Cancer Cell International最新文献

Background: Tumorigenesis is a complex and dynamic process in which the tumor microenvironment (TME) plays a central role. In solid tumors, the TME contributes to key mechanisms of tumor progression, including metastasis, immune evasion, and resistance to therapies. One major challenge in preclinical cancer research is the development of reliable three-dimensional (3D) in vitro models, which more accurately replicate the in vivo tumor architecture and microenvironmental conditions, such as hypoxia and extracellular matrix (ECM) organization. However, reproducing functional vascular networks and neo-angiogenesis within these models remains a key challenge.

Methods: In this study, an advanced 3D tumor model, referred to as angiotumoroids, was developed by co-culturing primary murine breast tumor cells (PTCs) with species-specific adipose-derived microvascular fragments (MVFs). Angiotumoroids were characterized using scanning electron microscopy and immunostaining, and angiogenesis was evaluated through collagen gel sprouting assays. High-resolution proteomic profiling was conducted, focusing on signatures associated with angiogenesis, extracellular matrix (ECM) composition, and tissue remodeling. Additionally, the response and internalization to anticancer drug treatments were evaluated.

Results: MVFs are successfully integrated in angiotumoroids, resulting in the formation of vasculature-like structures and demonstrating robust structural organization with dynamic modulation of matrix metalloproteinase 9. Formation of neovasculature was visualized through sprouting and branching, driven by both direct PTC-MVF interactions and PTC-conditioned media, highlighting the roles of juxtacrine and paracrine signaling. Proteomic profiling revealed distinct expression patterns associated with angiogenesis, ECM components (including collagen types I and IV), and active ECM remodeling with elevated MMP expression. Additionally, angiotumoroids showed increased expression of ATP-binding cassette (ABC) transporters, particularly ABCB1 (P-glycoprotein), suggesting potential mechanisms of drug efflux. Functionally, angiotumoroids demonstrated reduced sensitivity to doxorubicin compared to PTC spheroids, maintaining structural integrity and higher cell viability post-treatment. Time-course analysis revealed preferential doxorubicin accumulation in MVF-enriched regions, as confirmed by colocalization with CD31, indicating a spatially regulated distribution of the drug mediated by the vascular compartment.

Conclusions: Collectively, these findings establish angiotumoroids as a robust and physiologically relevant in vitro model for studying tumor vascularization, ECM dynamics, and therapeutic response. This platform holds significant promise for predictive cancer research and preclinical drug screening, bridging the gap between traditional in vitro systems and in vivo models.

Long non-coding RNAs (lncRNAs) are broad-spectrum cellular transcripts that can directly act as RNA regulators and/or partly encode functional peptides (lncRNA-encoded peptides, LRPs) in cancer cells. Recently, cancer LRPs have been found to be involved in cancer cell variability and proliferation, thus gaining widespread attention for their potential in cancer diagnosis, prognosis and therapy. As structures determine functions, the structural diversities of LRPs are the sources of functional variations of LRPs in cancers. Since 6135 cancer LRPs are listed in SPENCER database and 24 SPENCER-unlisted cancer LRPs are reported in several previous studies, this article reviews recent advances of cancer LRPs, analyzes amino acid compositions of them, and undertakes in silico evaluations to assess their structural and functional attributes. These LRPs are dominated by the amino acids Glu, Leu, and Ser and are rarer in the amino acids Cys, His, and Trp, and that many of the LRPs are rich in secondary or tertiary structures. Like mRNA-encoded peptides, these structure-rich cancer LRPs have a wide range of functions, including anti-cancer, cell-penetrating, anti-inflammatory, and antibacterial activities. Relatively, two groups of anticancer values (predicted by AntiCP 2.0 and PreTP-Stack) of these LRPs commonly showed positive and negative correlations with their total charge content and metal-bind aa content, respectively. The increasing amount of data and analysis on cancer LRPs, as reported here, offers opportunities to enhance practical cancer diagnosis and treatment, and to overcome remaining research challenges for cancer LRPs.

