Search Results (126)

Background: Bone marrow mesenchymal stem cells (BM-MSCs) are significant in chemo- and radiotherapy resistance. Previous research has focused on BM-MSCs, demonstrating their functional involvement in cancer progression as mediators in the tumor microenvironment. They play multiple roles in tumorigenesis, angiogenesis, and metastasis. BM-MSC-derived exosomes (BM-MSCs-exo) are small vesicles, typically 50–300 nm in diameter, isolated from BM-MSCs. Some studies have demonstrated the tumor-suppressive effects of BM-MSCs-exo. Objective: This study aimed to investigate their role in modulating the impact of chemoradiotherapy (CRT) in different types of cervical cancer spheroid cells. Methods: The spheroids after treatment were subject to size measurement, cell viability, and caspase activity. Then, the molecular mechanism was elucidated by Western blot analysis. Results: We observed a reduction in spheroid size and an increase in cell death in HeLa spheroids, while no significant changes in size or cell viability were found in SiHa spheroids. At the molecular level, CRT treatment combined with BM-MSCs-exo in HeLa spheroids induced apoptosis through the activation of the NF-κB pathway, specifically via the NF-κB1 (P50) transcription factor, leading to the upregulation of apoptosis-related molecules. In contrast, CRT combined with BM-MSCs-exo in SiHa spheroids exhibited an opposing effect: although cellular viability decreased, caspase activity also decreased, which correlated with increased HSP27 expression and the subsequent downregulation of apoptotic molecules. Conclusion: Our study provides deeper insight into the potential of BM-MSCs-exo in cervical cancer treatment, supporting the development of more effective and safer therapeutic strategies for clinical application. Full article

Background/objectives: Despite advancements in early diagnosis and clinical practices guided by standardized care protocols, Merkel cell carcinoma (MCC) is marked by an unfavorable prognosis with a 5-year relative survival rate of 65%, based primarily on data collected prior to the introduction of immunotherapy. Regional nodal metastases affect 40–50% of MCC patients, while approximately 33% experience distant dissemination. Among these, bone and bone marrow metastases are particularly notable, although the characteristics and clinical implications of this metastatic disease in MCC remain poorly understood. Methods: A comprehensive review was conducted using the Medline database (via PubMed) up to January 2025. The search strategy included the string “(Merkel cell carcinoma AND (bone OR marrow))”. Results: A total of 1133 (69.3% male and 30.7% female) patients diagnosed with advanced MCC were collected. The median (IQR) age at diagnosis was 67.5 (12.65) years old. Overall, 201 (20.8%) cases of bone and/or bone marrow metastases were identified and linked to a primary known MCC in 75.7% of cases. Bone metastases (BMs) appear as the third most common metastatic site, following the liver (second) and lymph nodes (first). They show mixed biological and radiological behavior, with a marked preference for the axial skeleton over the appendicular one. Addressing the characteristics of metastatic bone disease, neurological symptoms were the most documented, whereas bone marrow involvement and leukemic spread seemed to be primarily related to immunosuppression. Multimodal treatment strategies, including platinum-based chemotherapy and radiotherapy, were the primary approaches adopted, reflecting therapeutic practices from the pre-immunotherapy era. Conclusions: The pattern of metastatic spread in MCC differs among studies, with the bones resulting as the third most common site of distant spread. Excluding head and neck MCC, which seems to be more regularly associated with liver metastases, the relationship between the primary tumor site and the development of bone or bone marrow metastases appears inconsistent. Overall, BMs mostly correlated with advanced MCC stages and poorer survival outcomes, with a median overall survival (OS) of 8 months (range 12.75–4). The integration of international guidelines, evolving evidence from clinical trials, and the expanding role of immune checkpoint inhibitors (ICIs) will contribute to improving systemic disease control and enhance patient care. Full article

