Mesenchymal Stem Cells-Derived Small Extracellular Vesicles and Their Validation as a Promising Treatment for Chondrosarcoma in a 3D Model in Vitro.

Chondrosarcomas (CHS) constitute approximately 20% of all primary malignant bone tumors, characterized by a slow growth rate with initial manifestation of few signs and symptoms. These malignant cartilaginous neoplasms, particularly those with dedifferentiated histological subtypes, pose significant therapeutic challenges, as they exhibit high resistance to both radiation and chemotherapy. Ranging from relatively benign, low-grade tumors (grade I) to aggressive high-grade tumors with the potential for lung metastases and a grim prognosis, there is a critical need for innovative diagnostic and therapeutic approaches, particularly for patients with more aggressive forms.

Bone on-a-chip: a 3D dendritic network in a screening platform for osteocyte-targeted drugs.

Age-related musculoskeletal disorders, including osteoporosis, are frequent and associated with long lasting morbidity, in turn significantly impacting on healthcare system sustainability. There is therefore a compelling need to develop reliable preclinical models of disease and drug screening to validate novel drugs possibly on a personalized basis, without the need ofassay. In the context of bone tissue, although the osteocyte (Oc) network is a well-recognized therapeutic target, currentpreclinical models are unable to mimic its physiologically relevant and highly complex structure.

Behavioral Voluntary and Social Bioassays Enabling Identification of Complex and Sex-Dependent Pain-(-Related) Phenotypes in Rats with Bone Cancer.

Cancer-induced bone pain (CIBP) is a common and devastating symptom with limited treatment options in patients, significantly affecting their quality of life. The use of rodent models is the most common approach to uncovering the mechanisms underlying CIBP; however, the translation of results to the clinic may be hindered because the assessment of pain-related behavior is often based exclusively on reflexive-based methods, which are only partially indicative of relevant pain in patients. To improve the accuracy and strength of the preclinical, experimental model of CIBP in rodents, we used a battery of multimodal behavioral tests that were also aimed at identifying rodent-specific behavioral components by using a home-cage monitoring assay (HCM).

The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma.

Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases.

3D Printing and Bioprinting to Model Bone Cancer: The Role of Materials and Nanoscale Cues in Directing Cell Behavior.

Bone cancer, both primary and metastatic, is characterized by a low survival rate. Currently, available models lack in mimicking the complexity of bone, of cancer, and of their microenvironment, leading to poor predictivity. Three-dimensional technologies can help address this need, by developing predictive models that can recapitulate the conditions for cancer development and progression.

Acid Microenvironment in Bone Sarcomas.

In bone sarcomas, extracellular proton accumulation is an intrinsic driver of malignancy. Extracellular acidosis increases stemness, invasion, angiogenesis, metastasis, and resistance to therapy of cancer cells. It reprograms tumour-associated stroma into a protumour phenotype through the release of inflammatory cytokines.

Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis.

Bone metastasis (BM) is a dismal complication of cancer that frequently occurs in patients with advanced carcinomas and that often manifests as an osteolytic lesion. In bone, tumor cells promote an imbalance in bone remodeling via the release of growth factors that, directly or indirectly, stimulate osteoclast resorption activity. However, carcinoma cells are also characterized by an altered metabolism responsible for a decrease of extracellular pH, which, in turn, directly intensifies osteoclast bone erosion.

Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma.

In the tumor microenvironment, mesenchymal stromal cells (MSCs) are key modulators of cancer cell behavior in response to several stimuli. Intratumoral acidosis is a metabolic trait of fast-growing tumors that can induce a pro-tumorigenic phenotype in MSCs through the activation of the NF-κB-mediated inflammatory pathway, driving tumor clonogenicity, invasion, and chemoresistance. Recent studies have indicated that curcumin, a natural ingredient extracted from , acts as an NF-κB inhibitor with anti-inflammatory properties.

Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target.

Acidity is a key player in cancer progression, modelling a microenvironment that prevents immune surveillance and enhances invasiveness, survival, and drug resistance. Here, we demonstrated in spheroids from osteosarcoma cell lines that the exposure to acidosis remarkably caused intracellular lipid droplets accumulation. Lipid accumulation was also detected in sarcoma tissues in close proximity to tumor area that express the acid-related biomarker LAMP2.

Unravelling the Effect of Citrate on the Features and Biocompatibility of Magnesium Phosphate-Based Bone Cements.

In the framework of new materials for orthopedic applications, Magnesium Phosphate-based Cements (MPCs) are currently the focus of active research in biomedicine, given their promising features; in this field, the loading of MPCs with active molecules to be released in the proximity of newly forming bone could represent an innovative approach to enhance the in vivo performances of the biomaterial. In this work, we describe the preparation and characterization of MPCs containing citrate, an ion naturally present in bone which presents beneficial effects when released in the proximity of newly forming bone tissue. The cements were characterized in terms of handling properties, setting time, mechanical properties, crystallinity, and microstructure, so as to unravel the effect of citrate concentration on the features of the material.

Sarcoma treatment in the era of molecular medicine.

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling.

Pre-clinical Models for Studying the Interaction Between Mesenchymal Stromal Cells and Cancer Cells and the Induction of Stemness.

