Breast Cancer Bone Metastasis Research Articles

Molecular mechanism of bone metastasis in breast cancer

Bone metastasis is a debilitating complication that frequently occurs in the advanced stages of breast cancer. However, the underlying molecular and cellular mechanisms of the bone metastasis remain unclear. Here, we elucidate how bone metastasis arises from tumor cells that detach from the primary lesions and infiltrate into the surrounding tissue, as well as how these cells disseminate to distant sites. Specifically, we elaborate how tumor cells preferentially grow within the bone micro-environment and interact with bone cells to facilitate bone destruction, characterized as osteoclastic bone metastasis, as well as new bone matrix deposition, characterized as osteoblastic bone metastasis. We also updated the current understanding of the molecular mechanisms underlying bone metastasis and reasons for relapse in breast cancer, and also opportunities of developing novel diagnostic approaches and treatment.

Harnessing curcumin and nanotechnology for enhanced treatment of breast cancer bone metastasis.

Breast cancer (BC) bone metastasis poses a significant clinical challenge due to its impact on patient prognosis and quality of life. Curcumin (CUR), a natural polyphenol compound found in turmeric, has shown potential in cancer therapy due to its anti-inflammatory, antioxidant, and anticancer properties. However, its metabolic instability and hydrophobicity have hindered its clinical applications, leading to a short plasma half-life, poor absorption, and low bioavailability. To enhance the drug-like properties of CUR, nanotechnology-based delivery strategies have been employed, utilizing polymeric, lipidic, and inorganic nanoparticles (NPs). These approaches have effectively overcome CUR's inherent limitations by enhancing its stability and cellular bioavailability both in vitro and in vivo. Moreover, targeting molecules with high selectivity towards bone metastasized breast cancer cells can be used for site specific delivery of curcumin. Alendronate (ALN), a bone-seeking bisphosphonate, is one such moiety with high selectivity towards bone and thus can be effectively used for targeted delivery of curcumin loaded nanocarriers. This review will detail the process of bone metastasis in BC, elucidate the mechanism of action of CUR, and assess the efficacy of nanotechnology-based strategies for CUR delivery. Specifically, it will focus on how these strategies enhance CUR's stability and improve targeted delivery approaches in the treatment of BC bone metastasis.

Bone mineral density affects tumor growth by shaping microenvironmental heterogeneity

Breast cancer bone metastasis is a major cause of mortality in patients with advanced breast cancer. Although decreased mineral density is a known risk factor for bone metastasis, the underlying mechanisms remain poorly understood because studying the isolated effect of bone mineral density on tumor heterogeneity is challenging with conventional approaches. Moreover, mineralized biomaterials are commonly utilized for clinical bone defect repair, but how mineralized biomaterials affect the foreign body response and wound healing is unclear. Here, we investigate how bone mineral affects tumor growth and microenvironmental complexity in vivo by combining single-cell RNA-sequencing with mineral-containing or mineral-free decellularized bone matrices. We discover that the absence of bone mineral significantly influences fibroblast and immune cell heterogeneity, promoting phenotypes that increase tumor growth and alter the response to injury or disease. Importantly, we observe that the stromal response to bone mineral content depends on the murine tumor model used. While lack of bone mineral induces tumor-promoting microenvironments in both immunocompromised and immunocompetent animals, these changes are mediated by altered fibroblast phenotype in immunocompromised mice and macrophage polarization in immunocompetent mice. Collectively, our findings suggest that bone mineral density affects tumor growth by impacting microenvironmental complexity in an organism-dependent manner.

Identification Of Risk Factors Of Bone Metastasis Among Iraqi Breast Cancer Women