Background: Bone marrow (BM)-derived myeloid–lymphatic endothelial cell progenitors (M-LECPs) promote formation of tumor lymphatics that are responsible for metastasis to lymph nodes. The regenerative capacity of BM progenitors to other lineages is mediated through cell fusion, a process that delivers a pro-mitotic message directly to division-restricted cells. This suggested that M-LECPs might use a similar mechanism to induce division of lymphatic endothelial cells (LECs). Methods: To test this hypothesis, we determined expression of fusogenic markers in M-LECP produced in vitro and recruited to human or mouse tumors in vivo as well as quantified their fusion with LECs in both settings. Fusion in vivo was determined in female chimera mice grafted with male BM that have been implanted with MDA-MB-231 or EMT6 breast tumors. Co-staining for Y-chromosome and LEC-specific markers allowed us to quantify tumor lymphatic vessels fused with BM progenitors. Results: We found that both tumor-recruited and in-vitro-produced M-LECPs expressed multiple fusogenic regulators and possessed a significant fusogenic activity towards cultured and vessel-lining LECs. Y-chromosomes, a marker of fusion, were detected in nearly half of tumor lymphatics and were associated with mitotic division, vessel formation, and node metastasis. Both in vitro and in vivo assays showed dependency of fusion on Th2 and Toll-like receptor-4 (TLR4) pathways. Conclusions: This novel mechanism of tumor lymphatic formation triggered by fusion with BM myeloid–lymphatic progenitors suggests a variety of new targets for inhibition of metastatic spread. Full article

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity and microenvironmental adaptation of prostate cancer bone metastases using single-cell transcriptomics. Methods: We integrated the largest single-cell transcriptome dataset to date, encompassing 124 samples from primary prostate tumors, various bone metastatic sites, and non-malignant tissues (e.g., benign prostatic hyperplasia, normal bone marrow). After quality control, 602,497 high-quality single-cell transcriptomes were analyzed. We employed unsupervised clustering, gene expression profiling, mutation analysis, and metabolic pathway reconstruction to characterize cancer cell subtypes and tumor microenvironmental remodeling. Results: Cancer epithelial cells dominated the tumor microenvironment but exhibited pronounced heterogeneity, posing challenges for conventional clustering methods. By integrating genetic and metabolic features, we revealed key evolutionary trajectories of epithelial cancer cells during metastasis. Notably, we identified a novel epithelial subpopulation, NEndoCs, characterized by unique differentiation patterns and distinct spatial distribution across metastatic niches. We also observed significant metabolic reprogramming and recurrent mutations linked to prostate-to-bone microenvironmental transitions. Conclusions: This study comprehensively elucidates the mutation patterns, metabolic reprogramming, and microenvironment adaptation mechanisms of bone metastasis in prostate cancer, providing key molecular targets and clinical strategies for the precise treatment of bone metastatic prostate cancer. Full article

Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that promote proliferation, invasion, and metastasis. The CXCR4/CXCL12 signaling pathway is gaining attention as a promising target for cancer therapy. CXCR4, a chemokine receptor, is often overexpressed in various types of cancer, including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas. When it binds to its endogenous ligand, CXCL12, it promotes cell survival, proliferation, and migration, crucial mechanisms for the retention of hematopoietic stem cells in the bone marrow and the movement of lymphocytes. The extensive expression of CXCR4 in cancer, coupled with the constant presence of CXCL12 in various organs, drives the activation of this axis, which in turn facilitates angiogenesis, tumor progression, and metastasis. Given the detrimental role of the CXCR4/CXCL12 axis, the search for drugs acting selectively against this protein represents an open challenge. This review aims to summarize the recent advancements in the design and development of CXCR4 antagonists as potential anticancer agents. Full article

Sympathetic nerves innervate bone marrow and various immune organs, where norepinephrine—the primary sympathetic neurotransmitter—directly interacts with immune cells that express adrenergic receptors. This article reviewed the key molecular pathways triggered by sympathetic activation and explored how sympathetic activity influences immune cell migration. Norepinephrine serves as a chemoattractant for monocytes, macrophages, and stem cells, promoting the migration of myeloid cells while inhibiting the migration of lymphocytes at physiological concentrations. We also examined the role of immune cell infiltration in cardiovascular diseases and cancer. Evidence suggests that sympathetic activation increases myeloid cell infiltration into target tissues across various cardiovascular diseases, including atherosclerosis, hypertension, cardiac fibrosis, cardiac hypertrophy, arrhythmia, myocardial infarction, heart failure, and stroke. Conversely, inhibiting sympathetic activity may serve as a potential therapeutic strategy to treat these conditions by reducing macrophage infiltration. Furthermore, sympathetic activation promotes macrophage accumulation in cancer tissues, mirroring its effects in cardiovascular diseases, while suppressing T lymphocyte infiltration into cancerous sites. These changes contribute to increased cancer growth and metastasis. Thus, inhibiting sympathetic activation could help to protect against cancer by enhancing T cell infiltration and reducing macrophage presence in tumors. Full article

