Cancer Biology & Therapy最新文献

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally with high mortality rates, highlighting the urgent need for novel therapeutic strategies. We investigated the efficacy of combining phosphoinositide 3-kinase gamma (PI3Kγ) inhibition with programmed death-ligand 1 (PD-L1) blockade in a poorly immunogenic HNSCC model.

Materials and methods: Mouse bone marrow-derived macrophages (BMDMs) were differentiated and polarized in the presence or absence of the PI3Kγ inhibitor IPI-549 or culture supernatants from MOC2 cells treated with or without IPI-549. MOC2 cells were orthotopically injected into C57BL/6 mice, and treated with anti-PD-L1, IPI-549, combined anti-PD-L1 and IPI-549 or vehicle control. Tumor burden, survival, and immunological responses were evaluated.

Results and conclusion: Dual inhibition of PI3Kγ (using IPI-549) and PD-L1 demonstrated nearly significant reduction in primary tumor burden and significantly increased survival compared to single or control treatments. PI3Kγ inhibition promoted macrophage differentiation toward an antitumoral M1 phenotype. In the bone marrow, dual therapy significantly increased MHC-II expression across various myeloid cell subsets and effectively normalized myelopoiesis. Notably, combination therapy increased CD8+ T-cell infiltration into tumors while decreasing T-cell exhaustion marker (LAG-3, CTLA-4, and TIM-3) and protumoral cytokine (IL-4). Combined PI3Kγ and PD-L1 inhibition offers a promising strategy for treating poorly immunogenic HNSCC by simultaneously targeting multiple immunosuppressive mechanisms. These findings provide a strong rationale for combining PI3Kγ and PD-L1 inhibitors as a therapeutic strategy for poorly immunogenic HNSCC, potentially improving clinical outcomes for patients.

Background: Gliomas, including glioblastomas (GB) and high-grade astrocytomas (HGA), are the most common brain tumors in adults, with poor survival rates around 15 months. Hormonal factors, particularly progesterone receptor (PR) activation, promote tumor growth. Current treatment involves surgery, radiotherapy and chemotherapy (temozolomide), but survival rates remain low. Repurposing mifepristone (MF), a contraceptive drug, shows promise for GB treatment, warranting further study.

Methods: PR expression in U87, U251 and C6 cell lines were assessed using immunofluorescence and Western Blot. PR isoforms were quantified by densitometry. Progesterone (P4) and 5α-dihydroprogesterone (5α-DHP) synthesis were evaluated using LC/MS. MF's effect on cell viability was determined by IC₅₀ and IC₂₀ values. Its impact on non-tumoral cells and 3D glioma sphere formation was also analyzed. The effects of in situ administration of MF were assessed in vivo using a rat model with C6 glioma implants. Clinical outcomes were evaluated in GB patients receiving MF alongside standard treatment.

Results: PR was predominantly nuclear in all cell lines, with U87 showing the highest PR-B isoform levels. Only U251 synthesized 5α-DHP significantly. MF reduced viability in U251, U87 and C6 cells without affecting non-tumoral cells. Sphere formation efficiency decreased with MF treatment. In rats, MF reduced tumor volume dose-dependently. Clinically, MF improved patient survival from 165 to 588days and enhanced quality of life without severe adverse effects.

Conclusion: MF effectively reduces GB cell viability, sphere formation efficacy and tumor volume. These findings support further investigation of MF as a therapeutic strategy in GB treatment.

Précis (condensed abstract): Our research highlights the critical role PR in GB progression using in vitro and in vivo models. MF, a PR modulator, effectively reduced cell viability and sphere formation in cellular assays and significantly decreased tumor volume in an in vivo study. The pilot trial demonstrated the pharmacological safety of using MF as an adjuvant in GB treatment. Patients treated with MF showed a significant increase in survival, with an 80% survival rate at 1 year compared to 0% in those who were treated with the standard treatment.

Background: The potential of Lenvatinib to synergize with combined radiotherapy and immunotherapy in LUAD remains incompletely characterized.

Methods: We investigated Lenvatinib's effects on radiation-induced PD-L1 in LUAD cells and VEGFR2 in HUVECs via Western blot, VEGFA expression via RT-qPCR/ELISA, and angiogenesis via immunofluorescence. LUAD-HUVEC crosstalk was modeled in vitro. In C57BL/6 mice bearing LUAD tumors, we evaluated the efficacy of RT and anti-PD-L1 with or without Lenvatinib, monitoring tumor growth, survival, and profiling the tumor microenvironment by mIHC and flow cytometry.

