Metastatic Bone Tumors Research Articles

Alleviating role of ketamine in breast cancer cell-induced osteoclastogenesis and tumor bone metastasis-induced bone cancer pain through an SRC/EGR1/CST6 axis

AimsThe analgesic effect of ketamine in cancer pain remains controversial. This research investigates the role of ketamine in bone metastasis-induced cancer pain in breast cancer (BC) and its associated molecular network.MethodsBC cell lines MDA-MB-231 and ZR-75-1 were treated with ketamine and malignant behaviors were assessed through CCK-8, colony formation, and Transwell assays. To evaluate the pro-osteoclastic effect in vitro, BC cells were co-cultured with RAW 264.7 cells. Alterations in the expression of SRC proto-oncogene (SRC), early growth response 1 (EGR1), and cystatin E/M (CST6) were induced in BC cells using lentivirus. MDA-MB-231 cells were injected intracardially into nude mice to examine tumor bone metastasis in vivo. Molecular interactions between SRC and EGR1, as well as between EGR1 and CST6 were analyzed via immunoprecipitation and luciferase assays.ResultsKetamine treatment suppressed viability, proliferation, migration and invasiveness, epithelial-mesenchymal transition, and pro-osteoclastic effect in BC cells. Ketamine also reduced osteoclastogenesis and tumor bone metastasis burden and alleviated pain in nude mice. SRC was identified as a target of ketamine. Overexpression of SRC in BC cells blocked the effects of ketamine. SRC bound to the EGR1 promoter, suppressing EGR1 transcription, whereas EGR1 activated CST6 transcription. Either EGR1 or CST6 overexpression counteracted the function of SRC overexpression and decreased the viability of BC cells and their pro-osteoclastic effect in vitro and in vivo.ConclusionThis study demonstrates that ketamine alleviates BC cell-induced osteoclastogenesis and tumor bone metastasis by suppressing SRC and restoring the EGR1/CST6 axis.

Analysis of the application value of SUV in quantitative SPECT/CT for diagnosing benign and malignant bone lesions.

To analyze the application value of standardized uptake value (SUV) in quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) based on the maximum expectation reconstruction algorithm for diagnosing benign and malignant bone lesions. A retrospective analysis was conducted on the clinical data of 83 patients suspected of bone metastasis who underwent quantitative SPECT/CT bone scans in our hospital from September 2023 to July 2024. A total of 91 high-metabolic bone lesions were outlined for SUV measurement, while the spinal SUV of patients with normal bone metabolism were outlined as the control group (46 vertebral bodies). The maximum SUV (SUVmax), mean SUV (SUVmean), and minimum SUV (SUVmin) of benign lesions (benign group), malignant lesions (malignant group), and the control group were measured and compared. Receiver operating characteristic (ROC) curves were plotted to analyze the diagnostic value of SUV in differentiating benign and malignant bone lesions using quantitative SPECT/CT. Based on the final diagnosis determined by pathology and/or imaging follow-up for 6-12 months or more, 50 malignant bone lesions and 41 benign bone lesions were identified. The levels of SUVmax, SUVmean, and SUVmin in the malignant and benign groups were higher than those in the control group, with the malignant group showing higher levels than the benign group (P<0.05). Receiver operating characteristic curve analysis showed that the areas under the curves for SUVmax, SUVmean, and SUVmin were 0.867, 0.909, and 0.896, respectively. The optimal cut-off value for SUVmax was 26.58g/mL, with a specificity of 100% and a sensitivity of 65.27%; for SUVmean, the optimal cutoff value was 12.75g/mL, with a sensitivity of 78.36% and a specificity of 93.54%; for SUVmin, the optimal cut-off value was 9.13g/mL, with a sensitivity and specificity of 81.42% and 89.87%, respectively. The diagnostic detection rate of quantitative SPECT/CT fusion imaging combined with SUVmean analysis (91.21%) was higher than that of conventional SPECT/CT fusion imaging qualitative analysis (74.73%) (P<0.05). Standardized uptake value in quantitative SPECT/CT to some extent supplements the qualitative analysis of tumor bone metastasis and benign bone lesions, offering a higher accuracy in diagnosing tumor bone metastasis and differentiating between benign and malignant lesions compared to conventional SPECT/CT bone fusion imaging.

