Reorganization of the osteocyte lacuno-canalicular network characteristics in tumor sites of an immunocompetent murine model of osteotropic cancers

Hemmatian, Haniyeh; Conrad, Stefanie; Furesi, Giulia; Mletzko, Kathrin; Krug, Johannes; Faila, Antonio Virgilio; Kuhlmann, Jan Dominik; Rauner, Martina; Busse, Björn; Jähn‐Rickert, Katharina

doi:10.1016/j.bone.2021.116074

Cited by 13 publications

(13 citation statements)

References 30 publications

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“…Changes in the volume and shape of osteocytes were identified in previous studies of bone metastasis from breast and prostate and were indicators of osteolysis [13][14][15][16] . However, high resolution microCT characterization of osteocyte lacunae in human bone biopsies of MGUS, SMM and newly diagnosed MM has not yet been performed, nor have changes in morphology of osteocytes been linked to patterns of osteolysis and disease progression.…”

Section: Discussionmentioning

confidence: 88%

“…Also, breast cancer cells induced osteocyte apoptosis and altered osteocyte function 15 . Recently, a study of osteotropic cancers in rodents revealed that the spatial distribution of cortical bone microporosity, osteocyte lacunae volume and the LCN characteristics were influenced by the presence of tumor cells in osteolytic lesions 16 . Taken together, changes in the volume and shape of osteocyte lacunae are an indicator of osteolysis in bone metastasis of osteotropic cancers.…”

Section: Introductionmentioning

confidence: 99%

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3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

Moreno-Jiménez,

Heinig,

Heras

et al. 2023

Preprint

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Osteocytes are bone-embedded cells connected via canaliculi and they regulate the bone resorption/formation balance. Osteocyte function is altered in skeletal disorders including cancer. Multiple myeloma (MM) is a hematological malignancy, whereby plasma cells disrupt the bone homeostasis and induce excessive resorption of the mineralized extracellular matrix (ECM), as evidenced by clinical computed tomography (CT). However, morphometric analyses of the mineralized ECM and bone microporosity are not yet performed in patients with MM, nor in the precursor conditions of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Here, we characterize changes in 3D osteocyte lacunar morphology in bone biopsy samples obtained from patients with MGUS, SMM and newly diagnosed MM, using high resolution microCT. In the small lacunae 20-900 um3 range, we found a trend for lower lacunar density and increasing 50% cutoff of the lacunar volume cumulative distribution for diseased samples. In the larger lacunae 900-3000 um3 range, we found significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group, though the differences were not statistically significant. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae morphology, which could be an indicator for impaired bone quality. Future studies are needed to show whether these are consistent within comparable anatomical sites and could serve as a diagnostic or prognostic marker.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

Moreno-Jiménez,

Heinig,

Heras

et al. 2023

Preprint

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“…Recent studies have shown that osteocytes can directly alter their local bone architecture through peri-lacunocanalicular remodeling, a process highly regulated by TGF- β signaling ( Schurman et al, 2021 ). Disruption of this osteocyte network has been observed as the pre-metastatic niche develops ( Hemmatian et al, 2021 ). We did not observe changes to the network within our histological analysis or any changes to TGF-β signaling, however, we cannot conclusively rule out more subtle alterations.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles

Brown,

Rutland,

Choi

et al. 2024

Front. Cell Dev. Biol.

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Prostate cancer (PCa) is a leading male malignancy worldwide, often progressing to bone metastasis, with limited curative options. Extracellular vesicles (EVs) have emerged as key players in cancer communication and metastasis, promoting the formation of supportive microenvironments in distant sites. Our previous studies have highlighted the role of PCa EVs in modulating osteoblasts and facilitating tumor progression. However, the early pre-metastatic changes induced by PCa EVs within the bone microenvironment remain poorly understood. To investigate the early effects of repeated exposure to PCa EVs in vivo, mimicking EVs being shed from the primary tumor, PCa EVs isolated from cell line PC3MLuc2a were fluorescently labelled and repeatedly administered via tail vein injection to adult CD1 NuNu male mice for a period of 4 weeks. In vivo imagining, histological analysis and gene expression profiling were performed to assess the impact of PCa EVs on the bone microenvironment. We demonstrate for the first time that PCa EVs home to both bone and lymph nodes following repeated exposures. Furthermore, the accumulation of EVs within the bone leads to distinct molecular changes indicative of disrupted bone homeostasis (e.g., changes to signaling pathways such as Paxillin p = 0.0163, Estrogen Receptor p = 0.0271, RHOA p = 0.0287, Ribonucleotide reductase p = 0.0307 and ERK/MAPK p = 0.0299). Changes in key regulators of these pathways were confirmed in vitro on human osteoblasts. In addition, our data compares the known gene signature of osteocytes and demonstrates a high proportion of overlap (52.2%), suggesting a potential role for this cell type in response to PCa EV exposure. No changes in bone histology or immunohistochemistry were detected, indicating that PCa EV mediated changes were induced at the molecular level. This study provides novel insights into the alterations induced by PCa EVs on the bone microenvironment. The observed molecular changes indicate changes in key pathways and suggest a role for osteocytes in these EV mediated early changes to bone. Further research to understand these early events may aid in the development of targeted interventions to disrupt the metastatic cascade in PCa.

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“…The disruption of these patterns and the apoptosis of osteocytes could in return change the 'biophysical sensitivity' of larger bone areas. In addition, the network architecture could get hijacked by cancer cells for long distance signaling to other bone parts, as they have been shown to get in direct contact with osteocytes 28 .…”

Section: Discussionmentioning

confidence: 99%

From breast cancer cell homing to the onset of early bone metastasis: dynamic bone (re)modeling as a driver of metastasis

Young

Heller

Garske

et al. 2023

Preprint

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Breast cancer often metastasizes to bone and causes osteolytic lesions. Dynamic changes in the bone microenvironment are rarely studied but are hypothesized to influence the establishment and progression of bone metastatic lesions. Here, we developed an experimental bone metastasis mouse model to detect and characterize breast cancer cell homing and the onset of early bone metastasis. We studied the dissemination of cancer cells to (intact) bones, their proliferative state and direct microenvironment, using 3D light-sheet fluorescence microscopy (LSFM) and multiscale correlative tissue characterization. We show that cancer cells home in all bone compartments using intact bones, with a preference for small clusters in the bone marrow and larger clusters in the periosteum. We developed an image analysis tool to detect and track early bone osteolytic lesions, quantifying their onset, location and growth. Osteolytic lesions were only detected in the metaphysis and were classified as three different types depending on location. Surprisingly, we observed altered bone (re)modeling with increased new bone formation in animals without detectable osteolytic lesions. Our study suggests an early systemic effect of breast cancer cells in the bone microenvironment and provides novel insights of the structural and biophysical changes during the early phase of metastasis.

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Reorganization of the osteocyte lacuno-canalicular network characteristics in tumor sites of an immunocompetent murine model of osteotropic cancers

Cited by 13 publications

References 30 publications

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles

From breast cancer cell homing to the onset of early bone metastasis: dynamic bone (re)modeling as a driver of metastasis

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