Results: Lenvatinib suppressed radiation-induced PD-L1 and VEGFR2 expression, inhibited angiogenesis, and disrupted HUVEC-facilitated LUAD proliferation. The triple-combination (RT + anti-PD-L1 + Lenvatinib) significantly suppressed tumor progression (P < 0.05) and extended median survival (34 vs. 29.5 days, P < 0.05) versus dual therapy. It also enhanced intratumoral CD8⁺ T-cell infiltration and cytotoxicity, promoted M1-like macrophage polarization, and reduced regulatory T cell frequency and microvessel density.

Conclusions: Lenvatinib potentiates RT and anti-PD-L1 therapy in LUAD through dual immune-vascular modulation, supporting the clinical translation of this triple-combination strategy.

Background: CD276/B7-H3 is an immune checkpoint molecule often overexpressed in cancers, representing a potential therapeutic target. The underlying mechanisms for CD276 upregulation remain unclear. This study investigates how glutamine metabolism affects CD276 protein stability and esophageal squamous cell carcinoma (ESCC) progression.

Methods: CD276 and SLC1A5 expression were analyzed in 90 ESCC clinical tissues and TCGA/GEO datasets. CCK-8, colony formation, wound healing and transwell assays were performed in KYSE150 and KYSE450 cells. Autophagy was quantified by immunofluorescence and western blot. Mitochondrial reactive oxygen species (ROS) levels measured by flow cytometry. Rescue experiments used N-acetylcysteine (NAC) and chloroquine (CQ). Finally, antitumor effects of SLC1A5 inhibitor V9302 in the presence or absence of CD276 were evaluated in NOD/SCID mice (n = 5 per group) bearing KYSE150 xenografts.

Results: CD276 and SLC1A5 upregulated in ESCC tissues (P < 0.05). CD276 overexpression enhanced ESCC cell proliferation and migration by 42.3% and 58.7%, respectively (P < 0.01). CQ but not MG-132 increased CD276 expression in ESCC cells. SLC1A5 stabilized CD276 protein without altering CD276 mRNA levels, by suppressing ROS-dependent autophagic degradation. NAC reversed ROS-induced CD276 degradation, while CQ abrogated CD276 downregulation upon glutamine metabolism inhibition. Inhibiting glutamine metabolism could reverse ESCC cell proliferation induced by CD276 overexpression. Moreover, combination of V9302 and CD276 knockout significantly reduced KYSE150 cell-derived xenograft tumor volume by 65.2% (95% CI 58.3-72.1%, P < 0.001) in NOD/SCID mice, without affecting mouse body weight (P > 0.05).

Conclusion: SLC1A5 enhances CD276 stability by suppressing ROS-autophagy signaling, promoting ESCC progression. Targeting glutamine metabolism to enhance CD276 degradation might be a novel therapeutic strategy for ESCC.

Background: Current risk stratification for neuroblastoma (NB) relies on limited markers like MYCN amplification. Coilin, a key Cajal body component, regulates cellular processes. This study investigates whether coilin expression in bone marrow (BM) serves as a predictive biomarker for NB progression and elucidate its function in this disease.

Methods: The functions and molecular mechanisms of coilin were investigated by employing cell lines and animal models. Coilin mRNA levels in patient samples were measured by RT-PCR, and their relationships with clinicobiological characteristics and outcomes were analyzed.

Results: Cisplatin induced dramatic changes of coilin distribution and expression. Databases showed that high expression of coilin exerted predictive values for poor outcome in NB. Coilin promoted proliferation in vitro and in vivo. Knockdown of coilin expression inhibited cell migration and invasion, promoted apoptosis and increased the Cisplatin drug sensitivity. Moreover, coilin activates p53/p21 signaling pathway and was a direct target of MYCN. Analysis of BM samples demonstrated that high expression of coilin was obviously associated with adverse clinical biological features. Importantly, the levels of coilin at diagnosis were markedly higher than those at the time before maintenance treatment in the exact paired patients. Survival analysis presented that high coilin expression in BM is associated with poor prognosis.

Conclusions: A novel and accessible coilin-targeted liquid biopsy method was developed, capable of detecting minimal residual disease (MRD) in early-stage NB and predicting disease progression and recurrence. Coilin was transcriptionally regulated by MYCN, offering potential avenues for the development of novel drugs or intervention strategies.

Background: ZMIZ2, an androgen receptor (AR) transcriptional co-regulator, promotes prostate cancer (PCa) cell proliferation by interacting with AR to upregulate genes associated with cell proliferation; however, its specific cooperative mechanisms remain unclear. This study aims to elucidate these mechanisms.

