Journal of Cancer最新文献

Cisplatin remains a standard first-line therapy for epithelial ovarian cancer; however, chemoresistance leads to poor prognosis and high recurrence. Analysis of The Cancer Genome Atlas confirmed improved overall survival in cisplatin-sensitive tumors, underscoring the need for strategies to overcome resistance in clinical settings. Integrative bioinformatics of cisplatin-treated ovarian cancer datasets from the Gene Expression Omnibus (n=255) identified six molecular drivers of resistance: Kaiso (ZBTB33), pregnane X receptor (PXR), NF-κB, HER2 (ERBB2), P-glycoprotein (P-gp/ABCB1), and HIF1A. These targets were validated in ovarian tumor specimens via immunohistochemistry, confirming elevated expression in chemo-resistant disease. Additionally, the quantitative real-time PCR analysis confirms the transcriptional upregulation of the six resistance-associated genes in cisplatin-resistant SKOV3 and OVCAR-5 ovarian cancer cells, consistent with the immunohistochemistry findings. The average fold change in mRNA transcripts ranged from 2.4 for P-glycoprotein to 5 for both NF-kB and Kaiso. Although less well studied in ovarian cancer, Kaiso is known to regulate EMT and tumor invasion in other solid tumors. Functional studies using SKOV3 and OVCAR-5 cell lines demonstrated that knockdown of Kaiso via RNA interference significantly increased cisplatin-induced cell death, indicating a direct role in therapeutic resistance. Furthermore, we investigated the synergistic effects of combining stearidonic acid (SDA), a plant-based omega-3 fatty acid known to inhibit NF-κB, with cisplatin on cell death in SKOV3 and OVCAR-5 cell lines, and compared the results with those of each compound used individually. Interestingly, co-treatment with stearidonic acid (SDA) synergistically enhanced the cytotoxicity of cisplatin at a lower dose in both cell models. These findings reveal a clinically relevant resistance signature and highlight the therapeutic potential of combinatorial strategies that target both transcriptional regulators (e.g., Kaiso) and inflammatory signaling (e.g., NF-κB). Dual targeting of these pathways may resensitize tumors to cisplatin and improve outcomes for patients with advanced ovarian cancer.

Glioblastomas represent the most prevalent primary brain tumors in adults. Due to their highly malignant biological behavior, they are classified as grade 4 according to the World Health Organization (WHO) classification of brain tumors. Despite the progress in understanding the molecular pathogenesis of these tumors, no curative therapy has been developed for patients with glioblastoma. In this study, an integrated comparative analysis of cyclin-dependent kinase inhibitor (CDKN) 2A/B chromosomal deletion was performed on 45 glioblastomas, representing the most frequent molecular subtypes of glioblastomas, receptor tyrosine kinase (RTK) I (n=13), RTK II (n=15), and the mesenchymal subtype (MES) (n=17). The analysis of copy number variation (CNV) profiles was conducted on CDKN2A/B losses. Subsequent statistical analysis was then applied to correlate the collected data with molecular glioblastoma epigenotypes. Loss of CDKN2A/B was found 44% (20/45) of all glioblastomas, thereby, in 46% (6/13) of RTK I, 67% (10/15) RTK II, and 24% (4/17) of MES. Statistical analysis showed that loss of CDKN2A/B is significant (p < 0.01) in RTK II compared with MES. Even though CDKN2A/B does not per se function as a molecular target, there is great potential for enhancing treatment outcomes through the restoration of the tumor-suppressing capabilities of CDKN2A/B. This strategy can be employed in therapeutic interventions and is a promising avenue for research. This efficacy of this approach demonstrates high potential, as evidenced by its efficacy in other tumors, including melanoma.

