Cardiac metastasis from colorectal cancer (CRC) is exceedingly rare and remains poorly defined in the literature. As survival improves and metastatic patterns evolve, recognizing the clinical and anatomical characteristics of cardiac involvement is increasingly important. This systematic review synthesizes published cases of CRC with cardiac metastases identified through a systematic search to clarify presentation, metastatic pathways, management, and outcomes. Following PRISMA 2020 guidelines, we systematically searched PubMed, Scopus, and Web of Science from inception to October 2025 for case reports and case series describing CRC metastasis to the heart. Eligible reports were screened by two independent authors. Detailed clinical, pathological, imaging, management, and outcome data were extracted using a standardized template. Descriptive statistics were performed using Jamovi v2.7 without inferential analyses given the nature of the data. Fifty-three cases met inclusion. The mean age was 62.7 ± 11.75 years (median 66; IQR 55.5–71), with a slight male predominance (53.8
Spinal metastases are a common and morbid complication of advanced malignancies. While vertebral involvement is often attributed to anatomical factors, emerging evidence implicates the chemokine CX3CL1 and its receptor in guiding tumor cells to the spine and reshaping the bone microenvironment. To systematically review the role of the CX3CL1/CX3CR1 axis in spinal metastasis from primary breast, prostate, and liver tumours, synthesizing mechanistic, preclinical, and translational findings. Following PRISMA guidelines, we searched Medline, EMBASE, Web of Science, and Scopus from inception to May 27, 2025, identifying original studies on CX3CL1/CX3CR1 signalling in spinal metastasis. Ten studies met inclusion criteria. Data were extracted across study design, tumour model, expression analysis, mechanisms, and therapeutic or prognostic outcomes. We also analysed experimentally determined CX3CL1 and CX3CR1 structures to identify features relevant to inhibitor design. CX3CL1 expression was three-fold higher in spinal metastases than in primary tumours or non-spinal bone. Mechanistic studies showed roles in chemotaxis, Src/FAK and PI3K/AKT activation, EMT, vascular permeability, and immunomodulation. CX3CL1 also activated stromal pathways promoting osteolysis. Pharmacologic inhibition reduced spinal metastasis and restored chemosensitivity in murine models. Elevated serum CX3CL1/CX3CR1 levels correlated with disease burden in patient cohorts. The CX3CL1/CX3CR1 axis contributes to spinal metastasis by integrating tumour-intrinsic signalling with vertebral niche remodelling, extending the seed-and‑soil hypothesis. Its consistent activity and tractability highlight its promise as both biomarker and therapeutic target in metastatic spine disease.
Cancer metastasis is a multistep and highly inefficient process that depends on reciprocal interactions between tumor cells and the host microenvironment. Among the most important host contributors, platelets have emerged as active facilitators of metastatic dissemination, supporting the survival of circulating tumor cells, immune evasion, endothelial arrest, extravasation, and early colonization. More recently, platelet-derived mitochondrial transfer has been recognized as a novel mechanism by which platelets may enhance tumor aggressiveness through metabolic reprogramming. This review critically synthesizes the current literature on platelet-mediated mitochondrial transfer in cancer, with emphasis on its biological mechanisms, functional consequences, and translational implications. Emerging evidence in selected osteosarcoma and triple-negative breast cancer models indicates that activated platelets can donate functional mitochondria to cancer cells through direct contact and microparticle-mediated pathways, potentially increasing oxidative phosphorylation, ATP production, redox adaptability, proliferative capacity, and migratory behavior. Mechanistically, platelet mitochondrial transfer may involve pathways linked to mitochondrial quality control and trafficking, including PINK1/Parkin–MFN2 signaling, while also intersecting with broader platelet–tumor crosstalk that promotes epithelial–mesenchymal transition, anoikis resistance, and immune escape. In parallel, platelet-derived mitochondrial cargo and related extracellular vesicle signatures may offer new opportunities for liquid biopsy-based biomarker development. However, major challenges remain, including the need for rigorous in vivo validation, discrimination of intact mitochondria from fragmented mitochondrial material, and clarification of context-dependent effects across tumor types. Collectively, platelet-derived mitochondrial transfer represents an emerging layer of intercellular communication that may link thrombosis, metabolism, and metastasis, and it offers promising avenues for both biomarker discovery and therapeutic intervention.
