Oncology Research最新文献

Objectives: Cisplatin (CDDP) therapy for glioblastoma (GBM) is linked with several limitations, which include poor penetration of the blood-brain barrier (BBB), systemic toxicity, and the development of drug resistance mechanisms implicating oxidative stress dysregulation and compromised apoptotic pathways. This study evaluates C-Phycocyanin (C-PC) as a potential adjuvant to enhance CDDP efficacy by modulating redox balance and apoptosis.

Methods: GBM cells (U87 and U87-EGFRvIII) were treated with CDDP, C-PC, or their combination. Cell viability was assessed by MTT assay; apoptosis was evaluated by DAPI staining and Western blot analysis of cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP). Both intracellular and extracellular reactive oxygen species (ROS) were measured using 2^',7^'-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence and lucigenin chemiluminescence, respectively. Catalase activity was quantified via hydrogen peroxide (H₂O₂) decomposition assay, and manganese superoxide dismutase (MnSOD) expression by Western blot.

Results: C-PC selectively decreased U87 GBM cell viability while sparing normal cells. C-PC enhanced CDDP cytotoxicity, reducing viability to 26.5% vs. 53.2% for CDDP alone. This effect correlated with increased apoptosis, evidenced by DNA fragmentation and higher cleaved caspase-3 and PARP levels. Combined treatment lowered ROS below survival thresholds while upregulating MnSOD and catalase activity. In U87-EGFRvIII cells, CDDP reduced viability modestly (85.2%), C-PC alone decreased viability significantly (51.5%) and induced cell death, but the combination did not further increase apoptosis. Here, C-PC's pro-apoptotic effects, alone or with CDDP, were also associated with reduced oxidative stress in cells.

Conclusion: We demonstrate that C-PC enhances CDDP cytotoxicity in sensitive U87 cells by promoting apoptosis and modulating ROS, suggesting potential for improved therapeutic efficacy with reduced systemic toxicity. Compared to the combination, C-PC monotherapy achieves superior cytotoxicity in CDDP-resistant U87-EGFRvIII cells, underscoring its potential as a standalone therapeutic approach for chemotherapy-resistant glioblastoma subtypes.

Background: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare subtype of primary non-small cell lung cancer (NSCLC), with no established treatment guidelines. We present a case of a young female with PPLELC who achieved a pathological complete response (pCR) in both primary and metastatic lesions after receiving combined immunotherapy and radiotherapy.

Case description: We present a 33-year-old female patient with stage IVa (cT2bN0M1b) PPLELC. As a first-line treatment, the patient received seven cycles of nab-paclitaxel combined with toripalimab (a PD-1 inhibitor) and achieved stable disease. This was followed by toripalimab maintenance therapy for nearly 30 months. During toripalimab maintenance therapy, the patient demonstrated slight enlargement of both lung lesions and brain lesions. Radiotherapy was subsequently administered to both locations. However, after radiotherapy, the patient exhibited radiographic progression in both lesions with associated worsening of clinical symptoms. Surgical resection of the localized lesions was clinically warranted. Unexpectedly, the final postoperative pathology revealed a pCR. The patient maintained progression-free survival (PFS) exceeding 70 months, confirming that the prior radiographic progression represented pseudoprogression. Pseudoprogression is commonly defined as radiologic tumor progression from baseline that is not confirmed as progression on subsequent radiologic evaluation. Most of the patients experiencing pseudoprogression had a good performance status (PS), were paucisymptomatic, and even experienced the improvement of tumoral symptoms. In contrast, our case presented with worsening clinical symptoms and general conditions, which we term "harmful" pseudoprogression. To our knowledge, such a case of PPLELC with a "harmful" pseudoprogression is rarely reported; moreover, the term "harmful" pseudoprogression is our original creation.

Conclusion: Our case highlights the critical role of re-biopsy and re-evaluation of imaging criteria in assessing the response to immunotherapy.