Crosstalk between bone metastatic cancer cells and sensory nerves in bone metastatic progression.

Although the role of peripheral nerves in cancer progression has been appreciated, little is known regarding cancer/sensory nerve crosstalk and its contribution to bone metastasis and associated pain. In this study, we revealed that the cancer/sensory nerve crosstalk plays a crucial role in bone metastatic progression. We found that (i) periosteal sensory nerves expressing calcitonin gene-related peptide (CGRP) are enriched in mice with bone metastasis; (ii) cancer patients with bone metastasis have elevated CGRP serum levels; (iii) bone metastatic patient tumor samples express elevated calcitonin receptor-like receptor (CRLR, a CGRP receptor component); (iv) higher CRLR levels in cancer patients are negatively correlated with recurrence-free survival; (v) CGRP induces cancer cell proliferation through the CRLR/p38/HSP27 pathway; and (vi) blocking sensory neuron-derived CGRP reduces cancer cell proliferation in vitro and bone metastatic progression in vivo. This suggests that CGRP-expressing sensory nerves are involved in bone metastatic progression and that the CGRP/CRLR axis may serve as a potential therapeutic target for bone metastasis.

How Arterial Embolization Is Transforming Treatment of Oncologic and Degenerative Musculoskeletal Disease

Background: Arterial embolization is a minimally invasive treatment that occludes blood vessels supplying pathological tissue. Developed to control bleeding without surgery, it has evolved over decades and is now applied in musculoskeletal oncology as a preoperative treatment, palliative care, or standalone therapy for select tumors. Recently, its use has expanded globally in treating chronic pain syndromes and osteoarthritis. Materials and Methods: We reviewed the literature on arterial embolization in various musculoskeletal conditions. The focus was on established oncologic indications for primary and metastatic bone or soft tissue tumors, and emerging evidence on degenerative diseases like osteoarthritis, inflammatory musculoskeletal pathology, and intractable pain. Emphasis was placed on leading studies regarding efficacy, complications, and recurrence rates. Discussion: Arterial embolization has progressed from bleeding control to a versatile therapeutic option in musculoskeletal medicine. It offers symptom relief, reduces tumor size, and improves quality of life. Applications include oncologic interventions and management of degenerative and inflammatory conditions. Despite its benefits, variations in complications and recurrence rates highlight the need for standardized protocols and further research. Conclusions: Arterial embolization is a safe and effective minimally invasive tool in the multidisciplinary management of a wide range of musculoskeletal pathologies. Ongoing research is crucial to understand long-term efficacy, optimize protocols, and broaden its applications.

A water-soluble aggregation-induced emission luminogen for NIR-I/NIR-II fluorescence imaging of breast cancer bone metastases

Advanced breast cancer is prone to bone metastasis, which is the most common bone metastatic tumor. Current clinical methods for diagnosing breast cancer bone metastases rely on serological markers, computed tomography and magnetic resonance imaging. However, these technologies cannot meet patients' needs due to the delayed screening, complex procedures and expensive equipment. Optical imaging currently exhibits inexhaustible and vigorous vitality in the field of diagnosis thanks to its advantages of simplicity, good controllability and high resolution. Nevertheless, the development of prominent chromophores for the diagnosis of breast cancer bone metastases is an appealing yet significantly challenging task. In this contribution, we rationally designed and synthesized three water-soluble aggregation-induced emission (AIE) luminogens, named PEGTPA-BTD, PEGTPA-NTD, and PEGTPA-NSD, by introducing different moieties as electron acceptors and PEGylated triphenylamine derivatives as electron donors and hydrophilic moieties. In vitro experiments showed that PEGTPA-NSD has a longer absorption and emission wavelength, where the emission wavelength can extend into NIR-II region. Besides, PEGTPA-NSD could self-assemble into stable nanoparticles in aqueous solution. Cell experiments showed that PEGTPA-NSD had no obvious dark toxicity to tumor cells or normal cells, and were easily taken in by tumor cells for cell imaging. What's more, PEGTPA-NSD NPs possessed excellent fluorescence imaging performance and biocompatibility in vivo for breast cancer bone metastases in NIR-I and NIR-II region, respectively. In summary, PEGTPA-NSD is the first reported aggregation-induced emission luminogens (AIEgens) that can self-assemble to nanoparticles in aqueous solution for NIR-I/NIR-II fluorescence imaging of breast cancer bone metastases. These findings would provide new strategies for optical diagnostic imaging of breast cancer bone metastases to better advance clinical technology development.

