American journal of cancer research最新文献

This study investigated the role of urinary exosomal miR-664a-5p as a potential therapeutic target in prostate cancer (PCa). Small RNA sequencing of urinary exosomes from PCa patients with different responses to PARP inhibitors revealed that miR-664a-5p was significantly upregulated in responsive patients. Overexpression of miR-664a-5p enhanced the sensitivity of PCa cells to PARP inhibitors by directly targeting FOXM1, a transcription factor involved in DNA damage repair, leading to the downregulation of DNA damage response genes. Combined treatment with miR-664a-5p and olaparib synergistically inhibited tumor growth in a PC-3 xenograft mouse model. These findings suggest that urinary exosomal miR-664a-5p is a potential therapeutic biomarker for PARP inhibitor response in PCa patients, and targeting FOXM1 via miR-664a-5p represents a promising strategy for enhancing PARP inhibitor efficacy in PCa treatment.

This study aimed to analyze HER-2 zero or HER-2 low conversion in HER-2 negative patients after neoadjuvant chemotherapy (NAC) and evaluate its prognostic significance. HER-2 negative patients with breast cancer with residual disease after NAC and paired pre- and post-therapeutic HER-2 testing results were analyzed retrospectively. HER-2 low, defined as immunohistochemistry (IHC) scores of 1+ or 2+/in situ hybridization (ISH), were not amplified. HER-2 zero is defined as an IHC score of 0. A total of 571 patients were enrolled, including primary HER-2 zero (n=201, 35.2%) and HER-2 low (n=370, 64.8%). The overall HER-2 change rate was 32.4%. Multivariable logistic regression showed that patients with hormone receptor-positive status before NAC was significantly associated with the conversion of HER-2 zero to low (OR=3.436, P < 0.0001). The median follow-up time was 50.0 months. In patients who are primary HER-2 zero, HER-2 zero to low was significantly associated with better disease-free survival (DFS) than constant HER-2 zero (HR=0.49, P=0.01) after adjustment (4-year DFS 80.1% vs 55.7%, Log-rank P=0.033). Subgroup analysis revealed that among patients who are primary HER-2 zero with hormone receptor-positive, HER-2 zero to low had a significantly better DFS than constant HER-2 zero (Log-rank P=0.037). In contrast, patients with hormone receptor-negative status did not. In conclusion, almost one-third of patients who are HER-2 negative underwent HER-2 zero or HER-2 low conversion after NAC. HER-2 zero to low conversion was associated with better DFS in patients who are HER-2 zero. These results provide a valuable reference for the potential application of anti-HER-2 ADC in an adjuvant setting for patients with residual disease after NAC.

Paraneoplastic leukocytosis (PNL) in genitourinary cancer, though rare, can indicate aggressive behavior and poor outcomes. It has been potentially linked to cancer expressing G-CSF and GM-CSF, along with their respective receptors, exerting an autocrine/paracrine effect. In our study, we successfully established four patient-derived xenograft (PDX) lines and related cell lines from urothelial cancer (UC), conducting next-generation sequencing (NGS) for genetic studies. UC-PDX-LN1, originating from bladder cancer, exhibited two druggable targets - HRAS and ERCC2 - responding well to chemotherapy and targeted therapy, though not to tipifarnib, an HRAS inhibitor. Transcriptome analysis post-treatment illuminated potential mechanisms, with index protein analysis confirming their anticancer pathways. Mice implanted with UC-PDX-LN1 mirrored PNL observed in the patient's original tumor. Cytokine array and RT-PCR analyses revealed high levels of G-CSF and GM-CSF in our PDX and cell lines, along with their presence in culture media and tumor cysts.Leukocytosis within small vessels in and around the tumor, associated with NETosis and thrombus formation, suggested a mechanism wherein secreted growth factors were retained, further fueling tumor growth via autocrine/paracrine signaling. Disrupting this cancer cell-NETosis-thrombosis cycle, we demonstrated that anti-neutrophil or anticoagulant interventions enhanced chemotherapy's antitumor effects or prolonged survival in mice, even though these drugs lacked direct antitumor efficacy when used independently. Clinical observations in bladder cancer patients revealed PNL in 1.61% of cases (35/2162) with associated poor prognosis. These findings propose a novel approach, advocating for the combination of anticancer/NETosis/thrombosis strategies for managing UC patients presenting with PNL in clinical settings.