Objective: This study aimed to evaluate the outcomes and predictive factors of I-125 radioactive plaque therapy for recurrent and refractory retinoblastoma (Rb) cases that failed primary systemic chemotherapy and focal therapies. Methods: A retrospective study of 20 eyes with intraocular Rb treated with I-125 radioactive plaque therapy (Apex dose 45 Gy) from 2013 to 2023 was conducted. Data on tumor characteristics, treatments, and outcomes were collected over a follow-up period of at least one year. Results: There were 11 (55%) males and 8 (40%) patients who had bilateral disease. All 20 treated eyes (100%) showed initial tumor regression, while long-term tumor control and eye salvage were achieved in 14 eyes (70%). Six eyes (30%) experienced uncontrollable tumor recurrence after a mean of 6 months (range: 3–12 months) after plaque therapy. Recurrence included main tumor activity in six eyes and additional resistant vitreous seeds in two of them. Poor predictive factors for eye salvage included Group D at diagnosis (p = 0.044), active vitreous seeds at the time of plaque therapy ((p = 0.045), tumor thickness >5.0 mm (p = 0.045), and tumor base dimension >12 mm (p = 0.023). Post-plaque complications included cataracts in seven eyes (35%), tumor hemorrhage in six eyes (30%), retinal detachment in four eyes (20%), radiation retinopathy in three eyes (15%), and neovascular glaucoma in one eye (5%). Five (83%) of those with tumor hemorrhage had plaque surgery performed within less than 6 months of the last cycle of systemic chemotherapy. At a mean follow-up of 36 months (range: 12–96 months), five eyes (25%) were enucleated, and high-risk pathological features were identified in three eyes, including post-laminar optic nerve infiltration (one eye) and massive choroidal invasion (two eyes). All patients were alive and free of metastasis except one patient (5%) whose parents refused enucleation and came back with extra-scleral extension and bone marrow metastasis and eventually passed away. Conclusions: I-125 radioactive plaque therapy is a valuable salvage treatment for recurrent and refractory retinoblastoma, achieving tumor control and eye salvage in 70% of cases with an acceptable safety profile. However, the observed recurrence rate (30%) at an apex dose of 45 Gy suggests a need for dose optimization and individualized treatment strategies. Identifying high-risk features, such as Group D disease, active vitreous seeds, and larger tumors, is crucial for patient selection and outcome prediction. Future research should explore alternative dosing strategies, combination therapies, and improved predictive models to enhance long-term tumor control while minimizing complications. Full article

Sialic acids serve as crucial terminal sugars on glycoproteins or glycolipids present on cell surfaces. These sugars are involved in diverse physiological and pathological processes through their interactions with carbohydrate-binding proteins, facilitating cell–cell communication and influencing the outcomes of bacterial and viral infections. The role of hypersialylation in tumor growth and metastasis has been widely studied. Recent research has highlighted the significance of aberrant sialylation in enabling tumor cells to escape immune surveillance and sustain their malignant behavior. Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy that primarily affects children and is the second leading cause of mortality among individuals aged 1 to 14. ALL is characterized by the uncontrolled proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and various organs. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are cell surface proteins that can bind to sialic acids. Activation of Siglecs triggers downstream reactions, including induction of cell apoptosis. Siglec-7 and Siglec-9 have been reported to promote cancer progression by driving macrophage polarization, and their expressions on natural killer cells can inhibit tumor cell death. This comprehensive review aims to explore the sialylation mechanisms and their effects on ALL in children. Understanding the complex interplay between sialylation and ALL holds great potential for developing novel diagnostic tools and therapeutic interventions in managing this pediatric malignancy. Full article

Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells, with extramedullary myeloma (EMM) being an aggressive form involving malignant infiltration beyond the bone marrow. Copper metabolism is essential for tumor proliferation and metastasis, with copper metabolism MURR1 domain (COMMD) proteins regulating these processes and maintaining copper homeostasis. Dysregulated copper homeostasis contributes to cancer progression, including MM, with elevated copper levels linked to disease aggressiveness and poor prognosis. This study investigates the role of the COMMD3 in mediating MM cell progression, particularly its influence on copper metabolism. Methods: Comprehensive bioinformatics analyses were conducted on bone marrow and extramedullary samples to determine the expression of COMMD3, which was validated through in vitro and in vivo functional assays. The MM cell lines RPMI8226 and MM1S underwent lentiviral transfection for COMMD3 overexpression and knockdown. RNA sequencing was conducted on COMMD3 knockdown cells to identify differentially expressed genes. Functional assays measured cell proliferation, migration, apoptosis, and copper metabolism, with a non-obese diabetic severe combined immune-deficiency gamma (NSG) mouse xenograft model providing in vivo validation. Results: Elevated COMMD3 expression was correlated with extramedullary myeloma and poor prognosis in MM patients. COMMD3 promoted MM cell proliferation and migration, modulating intracellular copper levels, likely through the ATOX1-ATP7A-LOX copper-metabolism-related pathway. High ATOX1 expression was correlated with worse outcomes, and ATOX1 inhibition abolished COMMD3’s effects. Conclusions: This study highlights the pivotal role of COMMD3 in MM progression, particularly via the ATOX1-ATP7A-LOX axis. These findings provide insights into EMM mechanisms and position COMMD3 as a potential therapeutic target. Future research is needed to validate these findings in larger clinical cohorts and to unravel the precise molecular interactions between COMMD3 and copper metabolism proteins. Full article

Objective: This study aimed to compare bone marrow aspirate (BMA) multicolor flow cytometry (MFC) analysis and bone marrow biopsy (BMB) in detecting bone marrow (BM) involvement in children with neuroblastoma (NB) at diagnosis and during follow-up. Materials and Methods: A total of 132 BM samples from 39 patients (M/F ratio: 19/20; median age: 38 months) with neuroblastoma were simultaneously obtained for evaluation. The samples were investigated for BM involvement using BMB and MFC. Results: A comparison between MFC (n: 60) and BMB (n: 60) was possible for 120 samples. When BMB was considered as the reference standard, MFC had diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of 86%, 58%, 54%, and 88%, respectively, and values of 90%, 57%, 60%, and 89%, respectively, at diagnosis. The median proportion of CD45−/CD56+ cells in MFC was 0.028% (range 0–35%). The event-free survival (EFS) rates for MFC (+) and MFC (−) patients according to the analysis results of the BM samples at the time of diagnosis were 70.6% and 81.8%, respectively (p = 0.607), and the overall survival (OS) rates were 88.2% in MFC (+) patients and 90.9% in MFC (−) patients (p = 0.583). Conclusion: Multicolor flow cytometry may be used as an adjunct to cytomorphology to achieve more sensitive and accurate results as an objective, quantitative method with fast results in detecting bone marrow involvement in children with NB. Full article

