Anticancer research最新文献

Background/aim: The role of tumor-associated neutrophils (TANs) in the tumor microenvironment (TME) remains unclear in lung cancer. Various aspects of TANs, such as their maturation stage, activation state, and enzyme release, are controversial. This study focused on neutrophil elastase (NE) from TANs, aiming to evaluate its role in lung cancer and determine whether NE could be a potential therapeutic target.

Materials and methods: Lung cancer and promyelocytic leukemia cell lines were used to evaluate whether NE is associated with neutrophil recruitment using a chemotaxis assay. The association between NE and lung cancer cell malignancy was evaluated using cell viability, motility and invasion assays. The effects of NE inhibition on lung cancer growth and cytotoxic anticancer therapy were evaluated in a mouse model. Immunohistochemical analysis was used to examine the association between TANs infiltration of TME and prognosis of patients received lung cancer surgery.

Results: TANs secreted NE to recruit neutrophils into the TME. Furthermore, NE-secreting TANs enhanced lung cancer cell motility and invasion, contributing to tumor growth. Selective inhibition of NE reduced intratumoral infiltration of NE-expressing TANs and suppressed lung cancer progression. Moreover, NE inhibition enhanced the efficacy of cisplatin treatment. In human lung cancer, infiltration by NE-expressing TANs correlated with postoperative recurrence and poor prognosis, specifically associating with distant metastases. High NE expression was also a predictive factor for vascular invasion by lung cancer cells.

Conclusion: NE secreted by TANs in lung cancer tissues facilitates further TAN recruitment, leading to a TAN-rich TME that promotes tumor progression. Additionally, NE promotes distant metastasis by enhancing lung cancer cell motility and vascular invasion. These findings suggest that NE is a promising therapeutic target for lung cancer treatment.

Background/aim: Lung cancer patients often suffer from chemotherapy-associated complications such as pneumonia and respiratory infections, which are caused by damage to normal cells and airway epithelial tissue. Mucociliary clearance (MCC) involves adsorption of foreign substances by mucus secreted by goblet cells, followed by propulsion into the airway by ciliated cells. MCC is a crucial mechanism that protects against infection. Previously, we demonstrated that ginsenoside Rd (Rd) activates MCC by increasing ciliary beat frequency (CBF). The aims of this study were to assess whether anticancer drugs decrease the CBF of murine airway ciliated cells, and to examine the effects of Rd on CBF suppression.

Materials and methods: The CBF of primary epithelial cells isolated from B6.SJL-Ptprca Pepcb/BoyJ (B6.CD45.1) mice were measured in the presence of various anticancer drugs, either alone or in combination with Rd. Intracellular cAMP concentrations ([cAMP]_i) were measured in A549 PinkFlamindo cells, and intracellular Ca²⁺ concentrations ([Ca²⁺]_i) were evaluated in A549 cells stained with Fluo-4, in the presence/absence of anticancer drugs and Rd.

Results: Doxorubicin, cisplatin, pemetrexed, paclitaxel, and docetaxel decreased the CBF of murine airway ciliated cells; however, this effect was ameliorated by Rd. In addition, paclitaxel and docetaxel decreased [Ca²⁺]_i. Rd improved anticancer drug-induced airway ciliary motility by increasing [cAMP]_i.

Conclusion: Anticancer drugs suppress CBF, suggesting that treatment may cause airway infections. Anticancer drug-induced suppression of CBF was ameliorated by Rd, indicating that Rd may reduce the risk of pneumonia and respiratory infections in patients with lung cancer.

Background/aim: Combined prompt cancer diagnosis and treatment is a key pursuit of the scientific community. Since the 20^th century, a variety of early cancer detection methods (screening tests) have been developed. Histopathological examination of cancerous tissues is the "gold standard" in establishing the final diagnosis, as well as documenting the adequacy of the therapeutic intervention, although unable to detect neoplastic/malignant cells in real-time. In the current experimental research, we present a novel, innovative medical diagnostic device and demonstrate its potential utilization as a screening test for the early detection of neoplastic/malignant lesions in real-time.