Thrombospondin-2 (THBS2) has emerged as a pivotal yet paradoxical regulator within the breast cancer (BC) tumor microenvironment (TME). This review synthesizes current evidence to elucidate its context-dependent duality and its potential as a novel therapeutic target. While THBS2 can function as a tumor suppressor by inhibiting angiogenesis, it more frequently exhibits pro-tumorigenic activities in aggressive subtypes like triple-negative breast cancer (TNBC). Here, THBS2, predominantly secreted by cancer-associated fibroblasts, drives metastasis by activating key oncogenic pathways including PI3K/AKT, Notch, and Wnt/β-catenin, thereby promoting epithelial-mesenchymal transition (EMT) and stemness. Its expression and functional output are further complicated by competitive endogenous RNA (ceRNA) network regulation, explaining contradictory clinical associations. Crucially, THBS2 is a key architect of an immunosuppressive "cold" TME. It constructs dual barriers: a physical barrier through extracellular matrix remodeling that impedes T-cell infiltration, and a chemical barrier by potentially suppressing CD36⁺ T-cell function. Consequently, therapeutic inhibition of THBS2 presents a promising integrative "cold-to-hot" conversion strategy. By simultaneously dismantling stromal architecture and alleviating local immune suppression, targeting THBS2 could enhance T-cell trafficking and reactivate anti-tumor immunity, potentially overcoming resistance to current immunotherapies. Future research must adopt a network-based approach to decipher THBS2's contextual roles and translate its targeting into effective combination strategies for advanced breast cancer.
The identification of quantitative non-invasive imaging biomarkers, including radiomics, may complement molecular characterization and thereby improve clinical management of neuro-oncological patients. We aimed to identify imaging predictors with improved performance over clinical parameters to stratify patients with brain metastases into high and low-risk groups for overall survival (OS). 422 patients recruited by two neuro-oncological centers were included with first diagnosis of brain metastases from different primary tumors. From each patient, 15 clinical parameters and a total of 321 radiomic features extracted from cerebral MRI were employed in prediction models to classify patients into low- and high-risk groups for OS. The best performing model was a bootstrap aggregating model including only clinical features (test set: macro F-1 = 0.62, accuracy = 0.72), while the combined and radiomic datasets led to poorer results (test set: macro F-1 = 0.60, accuracy = 0.67; test set: macro F-1 = 0.62, accuracy = 0.52, respectively). However, in the subgroup of melanoma patients (n = 54), the radiomic dataset showed better predictive power over clinical and combined dataset (test set: macro F-1 score = 0.71, accuracy = 0.77). 80
Leptomeningeal Metastasis (LM) is a catastrophic complication of systemic malignancies with poor prognosis and significant diagnostic challenges. Extracellular vesicle (EV)-based liquid biopsy is an emerging technology that may improve the detection, prognosis, and therapeutic monitoring for LM. This systematic review aims to critically appraise and synthesize existing evidence on the use of EV-derived biomarkers from cerebrospinal fluid (CSF) or serum for the diagnosis, prognosis, and therapeutic monitoring of LM. A systematic search of PubMed, ScienceDirect, Semantic Scholar, and Google Scholar was conducted up to January 2025. Eligible studies evaluated EV-associated molecular biomarkers (microRNAs or proteins) in LM patients using CSF or serum samples. Data extraction included study design, sample source, EV isolation method, biomarker type, validation method, and diagnostic/prognostic relevance. Risk of bias was assessed using QUADAS-2. Ten studies met inclusion criteria, encompassing EV miRNA and proteomic profiling in LM, primarily from non-small cell lung cancer (NSCLC) and medulloblastoma. miR-21 consistently correlated with poor prognosis and therapy resistance. Novel candidates such as miR-183-5p demonstrated high diagnostic accuracy (AUC 1.0 in a discovery cohort), targeting PTEN pathways. EV-derived proteins including fibronectin-1 (FN1), transketolase (TKT), and complement C2 also showed strong discriminative potential. Heterogeneity in EV isolation techniques and small sample sizes limited meta-analysis feasibility. EV-based liquid biopsy holds cautious promise as a minimally invasive tool for LM diagnosis, prognosis, and therapeutic monitoring. Larger, multicenter studies with standardized protocols are required to validate these findings and facilitate clinical translation.