Evidence and Multi-institutional Prospective Observational Study of Radiotherapy for Metastatic Bone Tumor

Evidence and Multi-institutional Prospective Observational Study of Radiotherapy for Metastatic Bone Tumor

Abstract B005: Denosumab Enhances Cytotoxic T Cell Infiltration by supressing SPP1 Expression in Giant Cell Tumour of Bone

Abstract Denosumab, a RANKL inhibitor, is primarily used to prevent osteoclastogenesis for the treatment of conditions like osteoporosis, bone metastasis, and giant cell tumor of bone (GCTB). RANKL is also key in immunity, activating NFκB and its target genes, including the osteopontin-coding gene SPP1, which is linked with CXCL9:SPP1 macrophage polarization and prognosis. Retrospective studies of bone metastasis have demonstrated improved clinical outcomes when immune checkpoint inhibitors (ICIs) are combined with denosumab. We undertook a study to explore denosumab's direct role in anti-tumor immunity. Single-cell RNA sequencing was performed on nine primary human GCTB samples, including three untreated and six treated solely with denosumab, to exclude confounding treatment factors linked with bone metastasis samples. Furthermore, we utilized immunohistochemistry staining from paired pre- and post-denosumab treated samples from a cohort of nine GCTB patients and conducted pan-cancer analysis on primary tumors, spanning 31 distinct types of cancers, sourced from the Genomic Data Commons Data Portal. Our single-cell analysis of GCTB resulted in a comprehensive cell atlas of this rare disease, revealing denosumab's role in inhibiting SPP1 expression and augmenting cytotoxic T cell infiltration. This was confirmed in nine pairs of pre- and post-denosumab treated GCTB samples using immunohistochemistry staining. The pan-cancer analysis indicated a negative correlation between SPP1 expression and CD8A levels across most tumor types, with the CD8A/SPP1 ratio correlating with clinical outcomes in 14 cancer types. Our research provides robust clinical evidence that denosumab improves anti-tumor immunity by inhibiting SPP1 expression, presenting a significant step towards patient selection for combined ICI and denosumab therapy. Citation Format: Zezhuo Su, Maximus Chun Fai Yeung, Jason Pui Yin CHEUNG, Kelvin Sin Chi Cheung. Denosumab Enhances Cytotoxic T Cell Infiltration by supressing SPP1 Expression in Giant Cell Tumour of Bone [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B005.

Efficacy of Surgical Intervention in Treating Pathological Fractures of the Upper Extremity: A Retrospective Case Series.

We conduct a retrospective analysis of patients with pathological fractures resulting from upper extremity malignancies, focusing on the evaluation of treatment strategies employed. We retrospectively studied 10 patients with metastatic bone tumors of the upper extremities. The study variables included tumor site, primary pathology, duration from the first diagnosis of the primary lesion to the occurrence of the pathological fracture, use of bone-modifying drugs, surgical technique, adjuvant therapy, postoperative functional assessment, Katagiri's score, American Society of Anesthesiologists physical status (ASA-PS), outcome, and correlations between the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and Musculoskeletal Tumor Society (MSTS) score. The sites involved were the humerus and radius in eight and two patients, respectively. Primary pathologies were liver cancer in three patients, lung cancer and renal cancer in two patients each, and one patient each with multiple myeloma, plasmacytoma, and Hodgkin's lymphoma. Nine patients experienced pathological fractures, and one had an impending fracture. The median time from primary tumor diagnosis to fracture was 12.5 months. Bone-modifying drugs were administered in all cases. Surgical procedures included intramedullary nails in seven patients and plate fixation in two. Chemotherapy served as adjuvant therapy in nine cases. The mean MSTS score was 26.5, and Katagiri's score averaged 6. The median ASA-PS stood at 2. Outcomes showed seven patients alive with disease and three dead from disease. A significant association between the ECOG-PS and MSTS score was not observed. Pathological fractures caused by malignant bone tumors of the upper extremity should be treated proactively with surgery regardless of prognosis.