Bone metastasis and steroids are known to activate the coagulation system and induce osteoporosis, pathological bone fractures, and bone pain. Heparanase is a protein known to enhance the hemostatic system and to promote angiogenesis, metastasis, and inflammation. The objective of the present study was to evaluate the effects of steroids and malignancy on the coagulation factors and osteoblast activity in the bone tissue. The effects of dexacort and malignant medium were evaluated in osteoblasts derived from human bone marrow mesenchymal stem cells and human umbilical vein endothelial cells (HUVECs). The bones of mice treated with dexacort for 1 month were studied. Bone biopsies of ten patients with bone metastasis, ten with steroid-induced avascular necrosis (AVN), and ten with osteoarthritis were compared to ten controls. We found that dexacort and malignant medium significantly increased the heparanase levels in osteoblasts and HUVECs and decreased the levels of alkaline phosphatase (ALKP). Peptide 16AC, derived from heparanase, which interacts with tissue factor (TF), further increased the effect, while peptide 6, which inhibits interactions between heparanase and TF, reversed the effect in these cells. The bone microcirculation of mice treated with dexacort exhibited significantly higher levels of heparanase, TF, TF pathway inhibitor (TFPI), TFPI-2, thrombin, and syndecan-1, but reduced levels of osteocalcin and ALKP. The pathological human bone biopsies’ microcirculation exhibited significantly dilated blood vessels and higher levels of heparanase, TF, TFPI, TFPI-2, and fibrin. In summary, steroids and malignancy increased the activation of the coagulation system in the bone microcirculation and reduced the osteoblast activity. Heparanase inhibitors should be further investigated to attenuate bone fractures and pain. Full article

Multiple myeloma (MM) is a malignant plasma cell disorder characterized by the accumulation of abnormal plasma cells in the bone marrow. Mesenchymal stem cells (MSCs) and reticulated platelets (RPs) have been implicated in the pathogenesis of MM. This narrative review aims to explore the role of MSCs and RPs in the pathophysiology of MM, particularly their clinical use as possible variables of prognostic value in this hematologic neoplasia. The interaction between MSCs and MM cells within the bone marrow microenvironment supports MM cell survival, proliferation, and drug resistance. MSCs contribute to the development and maintenance of MM through the secretion of various factors, including cytokines, chemokines, and growth factors. Moreover, RPs, young and highly reactive platelets, have been implicated in promoting angiogenesis, tumor growth, and metastasis in MM. Several studies show that cells such as MSCs and platelets participate actively in the biology of the disease. Still, in clinical practice, they are not considered part of evaluating affected patients. In this review, we explore the possibility of including the evaluation of MSCs and PRs in the clinical practice for patients with MM as part of the strategies to improve the outcomes of this disease. Full article

Background: Angiosarcomas are highly aggressive malignancies with endothelial differentiation, presenting considerable challenges in oncology, especially when arising in rare locations such as the spleen. These tumors predominantly affect adults and are commonly found in the skin, breast, liver, or soft tissues, with more unusual occurrences in other organs. Angiosarcomas have a high propensity for metastasis, typically spreading to the liver, lungs, lymph nodes, and gastrointestinal tract. Splenic angiosarcoma, with fewer than 300 documented cases, is an especially rare and complex form of this malignancy. Case presentation: This report details a case of splenic angiosarcoma in a 45-year-old male, where bone marrow metastases were the first clinical presentation, initially mimicking myelodysplastic syndrome (MDS) due to persistent pancytopenia. Conclusions: The eventual identification of the splenic origin underscores the diagnostic difficulties and clinical challenges inherent in managing such atypical and rare presentations. Full article

Metastasis frequently targets bones, where cancer cells from the primary tumour migrate to the bone marrow, initiating new tumour growth. Not only is bone the most common site for metastasis, but it also often marks the first site of metastatic recurrence. Despite causing over 90% of cancer-related deaths, effective treatments for bone metastasis are lacking, with current approaches mainly focusing on palliative care. Circulating tumour cells (CTCs) are pivotal in metastasis, originating from primary tumours and circulating in the bloodstream. They facilitate metastasis through molecular interactions with the bone marrow environment, involving direct cell-to-cell contacts and signalling molecules. CTCs infiltrate the bone marrow, transforming into disseminated tumour cells (DTCs). While some DTCs remain dormant, others become activated, leading to metastatic growth. The presence of DTCs in the bone marrow strongly correlates with future bone and visceral metastases. Research on CTCs in peripheral blood has shed light on their release mechanisms, yet investigations into bone marrow DTCs have been limited. Challenges include the invasiveness of bone marrow aspiration and the rarity of DTCs, complicating their isolation. However, advancements in single-cell analysis have facilitated insights into these elusive cells. This review will summarize recent advancements in understanding bone marrow DTCs using single-cell analysis techniques. Full article

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial–mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments. Full article