Journal of Experimental & Clinical Cancer Research最新文献

Background: Hepatocellular carcinoma (HCC) presents a significant therapeutic challenge, as current treatment options provide limited long-term benefits due to issues surrounding their effectiveness and associated adverse effects. Our previous research demonstrated that Proteoglycan-4 (PRG4) enhances the anti-proliferative effect of the multi-kinase inhibitor regorafenib in simple in vitro two-dimensional HCC models. In this study, we aimed to investigate the potential adjuvant role of PRG4 in improving the efficacy of regorafenib within both three-dimensional in vitro and in vivo HCC models.

Methods: Human HCC cells were engineered to stably overexpress PRG4. The effects of PRG4 on cell proliferation, both alone and in combination with regorafenib, were tested in monolayer cultures, Matrigel-embedded spheroids, and an orthotopic xenograft HCC mouse model. Additionally, transcriptomic profiling of spheroids generated from control or PRG4-overexpressing HCC cells, either untreated or treated with regorafenib, was performed.

Results: PRG4 expression partially inhibited HCC tumor growth in vivo and enhanced regorafenib antiproliferative activity, leading to a near-complete tumor regression. This synergistic PRG4 + regorafenib interaction in impairing HCC cell growth was further confirmed in 2D and 3D HCC models in vitro. In addition, PRG4 restrained angiogenesis by hindering endothelial tubulogenesis in vitro. By transcriptomic analysis of matrigel-embedded HCC cell spheroids exposed to PRG4 and/or regorafenib, PDGF pathway emerged as a target of PRG4 + regorafenib, corroborating the role of PRG4 in impairing angiogenesis. The G₀/G₁ phase of the cell cycle was more delayed in spheroids exposed to both PRG4 and regorafenib compared to those treated with regorafenib alone, relative to untreated cells.

Conclusions: PRG4 demonstrated antitumor activities in vivo and shows promise as an adjuvant to enhance therapeutic interventions in HCC.

Background: Tumor invasion and metastasis are strongly influenced by cell membrane fluidity, regulated by lipid metabolism. In choroidal melanoma (CM), a highly metastatic cancer, the relationship between lipid metabolism, membrane fluidity, and metastatic mechanisms remains unclear.

Methods: We examined m⁶A methylation in CM patient samples. Lipidomic profiling was performed in control, METTL14-silenced, or SCD1-silenced CM cells. Transcriptomics were analyzed after METTL14 manipulation. Transmission electron microscopy assessed ultrastructural changes, while multiplex immunohistochemistry validated the clinical relevance of the MAFG-METTL14-SCD1 axis. The anti-metastatic effect of combining the SCD1 inhibitor aramchol with a stearate-rich diet (S-HFD) was tested in nude mouse CM metastasis models.

Results: Lipidomics revealed that SCD1 promotes CM progression via cardiolipin and fatty acid metabolism pathways. Silencing SCD1 reduced membrane fluidity, while its upregulation in CM was driven by METTL14-mediated m⁶A methylation at the 2492 mRNA site. Elevated MAFG expression further activated METTL14. Mechanistically, this MAFG-METTL14-SCD1 axis enhanced CM invasiveness. In preclinical models, aramchol combined with S-HFD markedly suppressed distant metastasis.

Conclusions: Our study identifies SCD1-mediated lipid remodeling as a key driver of enhanced membrane fluidity and metastatic potential in CM. Inhibition of SCD1 increases lipid saturation, reduces membrane fluidity, induces oxidative stress, and suppresses liver and lung metastasis. The MAFG-METTL14-SCD1 axis thus represents a critical regulator of CM progression, and combined therapeutic targeting with aramchol and S-HFD offers promising translational potential.

The development and progression of gastrointestinal (GI) cancers not only depend on the malignancy of the tumor cells, but is also defined by the complex and adaptive nature of the tumor microenvironment (TME). The TME in GI cancers exhibits a complex internal structure, typically comprising cancer cells, cancer stem cells, cancer-associated fibroblasts, immune cells, and endothelial cells, all embedded within a dynamic extracellular matrix. This intricate ecosystem fuels tumor initiation, progression, metastasis, recurrence and therapy response through the heterogeneity and plasticity. Recent advances in single-cell sequencing have provided unprecedented resolution in profiling the cellular diversity and interactions within the TME. These technologies have uncovered previously unknown cell subtypes and intricate communication networks that drive therapy resistance and tumor relapse. In this review, we summarize and discuss the latest findings from single-cell sequencing of key cellular players and their interactions within the TME of GI cancers. We highlight single cell insights that are reshaping our understanding of tumor biology, with particular focus on their implications for overcoming therapy resistance and improving clinical outcomes. We believe that a deeper understanding of TME heterogeneity and plasticity at the single-cell level promises to transform the landscape of precision treatment in GI cancers.