Bilateral atypical femur fracture in a patient with breast cancer taking zoledronic acid and denosumab: a case report.

A 54-year-old woman developed stage IV breast cancer 8 years prior. Chemotherapy was administered, and she was started on zoledronic acid treatment for her bone metastases. Her chemotherapy regimen was then switched, owing to disease progression. Fifty-seven months after starting treatment with zoledronic acid, the patient suffered an atypical femoral fracture of her right femur, for which she underwent surgery. Twenty months later, she developed another atypical femoral fracture in her left femur and underwent intramedullary nail fixation. Zoledronic acid and denosumab use in patients with metastatic bone tumors caused by breast cancer should be done cautiously, considering atypical femoral fracture risk.

Deep bone oncology Diagnostics: Computed tomography based Machine learning for detection of bone tumors from breast cancer metastasis

PurposeThe objective of this study is to develop a novel diagnostic tool using deep learning and radiomics to distinguish bone tumors on CT images as metastases from breast cancer. By providing a more accurate and reliable method for identifying metastatic bone tumors, this approach aims to significantly improve clinical decision-making and patient management in the context of breast cancer. MethodsThis study utilized CT images of bone tumors from 178 patients, including 78 cases of breast cancer bone metastases and 100 cases of non-breast cancer bone metastases. The dataset was processed using the Medical Image Segmentation via Self-distilling TransUNet (MISSU) model for automated segmentation. Radiomics features were extracted from the segmented tumor regions using the Pyradiomics library, capturing various aspects of tumor phenotype. Feature selection was conducted using LASSO regression to identify the most predictive features. The model’s performance was evaluated using ten-fold cross-validation, with metrics including accuracy, sensitivity, specificity, and the Dice similarity coefficient. ResultsThe developed radiomics model using the SVM algorithm achieved high discriminatory power, with an AUC of 0.936 on the training set and 0.953 on the test set. The model’s performance metrics demonstrated strong accuracy, sensitivity, and specificity. Specifically, the accuracy was 0.864 for the training set and 0.853 for the test set. Sensitivity values were 0.838 and 0.789 for the training and test sets, respectively, while specificity values were 0.896 and 0.933 for the training and test sets, respectively. These results indicate that the SVM model effectively distinguishes between bone metastases originating from breast cancer and other origins. Additionally, the average Dice similarity coefficient for the automated segmentation was 0.915, demonstrating a high level of agreement with manual segmentations. ConclusionThis study demonstrates the potential of combining CT-based radiomics and deep learning for the accurate detection of bone metastases from breast cancer. The high-performance metrics indicate that this approach can significantly enhance diagnostic accuracy, aiding in early detection and improving patient outcomes. Future research should focus on validating these findings on larger datasets, integrating the model into clinical workflows, and exploring its use in personalized treatment planning.

Nonviral genetic manipulation system with microenvironmental cascade sensitivity for the treatment of TNBC-associated metastatic bone tumor

Gene therapy is an efficacious therapeutic modality for triple negative breast cancer (TNBC). However, the practicable applicability is strictly confined in TNBC-associated metastatic bone tumor due to the low blood flow and poor accumulation in bone tissue, as well as the vicious cycle of mutual promotion between tumor growth and bone erosion. To address those problems, a versatile nonviral genetic manipulation system PSMCA/miR-34a, with caveolae-activated endocytosis and microenvironmental cascade-responsive release profile was exploited. In vitro and in vivo experiments confirmed that PSMCA/miR-34a not only possessed bone-targeting properties to accumulate at bone tumor tissue, also could respond to the bone tumor microacidic environment to release alendronate to inhibit the bone erosion. After internalized into cells mainly through caveolae-mediated endocytosis, it was spurred to disassemble for controlling release the miR-34a by high intracellular GSH environment, generating an effective anti-tumor effect. Moreover, due to the synergistic effect, PSMCA/miR-34a could breakdown the vicious cycle between bone destruction and tumor growth in the tumor microenvironment, showing high potential in the clinical gene therapy for TNBC-associated metastatic bone tumor.

