Anticancer research最新文献

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.

Background/aim: Methionine addiction is a fundamental and general hallmark of cancer, known as the Hoffman effect. The aim of the present study was to target methionine addiction of cancer cells co-cultured with normal cells with various doses of recombinant methioninase (rMETase) to precisely eliminate cancer cells and to determine the timing of rescue of cancer cells by methionine supplementation.

Materials and methods: HCT116 human colon cancer cells were co-cultured with Hs-27 diploid human normal fibroblasts in 12-well tissue-culture plates containing Dulbecco's Modified Eagle's Medium (DMEM) with 10% fetal bovine serum. rMETase was added to the co-cultures at 0.25, 0.5, or 1.0 U/ml. In attempts to rescue the cancer cells, normal DMEM which contains 0.2 mM of methionine, replaced DMEM containing rMETase on days -2, -4 or -6. Co-cultures were observed for cell viability and proliferation using phase-contrast microscopy.

Results: The efficacy of rMETase to eliminate cancer cells co-cultured with normal cells was dose-dependent. rMETase at 0.25 U/ml allowed large numbers of cancer cells to remain in the co-cultures by day 12. rMETase at 0.5 U/ml and 1.0 U/ml largely eliminated the cancer cells from the co-cultures by day 12. rMETase at 1.0 U/ml was slightly toxic to the normal cells. However, at each dose of rMETase, even at 1.0 U/ml, DMEM could rescue the cancer cells even when added on day 6.

Conclusion: The ability of rMETase to eliminate cancer cells co-cultured with normal cells is dose-dependent. Even at high effective doses of rMETase, the cancer cells could be rescued by methionine supplementation up to at least day-6, indicating the need for the continuous presence of rMETase to selectively inhibit the cancer cells.

Background/aim: Response to neoadjuvant chemoradiotherapy (nCRT) in rectal cancer varies. Recent studies have highlighted the role of the tumor immune microenvironment in influencing tumor behavior. Herein, we aimed to assess immune-related gene expression in rectal cancer following nCRT and to investigate their potential as predictive and prognostic biomarkers.

Materials and methods: Expression profiling of 730 immune-related genes was conducted in 48 post-nCRT rectal cancer using the NanoString nCounter platform and the PanCancer Immune Profiling panel. Differentially expressed genes were compared between good and poor responders, and gene set enrichment analysis was conducted. The prognostic significance of these genes was analyzed. A genetic model was generated to predict nCRT responses.

Results: We identified 24 immune-associated genes that were differentially expressed between good and poor responders, among which S100A8, SPINK5, ANXA1, FOXJ1, and CLEC7A showed high expression levels in good responders (Log2 fold change >1, p<0.05). Pathway analysis revealed that these genes were mainly involved in biological process associated with natural killer cell-mediated cytotoxicity. S100A8 and SPINK5 expression levels were associated with relapse-free survival (p=0.001 and 0.036, respectively), and these findings were validated in a publicly available dataset (S100A8; p=0.015, and SPINK5; p=0.024). The accuracy of the predictive model comprising TLR4, CCND3, TCF7, CREB5, TNFRSF10B, DPP4, PBK, DUSP4, and MUC1 was 85.7%.

Conclusion: Immune-related gene expression patterns are associated with response to nCRT in rectal cancer. High expression levels of S100A8, SPINK5, ANXA1, FOXJ1, and CLEC7A were indicative of favorable treatment response, and S100A8 and SPINK5 were associated with prognosis. A machine learning-based model composed of immune-related genes showed strong predictive potential. Our results support the use of immune gene signatures to guide personalized therapy in rectal cancer.

Background/aim: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic progress. Adenylate kinase 2 (AK2), a mitochondrial isoenzyme involved in nucleotide metabolism and apoptosis regulation, has been implicated in tumorigenesis, but its role in SCLC remains undefined. This study aimed to investigate the oncogenic function of AK2 in SCLC and its regulatory mechanism through the PI3K/AKT/mTOR signaling pathway.

Materials and methods: AK2 expression was analyzed using the GSE60052 dataset and validated using western blotting in SCLC cell lines. Functional assays, including MTT, proliferation, colony formation, and phospho-kinase array profiling, were performed following siRNA-mediated AK2 knockdown in HCC-33 and H417 cells. Western blotting was used to confirm pathway alterations. In vivo tumorigenicity was assessed in xenograft models.

Results: AK2 was markedly up-regulated in SCLC tissues and cell lines. Silencing AK2 significantly inhibited proliferation and clonogenic growth of SCLC cells and reduced tumorigenicity in vivo. Phospho-kinase analysis and western blot validation demonstrated that AK2 knockdown altered phosphorylation of key components in the PI3K/AKT/mTOR pathway, including AKT and mTOR.

Conclusion: AK2 acts as an oncogenic driver in SCLC, promoting tumor progression through PI3K/AKT/mTOR signaling. Targeting AK2 may represent a novel therapeutic strategy and predictive biomarker in SCLC management.

Background/aim: Regorafenib, a multikinase inhibitor widely used to treat metastatic colorectal cancer (mCRC), is associated with elevations in pancreatic enzyme levels. However, clinical predictors of this adverse event have yet to be adequately defined. This study aimed to identify risk factors for regorafenib-induced enzyme elevation in routine clinical practice.

Patients and methods: We retrospectively evaluated 47 patients with mCRC who received regorafenib between May 2013 and October 2024. Pancreatic enzyme elevation was defined as a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥1 increase in serum lipase or amylase levels within 28 days of treatment initiation. Clinical data were extracted from medical records, and risk factors were assessed using univariate and multivariate logistic regression. Sensitivity analyses were performed to confirm the robustness of the findings.