Gastric cancer (GC) is a very aggressive cancer with a high potential for metastasis. A naturally occurring flavonoid, luteolin (Lut) has metabolic regulation and anti-cancer properties. This work investigates whether Lut modulates glucose metabolism and targets AKR1B1 to prevent the epithelial-mesenchymal transition (EMT) in GC. Lut was used to treat human GC cell lines that were grown in both normal and high-glucose environments. Western blotting and qPCR were used to assess the expression levels of EMT markers and AKR1B1. The CCK-8 assay, the scratch assay, and the Transwell assay were used to measure cell movement, invasion, and proliferation, respectively. Metabolic flux analysis was used to measure fructose and lactate generation in order to assess glycolytic activity. We carried out AKR1B1 overexpression and knockdown experiments to elucidate the functional involvement of AKR1B1 in the action of Lut. In order to fully assess the anticancer effects of Lut and its underlying mechanisms, a high-glucose paradigm in nude mice was developed for in vivo validation. AKR1B1 expression was markedly elevated in GC cells under high-glucose circumstances, and this was accompanied by increased glycolytic activity. At the same time, the cells showed signs of EMT, including enhanced migratory and invasion capacities. Subsequent research showed that Lut therapy substantially alleviated anomalies in glucose metabolism by drastically suppressing AKR1B1 expression, downregulating important glycolytic enzymes, and reducing the generation of fructose and lactate. Additionally, by boosting E-cadherin expression, lowering vimentin and N-cadherin levels, and preventing cell migration and invasion, luteolin dramatically corrected high-glucose-induced EMT. The inhibitory effects of luteolin on glycolysis and EMT were largely offset by AKR1B1 overexpression, according to functional experiments; on the other hand, inhibition of AKR1B1 considerably reduces AKT pathway activation, which suppresses the malignant phenotype of gastric cancer cells. Together, these findings show how important AKR1B1 is to this regulatory axis. According to these results, luteolin inhibits high-glucose-induced metabolic reprogramming and EMT in gastric cancer cells via acting on AKR1B1, which lowers the cells' capacity for metastasis. Lut may reduce the metabolic dysregulation brought on by hyperglycemia by blocking AKR1B1, which in turn prevents GC cells from undergoing the epithelial-mesenchymal transition. This discovery highlights Lut as a potential metabolic therapeutic drug and offers mechanistic insight into the evolution of gastric cancer caused by hyperglycemia.
Metastasis contributes to treatment failure and poor prognosis of esophageal squamous cell carcinoma (ESCC) patients. The 5’-3’ exoribonuclease 2 (XRN2) is related to the pathogenesis and progression of various malignancies through its roles in transcription termination and metastasis promotion, but its function in ESCC remains unclear. Bioinformatic analysis showed that XRN2 was significantly overexpressed in ESCC tissues and was identified as a risk factor for ESCC patients. The analysis of our own cohort confirmed that XRN2 expression was overexpressed and significantly correlated with cancer stage in patients (P = 0.0100). Gain- and loss- of function analyses revealed that XRN2 promoted ESCC cell growth, migration and invasion capabilities, as well as experimental lung colonization foci. Interestingly, we found that the RNA level of XRN2 was upregulated by the RNA-binding protein polypyrimidine tract binding protein 3 (PTBP3). Specifically, PTBP3 bound to CUUUC motifs of the 3’UTR of XRN2, prolonging the half-life of XRN2 RNA. PTBP3 was found to be significantly overexpressed in ESCC, where its expression level correlated with tumor stage (P = 0.0164) and tumor size (P = 0.0495), positioning it as a risk factor for ESCC patients. PTBP3 upregulation promoted ESCC cell growth, migration, and invasion in vitro and in vivo. Notably, knockdown of XRN2 reversed the tumor promotion effects induced by PTBP3 overexpression. Collectively, our data reveal a novel function of XRN2 in ESCC metastasis and the critical roles of the PTBP3/XRN2 axis in ESCC metastasis, highlighting its promise as a novel therapeutic target in ESCC.
