Bone marrow niches in the regulation of bone metastasis

The bone marrow hosts skeletal progenitor cells which have most widely been referred to as Mesenchymal Stem or Stromal Cells (MSCs), a heterogeneous population of adult stem cells possessing the potential for self-renewal and multilineage differentiation. A consensus agreement on minimal criteria has been suggested to define MSCs in vitro, including adhesion to plastic, expression of typical surface markers and the ability to differentiate towards the adipogenic, osteogenic and chondrogenic lineages but they are critically discussed since the differentiation capability of cells could not always be confirmed by stringent assays in vivo. However, these in vitro characteristics have led to the notion that progenitor cell populations, similar to MSCs in bone marrow, reside in various tissues. MSCs are in the focus of numerous (pre)clinical studies on tissue regeneration and repair.Recent advances in terms of genetic animal models enabled a couple of studies targeting skeletal progenitor cells in vivo. Accordingly, different skeletal progenitor cell populations could be identified by the expression of surface markers including nestin and leptin receptor. While there are still issues with the identity of, and the overlap between different cell populations, these studies suggested that specific microenvironments, referred to as niches, host and maintain skeletal progenitor cells in the bone marrow. Dynamic mutual interactions through biological and physical cues between niche constituting cells and niche inhabitants control dormancy, symmetric and asymmetric cell division and lineage commitment. Niche constituting cells, inhabitant cells and their extracellular matrix are subject to influences of aging and disease e.g. via cellular modulators. Protective niches can be hijacked and abused by metastasizing tumor cells, and may even be adapted via mutual education. Here, we summarize the current knowledge on bone marrow skeletal progenitor cell niches in physiology and pathophysiology. We discuss the plasticity and dynamics of bone marrow niches as well as future perspectives of targeting niches for therapeutic strategies.

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Long non‐coding RNA NORAD promotes the prostate cancer cell extracellular vesicle release via microRNA-541-3p-regulated PKM2 to induce bone metastasis of prostate cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01891-0 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Chuan-yi Hu ◽

Juan Chen ◽

Xin-hua Qin ◽

Pan You ◽

Jie Ma ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Bone Metastasis ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Downstream Target ◽

Non Coding Rna ◽

Target Molecules ◽

Long Non Coding Rna

Abstract Background Bone metastasis is the leading cause of mortality and reduced quality of life in patients with metastatic prostate cancer (PCa). Long non-coding RNA activated by DNA damage (NORAD) has been observed to have an abnormal expression in various cancers. This article aimed to explore the molecular mechanism underlying the regulatory role of NORAD in bone metastasis of PCa. Methods NORAD expression in clinical PCa tissues and cell lines was detected with the application of qRT-PCR. Cancer cells were then transfected with plasmids expressing NORAD, after which Transwell assay and CCK-8 assay were carried out to detect proliferation, migration, and bone metastasis of PCa. NORAD downstream target molecules were screened through bioinformatics analysis, followed by further verification using dual luciferase assay. Extracellular vesicles (EVs) were labeled with PKH67 and interacted with bone marrow stromal cells. The gain- and loss-function method was applied to determine the internalization and secretion of PCa cells-derived EVs under the intervention of downstream target molecules or NORAD. Results PCa tissues and cell lines were observed to have a high expression of NORAD, particularly in tissues with bone metastasis. NORAD knockdown resulted in reduced secretion and internalization of EVs, and suppressed proliferation, migration, and bone metastasis of PCa cells. It was indicated that NORAD interacted with miR-541-3p, leading to the upregulation of PKM2. Forced expression of PKM2 promoted the transfer of PKH67-labeled EVs to bone marrow stromal cells. Conclusions NORAD might serve as a ceRNA of miR-541-3p to promote PKM2 expression, thereby enhancing the development of bone metastasis in PCa by promoting internalization and transfer of EVs of cancer cells, providing an insight into a novel treatment for the disorder.

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Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Oncogene ◽

10.1038/s41388-020-01603-6 ◽

2021 ◽

Author(s):

Francesco Pantano ◽

Martine Croset ◽

Keltouma Driouch ◽

Natalia Bednarz-Knoll ◽

Michele Iuliani ◽

...

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Bone Metastasis ◽

Tumor Cell ◽

Cancer Patients ◽

Breast Cancer Patients ◽

Osteolytic Lesions ◽

Cell Colonization

AbstractBone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

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Combining Intravital Fluorescent Microscopy (IVFM) with Genetic Models to Study Engraftment Dynamics of Hematopoietic Cells to Bone Marrow Niches

Journal of Visualized Experiments ◽

10.3791/54253 ◽

2017 ◽

Author(s):

Lin Wang ◽

Malgorzata M. Kamocka ◽

Amy Zollman ◽

Nadia Carlesso

Keyword(s):

Bone Marrow ◽

Fluorescent Microscopy ◽

Hematopoietic Cells ◽

Genetic Models ◽

Bone Marrow Niches ◽

Intravital Fluorescent Microscopy

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Mouse Basophils Reside in Extracellular Matrix-Enriched Bone Marrow Niches Which Control Their Motility

PLoS ONE ◽

10.1371/journal.pone.0070292 ◽

2013 ◽

Vol 8 (9) ◽

pp. e70292 ◽

Cited By ~ 2

Author(s):

Salete Smaniotto ◽

Elke Schneider ◽

Nicolas Goudin ◽

Rachel Bricard-Rignault ◽

François Machavoine ◽

...

Keyword(s):

Bone Marrow ◽

Extracellular Matrix ◽

Bone Marrow Niches

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The Roles of Bone Marrow-Resident Cells as a Microenvironment for Bone Metastasis

Advances in Experimental Medicine and Biology - Tumor Microenvironments in Organs ◽

10.1007/978-3-030-36214-0_5 ◽

2020 ◽

pp. 57-72 ◽

Cited By ~ 1

Author(s):

Yusuke Shiozawa

Keyword(s):

Bone Marrow ◽

Bone Metastasis

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B cells suppress medullary granulopoiesis by an extracellular glycosylation-dependent mechanism

eLife ◽

10.7554/elife.47328 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Eric E Irons ◽

Melissa M Lee-Sundlov ◽

Yuqi Zhu ◽

Sriram Neelamegham ◽

Karin M Hoffmeister ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

B Cells ◽

Progenitor Cell ◽

Hematopoietic Progenitors ◽

Myeloma Cells ◽

Human B Cells ◽

Extrinsic Cues ◽

Bone Marrow Niches ◽

Dependent Mechanism

The immune response relies on the integration of cell-intrinsic processes with cell-extrinsic cues. During infection, B cells vacate the marrow during emergency granulopoiesis but return upon restoration of homeostasis. Here we report a novel glycosylation-mediated crosstalk between marrow B cells and hematopoietic progenitors. Human B cells secrete active ST6GAL1 sialyltransferase that remodels progenitor cell surface glycans to suppress granulopoiesis. In mouse models, ST6GAL1 from B cells alters the sialylation profile of bone marrow populations, and mature IgD+ B cells were enriched in sialylated bone marrow niches. In clinical multiple myeloma, ST6GAL1 abundance in the multiple myeloma cells negatively correlated with neutrophil abundance. These observations highlight not only the ability of medullary B cells to influence blood cell production, but also the disruption to normal granulopoiesis by excessive ST6GAL1 in malignancy.

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