Background: The most common site of metastases in people with breast cancer is bone metastasis. Patients with advanced phases of cancer are associated with an increased prevalence of several types of metastases, one of which is bone metastasis. Object: Assessment of the risk factors for bone metastases in patients with breast cancer. Patients and Methods: This is a retrospective study of 316 patients with breast cancer who either had bone metastases at the time of diagnosis or developed it later on. The study was carried out between January 2013 and April 2018. Three hundred and sixteen patients were assigned into two groups. In the case group, 100 patients with breast cancer had been diagnosed with bone metastasis by CT, MRI, bone scan, and PET scan; in the control group, there were 216 cases in are control group with breast cancer metastasis to sites other than bone. The questionnaire was created to record all factors (with the exception of demographic information), such as age, histopathological reading for invasive lobular carcinoma, invasive ductal carcinoma, or another type of cancer, ER status, PR status, Her2neu status, lymph node status and stage, and menopausal status. Results: The majority were 45 years of age or younger, and 96.5% of them had invasive ductal carcinoma in terms of hormonal status. Positive ER and PR status is found in 67.7% and 67.1% of the cases, respectively; 40.5% of the cases had amplified Her2neu receptors, 78.5% of the cases had positive lymph nodes, and 41.9% of the cases had (N1) stage. The highest proportion of bone metastasis was associated with negative ER and PR receptors (46.2% and 49%, respectively), while no significant statistical association (P= 0.65). Conclusion: negative ER, PR status, and Her2neu receptors not amplified, lymph node involvement, age 45 and less, infiltrating lobular carcinoma (ILC) histological type, and menopausal state are significant risk factors for bone metastasis in breast cancer.

Sea buckthorn and its flavonoids isorhamnetin, quercetin, and kaempferol favorably influence bone and breast tissue health.

Bone tissue and breast tissue are interrelated, as demonstrated by breast microcalcifications, breast cancer bone metastases, bone morphogenetic proteins, and Wnt signaling. In addition, osteoblasts and osteoclasts represent an important switch of tumor cell dormancy during bone metastasis. Damage to both types of tissues mentioned above is highly prevalent, especially in postmenopausal women, and manifests itself in osteoporosis and breast cancer. Sea buckthorn (Elaeagnus rhamnoides L.), a botanical drug with high antioxidant, antitumor, anti-inflammatory, immunomodulatory, and regenerative properties, has great therapeutic potential due to the unique composition of its bioactive metabolites. This review aimed to summarize the current knowledge from in vitro and in vivo studies on the effect of sea buckthorn, as well as its most widespread flavonoids isorhamnetin, quercetin, and kaempferol, on bone and breast tissue health. In vitro studies have revealed the beneficial impacts of sea buckthorn and aforementioned flavonoids on both bone health (bone remodeling, mineralization, and oxidative stress) and breast tissue health (cancer cell proliferation, apoptosis, tumor growth, and metastatic behavior). In vivo studies have documented their protective effects against disturbed bone microarchitecture and reduced bone strength in animal models of osteoporosis, as well as against tumor expansion and metastatic properties in animal xenograft models. In any case, further research and clinical trials are needed to carefully evaluate the potential therapeutic benefits of sea buckthorn and its flavonoids. Based on the available information, however, it can be concluded that these bioactive metabolites favorably affect both bone and breast tissue health.

Breast Cancer Bone Metastasis Therapy and Tumor‐Associated Bone Destruction Repair by Versatile Semiconducting Nanointegrators with X‐Ray Adjuvant

AbstractTumor progress and tumor‐associated osteolysis are two key issues of breast cancer bone metastasis, which makes it challenging for bone metastasis treatment. To settle these two issues concurrently, a versatile semiconducting nanointegrator (termed as SPNCpG/Ca) containing semiconducting polymer nanoparticle (SPN), Ca2+ and cytosine‐phosphate‐guanine (CpG) oligonucleotides conjugated on the surface via a singlet oxygen (1O2)‐responsive linker, is designed. The antitumor effect can be triggered with X‐ray irradiation as an adjuvant, in which SPN works as a radiosensitizer to produce 1O2 for radiotherapy and controlled release of CpG via disrupting 1O2‐responsive linkers. The Ca2+ accumulation via SPNCpG/Ca delivering causes tumor cell death and the released CpG activates immune response to realize immunotherapy. The combinational action of radiotherapy, Ca2+ overloading, and immunotherapy results in complete clearance of metastatic tumor cells in 4T1 breast cancer‐based bone metastasis mouse models. Furthermore, Ca2+ can accelerate osteogenesis of bone marrow mesenchymal stem cells while CpG inhibits osteoclast differentiation in the bone metastasis microenvironment to alleviate osteolysis, which synergistically contributes to repair of tumor‐associated bone destruction. SPNCpG/Ca represents a versatile therapeutic nanosystem with the abilities to treat bone metastasis and repair tumor‐associated bone destruction, providing a new tactic for bone metastasis therapy.

