Metastasis remains the primary cause of mortality in colorectal cancer (CRC), with a 5-year survival rate of ~14%, despite therapeutic advances. SPP1+ tumor-associated macrophages (TAMs) are implicated in promoting tumor progression, angiogenesis, and immune evasion. Osteopontin (OPN), encoded by the SPP1 gene, is a critical regulator of TAMs M2 polarization and CRC metastasis when derived from TAMs. However, it remains unclear whether CRC-derived OPN interacts with M2-like TAMs to promote metastasis and what the underlying mechanisms are. Here, we found that OPN is highly expressed in metastatic CRC and is associated with poor prognosis. Contrary to prior reports, neither knockdown nor overexpression of OPN in CRC cells directly altered tumor cell invasion and migration. Rather, OPN expression levels were positively correlated with M2-like TAMs infiltration. The co-culture system revealed bidirectional chemotactic interactions between CRC cells-derived OPN and M2-like TAMs. Mechanistically, high OPN expression activates the PI3K/AKT signaling pathway in macrophages, promoting the secretion of CSF1, which induces M2-like polarization of macrophages to facilitate tumor metastasis. Finally, in a mouse metastasis model, blocking the CSF1/CSF1R axis with a CSF1R inhibitor reduced the M2-like TAMs recruitment and CRC tumor metastasis burden. Our study demonstrates that the OPN/PI3K/AKT/CSF1-CSF1R axis plays a crucial role in CRC metastasis. Blocking the CSF1/CSF1R axis reduces M2-like TAMs infiltration and tumor metastasis, offering a promising strategy for metastatic CRC.

The authors' accepted manuscript "TACE Combined with Hepatic Arterial Infusion of Nivolumab for Inhibiting Tumor Angiogenesis in Hepatocellular Carcinoma" [Oncol Res Treat. 2025; https://doi.org/10.1159/000549516] by Sujing Zhang, Zheng Zheng, Changwang Zhang, Xueqian Liu, Xinlei Shi, and Wenhua Ma has been retracted by the Publisher and the Editor on behalf of the authors.After peer review, the accepted, unedited manuscript was published online as Early View. Subsequently, the authors requested to withdraw the manuscript from the journal. As the article is not approved by the authors for publication, we are retracting the Early View accepted, unedited manuscript.

Oncolytic viruses (OVs) represent a promising strategy in cancer immunotherapy, as they selectively infect and lyse tumor cells while simultaneously triggering robust antitumor immune responses. By inducing immunogenic cell death, OVs enhance tumor antigen presentation and initiate a systemic immune response, effectively transforming the tumor microenvironment from an immune-suppressive state to an immune-permissive state. In addition to exerting direct oncolytic effects, OVs modulate key tumor-associated biological processes, including tumor angiogenesis and extracellular matrix remodeling, disrupting tumor progression and metastasis. Notably, recent advances have highlighted the therapeutic potential of combining OVs with conventional and emerging cancer treatments, such as chemotherapy, radiotherapy, immune checkpoint inhibitors, adoptive cell therapy, and epigenetic-targeted drugs. These combination strategies demonstrate synergistic effects by improving tumor selectivity, increasing antitumor immunity, and overcoming treatment resistance. Nevertheless, persistent challenges, such as viral dissemination dynamics, therapy resistance, and regulatory complexities, impede the broad clinical implementation of oncolytic virus therapy (OVT). In this Review, we illustrate recent advancements and innovative therapeutic strategies in OVT within the context of contemporary cancer treatment paradigms. First, we outline the historical evolution and key milestones in OVT development. We then discuss the classification of OVs and their multimodal mechanisms that target tumorigenesis, metastasis, disease recurrence, and therapy resistance. Finally, we evaluate the clinical research progress of OVT applications, focusing on their integration with other therapies, analyze the translational barriers hindering clinical implementation, and propose evidence-based future directions for optimizing cancer treatment.