Cryoablation in Chronic Pain Management: A Narrative Review

Abstract Cryoneurolysis is a technique of applying extreme cold temperatures to specific sensory nerves, causing a prolonged period of loss of conduction through that nerve. This technique has found widespread application in the field of interventional pain medicine in a variety of conditions including chronic postsurgical pain, phantom limb pain (PLP), and cancer pain. Its use in chronic pain states has been aided further by the advent of handheld cryoneurolysis devices and the widespread use of ultrasonographic imaging to guide and target nerves accurately. Chronic pain states – chronic knee pain from osteoarthritis, refractory PLP, temporomandibular disorders, cervicogenic headaches, low back pain, different peripheral neuropathies, and metastatic bone tumor pain – are some of the conditions where cryoneurolysis has been proven to benefit patients in cases where the symptoms were refractory to other conventionally used modalities. Chronic pain is a complex and multifaceted condition and hence requires a variety of individualized treatment approaches. Current research on this treatment method for chronic pain indicates that it carries low risk and, when used correctly, offers extended pain relief without causing motor function loss. This narrative review includes all types of scientific studies, published between 2010 and 2023, which were selected using a specific set of keywords through two different literature search engines. In conclusion, it explains how cryoneurolysis works to provide long-term pain relief and summarizes the latest evidence supporting its use in chronic pain management.

Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review).

The incidence of prostate cancer (PCa) is increasing, making it one of the prevalent malignancies among men. Metastasis of PCa to the bones poses the greatest danger to patients, potentially resulting in treatment ineffectiveness and mortality. At present, the management of patients with bone metastasis focuses primarily on providing palliative care. Research has indicated that the spread of PCa to the bones occurs through the participation of numerous molecules and their respective pathways. Gaining knowledge regarding the molecular processes involved in bone metastasis may result in the development of innovative and well‑tolerated therapies, ultimately enhancing the quality of life and prognosis of patients. The present article provides the latest overview of the molecular mechanisms involved in the formation of bone metastatic tumors from PCa. Additionally, the clinical outcomes of targeted drug therapies for bone metastasis are thoroughly analyzed. Finally, the benefits and difficulties of targeted therapy for bone metastasis of PCa are discussed, aiming to offer fresh perspectives for treatment.

Indications and Long-Term Outcomes of Intercalary Reconstruction Techniques for Diaphyseal Bone Tumors

Objective: Intercalary reconstruction after resection of diaphyseal bone tumors allows for adjacent-joint preservation; however, despite implant advancements they continue to experience high failure rates. Free fibular autograft (FFA), allograft interposition, and metallic endoprostheses are used, but there is no consensus on optimal construct. Methods: We conducted an IRB-approved retrospective review of patients who underwent intercalary reconstruction for oncologic indications at a single institution (1999 to 2022). Inclusion criteria included intercalary reconstruction with FFA, allograft, or endoprosthesis for oncologic indications and with minimum follow-up of 3 months. Primary outcome was implant survival. Secondary outcomes included complication type, rate, and timing, resection length, distance from articular surface, and failure modes. Results: Thirty-five patients met inclusion criteria, 23 men and 12 women. Reconstructive options included: FFA (N=8), endoprosthesis (N=16), and allograft (N=11). Average follow-up was 3.9 years. Average patient age was 41.8 years; FFA patients were younger than endoprosthesis patients (P=0.0002). FFAs were closer to the articular surface than endoprostheses (P=0.0003). Overall implant survival was 36.6% at 21 years; median survival was 2.04 years. Overall complication rate was 65.7%, with no difference between groups. Ten patients (28.5%) ultimately ended with a joint-sacrificing operation. Conclusions: This study supports the existing literature’s reported high rate of complication and implant failure of intercalary reconstructions. Salvage options are available, including those for secondary joint-sparing operations; however, they often result in a joint-sacrificing endoprosthesis limiting function and longevity. With patients having improved life expectancy for both metastatic and primary bone tumors, implant optimization is critical.

Augmented Reality Navigation System (SIRIO) for Neuroprotection in Vertebral Tumoral Ablation.