Mechanobiological cues to bone cells during early metastasis drive later osteolysis: a computational mechanoregulation framework prediction

Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation, but also by resorbing bone matrix (osteolysis) that releases further stimulatory factors for tumour growth in a vicious cycle. Changes in the local mechanical environment of bone tissue occur during early metastasis, which might activate mechanobiological responses by resident bone cells (osteocytes) to activate resorption (osteoclasts) and thereby contribute to tumour invasion. The objective of this study is to investigate whether bone osteolysis is driven by early changes in the bone mechanical environment during metastasis by (a) implementing subject-specific FE models of metastatic femora to predict the mechanical environment within bone tissue during early metastasis (3-weeks after tumour inoculation) and then (b) applying mechanoregulation theory to predict bone tissue remodelling as a function of the evolving mechanical environment within bone tissue during breast cancer-bone metastasis. We implemented a global resorption rate derived from an experimental model, but the mechanoregulation algorithm predicted localised bone loss in the greater trochanter region, the same region where osteolysis was prevalent after three weeks of metastasis development in the animal model. Moreover, the mechanical environment evolved in a similar manner to that reported in separate subject-specific finite element models of these same animals by 6 weeks. Thus, we propose that early changes in the physical environment of bone tissue during metastasis may elicit mechanobiological cues for bone cells and activate later osteolytic bone destruction.

Single-cell Transcriptomic Analysis Identifies Senescent Osteocytes that Trigger Bone Destruction in Breast Cancer Metastasis.

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression, which disrupts the balance between osteoclasts and osteoblasts and leads to bone lesions. A deeper understanding of the processes mediating this reprogramming could help develop interventions for treating patients with bone metastases. Here, we demonstrated that osteocytes in established breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified osteocytes from mice with breast cancer bone metastasis enriched in senescence, SASP markers, and pro-osteoclastogenic genes. Multiplex in situ hybridization and AI-assisted analysis depicted osteocytes with senescence-associated satellite distension, telomere dysfunction, and p16Ink4a expression in mice and patients with breast cancer bone metastasis. Breast cancer cells promoted osteocyte senescence and enhanced their osteoclastogenic potential in in vitro and ex vivo organ cultures. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that osteocytes undergo pathological reprogramming by breast cancer cells and identify osteocyte senescence as an initiating event triggering lytic bone disease in breast cancer metastases.

Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment

Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.

Diagnostic performance of 18F‑FDG PET/CT vs. 18F‑NaF PET/CT in breast cancer with bone metastases: An indirect comparative meta‑analysis.

Breast cancer remains the leading cause of cancer-related death in women, with 5-year survival rates of as high as 90% for patients with early-stage breast cancer without metastasis, falling to 10% once bone metastases (BM) occur. Currently, there is no cure for breast cancer with BM. However, appropriate treatment can extend survival and improve patients' quality of life. Therefore, it is important to accurately evaluate the presence of BM in patients with breast cancer. The present meta-analysis evaluated the diagnostic performance of 18F-FDG and 18F-NaF as PET/CT tracers for breast cancer-associated BM. The present study aimed to compare the diagnostic performance of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomographs (PET/CT) and 18F-sodium fluoride (18F-NaF) PET/CT in patients with breast cancer and BM. The PubMed and Embase databases were searched for English literature on the diagnostic performance of 18F-FDG PET/CT and 18F-NaF PET/CT for breast cancer BM, and two authors independently extracted data. All included studies presented data that could be used to construct a 2×2 contingency table. The methodological quality of the selected studies was assessed using QUADAS-2, and forest plots were generated based on the sensitivity and specificity of 18F-FDG PET/CT and 18F-NaF PET/CT in the diagnosis of BM associated with breast cancer. A total of 14 articles were identified, including eight on the analysis of 18F-FDG PET/CT, five on 18F-NaF PET/CT and one on both. The studies on 18F-FDG PET/CT and 18F-NaF PET/CT included 530 and 270 patients, respectively. The pooled sensitivities were 0.88 [95% confidence interval (95% CI), 0.76-0.94] for 18F-FDG PET/CT and 0.98 (95% CI, 0.92-1.00) for 18F-NaF PET/CT, and the pooled specificities were 0.99 (95% CI, 0.97-1.00) and 0.91 (95% CI: 0.76-0.97), respectively. The area under the summary receiver operating characteristic curve for both 18F-FDG PET/CT and 18F-NaF PET/CT was 0.99 (95% CI, 0.98-1.00). Lesion-based analysis using 18F-FDG PET/CT was performed for 909 lesions, with a sensitivity of 0.84 (95% CI, 0.67-1.00) and specificity of 1.00 (95% CI, 0.98-1.00). Compared with 18F-FDG PET/CT, 18F-NaF PET/CT showed higher sensitivity (98 vs. 88%) but lower specificity (91 vs. 99%), although the difference between methods was not statistically significant. In conclusion, the results of the present study indicated that 18F-NaF PET/CT and 18F-FDG PET/CT are both accurate methods for the detection of BM in patients with breast cancer, and have comparable diagnostic accuracy.