Materials and methods: We analyzed the expression level and prognostic significance of ZMIZ2 in PCa using bioinformatics methods. ZMIZ2 expression and its correlation with the Gleason score were analyzed using clinical samples. LNCaP cells with ZMIZ2 overexpression or AR knockdown were employed to evaluate cell proliferation. RNA-seq, qPCR, Western blot, and co-immunoprecipitation were used to explore the molecular mechanisms. In vivo xenograft models were utilized to validate the effects.

Results: ZMIZ2 expression was significantly higher in PCa tissues and positively correlated with the Gleason score. Overexpressing ZMIZ2 robustly promoted LNCaP cell growth, but this promoting effect was dramatically lessened in the absence of AR expression. Mechanistically, ZMIZ2 recruited multiple acetyltransferases and formed a transcriptional complex with the N-terminal domain of AR, which bound to the promoters of cell cycle-related genes CDK1, CCNA2, and CCNE2, leading to upregulated transcription. Both in vitro cell culture experiments and in vivo models supported ZMIZ2's role in promoting proliferation.

Conclusion: ZMIZ2 promotes PCa cell proliferation through the AR signaling pathway by regulating key cell-cycle genes, highlighting it as a potential therapeutic target.

Background: PARP inhibitors (PARPis) are new targeted agents that exploit homologous recombination DNA repair deficiencies (HRDs), which are present in 50% of high-grade serous carcinoma (HGSC) cases. Currently, olaparib is approved as maintenance therapy for BRCA1/2-mutated HGSC, and niraparib is approved for platinum-sensitive recurrent disease. However, research is currently expanding their potential as front-line agents or in combination with carboplatin, a standard HGSC chemotherapeutic.

Methods: Immortalized ovarian cancer (iOvCa) cell lines, developed from HGSC patient ascites, were treated with carboplatin, olaparib and niraparib to determine their sensitivity. Immunofluorescence analysis of RAD51 was conducted for HRD testing of all the cell lines. The cell lines were cultured as three-dimensional organoids and spheroids to mimic tumor growth and metastasis, respectively, and then treated to assess the effects of different drug combinations.

Results: The half-maximal inhibitory concentrations of olaparib and niraparib varied across our iOvCa cell lines, with iOvCa195 BRCA1-mutant line exhibiting the expected high sensitivity to both PARPis. Direct combination of carboplatin with olaparib or niraparib enhanced cell killing, yet achieved cell viability levels to those of carboplatin alone. In sequential experiments, carboplatin followed by either PARPi or vice versa showed no significant difference in cell viability to carboplatin alone, except in iOvCa195 organoids when treated with a PARPi first.

Conclusions: Overall, first-line carboplatin treatment remains ideal, yet there may be select utility for PARPi prior to chemotherapy. Using patient-derived tumor models such as spheroids and organoids may provide insights for on-going and future clinical trials to enhance therapeutic outcomes for HGSC patients.

Background: Accumulating evidence suggests that deregulated long non-coding RNAs (lncRNAs) drive breast cancer (BRCA) progression. This study investigated the expression profile and mechanism of PGM5P4 antisense RNA 1 (PGM5P4-AS1) in BRCA.

Materials: The differentially expressed lncRNAs in BRCA were identified using the GEO dataset. Cancer and adjacent tissues were obtained from BRCA patients. Real-time quantitative polymerase chain reaction was used to quantify the expression of PGM5P4-AS1, microRNA (miR)-3664-5p, and Krüppel-like factor 9 (KLF9). The Chi-squared test was used to assess the clinicopathological correlation of PGM5P4-AS1. Kaplan-Meier curves and Cox regression were used to evaluate their prognostic significance. Cell Counting Kit-8 kits, flow cytometry, and Transwell assays were used to assess cell proliferation, migration, invasion, and apoptosis. Dual-luciferase reporter and RNA immunoprecipitation assays were used to analyze the gene-target interactions.

Results: PGM5P4-AS1 downregulation in BRCA was consistently documented across three GEO datasets. In BRCA cancer tissues, both PGM5P4-AS1 and KLF9 were significantly downregulated, whereas miR-3664-5p was noticeably upregulated. A reduction in PGM5P4-AS1 was associated with tumor differentiation, tumor node metastasis staging, and lymph node metastasis. Low PGM5P4-AS1 expression independently predicts poor survival. Further, miR-3664-5p noticeably reverses the suppression of cell proliferation, migration, and invasion, as well as the promotion of apoptosis, induced by PGM5P4-AS1 overexpression. Mechanistically, miR-3664-5p targets PGM5P4-AS1/KLF9 directly, and KLF9 silencing reverses the cellular function inhibition caused by miR-3664-5p downregulation.

Conclusion: This study first shows that decreased PGM5P4-AS1 in BRCA patients links to poor prognosis, promotes malignancy via miR-3664-5p/KLF9 axis, offering new therapy and prognosis in sight.