(1) This study evaluates the impact of the CT-guided SIRIO augmented reality navigation system on the procedural efficacy and clinical outcomes of neuroprotection in vertebral thermal ablation (RTA) for primary and metastatic bone tumors. (2) Methods: A retrospective non-randomized analysis of 28 vertebral RTA procedures was conducted, comparing 12 SIRIO-assisted and 16 non-SIRIO-assisted procedures. The primary outcomes included dose-length product (DLP) and epidural dissection time. The secondary outcomes included technical success, complication rates, and pain scores at procedural time (VAS Time 0) and three months post-procedure (VAS Time 1). The statistical analyses included t-tests, Mann-Whitney U tests, and multiple regression. (3) Results: SIRIO-assisted procedures significantly reduced DLP (307.42 mGycm vs. 460.31 mGycm, p = 2.23 × 10-8) and procedural epidural dissection time (13.48 min vs. 32.26 min, p = 2.61 × 10-12) compared to non-SIRIO-assisted procedures. Multiple regression confirmed these reductions were significant (DLP: β = -162.38, p < 0.001; time: β = -18.25, p < 0.001). Pain scores (VAS Time 1) did not differ significantly between groups, and tumor type did not significantly influence outcomes. (4) Conclusions: The SIRIO system enhances neuroprotection efficacy and safety, reducing radiation dose and procedural time during spine tumoral ablation while maintaining consistent pain management outcomes.

Multi-institutional prospective observational study of radiotherapy for metastatic bone tumor.

Purpose of this study is to evaluate patient characteristics, treatments and outcomes in bone metastasis radiotherapy practice. Patients for whom radiotherapy for bone metastasis was planned at 26 institutions in Japan between December 2020 and March 2021 were consecutively registered in this prospective, observational study. Study measures included patient characteristics, pain relief, skeletal-related events (SREs), overall survival and incidence of radiation-related adverse events. Pain was evaluated using a numerical rating scale (NRS) from 0 to 10. Irradiated dose was analyzed by the biologically effective dose (BED) assuming α/β = 10. Overall, 232 patients were registered; 224 patients and 302 lesions were fully analyzed. Eastern Cooperative Oncology Group Performance Status was 0/1/2/3/4 in 23%/38%/22%/13%/4%; 59% of patients had spinal metastases and 84% had painful lesions (NRS ≥ 2). BED was <20Gy (in 27%), 20-30Gy (24%), 30-40Gy (36%) and ≥ 40Gy (13%); 9% of patients were treated by stereotactic body radiotherapy. Grade 3 adverse events occurred in 4% and no grade 4-5 toxicity was reported. Pain relief was achieved in 52% at 2months. BED is not related to pain relief. The cumulative incidence of SREs was 6.5% (95% confidence interval (CI) 3.1-9.9) at 6months; no factors were significantly associated with SREs. With spinal lesions, 18% of patients were not ambulatory at baseline and 50% of evaluable patients in this group could walk at 2months. The 6-month overall survival rate was 70.2% (95% CI 64.2-76.9%). In conclusion, we report real-world details of radiotherapy in bone metastasis.

Tumor-derived exosomal ICAM1 promotes bone metastasis of triple-negative breast cancer by inducing CD8+ T cell exhaustion

Exosomes, which are nanosized extracellular vesicles, have emerged as crucial mediators of the crosstalk between tumor cells and the immune system. Intercellular adhesion molecule 1 (ICAM1) plays a crucial role in multiple immune functions as well as in the occurrence, development and metastasis of cancer. As a glycoprotein expressed on the cell membrane, ICAM1 is secreted extracellularly on exosomes and regulates the immunosuppressive microenvironment. However, the role of exosomal ICAM1 in the immune microenvironment of breast cancer bone metastases remains unclear. This study aimed to elucidated the role of exosomal ICAM1 in facilitating CD8+ T cell exhaustion and subsequent bone metastasis in triple-negative breast cancer (TNBC). We demonstrated that TNBC cells release ICAM1-enriched exosomes, and the binding of ICAM1 to its receptor is necessary for the suppressive effect of CD8 T cell proliferation and function. This pivotal engagement not only inhibits CD8+ T cell proliferation and activation but also initiates the development of an immunosuppressive microenvironment that is conducive to TNBC tumor growth and bone metastasis. Moreover, ICAM1 blockade significantly impairs the ability of tumor exosomes to bind to CD8+ T cells, thereby inhibiting their immunosuppressive effects. The present study elucidates the complex interaction between primary tumors and the immune system that is mediated by exosomes and provides a foundation for the development of novel cancer immunotherapies that target ICAM1 with the aim of mitigating TNBC bone metastasis.