To investigate the role and potential mechanism of has_circ_RBMS3 in bone metastasis of breast cancer based on bioinformatics.

Circular RNAs (circRNAs) play a crucial regulatory role in malignant tumor metastasis. This study focused on the role of bone metastasis-related circRBMS3 in breast cancer. Two circRNA microarray datasets were obtained from the GEO database and overlapped bone metastasis-related circRNAs in breast cancer. CircRBMS3 expression was validated in bone metastasis tissues by RT-qPCR. Cellular CCK-8 assay and Transwell assays were performed to measure the effect of circRBMS3 in breast cancer cells. Bioinformatic analyses were performed to identify the binding miRNAs of circRBMS3 and downstream mRNAs. Online database STRING and Cytoscape software were used to analyze PPI interaction and conduct the ceRNA network. GEO database analysis showed that circRBMS3 was one of the upregulated circRNAs among all the metastatic cells. CircRBMS3 was increased in bone metastasis breast cancer tissues compared to non-bone metastasis tissues and associated with poor 3-year overall survival. CircRBMS3 knockdown repressed breast cancer cell proliferation, migration, and invasion, as well as bone resorption gene and osteoclast phenotype gene expression. CircRBMS3 was found to bind withmiR-654-3p. Subsequently, downstream mRNAs were predicted, and the circRBMS3 miR-654-3p-mRNA network was established. In conclusion, circRBMS3 expression was upregulated in bone metastasis breast cancer and might be a potential prognostic marker for patients. Silencing circRBMS3 restrained breast cancer cell proliferation, migration, and invasion, as well as associated with bone metastasis. The circRBMS3-miR-654-3p-mRNAs network elucidated potential mechanisms underlying bone metastasis in breast cancer.

Preoperative platelet distribution width predicts bone metastasis in patients with breast cancer

PurposeBone metastases occur in 50-70% of patients with breast cancer (BC) and result in high mortality. Platelet distribution width (PDW), a commonly used parameter of activated platelets, has been associated with a poor prognosis in BC. We aim to investigate the prognostic role of PDW for bone metastasis in BC patients.Methods515 patients who received BC surgery in the Harbin Medical University Cancer Hospital from July 1, 2016, to December 31, 2017, were reviewed. Patients’ characteristics and platelet indices upon enrollment in this study were collected. The Kaplan-Meier method was used to estimate the 5-year bone metastasis incidence. The univariate and multivariate Cox regression analyses were utilized to identify risk factors associated with bone metastasis.ResultsThe patients with bone metastases exhibited lower PDW levels than the patients without bone metastases. Moreover, decreased PDW was significantly correlated with histologic type, multifocal disease, and lymph node status. In addition, the patients with reduced PDW levels were more likely to develop bone metastasis. Multivariate analysis showed that PDW was an independent predictor for bone metastasis.ConclusionPDW is an independent predictor of bone metastasis in BC. Further research is warranted.

The dual roles of lymphotoxin-β in promoting breast cancer bone metastasis.

The dual roles of lymphotoxin-β in promoting breast cancer bone metastasis.

Lymphotoxin-β promotes breast cancer bone metastasis colonization and osteolytic outgrowth.