Background: A key challenge in cancer immunotherapy is that tumor vaccines formulated with conventional aluminum adjuvants often fail to elicit potent cellular immunity and sustained antitumor responses. Glycyrrhizae polysaccharides (NGUP), characterized by significant immunomodulation, multi-target antitumor efficacy, and low toxicity, represent promising candidates for next-generation vaccine adjuvants.

Methods: We employed transcriptome analysis, quantitative real-time PCR, and Western blot assays to investigate the mechanism of NGUP in activating bone marrow-derived dendritic cells in vitro. Using confocal microscopy, small animal in vivo imaging, and flow cytometry, we examined the process of tumor antigen-specific T cell response activation by the liposomal vaccine (NGUPL@OVA) in vivo. The efficacy of NGUPL@OVA was evaluated in murine melanoma models (B16-OVA and B16-F10) through immunohistochemistry, immunofluorescence and H&E staining.

Results: NGUP activates dendritic cells through the TLR4/MyD88/TRAF6/NF-κB signaling pathway. NGUPL@OVA demonstrates efficient lymph node targeting capacity, significantly enhancing dendritic cell maturation and antigen cross-presentation, thereby promoting robust CD8⁺ T cell activation and inducing potent cellular immune responses with long-term immunological memory. In both prophylactic and therapeutic settings, NGUPL@OVA exhibits significant melanoma growth inhibition without observable toxic side effects.

Conclusions: NGUP as a novel vaccine adjuvant for cancer immunotherapy effectively overcomes key limitations of conventional aluminum adjuvants, including weak induction of cell-mediated immunity and significant adverse effects, while exhibiting superior immune-stimulating properties.

The integration of Artificial Intelligence (AI) into cancer pathology offers an imperative solution to global pathologist shortages and increasingly complex diagnostic demands. This review summarized the rapid evolution of AI in the field, highlighting the paradigm shift from task-specific (TS) algorithms towards powerful, versatile foundation models (FMs), such as UNI, CONCH, GigaPath, mSTAR, and Atlas. These models, trained on massive and diverse datasets using self-supervised and multimodal learning, demonstrate remarkable capabilities in cancer classification, subtyping, outcome prediction, and biomarker discovery. The emergence of AI "copilots", such as PathChat, SmartPath, further promises to streamline workflows through conversational interfaces and autonomous task planning. However, significant challenges impede clinical translation, including a validation crisis underscored by poor generalizability in zero-shot testing, critical concerns regarding model explainability ("black-box" nature), risks of hallucinations in generative tools, and ensuring generalizability and fairness across diverse populations. Robust external validation, standardized benchmarking, development of explainable AI approaches, and novel regulatory frameworks are essential to responsibly harness the transformative potential of foundation models and realize their promise in improving diagnostic accuracy, efficiency, and patient outcomes in cancer pathology.

Tumor endothelial cells (TECs) play a critical role in regulating immune responses within the tumor microenvironment (TME). However, the mechanisms by which TECs modulate immune cell population remain unclear, particularly in non-small cell lung cancer (NSCLC). Here, we investigated how NSCLC cells tweak normal endothelial cells (NECs) into TECs and the subsequent effects on immune regulation. NECs were cocultured with various NSCLC cell lines, using 2D and 3D coculture models to evaluate TEC-mediated effects on immune cells. We show that direct coculture led to significant transcriptomic, proteomic and kinomic alterations in TECs, especially in pro-inflammatory pathways. We identified a downregulation of the co-stimulatory molecule OX40L in TECs compared to NECs, suggesting impaired T-cell proliferation support. While TECs showed a limited effect on CD8⁺ T-cell activation, TECs supported CD4⁺ T-cells polarization into Treg and Th22 subsets. Moreover, TECs also promoted M2-like macrophages polarization, thereby potentially contributing to the TME immunosuppression. State-of-the-art single-cell RNA sequencing of 3D multicellular tumor spheroids (MCTS) revealed formidable heterogeneity in the tumor cells and cancer-associated fibroblast compartments. It also unveiled distinct TEC subpopulations, including an inflammatory subset with an unfolded-protein response signature. This TEC cluster was absent in 2D-cultured NECs but present in freshly isolated and 2D-cultured TECs from NSCLC patients. Importantly, we identified a perivascular M2-like macrophage subset within MCTS that is in close contact with TECs, and is predicted to interact with them through MIF signaling. In conclusion, TECs in NSCLC tumors play a pivotal role in remodeling the TME immune landscape by promoting immune suppression. This study highlights the complex immunoregulatory functions of TECs within different in vitro models that mimic aspects of the TME. Our data may provide new insights into potential therapeutic strategies targeting TECs or regulatory signaling to improve the efficacy of immunotherapy in NSCLC.