The long-chain polyfluorinated alkyl substance perfluorohexane sulfonate (PFHxS) promotes bone marrow adipogenesis

Per- and polyfluoroalkyl substances (PFAS) bioaccumulate in different organ systems, including bone. While existing research highlights the adverse impact of PFAS on bone density, a critical gap remains in understanding the specific effects on the bone marrow microenvironment, especially the bone marrow adipose tissue (BMAT). Changes in BMAT have been linked to various health consequences, such as the development of osteoporosis and the progression of metastatic tumors in bone. Studies presented herein demonstrate that exposure to a mixture of five environmentally relevant PFAS compounds promotes marrow adipogenesis in vitro and in vivo. We show that among the components of the mixture, PFHxS, an alternative to PFOS, has the highest propensity to accumulate in bone and effectively promote marrow adipogenesis. Utilizing RNAseq approaches, we identified the peroxisome proliferator-activated receptor (PPAR) signaling as a top pathway modulated by PFHxS exposure. Furthermore, we provide results suggesting the activation and involvement of PPAR-gamma (PPARγ) in PFHxS-mediated bone marrow adipogenesis, especially in combination with high-fat diet. In conclusion, our findings demonstrate the potential impact of elevated PFHxS levels, particularly in occupational settings, on bone health, and specifically bone marrow adiposity. This study contributes new insights into the health risks of PFHxS exposure, urging further research on the relationship between environmental factors, diet, and adipose tissue dynamics.

A targeted and core-shell structured gambogic acid nanomedicine for ameliorating breast cancer-associated osteolysis

The treatment of breast cancer-associated bone tumors is of critical importance and highly challenging, primarily owing to the malignant interplay between tumor proliferation and osteolysis within the bone tumor microenvironment. Although many efforts have been devoted, it is still urgent and desirable to find a robust therapeutic agent that can simultaneously and efficiently inhibit the proliferation of bone tumor and osteoclast differentiation. In this work, we have fabricated a bone-targeting nanoplatform based on bioinspired polydopamine-coated gambogic acid nanoparticles (GA@PDA NPs) integrated with mild temperature photothermal therapy (PTT) and chemotherapy towards the treatment of bone tumors. In particular, GA not only inhibits osteoclast differentiation and proliferation of bone tumor cells, but also downregulates heat shock protein 90 (Hsp90) in the treated tumor cells to sensitize the PTT effect, and the resulting core-shell structured nanomedicine could allow the spatiotemporal control of chemotherapy and mild temperature PTT. Those bioinspired nanomedicine could exhibit excellent tumor suppression and osteolysis inhibition against a xenograft tumor bone metastasis model, and this novel nanoformulation provides a creative paradigm for the treatment of breast cancer-associated osteolysis.

Pharmacologic Hedgehog inhibition modulates the cytokine profile of osteolytic breast cancer cells

The establishment and progression of bone metastatic breast cancer is supported by immunosuppressive myeloid populations that enable tumor growth by dampening the innate and adaptive immune response. Much work remains to understand how to target these tumor-myeloid interactions to improve treatment outcomes. Noncanonical Hedgehog signaling is an essential component of bone metastatic tumor progression, and prior literature suggests a potential role for Hedgehog signaling and its downstream effector Gli2 in modulating immune responses. In this work, we sought to identify if inhibition of noncanonical Hedgehog signaling alters the cytokine profile of osteolytic breast cancer cells and the subsequent communication between the tumor cells and myeloid cells. Examination of large patient databases revealed significant relationships between Gli2 expression and expression of markers of myeloid maturation and activation as well as cytokine expression. We found that treatment with HPI-1 reduced tumor cell expression of numerous cytokine genes, including CSF1, CSF2, and CSF3, as well as CCL2 and IL6. Secreted CSF-1 (M−CSF) was also reduced by treatment. Changes in tumor-secreted factors resulted in polarization of THP-1 monocytes toward a proinflammatory phenotype, characterized by increased CD14 and CD40 surface marker expression. We therefore propose M−CSF as a novel target of Hedgehog inhibition with potential future applications in altering the immune microenvironment in addition to its known roles in reducing tumor-induced bone disease.