Bone metastasis is a lethal consequence of breast cancer. Here we used single-cell transcriptomics to investigate the molecular mechanisms underlying bone metastasis colonization-the rate-limiting step in the metastatic cascade. We identified that lymphotoxin-β (LTβ) is highly expressed in tumour cells within the bone microenvironment and this expression is associated with poor bone metastasis-free survival. LTβ promotes tumour cell colonization and outgrowth in multiple breast cancer models. Mechanistically, tumour-derived LTβ activates osteoblasts through nuclear factor-κB2 signalling to secrete CCL2/5, which facilitates tumour cell adhesion to osteoblasts and accelerates osteoclastogenesis, leading to bone metastasis progression. Blocking LTβ signalling with a decoy receptor significantly suppressed bone metastasis in vivo, whereas clinical sample analysis revealed significantly higher LTβ expression in bone metastases than in primary tumours. Our findings highlight LTβ as a bone niche-induced factor that promotes tumour cell colonization and osteolytic outgrowth and underscore its potential as a therapeutic target for patients with bone metastatic disease.

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.

Phosphate Ion-Responsive and Calcium Peroxide-Based Nanomedicine for Bone-Targeted Treatment of Breast Cancer Bone Metastasis.

The treatment of breast cancer bone metastasis is an unresolved clinical challenge, mostly because currently therapeutic approaches cannot simultaneously block the tumor growth and repair the osteolytic bone injuries at the metastatic site. Herein, the study develops a novel nanomedicine to treat breast cancer bone metastasis. The nanomedicine is based on phosphate ion-responsive and calcium peroxide-based nanoparticles carrying the bone-targeting agent zoledronic acid on the surface and loaded with the photosensitizer indocyanine green. Following intravenous administration to a mouse model of breast cancer bone metastasis, the nanoparticles efficiently accumulate at the bone metastasis site, react with free phosphate ions, and form hydroxyapatite nanoaggregates and O2, while releasing the photosensitizer. Hydroxyapatite nanoaggregates elicit the remineralization of the collagenous bone matrix and trigger tumor cell apoptosis. Upon irradiating tumor-bearing legs with an 808nm laser source, the O2 and free photosensitizer produced 1O2 by the reaction of the nanoparticles with phosphate ions, further boosting the anti-tumor effect. Tumor killing hampers the vicious cycle at the site of bone metastasis, translating to osteolysis blockade and further encouraging the remineralization of bone matrix. This work sheds light on the development of a novel, safe, and efficient approach for the treatment of breast cancer bone metastasis.

Development and validation of an artificial intelligence model for predicting de novo distant bone metastasis in breast cancer: a dual-center study

ObjectiveBreast cancer has become the most prevalent malignant tumor in women, and the occurrence of distant metastasis signifies a poor prognosis. Utilizing predictive models to forecast distant metastasis in breast cancer presents a novel approach. This study aims to utilize readily available clinical data and advanced machine learning algorithms to establish an accurate clinical prediction model. The overall objective is to provide effective decision support for clinicians.MethodsData from 239 patients from two centers were analyzed, focusing on clinical blood biomarkers (tumor markers, liver and kidney function, lipid profile, cardiovascular markers). Spearman correlation and the least absolute shrinkage and selection operator regression were employed for feature dimension reduction. A predictive model was built using LightGBM and validated in training, testing, and external validation cohorts. Feature importance correlation analysis was conducted on the clinical model and the comprehensive model, followed by univariate and multivariate regression analysis of these features.ResultsThrough internal and external validation, we constructed a LightGBM model to predict de novo bone metastasis in newly diagnosed breast cancer patients. The area under the receiver operating characteristic curve values of this model in the training, internal validation test, and external validation test1 cohorts were 0.945, 0.892, and 0.908, respectively. Our validation results indicate that the model exhibits high sensitivity, specificity, and accuracy, making it the most accurate model for predicting bone metastasis in breast cancer patients. Carcinoembryonic Antigen, creatine kinase, albumin-globulin ratio, Apolipoprotein B, and Cancer Antigen 153 (CA153) play crucial roles in the model’s predictions. Lipoprotein a, CA153, gamma-glutamyl transferase, α-Hydroxybutyrate dehydrogenase, alkaline phosphatase, and creatine kinase are positively correlated with breast cancer bone metastasis, while white blood cell ratio and total cholesterol are negatively correlated.ConclusionThis study successfully utilized clinical blood biomarkers to construct an artificial intelligence model for predicting distant metastasis in breast cancer, demonstrating high accuracy. This suggests potential clinical utility in predicting and identifying distant metastasis in breast cancer. These findings underscore the potential prospect of developing economically efficient and readily accessible predictive tools in clinical oncology.