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, ranks as the fourth leading cause of cancer-associated mortality globally. The heightened mortality associated with HCC is largely attributed to its propensity for recurrence and metastasis, which cannot be achieved without tumor stemness and angiogenesis. Here, we aimed to develop a novel signature of stemness and angiogenesis-related genes (SARGs) for the prediction of clinical prognosis and tumor microenvironment in HCC, with the overarching objective of uncovering novel therapeutic targets capable of concurrently disrupting these intertwined processes, thereby offering potential breakthroughs for more effective anti-HCC strategies. The differentially expressed SARGs were subjected to univariate Cox regression analysis to identify SARGs with prognostic significance. A nine-SARGs risk score model was constructed using Least Absolute Shrinkage Selection Operator (LASSO) Cox regression with 10-fold cross-validation. Furthermore, a nomogram incorporating the SARGs score and other clinicopathological features was developed for accurate prediction of survival rate in patients with HCC. Knockdown of ELOVL3 expression was performed, and its effects on tumor stemness and angiogenic potential were verified through in vitro and in vivo experiments. Patients with HCC were categorized into high- and low-risk groups based on the median risk score values, with higher risk scores indicating worse overall survival (log-rank P < 0.001). The nine-SARGs risk score, comprising DRD1, CDX2, ELOVL3, TKTL1, IGLON5, SHISA9, WNT1, CNTN6, and MMP3, demonstrated robust predictive performance (C-index: 0.72) for clinical prognosis, tumor microenvironment characteristics, and immunotherapy response in HCC. ELOVL3 knockdown reduced tumor stemness and angiogenic potential, leading to the inhibition of tumor growth and metastasis. This study established a direct molecular correlation between tumor stemness and angiogenesis, encompassing clinical features, tumor microenvironment, and immune response, thereby offering valuable insights for predicting clinical outcomes and immunotherapy responses in HCC. Our findings demonstrate that ELOVL3 correlates with cancer cell stemness and angiogenic potential, thereby identifying it as a promising therapeutic target. Further investigations are warranted to elucidate the downstream molecular pathways that mediate these functional effects.

Lung cancer (LC) remains the leading cause of global cancer-related death due to delayed diagnosis, poor therapeutic efficacy, and drug resistance. Traditional therapeutic methods like radiation, chemotherapy, and targeted medicines are often associated with high toxicity and often result in minimal survival improvements. Phytochemicals from medicinal plants are increasingly being considered as potential LC treatment agents due to their multi-targeted action, safety, and accessibility. These have anticancer properties by regulating key molecular signaling pathways like PI3K/Akt/mTOR, MAPK/ERK, NF-κB, STAT3, and apoptotic cascades. These compounds also promote apoptosis, increase chemotherapeutic medication sensitivity, and prevent tumor cell growth, angiogenesis, invasion, and metastasis. Phytochemicals have shown potential in reducing therapy-induced side effects and combating multidrug resistance, potentially enhancing treatment effectiveness. Despite promising discoveries, challenges such as low bioavailability, limited pharmacokinetic stability, and lack of extensive clinical validation inhibit their widespread use. This review provides clinical insights into phytochemical-based LC preventive and treatment approaches, focusing on their role in addressing molecular signaling pathways. It demonstrates the potential medicinal benefits, potential disadvantages, and potential applications of phytocompounds as supplementary or alternative treatments for LC.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that the statistical analysis in this study may not have employed the most appropriate statistical tests; namely, the paired Student's t‑test was used for comparisons between independent groups, which the reader considered may have inflated the statistical significance. Neither may the paired Student's t‑test have been the most appropriate test to have been selected for various of the migration and invasion assay experiments, wherein at least three groups were being compared. Owing to the fact that the Editorial Office has been made aware of the possibility of inappropriate statistics handling in this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Molecular Medicine Reports 1: 641‑646, 2008; DOI: 10.3892/mmr_00000005].