Glioblastoma multiforme (GBM) is the most fatal primary brain tumor which lacks effective treatment drugs. Alkaloids are known as a class of potential anti-tumor agents. Sophocarpine, a tetracyclic quinazoline alkaloid derived from Sophora alopecuroides L., possesses several pharmacological effects including anti-tumor effects in some malignancies. However, the effect and mechanism of sophocarpine on GBM remains to be explored. In this study, based on in vitro experiments, we found that sophocarpine significantly inhibited the viability, proliferation and migration of GBM cells including U251 and C6 cells in a dose- and time-dependent manner. Besides, sophocarpine arrested GBM cell cycle in G0/G1 phase and induced their apoptosis. Subsequently, we found that sophocarpine upregulated the expression of PTEN, a GBM tumor suppressor, and downregulated PI3K/Akt signaling in GBM cells. Moreover, inactivating of PTEN with bpV(phen) trihydrate partially restored the anti-GBM effects of sophocarpine via PI3K/Akt signaling. Finally, sophocarpine significantly inhibited the growth of tumor both in subcutaneous and orthotopic U251 xenograft GBM model in nude mice via PTEN/PI3K/Akt axis. Taken together, these results suggested that sophocarpine impeded GBM progression via PTEN/PI3K/Akt axis both in vitro and in vivo, providing with a promising therapy for treating GBM.

The objective of our study was to develop predictive models using Visually Accessible Rembrandt Images (VASARI) magnetic resonance imaging (MRI) features combined with machine learning techniques to predict the World Health Organization (WHO) grade, isocitrate dehydrogenase (IDH) mutation status, and 1p19q co-deletion status of high-grade gliomas. To achieve this, we retrospectively included 485 patients with high-grade glioma from the First Affiliated Hospital of Xinjiang Medical University, of which 312 patients were randomly divided into a training set (n=218) and a test set (n=94) in a 7:3 ratio. Twenty-five VASARI MRI features were selected from an initial set of 30, and three machine learning models - Multilayer Perceptron (MP), Bernoulli Naive Bayes (BNB), and Logistic Regression (LR) - were trained using the training set. The most informative features were identified using recursive feature elimination. Model performance was assessed using the test set and an independent validation set of 173 patients from Beijing Tiantan Hospital. The results indicated that the MP model exhibited the highest predictive accuracy on the training set, achieving an area under the curve (AUC) close to 1, indicating perfect discrimination. However, its performance decreased in the test and validation sets; particularly for predicting the 1p19q co-deletion status, the AUC was only 0.703, suggesting potential overfitting. On the other hand, the BNB model demonstrated robust generalization on the test and validation sets, with AUC values of 0.8292 and 0.8106, respectively, for predicting IDH mutation status and 1p19q co-deletion status, indicating high accuracy, sensitivity, and specificity. The LR model also showed good performance with AUCs of 0.7845 and 0.8674 on the test and validation sets, respectively, for predicting IDH mutation status, although it was slightly inferior to the BNB model for the 1p19q co-deletion status. In conclusion, integrating VASARI MRI features with machine learning techniques shows promise for the non-invasive prediction of glioma molecular markers, which could guide treatment strategies and improve prognosis in glioma patients. Nonetheless, further model optimization and validation are necessary to enhance its clinical utility.

RNF26 is an important E3 ubiquitin ligase that has been associated with poor prognosis in bladder cancer. However, the underlying mechanisms of RNF26 in bladder cancer tumorigenesis are not fully understood. In the present study, we found that RNF26 expression level was significantly upregulated in the bladder cancer tissues, and higher RNF26 expression is closely associated with poorer prognosis, lower immune cell infiltration, and more sensitive to immune checkpoint blockade drugs and chemotherapy drugs, including cisplatin, VEGFR-targeting drugs and MET-targeting drugs. RNF26 knockdown in UMUC3 and T24 cell lines inhibited cell growth, colony formation and migratory capacity. Meanwhile, RNF26 overexpression had the opposite effects. Mechanistically, RNF26 exerts its oncogenic function by binding to TRIM21 and promoting its ubiquitination and subsequent degradation. Moreover, we revealed ZHX3 as a downstream target of RNF26/TRIM21 pathway in bladder cancer. Taken together, we identified a novel RNF26/TRIM21/ZHX3 axis that promotes bladder cancer progression. Thus, the RNF26/TRIM21/ZHX3 axis constitutes a potential efficacy predictive marker and may serve as a therapeutic target for the treatment of bladder cancer.

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with a complex etiology involving genetic predispositions, environmental factors, and Epstein-Barr virus (EBV) infection. Despite progress in radiotherapy and chemotherapy, the prognosis for advanced NPC is still unfavorable, prompting the need for innovative therapeutic approaches. Metabolic reprogramming plays a crucial role in the development and progression of NPC, marked by substantial changes in glycolysis, lipid, and amino acid metabolism. These alterations aid tumor cell proliferation, survival under stress, and immune evasion, with features such as enhanced aerobic glycolysis (Warburg effect) and shifts in lipid and amino acid pathways. Oncogenic drivers like MYC, RAS, EGFR, and the loss of tumor suppressors such as TP53 and PTEN, along with key signaling pathways including mTOR, AMPK, and HIF-1α, orchestrate these metabolic changes. This review discusses the molecular mechanisms of metabolic reprogramming in NPC and outlines potential therapeutic targets within these pathways. Advances in metabolic imaging and biomarker discovery are also enhancing the precision of diagnostics and treatment monitoring, fostering personalized medicine in NPC treatment. This manuscript aims to provide a detailed overview of the current research and its implications for improving NPC management and patient outcomes through targeted metabolic therapies.