Materials and methods: A group of 215 patients were enrolled in the study. The innovative medical diagnostic device was used to collect a sufficient number of measurements from head and neck neoplastic -including skin - lesions. Using special software algorithms, the cell membrane was simulated with an equivalent electric circuit. The excitation response of the biological tissues was calculated by applying a dielectric spectroscopy method. The presence of neoplastic cells was detected as a significantly increased contribution of the capacitive reactance to the total impedance of the tissues under examination (θ angle).

Results: The θ angle extracted measurements were compared to the respective histopathologic reports. θ angle values were found to be statistically different between normal, non-neoplastic, and malignant tissues (p<0.001).

Conclusion: In terms of physics, the unknown complex impedance of the tissue under assessment as well as the capacitive reactance can be experimentally measured and therefore cancerous cells can be distinguished from healthy cells by the changes in the measured capacity reactance contribution (θ angle differences). The described innovative medical device leads reliable results for the early detection of neoplastic/malignant cells in real-time.

Background/aim: The recurrence rate of colon cancer after radical resection remains high at approximately 14%. Furthermore, evidence regarding the indications for adjuvant chemotherapy (Adj) for stage II/III colon cancer is limited. In this study, we used artificial intelligence (AI) to create a clinicopathological recurrence prediction model after radical resection for colon cancer, and we identified factors that predict disease recurrence.

Patients and methods: This study included 326 patients who underwent radical resection for stage II/III colon cancer at the Tokyo Medical University Hospital between 2000 and 2015. Analysis was performed using the AI system TabNet, with clinicopathological factors as covariates.

Results: The recurrence prediction accuracy was 96% in the Traininig group and 92% in the Test group. TabNet successfully identified the following recurrence prediction factors, ranked in descending order of the contribution importance: TNM-stage, Adj status, N-stage, venous invasion (v), histology, T-stage, sex, lymphatic invasion (Ly), and age.

Conclusion: Analysis using AI enabled the creation of a recurrence prediction model with higher accuracy than previously reported models. The application of Adj for colorectal cancer is anticipated to be refined in the future, leading to lower recurrence rates.

Background/aim: Bevacizumab (BV) is used in combination with paclitaxel to treat human epidermal growth factor receptor 2-negative advanced breast cancer. However, BV frequently causes hypertension. Because patients with advanced breast cancer already have an elevated cardiovascular risk, we investigated clinical factors associated with BV-induced severe hypertension in a real-world setting.

Patients and methods: Patients with advanced breast cancer receiving BV with paclitaxel (n=67) were retrospectively evaluated. The primary endpoint was determination of factors for the occurrence of grade ≥3 severe hypertension, considering clinical significance. We also assessed the time to symptom onset and variation in blood pressure after treatment between specific patient groups.

Results: Hypertension occurred in 73.1% of the patients, with grades 2 and 3 severity in 20.9% and 52.2%, respectively. Multivariate logistic regression analysis suggested that pre-existing hypertension at baseline was an independent risk factor for grade ≥3 hypertension (adjusted hazard ratio=3.12; 95% confidence interval=1.30-7.87; p=0.01), resulting in similar results in a sensitive analysis. Additionally, median time to symptom onset was 70 days (range=56-119 days) in patients with pre-existing hypertension and 175 days (147 days-not available) in patients without pre-existing hypertension (p=0.004). No significant difference was noted in the range of fluctuations in systolic and diastolic blood pressure during treatment between patients with and without pre-existing hypertension.

Conclusion: Pre-existing hypertension is a risk factor for BV-induced severe hypertension in patients with breast cancer.

Background/aim: Nasopharyngeal carcinoma (NPC) originates in the nasopharynx. Despite therapeutic advances, a subset of patients derives limited benefits and experiences poor outcomes. There is a continuing need for novel agents to improve prognosis.