The addition of immunotherapy to chemotherapy has improved prognosis of metastatic biliary tract cancer (BTC). The present systematic review aimed to assess frequency of treatment-emergent adverse events (TEAEs) among metastatic BTC patients receiving first-line immune checkpoint inhibitors (ICIs) plus chemotherapy in the two practice-changing TOPAZ-1 and KEYNOTE-966 clinical trials. The present systematic review and meta-analysis was recorded in the PROSPERO register with no. CRD420251137398. Incidence of TEAEs in patients receiving ICIs plus chemotherapy and in patients treated with placebo plus chemotherapy was collected. A total of two studies were included in these analyses including 1754 patients, comprising 1743 observations and 193 events for Grade 1/2 and 650 events for Grade ≥ 3. The risk of several TEAEs did not significantly differ between patients receiving chemoimmunotherapy versus those treated with chemotherapy alone. The present meta-analysis further confirms the tolerable safety profile of TOPAZ-1 and KEYNOTE-966 regimens as first-line therapy in advanced BTC. Future research should focus on identifying risk factors for TEAEs and develop prophylactic strategies to mitigate this risk without blunting antitumor efficacy. By improving our understanding and management of TEAEs, we might maximize the clinical benefits of ICIs and minimize harm, ultimately enhance clinical outcomes for BTC patients.
Metastatic organotropism in cutaneous melanoma remains incompletely understood at the genomic level. While prior work has linked BRAF and NRAS mutations to organ-specific metastasis patterns, the role of NF1 has not been systematically evaluated. We investigated whether NF1 mutation is specifically associated with lung metastasis in cutaneous melanoma. We analyzed 520 patients with metastatic cutaneous melanoma from the MSK-MET cohort, comparing 258 with documented lung metastasis to 262 without. Gene-level enrichment was tested across 118 genes meeting a 5
Bone metastasis remains a serious threat to breast cancer patients. This condition arises from the outgrowth of previously dormant tumour cells in this site. Dormant tumour cells are almost impossible to detect in human patents, and these cells acquire "stem like" characteristics rendering them resistant to current cancer therapies. Furthermore, the development of therapies to target this population has proved challenging. The bone marrow is a particularly permissive environment for tumour cell dissemination and dormancy, but the mechanisms regulating this process remain to be completely elucidated. Expansion of our understanding of the mechanisms underlying tumour dormancy is critical to the development of targeted therapies and thus, the prevention, or treatment, of metastatic disease. This review aims to explore mechanisms of tumour dormancy in bone, in detail, focusing specifically on breast cancer dormancy. In addition to subsequent discussion of traditional and new, state of the art, methods of studying dormancy to aid further research efforts.
Early liver metastasis is a major factor contributing to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Single-cell RNA sequencing (scRNA-seq) can analyze the heterogeneity between the primary tumor and metastatic lesions, but its wide clinical application is limited by costs, tissue requirements, and analytical complexity. In contrast, H E-stained sections are more commonly available. However, it is not clear whether the risk signals derived from images can truly reflect the biological characteristics related to metastasis. We integrated the single-cell RNA sequencing data (GSE154778) of primary and metastatic pancreatic ductal adenocarcinoma (PDAC) with TCGA transcriptome, clinical pathological, and H E image data. The copy number pattern based on InferCNV was used to distinguish malignant ductal cells with high copy numbers from ductal cells with low copy numbers. Differential expression and LASSO screening identified a transfer-related feature consisting of four genes (ARHGAP18, ASPH, EIF4EBP1, LY6D), and this feature was subsequently associated with image-derived features extracted through a dual-stream pathomics pipeline. The reproducibility of transcriptional levels in prognosis was evaluated in six independent GEO PDAC subgroups, and the locked pathological model was further tested on an external CPTAC subset using frozen cutoff values from TCGA. Pseudotime analysis suggested that a subset of metastatic malignant ductal cells occupied a progenitor-like transcriptional state. Cell–cell communication analysis indicated reduced antigen-presentation/prostaglandin-related signaling and relative enrichment of MIF- and laminin-associated pathways in metastases. The pathology model retained prognostic stratification in the internal TCGA validation split, although discrimination was lower than in training. Across six external GEO cohorts analyzed with cohort-specific optimal cutoffs, LY6D showed significant adverse survival associations in four cohorts, ARHGAP18 and ASPH in three cohorts each, and EIF4EBP1 in one cohort. In the external CPTAC cohort, the locked pathomics score also remained prognostic (HR 1.60, 95