Neoadjuvant immune checkpoint blockade (ICB) has achieved significant success in treating various cancers, leading to improved therapeutic responses and survival rates among patients. However, in colorectal cancer (CRC), ICB has yielded poor results in tumors that are mismatch repair proficient, microsatellite-stable, or have low levels of microsatellite instability (MSI-L), which account for up to 95% of CRC cases. The underlying mechanisms behind the lack of immune response in MSI-negative CRC to immune checkpoint inhibitors remain an open conundrum. Consequently, there is an urgent need to explore the intrinsic mechanisms and related biomarkers to enhance the intratumoral immune response and render the tumor "immune-reactive". Intestinal microbes, such as the oral microbiome member Fusobacterium nucleatum (F. nucleatum), have recently been thought to play a crucial role in regulating effective immunotherapeutic responses. Herein, we advocate the idea that a complex interplay involving F. nucleatum, the local immune system, and the tumor microenvironment (TME) significantly influences ICB responses. Several mechanisms have been proposed, including the regulation of immune cell proliferation, inhibition of T lymphocyte, natural killer (NK) cell function, and invariant natural killer T (iNKT) cell function, as well as modification of the TME. This review aims to summarize the latest potential roles and mechanisms of F. nucleatum in antitumor immunotherapies for CRC. Additionally, it discusses the clinical application value of F. nucleatum as a biomarker for CRC and explores novel strategies, such as nano-delivery systems, for modulating F. nucleatum to enhance the efficacy of ICB therapy.

Endometrial carcinoma (EC) is one of the three major malignancies of the female reproductive organs. With intense research of tumor molecular mechanisms and development of precision medicine in recent years, the traditional pathomorphological classification fails to meet the needs of clinical diagnosis and treatment for EC. This study aims to analyze the correlation of different Proactive Molecular Risk Classifier for Endometrial Cancer molecular subtypes with lymph node metastasis (LNM) and other clinical features in EC. 120 treatment-naive EC patients with surgery were enrolled in this study. The molecular subtypes of these patients were classified as follows by Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) molecular subtyping: mismatch repair deficiency (MMRd) in 22 cases (18.33%), polymerase epsilon exonuclease domain mutation (POLE EDM) in 2 cases (1.67%), p53 wild-type (p53-wt) in 64 cases (53.33%), and p53 abnormal (p53-abn) in 32 cases (26.67%). The clinicopathological features of 120 patients were retrospectively analyzed. Statistical significance was identified among the four molecular subtypes in terms of histological classification, International Federation of Gynecology and Obstetrics (FIGO) staging, pathological grading, and LNM. Among the enrolled cases, 26 had LNM and 94 had no lymph node involvement. According to the multivariate Logistic regression analysis, p53 wt (P=0.008, OR=0.078, 95% CI: 0.012-0.510) was a protective factor for LNM in EC patients, while poorly differentiated histology (P=0.001, OR=15.137, 95% CI: 3.013-76.044) was a risk factor. ProMisE classification system, being more objective and reproducible, can provide an important reference for preoperative decision-making. The patients with p53 wt by ProMisE had a low risk of LNM in preoperative diagnostic curettage specimens, while there was a higher risk of LNM among the patients with poorly differentiated EC.

Aberrant RSPO1 expression is implicated in tumor progression across various cancers and correlates with anti-cancer immune cell characteristics. However, the specific role of R-spondin 1 (RSPO1) in lung adenocarcinoma (LUAD) remains unclear. In this study, we utilized data from The Cancer Genome Atlas (TCGA) to assess RSPO1 expression across 33 tumor types. Kaplan-Meier (K-M) analysis revealed the prognostic significance of RSPO1 in various cancers. Using statistical software R, we examined RSPO1's associations with immune cell infiltration, methylation, mutation, and competing endogenous RNA (ceRNA) networks. Exploration via the Tumor Immune Single Cell Hub (TISCH) database uncovered RSPO1's link to the tumor microenvironment (TME) and identified potential small molecule drug targets. We further investigated RSPO1's impact on LUAD cell proliferation, metastasis, and the Wnt pathway in vitro. Our findings highlight RSPO1's role in cancer progression and suggest its potential as both a prognostic marker and therapeutic target in LUAD, implicating the modulation of the Wnt pathway.