Results: Lipase elevation occurred in 48.9% of patients, whereas amylase elevation was observed in 8.5% of patients. Severe enzyme elevation (CTCAE grade ≥3) was detected in 17.0% and exclusively involved lipase. The median onset time was 7 days, with no cases of acute pancreatitis reported. Multivariate analysis identified prior anti-vascular endothelial growth factor (VEGF) therapy lasting ≥300 days as an independent risk factor (adjusted odds ratio 5.99, 95% confidence interval 1.49-31.41, p=0.01). Sensitivity analyses supported this association.

Conclusion: The elevation of pancreatic enzymes, predominantly lipase, is a frequent early adverse event associated with regorafenib treatment. A history of prolonged anti-VEGF therapy may predispose patients to toxicity, highlighting the need for close monitoring during the initial treatment phase. These findings provide novel insights that may help to optimize the safe clinical use of regorafenib.

Background/aim: Recently, there have been numerous publications on the induction of ferroptosis by cysteine restriction in cancer cells. The present report aimed to determine whether cysteine restriction (CR) is a cancer-specific vulnerability in comparison with methionine restriction (MR), which is a known cancer-specific vulnerability.

Materials and methods: Human cancer cell lines (HCT116 colon cancer, 143B osteosarcoma or HT1080 fibrosarcoma) and normal human fibroblasts (Hs27) were cultured in Dulbecco's modified Eagle's medium (DMEM) with dialyzed fetal bovine serum from which methionine or cysteine or both or neither had been depleted. Cancer and normal cells were co-cultured in 12-well plates under the above conditions. HCT116 cells expressing green fluorescent protein, and 143B and HT1080 cells expressing red fluorescent protein, were visualized by fluorescence microscopy. Normal fibroblasts and cancer cells were visualized by phase-contrast microscopy as well.

Results: In co-culture, of either 143B, HCT116 or HT1080 with Hs27 human fibrosarcoma, CR was toxic to Hs27 normal fibroblasts as well as to all three cancer cell lines. In contrast, MR was toxic only to the cancer cells but not normal fibroblasts. Dual CR and MR was toxic to normal and cancer cells.

Conclusion: For all three cancer cell lines, HCT116 colon cancer, HT1080 fibrosarcoma and 143B osteosarcoma, both MR and CR were highly inhibitory in the co-cultures with Hs27 normal fibroblasts. In all cases MR had only a slight effect on normal fibroblasts, but CR was highly toxic to normal fibroblasts. Thus, MR is a cancer-specific vulnerability in contrast to CR which is toxic to both normal and cancer cells and is not a cancer-specificity vulnerability. Therefore, attempting to induce ferroptosis of cancer cells by CR does not appear to have potential as an effective cancer therapy.

Background/aim: Endocrine therapy combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is standard first-line treatment for hormone receptor (HR)-positive metastatic breast cancer (MBC). Although radiological complete response (rCR) is rarely achieved, the optimal management of such patients remains unclear. In human epidermal growth factor receptor 2 (HER2)-positive MBC, discontinuation of anti-HER2 therapy after rCR has been explored but treatment de-escalation in HR-positive MBC has not been sufficiently investigated.

Patients and methods: We retrospectively analyzed 178 patients with HR-positive MBC treated with CDK4/6i-based endocrine therapy at our Institution between December 2017 and October 2024. Clinicopathological factors, including immune-related markers (absolute lymphocyte count and neutrophil-to-lymphocyte ratio), were evaluated for associations with rCR. Bone metastases were considered rCR-equivalent only if radiological stability was maintained for ≥6 months. Patients who discontinued CDK4/6i after achieving rCR were further assessed.

Results: Nineteen patients (10.7%) achieved rCR (13 with measurable non-bone metastases and six with bone metastases). The median time to rCR was 11.9 months. rCR occurred more frequently in patients treated with abemaciclib (p=0.008) and those with smaller primary tumors (≤2 cm, p=0.040). Earlier-line treatment also showed a trend towards achieving higher rCR rates (p=0.104). Among the 19 patients with rCR, five discontinued CDK4/6i while maintaining endocrine therapy. Fatigue and diarrhea improved after discontinuation. Two patients experienced disease progression after 14.5 and 20.5 months of CDK4/6i withdrawal, respectively.

Conclusion: rCR following CDK4/6i therapy was an independent prognostic factor in HR-positive MBC. Patients with smaller primary tumors and early administration of abemaciclib were more likely to achieve rCR. Selected patients achieving rCR may be candidates for discontinuation of CDK4/6i as part of individualized treatment de-escalation strategies.

Background/aim: Evidence regarding the benefits of nutritional therapy after robotic pancreatectomy is limited. This randomized controlled trial aimed to investigate the effects of a polymeric formula (PF) on preventing body weight loss (BWL) following robotic pancreatectomy.

Patients and methods: This single-center, open-label, randomized trial was conducted to assign 46 patients undergoing robotic pancreatectomy in a 1:1 ratio to either the PF (ISOCAL Clear) or control group. The primary endpoint was the percentage of BWL on postoperative days 14 and 28. The secondary endpoints were postoperative outcomes.

Results: Of the 52 eligible patients between December 2023 and November 2024, 46 were analyzed using intention-to-treat principles: 23 in the ISOCAL group and 23 in the control group. The %BWL was significantly lower in the ISOCAL group compared with that in the control group on postoperative days 14 (4.8±3.5% vs. 6.6±3.2%, p=0.02) and 28 (6.4±3.0% vs. 8.4±3.5%, p=0.047). Postoperative outcomes, including major complications (p=0.55) and hospital stay (p=0.83), did not differ significantly between the groups.

Conclusion: This study demonstrates the safety and feasibility of administering PF to patients undergoing robotic pancreatectomy. The results showed the beneficial effects of PF on mitigating BWL without compromising short-term outcomes.