Objectives: Glioblastoma is a prevalent malignant brain tumor, and the actions of the long non-coding RNA HOXA10-AS in its invasion and migration remain unclear. Here, the function of HOXA10-AS in glioblastoma cell invasion and migration and associated mechanisms were investigated.

Methods: HOXA10-AS was knocked down in glioblastoma cells, and Transwell and wound healing assays were conducted to elucidate its impacts on cell invasion and migration. Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assessed HOXA10-AS's impact on the epithelial-mesenchymal transition (EMT). Microarray analysis identified differentially expressed genes, complemented by bioinformatics approaches to explore potential molecular participants and pathways. Rescue experiments validated our findings.

Results: HOXA10-AS knockdown significantly inhibits glioblastoma cell migration, invasion, and the EMT process. Specifically, HOXA10-AS siRNA transfection significantly reduced the migratory capacity of A172 cells by 50.5% and U251 cells by 61.4%, as well as their invasive capacities by 33.8% and 58.5%, respectively (all p < 0.05). HOXA10-AS acts as an miR-99a-3p sponge, and pathway analysis identified processes linked to tumorigenesis and metastasis, along with nine hub genes. HOXA10-AS upregulates the expression of integrin subunit beta 5 (ITGB5) through a competing endogenous RNA mechanism. The reduced tumorigenic behavior of glioblastoma cells due to HOXA10-AS knockdown can be rescued by ITGB5 overexpression or miR-99a-3p inhibitor.

Conclusion: These results indicate that HOXA10-AS promotes tumorigenic behavior in glioblastoma cells by regulating the EMT-like process and functioning as an miR-99a-3p sponge to modulate ITGB5 levels, providing insights into glioblastoma development and potential therapeutic targets.

Background: Colorectal cancer (CRC) is a predominant contributor to global cancer-associated mortality worldwide. Oxaliplatin (OXP), a foundational chemotherapeutic agent for CRC, often exhibits limited efficacy due to the emergence of drug resistance. Although endothelin-1 (EDN1) has been implicated in tumor drug resistance, its role in oxaliplatin resistance in CRC remains poorly defined. This work aimed to define how EDN1 contributes to oxaliplatin resistance and to explore its potential as a therapeutic target.

Methods: Public genomic datasets were analyzed to confirm EDN1 upregulation in colorectal cancer (CRC) and its association with poor prognosis. EDN1 expression was modulated in parental and oxaliplatin-resistant CRC cell lines via shRNA knockdown and lentiviral overexpression. Functional assays, including drug sensitivity, flow cytometry, and 5-Ethynyl-2^'-deoxyuridine (EdU) proliferation, were conducted to assess resistance. Mechanistic studies employed dual-luciferase reporter assays, Western blotting, co-immunoprecipitation, and immunofluorescence. CRC-derived subcutaneous xenograft models were used to evaluate the therapeutic efficacy of EDN1 targeting in vivo.

Results: The study identifies EDN1 as a pivotal mediator of oxaliplatin resistance in CRC. EDN1 expression is markedly upregulated in oxaliplatin-resistant CRC cells and is significantly associated with poor patient survival outcomes. Mechanistically, EDN1 overexpression activates the Yes-associated protein (YAP) signaling by promoting the nuclear translocation of β-arrestin1 (β-arr1), thereby facilitating chemoresistance. Importantly, the combinatorial inhibition of EDN1, in conjunction with oxaliplatin treatment, substantially enhances apoptosis and suppresses tumor growth both in vitro and in vivo.

Conclusion: The study demonstrates that EDN1 governs oxaliplatin resistance through the β-arr1/YAP axis and provides preclinical evidence for targeting EDN1 to overcome chemoresistance in CRC.