Mesenchymal stromal cells (MSC) have essential functions in building and supporting the tumour microenvironment, providing metastatic niches, and maintaining cancer hallmarks, and it is increasingly evident that the study of the role of MSC in cancer is crucial for paving the way to clinical opportunities for novel anti-cancer therapies. To date, the vast majority of preclinical models that have been used for studying the effect of reactive MSC on cancer growth, metastasis, and response to therapy has been mainly based on flat biology, including the co-culturing with cell compartmentalization or with cell-to-cell contact, and on cancer models with different routes of MSC inoculation. More complex 3D models based on spheroid structures that are formed by intermingled MSC and tumour cells are also capturing the interest in cancer research.

Effect of calcium phosphate heparinization on the in vitro inflammatory response and osteoclastogenesis of human blood precursor cells.

The immobilization of natural molecules on synthetic bone grafts stands as a strategy to enhance their biological interactions. During the early stages of healing, immune cells and osteoclasts (OC) modulate the inflammatory response and resorb the biomaterial, respectively. In this study, heparin, a naturally occurring molecule in the bone extracellular matrix, was covalently immobilized on biomimetic calcium-deficient hydroxyapatite (CDHA).

Cause and effect of microenvironmental acidosis on bone metastases.

Skeletal involvement is a frequent and troublesome complication in advanced cancers. In the process of tumor cells homing to the skeleton to form bone metastases (BM), different mechanisms allow tumor cells to interact with cells of the bone microenvironment and seed in the bone tissue. Among these, tumor acidosis has been directly associated with tumor invasion and aggressiveness in several types of cancer although it has been less explored in the context of BM.

Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma.

Cancer-induced bone pain (CIBP) is common in patients with bone metastases (BM), significantly impairing quality of life. The current treatments for CIBP are limited since they are often ineffective. Local acidosis derived from glycolytic carcinoma and tumor-induced osteolysis is only barely explored cause of pain.

MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: A new rationale for the pathogenesis of osteolytic bone metastases.

Recent progress in dissecting the molecular paracrine circuits of cancer and stromal cells in bone metastases (BM) are offering new options to improve current merely palliative approach. The study of tumor-stroma metabolic interplay may further ameliorate this scenario. In this context, we demonstrated that highly glycolytic MDA-MB-231 cancer cells, that form osteolytic BM in vivo, release a large amount of lactate at a significantly higher level than MCF7 cells.

Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss.

The extracellular acidic milieu in bones results in activation of osteoclasts (OC) and inhibition of osteoblasts (OB) causing a net loss of calcium from the skeleton and the deterioration of bone microarchitecture. Alkalinization through supplementation with potassium citrate (K citrate) has been proposed to limit the osteopenia progression, even though its pharmacological activity in bone microenvironment is not well defined. We evaluated if K citrate was able to prevent the adverse effects that acidic milieu induces on bone cells.

Focus Ion Beam/Scanning Electron Microscopy Characterization of Osteoclastic Resorption of Calcium Phosphate Substrates.

This article presents the application of dual focused ion beam/scanning electron microscopy (FIB-SEM) imaging for preclinical testing of calcium phosphates with osteoclast precursor cells and how this high-resolution imaging technique is able to reveal microstructural changes at a level of detail previously not possible. Calcium phosphate substrates, having similar compositions but different microstructures, were produced using low- and high-temperature processes (biomimetic calcium-deficient hydroxyapatite [CDHA] and stoichiometric sintered hydroxyapatite, respectively). Human osteoclast precursor cells were cultured for 21 days before evaluating their resorptive potential on varying microstructural features.

Osteoclast differentiation from human blood precursors on biomimetic calcium-phosphate substrates.

Unlabelled: The design of synthetic bone grafts to foster bone formation is a challenge in regenerative medicine. Understanding the interaction of bone substitutes with osteoclasts is essential, since osteoclasts not only drive a timely resorption of the biomaterial, but also trigger osteoblast activity. In this study, the adhesion and differentiation of human blood-derived osteoclast precursors (OCP) on two different micro-nanostructured biomimetic hydroxyapatite materials consisting in coarse (HA-C) and fine HA (HA-F) crystals, in comparison with sintered stoichiometric HA (sin-HA, reference material), were investigated.

Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation.

The role of mesenchymal stem cells (MSC) in osteosarcoma (OS), the most common primary tumor of bone, has not been extensively elucidated. We have recently shown that OS is characterized by interstitial acidosis, a microenvironmental condition that is similar to a wound setting, in which mesenchymal reactive cells are activated to release mitogenic and chemotactic factors. We therefore intended to test the hypothesis that, in OS, acid-activated MSC influence tumor cell behavior.

Energy metabolism in osteoclast formation and activity.

Osteoclastogenesis and osteolysis are energy-consuming processes supported by high metabolic activities. In human osteoclasts derived from the fusion of monocytic precursors, we found a substantial increase in the number of mitochondria with differentiation. In mature osteoclasts, mitochondria were also increased in size, rich of cristae and arranged in a complex tubular network.

Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment.

Objective: Hypoxia-inducible factor 1, a regulator of CA IX activity, is often overexpressed in human osteosarcoma (OS) but not in normal tissues, and its expression levels correlate with prognosis. In this study, we investigated the therapeutic potential of newly synthesized CA IX sulfonamide inhibitors in OS.

Methods: CA IX expression was evaluated in OS cell lines and bone marrow stromal cells (BMSC).