CD105 (endoglin) is a proliferation-associated transmembrane glycoprotein selectively expressed on activated endothelial cells in tumor neovasculature and serves as an attractive biomarker for imaging tumor angiogenesis. Here, we report the development of a novel CD105-targeted PET tracer, 68Ga-DOTA-CDP, based on a high-affinity peptide (KD = 13.5 nM) identified from a combinatorial library. The radiotracer was obtained with high radiochemical purity (>97%), excellent stability in phosphate-buffered saline and fetal bovine serum, and favorable hydrophilicity. In vitro confocal imaging and flow cytometry demonstrated specific binding of CDP to CD105-positive HUVECs with minimal uptake in CD105-negative cells. Micro-PET imaging in multiple tumor-bearing mouse models, including 4T1, A549, H1975, MDA-MB-231, and JIMT-1 xenografts, enabled rapid tumor visualization at early time points following injection. Tracer uptake was significantly higher in CD105-high tumors compared with CD105-low tumors, with the highest accumulation observed in the triple-negative breast cancer model MDA-MB-231. Biodistribution studies revealed predominant renal clearance, low hepatic uptake, and favorable tumor-to-background ratios. Blocking experiments with excess unlabeled peptide markedly reduced tumor uptake, confirming receptor-mediated targeting. Immunohistochemical analysis further validated heterogeneous CD105 expression in tumor neovasculature and demonstrated a positive correlation between CD105 expression levels and PET-derived tumor uptake. Overall, 68Ga-DOTA-CDP shows promise as a peptide-based PET tracer for noninvasive tumor angiogenesis imaging.

ABSTRACTObjectiveThe study is to investigate differential signaling pathways within the tumor microenvironment across molecular subtypes of breast cancer (BC).MethodsSingle‐cell RNA (scRNA‐seq) sequencing data of BC samples were obtained from the Gene Expression Omnibus database. Cell types were identified using the SingleR package, in conjunction with the analysis of marker genes. Subsequently, Monocle was used for pseudotime analysis of epithelial cells, fibroblasts, and macrophages to characterize their differentiation states. CellChat was employed to study the ligand‐receptor interactions among various cell types across different BC molecular subtypes. In addition, we used common bulk RNA sequencing data from The Cancer Genome Atlas to investigate the correlation between key signaling pathway factors identified by scRNA‐seq and clinical outcomes.ResultsInference of copy number variation analysis using T cells revealed significantly elevated copy number variation scores in epithelial cells and fibroblasts. In the communication between epithelial cells and fibroblasts, the ANGPTL pathway is critical in estrogen receptor‐positive breast cancer (ER+BC), while the PTN pathway plays a key role in both ER+BC and human epidermal growth factor receptor 2‐positive breast cancer (HER2+BC), and the GAS pathway is associated with poor prognosis in triple‐negative breast cancer (TNBC). In the interaction between fibroblasts and macrophages, the macrophage subpopulation supporting tumor angiogenesis exhibits significant activity in ER+BC, with the associated SPP1 and GRN pathways strongly influencing tumor progression. The SEMA3 pathway mainly acts through dividing tumor‐associated fibroblast clusters across all BC subtypes. When exploring the role of lymphocytes, the PTN pathway also plays a role in HER2+BC, while in TNBC, CXCL and CD70 pathways are significantly involved in immune response modulation.ConclusionOur comprehensive analysis of cell–cell communication networks among epithelial cells, fibroblasts, macrophages, and lymphocytes across BC subtypes focuses on ligand‐receptor interactions. This study revealed that certain molecules within these networks exhibit significant prognostic value and therapeutic promise.

