VEGF plays critical roles at several stages in the repair process. Using transgenic mice with osteoblast-specific deletion of Vegfa, we demonstrated that VEGF promoted macrophage recruitment and angiogenic responses in the inflammation phase, and optimal levels of VEGF were required for coupling of angiogenesis and osteogenesis in areas where repair occurs by intramembranous ossification. VEGF likely functions as a paracrine factor in this process because deletion of Vegfr2 in osteoblastic lineage cells enhanced osteoblastic maturation and mineralization. Furthermore, osteoblast- and hypertrophic chondrocyte-derived VEGF stimulated recruitment of blood vessels and osteoclasts and promoted cartilage resorption at the repair site during the periosteal endochondral ossification stage. Finally, osteoblast-derived VEGF stimulated osteoclast formation in the final remodeling phase of the repair process. These findings provide a basis for clinical strategies to improve bone regeneration and treat defects in bone healing.
| S-EPMC4731163 | biostudies-literature
Project description:Bone metastasis is the major deleterious event in prostate cancer (PCa). TMPRSS2-ERG fusion is one of the most common chromosomic rearrangements in PCa. However, its implication in bone metastasis development is still unclear. Since bone metastasis starts with the tropism of cancer cells to bone through specific migratory and invasive processes involving osteomimetic capabilities, it is crucial to better our understanding of the influence of TMPRSS2-ERG expression in the mechanisms underlying the bone tropism properties of PCa cells. We developed bioluminescent cell lines expressing the TMPRSS2-ERG fusion in order to assess its role in tumor growth and bone metastasis appearance in a mouse model. First, we showed that the TMPRSS2-ERG fusion increases cell migration and subcutaneous tumor size. Second, using intracardiac injection experiments in mice, we showed that the expression of TMPRSS2-ERG fusion increases the number of metastases in bone. Moreover, TMPRSS2-ERG affects the pattern of metastatic spread by increasing the incidence of tumors in hind limbs and spine, which are two of the most frequent sites of human PCa metastases. Finally, transcriptome analysis highlighted a series of genes regulated by the fusion and involved in the metastatic process. Altogether, our work indicates that TMPRSS2-ERG increases bone tropism of PCa cells and metastasis development.
| S-EPMC5355307 | biostudies-literature
Project description:Skeletal involvement in metastatic castrate-resistant prostate cancer (mCRPC) is common and results in significant morbidity and mortality. The interaction of prostate cancer with the bone microenvironment contributes to progression of cancer in the bone leading to skeletal-related events (SREs). Studies aimed at targeting the bone have been carried out over the recent years. Bisphosphonates are synthetic pyrophosphate analogs first investigated for their role in SRE prevention with zoledronic acid as the main bisphosphonate that is approved by the US Food and Drug Administration for retardation of skeletal events in men with metastatic prostate cancer. Denosumab is another bone-targeted agent against uncontrolled osteolysis and serves as a RANK ligand inhibitor, superior to zoledronic acid in delaying SREs. Radiopharmaceuticals have played a role in targeting the bone microenvironment mainly in pain palliation in mCRPC utilizing strontium or samarium in the remote past, but only radium-223 is the first radiopharmaceutical that has yielded improvement in overall survival. The combination and sequencing strategies of these agents is the subject of multiple ongoing trials to guide the best use of these emerging agents.
| S-EPMC4807885 | biostudies-literature
Project description:Clinically, the osteolytic phenotype is rare in prostate cancer (PCa), and the prognosis is generally worse than that of the osteoblastic phenotype. Osteoblastic prostate cancer (BPCa) is a major type of bone metastasis. Several factors responsible for osteogenesis have been identified, but the molecular mechanism of osteoblastic bone metastasis in PCa is not fully understood. Here, we show the osteogenic and tumor-suppressive roles of SERPINA3 and LCN2 in BPCa. In a co-culture of osteoblasts (OBs) and BPCa cells, SERPINA3 and LCN2 were remarkably upregulated in BPCa via OB-derived extracellular vesicles, while they were not in the co-culture of OBs and osteolytic prostate cancer (LPCa) cells. In both the co-culture system and mouse xenograft experiments with intracaudal injection, enhanced expression of SERPINA3 and LCN2 in PCa led to osteogenesis. Additionally, the addition of SERPINA3 and LCN2 to BPCa cells significantly suppressed the proliferative potential. Retrospective analysis also confirmed that high expression levels of SERPINA3 and LCN2 were significantly correlated with a better prognosis. Our results may partially explain how osteoblastic bone metastasis develops and why the prognosis for BPCa is relatively better than that for LPCa.
| S-EPMC10552899 | biostudies-literature
Project description:Basal-like breast cancer (BLBC) is an aggressive subtype of breast cancer which is often enriched with cancer stem cells (CSC), but the underlying molecular basis for this connection remains elusive. We hypothesized that BLBC cells are able to establish a niche permissive to the maintenance of CSCs and found that tumor cell-derived periostin (POSTN), a component of the extracellular matrix, as well as a corresponding cognate receptor, integrin α(v)β(3), are highly expressed in a subset of BLBC cell lines as well as in CSC-enriched populations. Furthermore, we demonstrated that an intact periostin-integrin β3 signaling axis is required for the maintenance of breast CSCs. POSTN activates the ERK signaling pathway and regulates NF-κB-mediated transcription of key cytokines, namely IL6 and IL8, which in turn control downstream activation of STAT3. In summary, these findings suggest that BLBC cells have an innate ability to establish a microenvironmental niche supportive of CSCs.The findings reported here indicate that POSTN produced by CSCs acts to reinforce the stem cell state through the activation of integrin receptors and the production of key cytokines.
| S-EPMC4715959 | biostudies-other
Project description:Medical oncology is moving toward personalized and precision treatments. This evolution is spearheaded by ongoing discoveries on the fundamental machinery that controls tumor and hosts microenvironment biological behavior. α-Particles with their high energy and short range had long been recognized as potentially useful in the treatment of cancer. More than a century after the discovery of radium by the Curies, 223Ra dichloride is now available in the expanding armamentarium of therapies for metastatic castration-resistant prostate cancer. This advance occurs in the context of several other novel therapeutics in advanced prostate cancer that include more effective androgen receptor pathway inhibition, better chemotherapy, and immunotherapy. We present a concise review on the therapeutic use of 223Ra dichloride in this clinically important setting including excerpts on the radium history, physical properties, the alpharadin in symptomatic prostate cancer clinical trial, and practical information on its use in the clinic. It is anticipated that, with the current emergence of 223Ra as a viable form of therapy, interest in and use of α-particle therapy in the management of cancer will grow.
| S-EPMC3874447 | biostudies-literature