Prospective comparison of 68Ga-DOTA-ibandronate and bone scans for detecting bone metastases in breast cancer.

68Ga labeled DOTA-Ibandronate (68Ga-DOTA-IBA) positron emission tomography/computed tomography (PET/CT), is a novel bone-targeting imaging tracer and promising diagnostic method for bone metastases detection. Therefore, this study aimed to compare 68Ga-DOTA-IBA PET/CT to the 99mTc-MDP whole-body bone scan (WBBS) for detecting bone metastases in breast cancer (BC). In this prospective study, 45 women with BC underwent imaging via 68Ga-DOTA-IBA PET/CT and 99mTc-MDP WBBS. Clinical and demographic information as well as BC imaging features were recorded. The two methods were compared in terms of their detection rate for bone metastases and the number of lesions. The 45 women were aged 53.5 ± 11.0 years. The bone metastases detection rate with 68Ga-DOTA-IBA PET/CT was 100% (45/45) and with 99mTc-MDP WBBS was 95.6% (43/45). A total of 546 bone metastases lesions were detected. The lesion detection rate using 68Ga-DOTA-IBA PET/CT was 100% (546/546) and using 99mTc-MDP WBBS was 67.8% (370/546). More lesions were found at each site via 68Ga-DOTA-IBA than via 99mTc-MDP WBBS. 68Ga-DOTA-IBA PET/CT is a more sensitive method than 99mTc-MDP WBBS for assessing bone metastases in BC and may therefore represent a useful imaging technique for bone metastases, while offering a visual basis for 177Lu-DOTA-IBA diagnosis and therapy response assessments for BC. Further validation using a broader study cohort is warranted to confirm these findings. https://www.chictr.org.cn/showproj.html?proj=170163, identifier ChiCTR2200064487.

Unraveling the metastatic niche in breast cancer bone metastasis through single-cell RNA sequencing.

Breast cancer (BRCA) is characterized by a unique metastatic pattern, often presenting with bone metastasis (BoM), posing significant clinical challenges. Through the study of the immune microenvironment in BRCA BoM offer perspectives for therapeutic interventions targeting this specific metastatic manifestation of BRCA. This study employs single-cell RNA sequencing and TCGA data analysis to comprehensively compare primary tumors (PT), lymph node metastasis (LN), and BoM. Our investigation identifies a metastatic niche in BoM marked by an increased abundance of cancer-associated fibroblasts (CAFs) and reduced immune cell presence. A distinct subtype (State 1) of BRCA BoM cells associated with adverse prognosis is identified. State 1, displaying heightened stemness traits, may represent an initiation phase for BoM in BRCA. Complex cell communications involving tumor, stromal, and immune cells are revealed. Interactions of FN1, SPP1, and MDK correlate with elevated immune cells in BoM. CD46, MDK, and PTN interactions drive myofibroblast activation and proliferation, contributing to tissue remodeling. Additionally, MDK, PTN, and FN1 interactions influence FAP+ CAF activation, impacting cell adhesion and migration in BoM. These insights deepen our understanding of the metastatic niche in breast cancer BoM.

Bone mineral density affects tumor growth by shaping microenvironmental heterogeneity.

Breast cancer bone metastasis is the leading cause of mortality in patients with advanced breast cancer. Although decreased mineral density is a known risk factor for bone metastasis, the underlying mechanisms remain poorly understood because studying the isolated effect of bone mineral density on tumor heterogeneity is challenging with conventional approaches. Here, we investigate how bone mineral content affects tumor growth and microenvironmental complexity in vivo by combining single-cell RNA-sequencing with mineral-containing or mineral-free decellularized bone matrices. We discover that the absence of bone mineral significantly influences fibroblast and immune cell heterogeneity, promoting phenotypes that increase tumor growth and alter the response to injury or disease. Importantly, we observe that the stromal response to matrix mineral content depends on host immunocompetence and the murine tumor model used. Collectively, our findings suggest that bone mineral density affects tumor growth by altering microenvironmental complexity in an organism-dependent manner.