Exosomal LRG1 derived from highly metastatic non-small cell lung cancer cells accelerates growth, metastasis, and angiogenesis by transcriptional factor NFKB1-mediated SHH upregulation.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype and lacks effective targeted therapies. Transmembrane protein 205 (TMEM205) has been implicated in tumor progression and immune resistance, but its precise role and mechanism in TNBC remain unclear. This study aims to explore the function and mechanism of TMEM205 in TNBC progression, as well as its impact on the tumor immune microenvironment. The expression and prognostic significance of TMEM205 in breast cancer were analyzed using datasets, such as TCGA and UALCAN. TMEM205 was overexpressed and knocked down in TNBC cell lines (MDA-MB-231 and BT-549), and the effects on cell biological activity were verified by functional assays, including CCK-8, colony formation, wound healing, and Transwell assays. A coculture system of tumor cells and THP-1-derived macrophages was established. Key signaling molecules of TNBC cells were detected by Western blot, and cytokine levels by ELISA, so as to study tumor cell-macrophage interactions. The role of TMEM205 in tumor growth and angiogenesis was further validated through xenograft mouse models and endothelial tube formation assays. TMEM205 was significantly upregulated in breast cancer tissues and associated with a poor prognosis. TMEM205 overexpression promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of TNBC cells, while TMEM205 knockdown inhibited their biological functions. Furthermore, TMEM205 overexpression not only increased the secretion of IL-6 but also activated the JAK2/STAT3 signaling axis, showing a positive correlation with M2 macrophage infiltration. The TNBC cell-conditioned medium with TMEM205 overexpression significantly promoted endothelial cell angiogenesis. TMEM205, as a multifunctional oncoprotein in TNBC, jointly drives tumor progression by promoting cell proliferation, metastasis, angiogenesis, and fostering an immunosuppressive microenvironment via M2 macrophage polarization. TMEM205 may be a promising therapeutic target for TNBC.

Introduction: Ovarian cancer is one of the most lethal gynaecological malignancies worldwide, largely due to its latestage diagnosis and high metastatic potential. The tumour microenvironment plays a crucial role in disease progression, with Extracellular Matrix (ECM) remodelling being a key process in tumour invasion and metastasis. Among the mediators of ECM degradation, Matrix Metalloproteinase-9 (MMP-9) has garnered significant attention due to its ability to degrade type IV collagen, a major component of the basement membrane. MMP-9, a member of the gelatinase subfamily of MMP, is involved in multiple oncogenic processes, including tumour growth, angiogenesis, and immune evasion. Overexpression of MMP-9 has been observed in various malignancies, including ovarian cancer, where it is associated with poor prognosis, increased tumour aggressiveness, and resistance to therapy. Aim: To analyse the expression of MMP-9 and its association with different clinicopathological parameters in surface epithelial ovarian carcinoma. Materials and Methods: This observational, cross-sectional descriptive study included 80 cases of epithelial ovarian carcinoma diagnosed at Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal, India. Tumour samples were collected and processed for histopathological examination, followed by immunohistochemical analysis to assess MMP-9 expression. Clinicopathological parameters, including histological type, grade, and stage, were recorded. The intensity of MMP-9 expression was categorised into two groups—high and low expression—based on a predetermined scoring system. The association between MMP-9 expression and various clinicopathological features (such as tumour laterality, histological type, tumour grade, tumour stage, and presence of malignant cells in ascitic fluid) was analysed using IBM Statistical Package for the Social Sciences (SPSS) for Windows, Version 10.0, Armonk, NY: IBM Corp.). Descriptive statistics were calculated in terms of frequency and percentages for the qualitative variables. Clinical features were evaluated by descriptive analysis; mean and median values were calculated. Differences between variables were assessed using the chi-square (χ2 ) test. A p-value &lt;0.05 was considered statistically significant. Results: Among the 80 samples analysed, high epithelial MMP-9 expression (moderate or strong) was observed in 63 (78.75%) cases, while 17 (21.25%) showed negative or weak expression. Stromal MMP-9 expression was detected in 76 (95.00%) out of 80 specimens, with 48 (60.00%) tumours demonstrating high stromal MMP-9 levels. High stromal MMP-9 expression was significantly associated with advanced stage (p-value=0.001), high grade (p-value=0.01), and serous histology (p-value=0.026). However, epithelial MMP-9 expression showed no statistically significant association with any clinicopathological parameters. Conclusion: High stromal MMP-9 expression is associated with poor prognosis in ovarian cancer patients. Down-regulation of MMP-9 may be an important therapeutic strategy to reduce cancer-related mortality.