Materials and methods: Human immortalized nasopharyngeal epithelial cells (NP69) and NPC cells (NPC/HK1) were used. Cell viability, clonogenic growth, cytokeratin-18 fragment levels, and protein expression were assessed by MTT assay, colony formation assay, ELISA, and immunoblotting, respectively.

Results: Protopanaxadiol reduced NPC/HK1 cell viability in a concentration-dependent manner without significantly affecting NP69 cells and markedly suppressed NPC/HK1 colony formation. Treatment with protopanaxadiol increased the cleaved PARP and cytokeratin-18 fragments, without significant changes in Beclin-1 or LC3-II, suggesting that apoptosis rather than autophagy occurred. Additionally, protopanaxadiol reduced ERK phosphorylation while increasing both total and phosphorylated p53 levels. It also up-regulated Fas and elevated levels of cleaved caspase-8 and cleaved caspase-3, whereas cleaved caspase-9 and Bax remained largely unchanged, indicating a preferential activation of the extrinsic apoptotic pathway. Functionally, blocking Fas or caspase-8 attenuated protopanaxadiol-induced cytokeratin-18 fragment release.

Conclusion: Protopanaxadiol selectively suppresses NPC/HK1 growth, induces apoptotic markers, and promotes apoptosis via the Fas/caspase-8 signaling pathway. These findings provide foundational evidence that protopanaxadiol is a promising candidate to improve NPC therapy.

Background/aim: Andrographolide, a compound derived from Andrographis paniculata, has exhibited promising antineoplastic effects; however, its effects on pluripotency and cancer stemness remain unclear. Since pluripotency and cancer stemness are key factors in treatment resistance and relapse, it is important to investigate how andrographolide affects these properties.

Materials and methods: MCF7 cells were treated with andrographolide (7.5-120 μM) for 24 or 48 h. Cell viability was evaluated using the MTT assay. Mitochondrial membrane potential was measured using TMRE. Gene expression of TOMM20, caspase-3, BAX, BCL2 and OCT4 was analyzed using RT-qPCR. Mammosphere and colony formation assays were performed to assess self-renewal and proliferation.

Results: MTT assays revealed a dose- and time-dependent reduction in the cell viability following andrographolide treatment. TMRE staining revealed a decrease in the mitochondrial membrane potential of andrographolide-treated MCF7 cells, indicating mitochondrial dysfunction. RT-qPCR analysis showed down-regulation of TOMM20 and caspase-3 expression, although MCF7 cells are typically caspase-3 deficient. Notably, BAX expression was up-regulated following treatment with 60 μM andrographolide, suggesting the induction of apoptosis. A dose-dependent increase in OCT4 expression was observed, with a 13.52-fold rise at 60 μM, indicating a potential shift toward a pluripotent-like state. Gene correlation analysis revealed a negative correlation between TOMM20 and OCT4 expression, suggesting that TOMM20 down-regulation enhances pluripotency. The positive correlation between OCT4 and BAX expression suggests a complex link between apoptosis and stemness. Immunocytochemistry confirmed TOMM20 localization in the cytoplasm. Reduced mammosphere and colony formation indicated decreased self-renewal and proliferation.

Conclusion: Andrographolide exerts anti-cancer effects through mitochondrial dysfunction and apoptosis, while paradoxically increases OCT4 expression. These findings may indicate an adaptive cellular survival mechanism, in which OCT4 up-regulation and TOMM20 down-regulation are correlated with cancer-like characteristics.

Background/aim: Human papillomavirus (HPV) is a known risk factor for oropharyngeal cancer (OPC); however, its role in atherosclerosis remains controversial. This study aimed to investigate the association between HPV type 16 infection status and coronary artery calcification (CAC) in patients with OPC.

Patients and methods: We retrospectively reviewed patients who were referred to our hospital for initial treatment of OPC between October 2013 and October 2024. The Agatston score was calculated using non-gated, non-contrast computed tomography scans. HPV status was assessed using p16 immunohistochemistry according to guidelines. Patient characteristics were compared between the HPV-negative and HPV-positive groups. Independent risk factors for severe CAC (Agatston score >400) were identified using a multivariable logistic regression model.

