Cancer Science最新文献

Stromal cells are an essential component of the tumor microenvironment (TME) in multiple myeloma (MM). Indoleamine 2,3-dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), plays an immunosuppressive role in the TME. We previously reported that a high Kyn/Trp ratio was associated with poor prognosis in lenalidomide-treated refractory/relapsed MM patients and that IDO expression in stromal cells was upregulated by co-culture with MM cells. Here, we analyzed the mechanism through which MM cells upregulate IDO in stromal cells and aimed to identify compounds that inhibit IDO upregulation. Two MM cell lines, XG-7 and IM-9, upregulated IDO in stromal cells both directly and indirectly. These two MM cell lines also upregulated programmed cell death ligand 1 (PD-L1) in stromal cells, which was closely related to IDO upregulation. RNA sequencing analysis revealed that cytokine signaling pathways were commonly upregulated in stromal cells co-cultured with these two MM cell lines. In stromal cells co-cultured with MM cells, signal transducer and activator of transcription 1 (STAT1) and nuclear factor-κB (NF-κB) p65 was phosphorylated, and interferon regulatory factor 1 (IRF1), which binds to the IDO promoter region, was strongly upregulated. This IDO and IRF1 upregulation were abolished by Janus kinase (JAK) inhibitor. In addition, stromal cells with knockout of IRF1 showed little upregulation of IDO when co-cultured with MM cells. These results suggest that the JAK-STAT1-NF-κB-IRF1 signaling pathway may be involved in IDO upregulation. JAK inhibitors may improve the TME in MM and positively influence immunotherapy outcomes.

Malignant ovarian germ cell tumors are rare neoplasms primarily affecting young women. Although generally responsive to chemotherapy, long-term adverse effects remain a concern. Improved understanding of the tumor microenvironment may reveal alternative therapeutic strategies; however, comprehensive analyses in malignant ovarian germ cell tumors remain limited. We analyzed 56 malignant ovarian germ cell tumor samples: 23 dysgerminomas, 14 yolk sac tumors, and 19 immature teratomas. Immune cell infiltration and immune checkpoint molecule expression were evaluated via immunohistochemistry, while immune-related gene expression was assessed using transcriptomic profiling. In dysgerminoma, T-cell exhaustion was characterized through multiplex immunofluorescence. Major histocompatibility complex class I expression was assessed across all subtypes. Dysgerminomas showed abundant CD4⁺ and CD8⁺ T-cell, B-cell, and M1 macrophage infiltration, with the presence of tertiary lymphoid structures, indicating an immunologically active "hot tumor" phenotype. Immune checkpoint molecules were upregulated, and transcriptomic analysis revealed enrichment of immunostimulatory and immunosuppressive pathways. Conversely, yolk sac tumors were dominated by M2 macrophages, while immature teratomas exhibited minimal immune cell infiltration, a "cold tumor" feature. In dysgerminomas with high programmed cell death protein 1 levels, most CD8⁺ T cells exhibited a nonexhausted phenotype. All tumor subtypes showed loss of major histocompatibility complex class I expression. These findings indicate that malignant ovarian germ cell tumor subtypes harbor distinct tumor microenvironments, with dysgerminoma characterized by abundant but potentially ineffective T-cell responses owing to absent major histocompatibility complex class I-mediated antigen presentation. Therapeutic strategies restoring major histocompatibility complex class I expression may enhance T cell-based immunotherapy efficacy in dysgerminomas.

R-loops are three-stranded nucleic acid structures comprising an RNA/DNA hybrid and a displaced single-stranded DNA. While transient R-loop formation is essential for various physiological processes, their persistent accumulation leads to genomic instability. Cancer cells exhibit elevated R-loop levels due to hypertranscription, replication stress, and impaired DNA repair pathways. In this review, we provide a comprehensive overview of the molecular machinery that resolves R-loops, including chromatin remodelers, transcriptional regulators, nucleases, and helicases. We also highlight the emerging roles of long noncoding RNAs (lncRNAs) in modulating R-loop dynamics and explore how these RNA-based mechanisms cooperate with canonical resolution pathways. Finally, we explore the potential of targeting R-loop regulatory networks as a novel therapeutic strategy in cancer treatment.