Phenol exposure promotes tumor-related signaling and blood vessel formation through the extracellular signal-regulated kinase/p38/hypoxia-inducible factor-1α pathway in cellular and zebrafish models.

Migrasomes in the tumor microenvironment: Functional roles and therapeutic potential.

Filopodia formation by tumor endothelial cells (TECs) is critical for tip cell-guided sprouting angiogenesis and tumor growth. However, the cytoskeletal organization that underlies this process remains elusive. Here, we demonstrates that TECs highly express actin-binding genes, with PDZ and LIM domain 5 (PDLIM5), a cytoskeletal protein, significantly upregulated in TECs and correlated with poor patient survival. Endothelial-specific deletion of Pdlim5 inhibits sprouting angiogenesis by disrupting filopodia formation through its interaction with actinin-1/actinin-4 (ACTN1/ACTN4) via its S593/F596 residues, promoting filamentous actin (F-actin) bundling. Pdlim5 knockout not only reduces tumor growth but also normalizes tumor vasculature, alleviates hypoxia, and enhances immunotherapy and chemotherapy responses. These findings highlight the PDLIM5's role in facilitating tumor angiogenesis via ACTN1/ACTN4-mediated F-actin bundling and tip cell filopodia formation, providing mechanistic insights that may inform future therapeutic strategies targeting this pathway.

Lactate-lactylation in tumor angiogenesis and progression: mechanisms, biomarker potential, and therapeutic implications.

Renal cell carcinoma (RCC) has been described as a metabolic disease as metabolic alterations are common in disparate RCC etiologies. Extracellular vesicles (EVs), the lipid bilayer-enclosed nanoparticles secreted by all living cells, have emerged as crucial mediators of intercellular and inter-organ communication, capable of shuttling functional proteins, lipids, and nucleic acids between cells. This review summarizes the essential events in tumor-associated metabolic reprogramming with a particular focus on renal cancers. We further explore how EVs released by metabolically deranged cells in cancer with altered cargos reprogram the renal cellular landscape, fostering tumor initiation, proliferation, angiogenesis, immune evasion, and therapy resistance. Understanding this EV-mediated axis not only elucidates the pathophysiological link between these conditions but also helps to unveil novel potential therapeutic targets for RCC patients.

Lung cancer remains a major public health challenge due to high incidence and mortality. The chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1) constitute a critical axis in tumor biology, influencing tumor cell proliferation, invasion, angiogenesis, and immune evasion. Aberrant CXCR4 expression is frequently observed in lung cancer and is closely associated with adverse prognosis, enhanced metastatic potential, and therapeutic resistance. Mechanistically, CXCR4 activates signaling pathways including PI3K/AKT, MAPK/ERK, JAK/STAT, and FAK/Src, promoting epithelial–mesenchymal transition, stemness, and survival. The CXCL12/CXCR4 axis also orchestrates interactions with the tumor microenvironment, facilitating chemotaxis toward CXCL12-rich niches (e.g., bone marrow and brain) and modulating anti-tumor immunity via regulatory cells. Regulation of CXCR4 occurs at transcriptional, epigenetic, and post-transcriptional levels, with modulation by hypoxia, inflammatory signals, microRNAs, and post-translational modifications. Clinically, high CXCR4 expression correlates with metastasis, poor prognosis, and reduced response to certain therapies, underscoring its potential as a prognostic biomarker and therapeutic target. Therapeutic strategies targeting CXCR4 include small-molecule antagonists (e.g., AMD3100/plerixafor; balixafortide), anti-CXCR4 antibodies, and CXCL12 decoys, as well as imaging probes for patient selection and response monitoring (e.g., 68Ga-pentixafor PET). Preclinical and early clinical studies suggest that CXCR4 blockade can impair tumor growth, limit metastatic spread, and enhance chemotherapy and immunotherapy efficacy, although hematopoietic side effects and infection risk necessitate careful therapeutic design. This review synthesizes the molecular features, regulatory networks, and translational potential of CXCR4 in lung cancer and discusses future directions for precision therapy and biomarker-guided intervention.