Clinical and radiological outcomes after Stereotactic radiosurgery (SRS) for lung cancer brain metastases are heterogeneous, and prescription dose selection is often guided by experience rather than individual patient and tumor specific features. A data-driven approach that links dose to quantitative local control and adverse effect predictions could improve planning and follow-up strategies. We performed a retrospective single-center cohort study of lung cancer brain metastases treated with GKRS at the University of Pittsburgh Medical Center (2014–2024). Using routinely available clinical, tumor, and dosimetric variables, we trained a tumor-level Random Survival Forest to predict Local Control and Dose Selection for Lung Cancer Brain Metastases after GKRS treatment. Internal validation used leakage-resistant patient-level grouped cross-validation. Performance was assessed using Harrell’s concordance index (C-index) and integrated Brier score (IBS). A connected dose-sweep decision layer evaluated predicted local control across a clinically feasible margin dose grid and selected the dose associated with the most favorable predicted profile at prespecified horizons. The survival model demonstrated good internal performance (C-index 0.83; IBS 0.15). A baseline dose imitation model predicted historical margin dose with low error (OOF MAE 1.59 Gy). The integrated decision layer generated individualized local control trajectories and returned horizon-specific local control probabilities and model-based prescription dose recommendations. An Artificial Intelligence framework integrating time-to-event prediction with outcome-linked dose sweeping can provide individualized GKRS decision support for lung cancer brain metastases by delivering quantitative local control forecasts and model-based dose recommendations.
Prostate cancer (PCa) exhibits a strong tropism for bone, where interactions with the bone microenvironment critically influence metastatic progression and therapeutic resistance. However, the complexity of tumor–bone interactions remains difficult to model in conventional systems. Here, we developed an engineered dual-niche platform that recapitulates both primary tumor and bone metastatic microenvironments using tunable extracellular matrix mechanics, bone matrix–derived soluble factors (BMSFs), and bone marrow stromal cells (BMSCs). Within the primary tumor–like niche, increasing matrix stiffness suppressed LNCaP-C4—2B cell proliferation while promoting cell dissemination. In contrast, BMSFs exerted a dual effect by inhibiting tumor proliferation while inducing osteomimetic differentiation through upregulation of Runx2 and Cbfa1. In vivo, BMSFs elicited inflammatory and vascular responses associated with suppressed tumor expansion. Notably, BMSCs primed with bone matrix factors markedly enhanced PCa cell proliferation and migration in vitro and accelerated tumor formation in vivo, revealing a stromal-driven pro-tumorigenic mechanism. Together, these findings uncover a functional dichotomy within the bone microenvironment, in which bone matrix–derived factors promote tumor adaptation and dormancy, while stromal components drive tumor expansion. This engineered dual-niche model provides a versatile platform to dissect microenvironment-specific mechanisms and may inform strategies targeting bone metastatic progression in prostate cancer.
Reactive oxygen and nitrogen species (ROS/RNS) are central regulators of cellular processes, governing signaling, metabolism, and stress responses. The source of reactive species, together with the capacity of antioxidant networks, determines whether redox signals support cell survival or provoke cytotoxicity. Dysregulation of redox homeostasis promotes genomic instability, metabolic reprogramming, immune evasion, and therapy resistance, thereby contributing to tumor initiation and progression. Tumors further adapt their metabolism and antioxidant defenses, which changes their sensitivity to oxidative stress. Consequently, redox biology emerges as a highly promising target for intervention. This review focuses on topical ROS‑based strategies for advanced skin cancer, offering an overview of fundamental redox principles and evaluating both conventional topical agents (e.g., 5‑fluorouracil and imiquimod) and direct ROS-producing modalities (e.g., photodynamic therapy and medical gas plasma). Topical ROS‑based interventions can impose defined oxidative stress on tumors, combining direct tumoricidal activity with immunogenic effects. While standard agents rely primarily on antiproliferative or immune‑stimulatory mechanisms, pro‑oxidant therapies intentionally generate ROS/RNS to induce tumor cell death and stimulate antitumor immunity. They therefore may synergize with drugs that impair antioxidant defenses or sensitize cells to ferroptosis. Advanced cutaneous malignancies are suited to topical redox interventions because their surface accessibility permits localized treatment that addresses unmet therapeutic needs. To translate these opportunities, harmonized delivery and dosimetry, validated biomarkers for tumor redox phenotypes, and prospective trials integrating pharmacodynamic and safety endpoints are required to guide patient selection and combination strategies.