The prognostic significance of mitochondrial status after neoadjuvant chemotherapy (NAC) and its association with the tumor microenvironment (TME) in esophageal squamous cell carcinoma (ESCC) remains unclear. We analyzed 202 ESCC patients who underwent NAC followed by surgical resection. Mitochondrial status was quantified using an objective, immunohistochemistry-based scoring system (Mito-score). The optimal cut-off value was determined by receiver operating characteristic curve analysis. Clinicopathological features, TME parameters (T-cell density and programmed death ligand-1 [PD-L1] expression), and survival outcomes were compared between high and low Mito-score groups. Multivariate Cox regression identified independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS). The high and low Mito-score groups comprised 140 (69.3%) and 62 (30.7%) patients, respectively. NAC response rates and ypStages III-IV frequencies were similar in the two groups. PD-L1 expression was significantly higher in high Mito-score tumors (p = 0.04), while T-cell densities did not differ. High Mito-score was associated with significantly worse OS (3-year OS: 51.9% vs. 72.6%, p = 0.001) across both ypStages I-II (p = 0.047) and ypStages III-IV (p = 0.01) subgroups. In ypStages III-IV, high Mito-score was also linked to poorer CSS (p = 0.01). Multivariate analysis confirmed high Mito-score to be an independent predictor of unfavorable OS and CSS. Overall, high Mito-score after NAC identifies ESCC patients with significantly poorer survival, particularly among those with advanced pathological stages, thereby possibly serving as an independent prognostic biomarker.

MYC and MYCN oncogenes are frequently upregulated in human liver cancers, yet their functional differences remain unclear. We used a mouse model of intrahepatic cholangiocarcinoma (CCA), constructed by transposon-mediated somatic gene integration of AKT and YAP into hepatocytes, to investigate the effects of additional integration of Myc or Mycn. Both Myc and Mycn induced a poorly differentiated hepatocellular carcinoma (HCC) component, resulting in the formation of combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Interestingly, the ratio of HCC to CCA components differed significantly; AKT/YAP/Mycn (AYN) tumors exhibited a lower proportion of CCA components than AKT/YAP/Myc (AYM) tumors. To explore the underlying mechanisms, we analyzed the expression levels of genes involved in liver differentiation. We found that AYN tumors, at both the mRNA and protein levels, exhibited lower expression of HNF1B, a transcription factor that is highly expressed in human CCA but not in HCC. When Hnf1b was co-introduced with AYN, the percentage of the CCA area increased significantly. Furthermore, these tumors exhibited increased expression of TEAD proteins, which interact with YAP to initiate transcription. Notably, treatment with a YAP-TEAD inhibitor suppressed AKT/YAP/Mycn/Hnf1b tumor growth. These findings indicate that Myc and Mycn play distinct roles in the phenotypic determination of primary liver tumors and suggest that their differential effects on Hnf1b expression and subsequent TEAD activation may be a key regulatory mechanism.

Decades of research into the immune regulation of cancer have revolutionized oncology, leading to the clinical success of immune checkpoint inhibitors. In contrast, the roles of nonimmune systems in tumor regulation remain largely undefined. Our recent study of cancer bone invasion has uncovered a previously unrecognized host defense mechanism: stromal cells in the periosteum, the membranous tissue enveloping the bone, actively respond to tumor proximity and facilitate periosteum thickening that physically impedes tumor invasion into the bone. We propose a new concept, "stromal defense against cancer (SDAC)," a unique mechanism of tumor regulation orchestrated by stromal cells. In this review, we summarize the molecular and cellular mechanisms underlying SDAC and discuss its clinical implications.