Cancer remains a significant global health burden despite advances in diagnosis and treatment. In recent years, drug repurposing has emerged as a promising strategy in oncology, offering reduced costs and shorter development timelines compared with de novo drug discovery. Among repurposed agents, the antifungal drug itraconazole has demonstrated anticancer activity across multiple tumor types, particularly when used in combination with other therapeutic modalities. In this review, we summarize current preclinical and clinical evidence supporting the use of itraconazole in cancer therapy, with a specific focus on its combination with chemotherapeutic agents and programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. We highlight proposed mechanisms underlying this synergy, including modulation of tumor metabolism, angiogenesis, and immune signaling pathways. Additionally, we discuss key challenges and limitations, such as drug–drug interactions and toxicity considerations, that must be addressed to optimize clinical translation. Overall, the combination of itraconazole with chemotherapy or anti-PD-1 therapy represents a promising therapeutic strategy warranting further investigation in well-designed trials.

Cancer continues to pose a worldwide health concern, requiring breakthrough therapeutic approaches that are both efficacious and minimally intrusive. Berberine, a natural isoquinoline alkaloid, has attracted considerable interest due to its various pharmacological features, particularly its strong anticancer effects. Nonetheless, its clinical application has been impeded by inadequate bioavailability, rapid metabolism, and systemic elimination. Recent breakthroughs in nanotechnology have mitigated these issues by creating BBR nanoparticles (BBR NPs), which provide increased solubility, precise delivery, and higher therapeutic efficacy. This paper extensively examines BBR and its nanoparticle forms for cancer treatment. The mechanisms of action, including apoptosis induction, tumour angiogenesis inhibition, antimetastatic effects, and oxidative stress modulation, are thoroughly examined. Essential synthesis approaches for BBR nanoparticles, including chemical reduction, green synthesis, and encapsulation in nanocarriers, are discussed together with their characterization methodologies. The report emphasizes comparative studies that illustrate the enhanced antitumor efficacy of BBR nanoparticles compared to free BBR in preclinical settings. Notwithstanding encouraging results, nanoparticle stability, scalability, and regulatory obstacles must be resolved for effective clinical translation. Future directions are examined, encompassing advancements in nanoparticle design and their prospective incorporation into personalized oncology. This review highlights the transforming potential of BBR and its nanoformulations as a novel therapeutic approach in cancer treatment.

Lung cancer remains a leading cause of cancer-related mortality worldwide, with a pathogenesis deeply influenced by the tumor microenvironment. Two central and interrelated factors –hypoxia and oxidative stress – contribute significantly to tumor progression, angiogenesis, metabolic reprogramming, and therapeutic resistance. In recent years, hydrogen sulfide (H 2 S), traditionally viewed as a toxic gas, has gained recognition as a critical gasotransmitter with a regulatory role in both hypoxic and redox signaling pathways in cancer biology. Endogenously produced by enzymes such as CBS, CSE, and 3-MST, H 2 S can promote or inhibit tumorigenesis depending on the context. In lung cancer, H 2 S has been shown to modulate hypoxia-inducible factor activity, support mitochondrial bioenergetics under low oxygen tension, and influence ROS dynamics, thereby maintaining redox balance that favors tumor cell survival. The complex crosstalk between H 2 S, hypoxia, and oxidative stress creates a permissive environment for tumor growth and immune evasion, but also offers potential vulnerabilities that can be therapeutically exploited. Targeting H 2 S signaling has emerged as a promising avenue in lung cancer management. Both inhibition and controlled supplementation of H 2 S are under investigation as strategies to disrupt tumor adaptation to hypoxia and oxidative stress. This review highlights the dualistic nature of H 2 S in lung cancer progression, explores its mechanisms of action in the context of hypoxic and oxidative stress pathways, and discusses the diagnostic and therapeutic potential of modulating the H 2 S axis for improved clinical outcomes.