Cancer stem cells (CSCs) play pivotal roles in tumor relapse, metastasis, and therapy resistance. Interleukin 17 receptor A (IL-17RA) is a key mediator in colorectal cancer (CRC) pathogenesis and progression. Our recent study demonstrated that reduced IL-17RA expression correlates with favorable prognosis in CRC patients and suppresses tumor growth in murine models. This study aimed to investigate the role of IL-17RA in promoting cancer stem-like properties and its impact on colorectal cancer prognosis and chemoresistance. Expression levels of IL-17RA and CSC markers in CRC cells were evaluated using quantitative real-time polymerase chain reaction and Western blotting. Kaplan-Meier analysis of 68 CRC patients revealed that high IL-17RA expression is associated with poor clinical outcomes. To investigate IL-17RA's functional role, CRC cells with stable IL-17RA overexpression were analyzed for changes in CSC marker expression, sphere formation, and 5-fluorouracil (5-FU) resistance. IL-17RA overexpression significantly increased CSC marker expression, including cluster of differentiation 133 (CD133), leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), sex determining region Y-box 2 (SOX2), and enhanced tumor sphere formation and 5-FU resistance in SW620 cells. Specific inhibitors of IL-17RA signaling, such as the STAT3 inhibitor Stattic, reduced the expression of CD133, LGR5, ALDHA1, SOX2 and c-MYC, as well as tumor sphere formation in SW620 cells. These findings elucidate a novel IL-17RA-STAT3 axis that regulates CSC properties in CRC and highlight IL-17RA as a promising prognostic biomarker and therapeutic target for CRC treatment.

Introduction: Appropriate patient selection is essential for optimising outcomes in individuals with peritoneal metastasis (PM) undergoing treatment with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC). This study investigated the prognostic value of pretreatment inflammatory biomarkers and explored their ability to predict the possibility of completion of three or more PIPAC treatments. Method: This observational study analysed prospectively collected data from patients with PM of gastrointestinal or ovarian origin enrolled in the PIPAC OPC-1 or OPC-2 studies between March 2015 and January 2022. Six biomarkers were examined: Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio, Systemic Immune-Inflammation Index (SII), C-reactive protein, modified Glasgow Prognostic Score, and Prognostic Nutritional Index. Biomarkers were obtained pretreatment, and treated as continuous variables. Survival was assessed using Kaplan-Meier and Cox regression analyses, adjusting for covariates available prior to the first PIPAC. ROC analysis was used to evaluate the predictive performance. A p-value less than 0.05 was considered statistically significant. Results: The cohort consisted of 130 patients, with a median overall survival (OS) of 8.7 months. Sixty percent of the patients received three or more PIPAC treatments. Elevated levels of all six biomarkers were significantly associated with reduced OS. In the multivariate analysis, five biomarkers remained independently associated with survival. NLR and SII demonstrated moderate discriminatory power (AUC > 0.70) for predicting the completion of three or more treatments. Conclusion: Pretreatment inflammatory biomarkers are objective, readily accessible and clinically applicable tools that may support the selection of appropriate candidates for PIPAC. The findings of this study encourage the integration of biomarker assessments into future PIPAC research protocols.

Exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2) catalyze heparan sulfate chain elongation and are increasingly implicated in cancer biology, but their roles in gliomas remain incompletely defined. Here, we performed an integrative multi-omics analysis to dissect the transcriptional, epigenetic, and microenvironmental landscape of EXT1 and EXT2 across gliomas. Bulk transcriptomic data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) revealed that both EXT1 and EXT2 are upregulated in high-grade gliomas and associate with adverse survival, with EXT1 showing the strongest and most consistent prognostic impact. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) indicated that EXT1-high tumors are enriched for DNA damage and replication stress programs, cell cycle progression, inflammatory response, and stromal activation pathways, whereas EXT2 expression is preferentially linked to extracellular matrix remodeling, cytoskeletal organization and angiogenesis-related signaling. Single-cell RNA sequencing and Immune deconvolution using Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) showed that EXT1 correlates with increased stromal and immune scores, and reduced cytotoxic T cell signatures, consistent with an immunosuppressive tumor microenvironment. EXT2 expression is enriched in gliomas with pronounced vascular and mesenchymal features, supporting a complementary role in invasive growth and tissue remodeling. Immunohistochemistry on a glioma tissue microarray validated the upregulation of EXT1 protein in high-grade tumors. The study findings identified EXT1 as a central glycosylation-linked regulator of replication stress tolerance and immune remodeling in gliomas, and suggest that EXT2 contributes to extracellular matrix and cytoskeletal reprogramming. The exostosin axis represents a promising source of prognostic biomarkers and potential therapeutic targets in glioma.