Traditional cancer therapies have limitations like poor efficacy on advanced tumors, healthy tissue damage, side effects, and drug resistance, creating an urgent need for new strategies. Hydrogels have good biocompatibility and controlled release, while extracellular vesicles (EVs) enable targeting and bioactive transport. This review systematically summarizes hydrogels and EVs, focusing on the construction of hydrogel-EV delivery system, key influencing factors, drug delivery mechanisms, and tumor therapy apps, clarifying their synergies. The system overcomes single-carrier flaws, construction methods/key factors affect performance, preclinical studies have confirmed efficacy in multiple therapies, but large-scale production and in vivo stability challenges remain, yet it promises to overcome the limits of traditional therapy for precision oncology.

Ovarian endometrioid carcinoma (OEC) accounts for ~10% of epithelial ovarian cancers and displays broad morphologic diversity that complicates diagnosis and grading. Recent data show that the endometrial cancer molecular taxonomy (DNA polymerase epsilon, catalytic subunit [POLE]-ultramutated, mismatch repair-deficient [MMRd], p53-abnormal, no specific molecular profile [NSMP]) also applies to OEC, and that OEC is enriched for Lynch syndrome-associated tumors, supporting routine MMR testing. We aimed to synthesize contemporary evidence spanning epidemiology, histopathology and immunophenotype, diagnostic pitfalls and differential diagnosis, and to evaluate the clinical utility of The Cancer Genome Atlas (TCGA)-surrogate molecular classification for risk stratification; we also summarize implications for Lynch screening, genetic counseling, and therapeutic opportunities including immune checkpoint inhibitors and targeted approaches, with practical recommendations for diagnostic workflows. Integrating morphology with molecular classification refines diagnosis and prognostication: POLEmut/MMRd subsets generally have excellent outcomes and are candidates for de-escalation or immunotherapy, whereas p53abn/high-grade tumors carry a poorer prognosis and may warrant intensified management and trials of homologous recombination deficiency (HRD)-directed strategies; routine MMR immunohistochemistry (IHC) with reflex germline testing improves Lynch detection, and future priorities include prospective validation and multi-omics to refine NSMP and identify new targets.

Background: The most aggressive forms of breast cancer are characterized by independence from steroid hormones but a strong dependence on growth factors. In such cancer cells, oncogenic receptors, including human epidermal growth factor receptor 2 (HER2), are activated, and their targeted inhibition represents an attractive therapeutic strategy. The study aimed to develop small-molecule potential dual heat shock protein 90 (HSP90)-HER2 inhibitors and evaluate them as anticancer agents in HER2-positive cells.

Methods: The research project involved obtaining a series of compounds with potential dual inhibitory activity against HSP90 and HER2 by targeted organic synthesis, which was preliminarily assessed using molecular modelling and calculation of key parameters of molecular dynamics. The potential therapeutic benefit of the obtained molecules was studied using basic molecular biological methods, including assessment of cytotoxic activity in vitro using the MTT test, as well as determination of a possible mechanism of action based on the expression of key participants in intracellular signaling (western blotting). Additionally, therapeutic combinations were developed and tested on a cellular model of the disease, including a lead compound and chemotherapeutic drugs used in clinical practice, in order to find synergistic pairs and improve the effectiveness of the treatment.

Results: In this work, novel dual HSP90-HER2 inhibitors, based on the fused thiazole-dihydrobenzisoxazole polycyclic scaffold, were designed and synthesized. The resulting compounds exhibited strong antiproliferative activity against HER2-positive breast cancer cells with high selectivity. Among them, ATF-2 demonstrated antiproliferative activity comparable to HER2 inhibitor lapatinib and significantly suppressed HER2 expression and activity, epidermal growth factor receptor (EGFR) activity, and cyclin-dependent kinase 6 (CDK6) expression in HCC1954 breast cancer cells.

Conclusion: These findings highlight ATF-2 as a promising dual HSP90-HER2 inhibitor with broader inhibitory effects on the HER2, EGFR, and CDK6 pathways.