To clarify locations and mutually exclusive subsets of SPP1⁺tumor associated macrophages (SPP1⁺TAMs) in lung adenocarcinoma (LUAD). Analyze the polarization type, mutually exclusive cell subset, and spatial location of SPP1⁺TAMs based on the transcriptome data of the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database, single-cell and spatial transcriptome data of the Gene Expression Omnibus database (GEO), immunohistochemical data of the Human Protein Atlas (HPA) database and local LUAD to provide a scientific basis for precision treatment of LUAD. Secreted phosphoprotein-1 (SPP1) was identified as the central regulatory gene of LUAD. The single-cell transcriptome data showed that SPP1 is up-regulated in invasive lung carcinoma (ILC), while macrophage receptor with collagenous structure (MARCO) is up-regulated in adenocarcinoma in situ (AIS). MARCO⁺M2 macrophages and SPP1⁺M2 macrophages clustered in different positions in the uniform manifold approximation and projection (UMAP) to form mutually exclusive cell subsets. SPP1⁺M2 plays a major role in ILC and MARCO⁺M2 plays a major role in AIS. The spatial transcriptome data showed that some SPP1⁺M2 were clustered at the edge of the tumor, and this particular spatial location may increase tumor invasiveness. Further spatial distance analysis showed that the distance was greater from the SPP1⁺M2 to alveolar type 2 epithelial cell (AT2) than from the MARCO⁺M2. Immunohistochemical analysis showed that SPP1 expression was up-regulated in the tumor or ILC group and notably higher in inflammatory cells. In summary, SPP1⁺M2 and MARCO⁺M2 form mutually exclusive cell subsets, and MARCO⁺M2 and SPP1⁺M2 synergistically promote different stages of tumor progression.

Redox regulation is a key mechanism supporting tumor survival and an attractive therapeutic target. In this study, we screened 1161 FDA-approved compounds to identify agents that induce reactive oxygen species (ROS) accumulation in head and neck squamous cell carcinoma (HNSCC) cells. Pimozide, a dopamine D2 receptor antagonist, emerged as the most potent ROS inducer. It selectively suppresses the growth of HNSCC cells with high oxidative stress resistance while exhibiting only modest effects on less resistant cells and normal keratinocytes. Notably, pimozide exhibited anti-tumor effects as a monotherapy and in combination with paclitaxel at clinically relevant doses. Mechanistic analysis revealed that pimozide rapidly induced ROS accumulation via a mechanism distinct from its known action on dopamine D2 receptors and STAT3/5. To identify markers of ROS-induced responses, we examined ROS-responsive genes and found that early growth response 1 (EGR1) was selectively induced in sensitive cells and correlated with pimozide responsiveness. Functional analysis revealed that EGR1 knockdown suppressed pimozide-induced cytotoxicity, suggesting its role as a functional pharmacodynamic marker of pimozide sensitivity. In a patient-derived xenograft model of HNSCC, pimozide significantly reduced the tumor burden alone and in combination with paclitaxel. While tumor volume reduction in the combination group was not statistically greater than that in the monotherapy group, fluorescence immunohistochemistry revealed a marked decrease in undifferentiated tumor cells, indicating enhanced therapeutic effects of combination treatment. Taken together, these findings indicate that pimozide is a promising candidate for repurposing as a novel therapeutic agent against HNSCC.

Unmet challenges in systemic therapy persist for advanced renal cell carcinoma (RCC) despite the widespread use of anti-angiogenetic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). We previously showed that dipeptidyl peptidase 4 inhibitor (DPP4i) improved TKI sensitivity using patient-derived RCC cells and experimental TKI-resistant models. To address whether DPP4i is clinically useful for the enhancement of RCC systemic therapy, including ICIs, we analyzed 320 cases with RCC who underwent systemic therapy. Patients with DPP4i treatment exhibited longer overall survival (hazard ratio: 0.50, 95% confidence interval: 0.30-0.82, p = 0.0060). In the Cox proportional hazards model, the use of DPP4is, along with BMI ≥ 25, no metastasis, low serum lactate dehydrogenase (LDH), and low serum C-reactive protein (CRP), was a favorable prognostic factor. Additionally, more pronounced tumor shrinkage was observed in a within-subgroup comparison of patients receiving TKI or ICI as first-line therapies. Consistently, we found that DPP4 high RCC tumors exhibit reduced immune infiltration and lower scores for effector T cell infiltration-related signatures based on the RNA sequencing data from the CheckMate-009, 010, and 025 studies. These findings can potentially change the interpretation of the prognostic impact of type 2 diabetes mellitus on RCC and bolster the rationale for initiating a prospective clinical trial to evaluate concurrent use of DPP4i with RCC therapeutic strategies.