Cancer cell dormancy is associated with tumor recurrence and metastasis. Chemotherapy usually induces dormancy as external pressure on the tumor. Dormant cells have considerable resistance to antitumor drugs, although they are not harmful to the host if they do not wake up. Chemotherapy induces a dormant phenotype through remodeling of the tumor microenvironment and alteration of intracellular signaling networks. Multiple adaptive mechanisms that confer drug resistance have been identified in these dormant cells, including the unfolded protein response to endoplasmic reticulum stress, metabolic reprogramming favoring oxidative phosphorylation to avoid damage from oxidative stress, and autophagy to realize the circular utilization of energy. However, dormancy is reversible. The conversion between dormancy and awakening of the tumor during chemotherapy and the recovery period after treatment is modulated by several factors, including the dose and cycle of treatment, and individual differences among patients. The direct elimination of cancer cells or permanent dormancy by chemotherapy predicts favorable outcomes. According to this theory, understanding the mechanisms of cancer dormancy and awakening under chemotherapy and improving prognosis using suitable treatment strategies requires further investigation. This review analyzed studies on cancer cell dormancy and response to chemotherapy to identify potential novel interests for future studies and probable strategies to optimize chemotherapy in clinical trials.

Metabolic reprogramming is an important feature in non-small cell lung cancer (NSCLC) that can result in therapeutic resistance. Exploring dysregulated lipid metabolism in NSCLC will accelerate the development of potential lipid biomarkers to target and control the malignant progression of NSCLC. In this study, RNA next-generation sequencing of 25 paired NSCLC specimens and adjacent normal tissues was used to find that carboxylesterase 3 (CES3) was upregulated in NSCLC. Knockdown of CES3 significantly inhibited NSCLC cell proliferation and invasion. Additionally, CES3 inhibition promoted lipid accumulation in NSCLC cells. Furthermore, we found transcription factor AP-2α (TFAP2A) could regulate CES3 levels in NSCLC. TFAP2A was found upregulated in NSCLC and correlated with poorer outcome. Inhibiting TFAP2A resulted in suppressed cell proliferation as well as invasion while increasing the lipid accumulation in NSCLC. CES3 overexpression could reverse the impact of TFAP2A inhibition on NSCLC progression. In summary, TFAP2A dysregulation resulted in CES3 overexpression and the following NSCLC tumorigenesis. Targeting the TFAP2A/CES3 axis may represent a promising therapeutic strategy for NSCLC in the future.

Colorectal cancer (CRC) is the third most common malignancy and leading cause of mortality worldwide. Tumor microenvironment (TME) strongly influences CRC growth, immune evasion, and metastasis. Among various immune cells, tumor-associated macrophages (TAMs) act as key regulators of cancer progression. Although traditionally classified as M1 (pro-inflammatory, anti-tumor) or M2 (anti-inflammatory, pro-tumor), single-cell RNA sequencing and spatial transcriptomics have revealed that macrophage phenotypes exist along a continuum, challenging the classic dichotomy. This review investigates macrophages throughout CRC development, from normal mucosa to adenoma, primary tumor, and liver metastasis. Early adenomas feature M1-like macrophages that drive local inflammation, whereas advanced adenomas and invasive CRC comprise M2-like macrophages promoting angiogenesis, extracellular matrix remodeling, and immunosuppression. TAMs are crucial in CRC metastasis, particularly to the liver. M2-polarized Kupffer cells express CD206 and CD163, secrete hepatocyte growth factor, and activate PI3K/AKT signaling, thus aiding extravasation, survival, and proliferation of metastatic cells. They also foster lymphangiogenesis and immunosuppression through release of IL-10 and TGF-β. CRC's consensus molecular subtype (CMS) impacts the profile of TAMs: CMS1 (microsatellite instability-high) tumors typically harbor an anti-tumor M1 macrophages, while CMS4 (mesenchymal) tumors are enriched in M2-like TAMs, which facilitate stromal remodeling and angiogenesis, ultimately contributing to a poor prognosis. Spatial distribution also matters. Abundant M1 macrophages at the invasive margin correlate with better outcomes, whereas M2 macrophages in tumor centers and metastatic sites drive disease progression. Some CD206+ macrophages, however, support vascular normalization, which can limit metastasis. These findings underscore the complexity of TAMs in CRC and highlight the necessity of multi-marker phenotyping. Given the limitations of the M1/M2 paradigm, advanced techniques such as spatial transcriptomics and single-cell RNA sequencing offer novel insights into TAM heterogeneity. Future therapeutic strategies targeting TAMs, including metabolic reprogramming, epigenetic modulators, and immune checkpoint inhibitors, hold promise for improving CRC patient outcomes by shifting the balance toward an anti-tumor immune response.