Objectives: Gastric cancer (GC) is often associated with high invasiveness, epithelial-mesenchymal transition (EMT), and resistance to 5-fluorouracil (5-FU), highlighting the need for novel therapeutic targets. This study explored whether diallyl disulfide (DADS) upregulates retinoic acid-related orphan receptor alpha (RORα) to weaken the protein kinase C alpha (PKCα)/RORα-mediated RORα/β-catenin pathway, thereby inhibiting GC cell invasion, epithelial-mesenchymal transition (EMT), and enhancing 5-FU sensitivity.

Methods: Human GC cell lines MGC-803 and SGC7901 were treated with DADS, RORα agonist SR1078/antagonist T0901317, and PKCα agonist TPA/antagonist GO6976. Cell proliferation (MTT), migration (scratch assay), invasion (Transwell), protein expression (Western blot), protein interactions (coimmunoprecipitation), and localization (immunofluorescence) were detected. Apoptosis and 5-FU sensitivity-related proteins were examined. Experiments were triplicated; statistics used t-test/ANOVA (p < 0.05).

Results: DADS/SR1078 inhibited GC cell proliferation/migration/invasion, upregulated RORα/E-cadherin, downregulated nuclear β-catenin/TGF-β1/Rac1/Vimentin, and weakened EMT (reversed by T0901317). DADS/TPA upregulated RORα/p-RORα/PKCα/p-PKCα, promoted PKCα-RORα binding, and downregulated RORα/β-catenin target genes (counteracted by GO6976). DADS upregulated caspase-3 and downregulated Bcl-2/P-gp/XIAP via RORα, promoting apoptosis and 5-FU sensitivity.

Conclusion: DADS inhibits GC progression and enhances 5-FU sensitivity by PKCα/RORα-mediated downregulation of RORα/β-catenin signaling, paralleling SR1078/TPA effects. It may act as a novel RORα agonist for GC therapy.

Cholangiocarcinoma (CCA) is an aggressive cancer originating from bile duct epithelium. Surgical resection remains the primary curative treatment for CCA. However, most CCA patients are diagnosed at an advanced stage, which limits the applicability of surgical resection. Gemcitabine is widely used as a first-line chemotherapeutic agent for unresectable CCA. Its efficacy is often compromised by the development of drug resistance, which leads to poor clinical outcomes and low survival rates of CCA patients. At present, the mechanisms underlying gemcitabine resistance in CCA remain unclear. This review aimed to comprehensively summarize the current knowledge on the molecular mechanisms underlying gemcitabine resistance in CCA and highlight emerging therapeutic strategies that may overcome this resistance. Gemcitabine resistance arises through multiple mechanisms, including reduced drug uptake and increased efflux, impaired drug activation, enhanced DNA repair, apoptosis evasion, aberrations in cell-cycle progression, induction of epithelial-mesenchymal transition, metabolic reprogramming, alteration of tumor, and activation of oncogenic pathways contributes to gemcitabine resistance. A deeper understanding of gemcitabine resistance mechanisms highlights the need for combining gemcitabine with pathway-specific inhibitors, which hold promise for overcoming resistance and improving patient outcomes.

Solid tumors comprise the majority of the global cancer burden, with their incidence and associated mortality posing considerable challenges to public health systems. With population growth and aging, the burden of these tumors is anticipated to increase further in the coming decades. The progression of solid tumors depends on dynamic interactions between malignantly transformed cells and the tumor microenvironment (TME). Immune checkpoint inhibitor therapy improves T cell-mediated antitumor activity by suppressing regulatory pathways, such as programmed cell death protein 1/programmed death-ligand 1. Nonetheless, its widespread application is constrained by drug resistance. In this comprehensive review, we elucidate the latest advances in understanding the mechanisms underlying drug resistance, explore pioneering approaches, such as combination therapeutic regimens and nanoscale drug delivery platforms, and propose future avenues for research. These include investigating the intricacies of drug resistance pathways, refining combination therapy strategies, and modulating the TME, along with other key areas.