Colorectal cancer (CRC) is a leading cause of cancer-related mortality in the Western world. While brain metastasis (BMs) are relatively uncommon in CRC, they represent the fourth most frequent cause of BMs overall, and their occurrence is increasingly recognized as a complication in advanced CRC, associated with poor prognosis and limited treatment options. The brain microenvironment presents unique metabolic challenges, including low oxygen levels and restricted lipid availability. In order to survive in this hostile environment, CRC cells must acquire metabolic adaptations allowing them to survive and proliferate. To identify key drivers that enable CRC cells to metastasize to and survive within the brain, we conducted a transcriptomic screen of CRC BMs and compared it to liver metastasis (LMs). FOXM1, a transcription factor critical for tumor progression, was identified among the upregulated genes, and these results were validated by immunohistochemistry. To study the role of the brain microenvironment in mediating FOXM1 expression, we examined FOXM1 expression in CRC cell lines grown in either astrocyte-conditioned media (A-CM) or hepatocyte-conditioned media (H-CM). We observed a marked upregulation of FOXM1 following exposure to A-CM. Moreover, using an intracranial CRC BMs mouse model, a significant FOXM1 overexpression was observed. In accordance with the importance of fatty acid metabolism in BMs, our study revealed a significant correlation between FOXM1 and fatty acid synthase (FASN) in the CRC BMs, in agreement with public databases. These findings suggest that FOXM1 plays a key role in CRC BMs progression and may serve as a promising therapeutic target in this challenging disease setting.
We evaluated the feasibility and clinical outcomes of MRIgSBRT for nodal recurrence in the oligometastatic disease (OMD) setting, focusing on per-lesion outcomes and prognostic factors. We collected clinical and dosimetric data from a retrospective single-center cohort of patients treated with a 0.35 T MRIgSBRT for nodal recurrences. Endpoints included the 1-year progression-free survival (PFS), local progression-free survival (LPFS), and 3-year overall survival (OS) rate from recurrence. Per-lesion Kaplan–Meier and Cox regression assessed clinical, dosimetric, and technical predictors. 71 patients received nodal MRIgSBRT, with a total of 115 treated metastatic lesions. Local control was high: LPFS 95.5
Metastatic Ewing sarcoma (EWS) has a poor prognosis. While metastasis-directed therapy benefits oligometastatic disease, the role of comprehensive all-site radiotherapy in widespread disease remains underexplored. This study aimed to preliminarily assess its short-term efficacy and safety. This retrospective analysis included 21 consecutive metastatic EWS patients treated with helical tomotherapy (Aug 2024–Jun 2025). All known metastases and unresected primary tumors received radiotherapy (45–55 Gy in 20 fractions for most sites; 12–45 Gy for lung/pleural metastases). Concurrent systemic therapies included chemotherapy, tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), or combinations. Primary endpoints were local objective response rate (ORR, RECIST 1.1) at 2 months post-radiotherapy and acute toxicity (CTCAE 5.0). Systemic therapy subgroup analyses were exploratory. Median follow-up was 6 months (range 2–11). Among 77 target lesions, ORR was 61.0
Pancreatic cancer has a poor prognosis. The present systematic review and meta-analysis evaluated progression free survival (PFS) and overall survival (OS) after gemcitabine-based therapy nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil for metastatic pancreatic ductal adenocarcinoma (PDAC) patients. The present systematic review and meta-analysis was registered in PROSPERO with id no. CRD42024608206. A systematic literature review was performed according to the PRISMA checklist, consulting Embase, PubMed, Scopus, and Web of Science databases. Screened studies considered median values for PFS and Hazard Ratio for OS. Heterogeneity among the selected studies was statistically significant both for PFS (P < 0.001; tau2 = 0.72; I2 = 98.67