Lung cancer remains the leading cause of cancer mortality. The AP-1 adaptor complex, including AP1AR, AP1S1, AP1S2, AP1S3, AP1M1, AP1M2, AP1B1, and AP1G1, functions as a conserved hub of vesicular trafficking, selecting cargo and coordinating clathrin-mediated transport. By shaping receptor recycling, membrane composition, and signal duration, AP-1 influences core cancer phenotypes such as proliferation, migration, and therapy response. However, the family-level role of AP-1 adaptors in lung cancer is incompletely defined. We systematically profiled all eight AP-1 adaptor genes using multi-omics datasets, survival resources, pharmacogenomic panels, Human Protein Atlas data, pathway enrichment, and single-cell RNA sequencing with cell-cell communication modeling. AP1AR was consistently upregulated in lung adenocarcinoma and independently associated with poorer overall survival. It was linked to cell-cycle progression, DNA replication checkpoints, hypoxia, and epithelial-to-mesenchymal transition (EMT). At single cell resolution, AP1AR also regulate malignant epithelial and fibroblast cell types. Pseudotime analyses revealed progressive activation along proliferative and EMT axes, and CellChat modeling indicated enhanced stromal and epithelial signaling. AP1S3 and AP1S1 showed complementary roles, associated with oncogenic/inflammatory signaling and immune-metabolic programs, respectively. These findings identify AP1AR as a clinically relevant biomarker and highlight AP-1 adaptor biology as an underexplored contributor to lung adenocarcinoma progression and therapeutic stratification.

Target therapy is effective for epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC). However, resistance often occurs after treatment for several months. Macrophages have difficulty in devouring resistant cells. Ganoderma immunomodulatory protein (GMI) exhibits anti-tumour and immunomodulatory activities. This study aimed to investigate whether GMI overcomes Osimertinib (Tagrisso) and Gefitinib (Iressa) resistance via enhancing macrophage polarization. GMI attenuated signal transducer and activator of transcription 3 (STAT3) phosphorylation and downstream CD47 expression in parental and resistant cells via Western blot and RT-qPCR. Overexpressed STAT3 restored GMI-induced apoptosis and GMI-reduced transcription of CD47 in HCC827 and H1975 lung cancer cells. Phospho-STAT3 inhibitor (W1131) also reduced the expression of CD47 in NSCLC cells. The interaction between GMI and W1131 was effective in reducing phosphorylated STAT3 and CD47. ImageXpress Pico analysis revealed that GMI enhanced phagocytotic activity of macrophages toward tumour cells with Red CMTPX and Green CMFDA dyes. The results showed that GMI enhanced macrophage phagocytosis of lung cancer cells by inhibiting STAT3 and reducing CD47 expression. In addition, GMI enhanced M1 inhibition of M2 polarization but had no effect on M1 differentiation. This is the first study to demonstrate that GMI enhances macrophage phagocytosis and modulates the STAT3-CD47 axis to overcome EGFR-TKI resistance in NSCLC, highlighting its potential as a novel adjunct immunotherapeutic agent.