Gliomas represent one of the most common types of primary brain tumor. Due to their poor prognosis and propensity for recurrence, new therapeutic targets are urgently required. A consensus is emerging that there is a significant relationship between tumor formation and embryonic development. However, the precise mechanisms and regulatory targets remain unclear. A variety of bioinformatics techniques, including GSVA, differential expression analysis, machine learning algorithms and others, were employed to elucidate the significance of germ layer development (GLD) in glioma and identify MEST as the key gene. To validate the results, in vivo and in vitro experiments were conducted, including tumor xenografts, RT-qPCR, immunocytofluorescence, transwell assays and others, which confirmed the central role of the selected oncogenic gene. Here, we performed a comprehensive bioinformatics analysis of GLD genes, providing a novel insight into the landscape of the GLD in gliomas, and confirmed the GLD-related gene MEST as a key oncogenic therapeutic target via machine learning feature selection framework. Furthermore, we have identified the core gene MEST and have conducted extensive research to elucidate its pivotal role in glioma progression through in vivo and in vitro experiments. We leveraged the GLD patterns in glioma and found that the MEST might promote the glioma development through activating RAS signaling and Wnt signaling.

Background: Oral cancer (OC) is the most common type of head and neck cancer, with a high mortality rate, and is a leading cause of cancer-related deaths worldwide. Drug-induced ferroptosis is a novel form of non-apoptotic cell death that offers a promising strategy for cancer therapy. Accumulating evidence has emphasized the significant role of methotrexate (MTX) in the treatment of many malignancies; however, its role in the ferroptosis pathway in OCs and its underlying mechanisms remain poorly understood.

Methods: After treating the OC cells with MTX, several cellular function assays were performed, including cell proliferation, apoptosis, colony formation, and wound healing assays. Distinctive features of ferroptosis were detected, and qPCR and western blot (WB) assays were performed to validate the expression of genes and proteins related to ferroptosis pathways in MTX-treated cells. In vitro experiments were conducted to further explore the mechanisms by which MTX regulates the stability of nuclear factor erythroid 2-related factor 2 (NRF2) in OC cells. Finally, in a mouse model using MOC1 cells, some experiments were performed to demonstrate MTX-induced ferroptosis and tumor suppression.

Results: In this study, based on in vitro and in vivo experiments, we found that MTX significantly reduced OC cell viability by inducing ferroptosis. Mechanistically, MTX administration increased the phosphorylation of Kelch-like ECH-associated protein 1 (KEAP1) at threonine 43 via activation of the ERK/MAPK signaling pathway, thereby maintaining the protein complex formed by KEAP1 and NRF2. As result of the decreased NRF2 expression, the levels of SLC7A11 and GPX4 proteins were markedly suppressed in MTX-treated OC cells, ultimately leading to the induction of ferroptosis in OC.

Conclusions: Our data demonstrated that MTX-mediated activation of the ERK/KEAP1 signaling pathway significantly induced ferroptosis by inhibiting the NRF2/HO-1/SLC7A11/GPX4 axis, thereby suppressing OC progression. These findings suggest that MTX is a promising candidate for OC treatment, offering a meaningful and effective therapeutic-strategy.

Protein tyrosine phosphatase receptor-type O (PTPRO), a member of the PTP family, has garnered attention for its diagnostic and prognostic potential through the methylation of circulating tumor DNA (ctDNA). However, the utility of ctDNA has shown limited sensitivity and specificity, particularly in early-stage lung adenocarcinoma (LUAD). Given the enhanced stability of tumor-derived DNA in small extracellular vesicles (sEVs) from cancer cells, this research investigates the feasibility of using PTPRO methylation in saliva-derived sEVs as a non-invasive and easily accessible biomarker for the early detection of LUAD. To explore the relationship between PTPRO methylation and prognosis in early-stage LUAD, we conducted Kaplan-Meier survival analyses and assessed the methylation status of the PTPRO promoter using methylation-specific PCR (MSP) and q-MSP. Saliva samples were collected from 60 early-stage LUAD patients, 30 pneumonia patients, and 21 healthy controls, with isolation and characterization of salivary sEVs through transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and immunoblotting. Kaplan-Meier analysis revealed hypermethylation of PTPRO was linked to poorer overall survival in early-stage LUAD patients. PTPRO methylation was detected in salivary sEVs of 73.3% of early-stage LUAD patients, compared to only 35% in plasma sEVs. Receiver operating characteristic (ROC) analysis confirmed that PTPRO methylation in salivary sEVs effectively distinguished early-stage LUAD patients from both pneumonia patients and healthy individuals. This suggests that PTPRO hypermethylation is associated with adverse prognosis in early-stage LUAD. The detection of PTPRO methylation in salivary sEVs demonstrates high sensitivity and specificity, indicating its potential as an epigenetic biomarker for the non-invasive diagnosis of early-stage LUAD.