Results: Among 114 patients, those with HPV-negative OPC had significantly higher Agatston scores compared to those with HPV-positive OPC [89.00 (0.00-864.25) vs. 2.20 (0.00-61.50), p=0.020]. They were also older, had lower body mass index and hemoglobin levels, and had a higher prevalence of diabetes. However, HPV infection status was not an independent risk factor for severe CAC.

Conclusion: Patients with HPV-negative OPC exhibited more severe CAC, likely due to their older age rather than HPV status itself.

Background/aim: Increases in cellular fibronectin (C-FN) in the stroma have been identified as one of the factors that induce epithelial-mesenchymal transition (EMT), which enhances cancer malignancy. We measured blood levels of sialic acid-fibronectin (S-FN), a form of C-FN secreted by pancreatic ductal adenocarcinoma (PDAC), along with total C-FN, to investigate whether their secretion is associated with tumor progression and EMT.

Patients and methods: Total blood C-FN and S-FN levels were measured using ELISA, and immunostaining for vimentin, CD-44, and cytokeratin was performed on 13 pancreatic tumors to examine their relevance to EMT.

Results: Four of 11 PDAC cases (36.4%) were blood S-FN-positive. Vimentin-positive cells (VPCs) in the stroma, which indicate an increase in cancer-associated fibroblasts (CAFs), numbered fewer than 50 per field of view in four of four S-FN-positive cases and three of seven S-FN-negative cases. These patients demonstrated partial therapeutic effects of chemoradiotherapy. In contrast, four of seven S-FN-negative cases had more than 50 VPCs and showed extensive fibrous growths in the stroma. No therapeutic effects were observed, and the prognoses were poor. In the four stage IV cases with metastases at the time of presentation, 80-90% of PDAC cells expressed CD-44 receptors, an EMT-related factor. CD-44 positivity was also found in CAFs around the PDCA, indicating cross-talk between PDAC and CAFs via CD-44.

Conclusion: In blood S-FN-negative cases with depleted autocrine FN, therapeutic effects were reduced owing to the increased presence of VPCs, presumed to be CAFs induced by EMT. CD-44-positive PDAC cells, which are partially EMT cells, are prone to early distant metastasis.

Background/aim: Toxicity-related discontinuation remains problematic in cisplatin-based cervical cancer treatment. This study aimed to evaluate the association between renal function assessed using individualized estimated glomerular filtration rate (eGFR) and the completion rate of cisplatin-based concurrent chemoradiotherapy (CCRT) in patients with cervical cancer.

Patients and methods: This retrospective study included patients with cervical cancer who received CCRT with cisplatin (40 mg/m²/week, six cycles) at our institution between April 2015 and March 2024. Exclusion criteria included a Cockcroft-Gault-estimated creatinine clearance rate (CGCCr) <60 ml/min, prior chemotherapy or radiotherapy, initial cisplatin dose reduction, and Eastern Cooperative Oncology Group Performance Status ≥2. The primary endpoint was the cisplatin treatment completion rate. Renal function was assessed using individualized eGFR, and a comparative analysis was performed between the completion and non-completion groups.

Results: A total of 80 patients were included, of whom 68 (85%) completed the planned cisplatin regimen. Although all patients had CGCCr ≥60 ml/min, individualized eGFR assessment revealed that 19% of patients had eGFR <60 ml/min. The proportion of patients with an eGFR <60 ml/min was significantly higher in the non-completion group (58% vs. 12%, p=0.001). Logistic regression analysis showed that patients with individualized eGFR <60 ml/min had a significantly higher risk of cisplatin treatment non-completion (adjusted odds ratio=8.69; 95% confidence interval=2.14-35.3, p=0.0025).

Conclusion: Patients with an individualized eGFR <60 ml/min showed significantly higher cisplatin non-completion rates even when their CGCCr was ≥60 ml/min. These findings suggest that individualized eGFR assessment, in addition to CGCCr, should be considered for optimizing cisplatin dosing in cervical cancer CCRT.