Anticancer research最新文献

Background/aim: Accumulation of reactive oxygen species (ROS), which is essential for normal cell function and signaling, can induce oxidative stress that leads to cellular damage and various diseases, including cancer, thereby underscoring the crucial role of intracellular antioxidant systems in maintaining ROS balance. The p53-binding protein 1 (53BP1) is a key regulator of DNA double-strand break (DSB) repair, however, its role in ROS regulation remains unclear. This study aimed to investigate the involvement of 53BP1 in ROS homeostasis and its potential impact on oxidative stress regulation.

Materials and methods: Fluorescence microscopy and flow cytometry using MitoSOX indicators were performed to measure the amount of ROS in 53BP1-deficient cells. To elucidate the ROS regulatory genes mediated by 53BP1, the expression of NOX1, MT1F, and MT2A mRNA was analyzed through quantitative real-time PCR (qRT-PCR).

Results: Silencing 53BP1 led to a significant increase in both ROS and mitochondrial superoxide levels, while transfection of 53BP1-deficient cells with a 53BP1 expression vector reduced ROS accumulation. In addition, 53BP1-depleted cells showed increased expression of NOX1 mRNA and decreased expression of MT1F and MT2A, suggesting a potential antioxidative mechanism.

Conclusion: 53BP1 plays a crucial role in maintaining ROS homeostasis by regulating genes involved in oxidative stress response. These results suggest that targeting ROS regulation through 53BP1-related pathways may provide novel insights into therapeutic strategies for diseases associated with oxidative stress.

Background/aim: Interleukin-12 (IL12) plays a crucial role in immune regulation and inflammation and is critical in developing colorectal cancer (CRC). This study investigated the association between IL12A rs568408, IL12A rs2243115, and IL12B rs3212227 polymorphisms and CRC susceptibility in a Taiwanese population.

Materials and methods: Genotypic and allelic distributions were analyzed in 362 non-cancer controls and patients with CRC via restriction fragment length polymorphism methods.

Results: All three polymorphisms fit well to the Hardy-Weinberg equilibrium (p>0.05). The frequencies of IL12A rs568408 GG, AG and AA genotypes were 73.5%, 22.9% and 3.6% in CRC cases, compared to 76.8%, 20.7%, and 2.5% in controls (p for trend=0.4973). No significant associations were observed for AG [odds ratio (OR)=1.16, 95% confidence interval (CI)=0.81-1.65, p=0.4752] or AA (OR=1.51, 95% CI=0.63-3.59, p=0.4715) genotypes. Dominant and recessive models showed no significant correlation (OR=1.22, 95% CI=0.87-1.71, p=0.2845; and OR=1.46, 95% CI=0.62-3.46, p=0.5160, respectively). Similarly, IL12A rs2243115 and IL12B rs3212227 genotypic distributions were comparable between cases and controls (p for trend=0.7209 and 0.5997, respectively). Allelic analysis further confirmed the lack of significant association: IL12A rs568408 A allele: OR=1.20, 95% CI=0.89-1.62, p=0.2552; IL12A rs2243115 G allele: OR=0.91, 95% CI=0.63-1.33, p=0.7019; and IL12B rs3212227 C allele: OR=0.90, 95% CI=0.73-1.10, p=0.3174.

Conclusion: These findings suggest that IL12A and IL12B polymorphisms are not significantly associated with CRC susceptibility in the Taiwanese population. Future research should explore other IL12A and IL12B polymorphisms, gene-gene and gene-phenotype interactions, and the role of IL12' in immune regulation, which may offer insights for clinical applications and therapies.

Background/aim: Leukemia is a group of hematologic malignancies that present considerable therapeutic challenges worldwide. Isosakuranetin, a 4'-O-methylated flavonoid, possesses various biological properties. However, its therapeutic potential against leukemia remains unexplored because of an incomplete understanding of its molecular mechanisms. This study investigated the anticancer effects of isosakuranetin on leukemia cells and elucidated the associated signaling pathways.

Materials and methods: The human leukemia cell lines HL-60 and U937 were treated with serial concentrations of isosakuranetin. Cell viability was evaluated using the Cell Counting Kit-8 assay. Apoptosis and autophagy assays were conducted through annexin V/propidium iodide (PI) staining and acidic vesicular organelle (AVO) staining, respectively. Cell cycle distribution was analyzed through PI staining and flow cytometry. The expression of apoptosis- and autophagy-related proteins in leukemia cells was analyzed using western blotting.

Results: Isosakuranetin exerted distinct regulatory effects on HL-60 and U937 cells over a 48-h treatment period. In HL-60 cells, it increased Beclin-1 expression and suppressed the JNK component of the mitogen-activated protein kinase pathway, up-regulated the PI3K/Akt signaling cascade, and modulated the expression of Bax and Bcl-2. Conversely, in U937 cells, isosakuranetin up-regulated both AMPK/PI3K/Akt and JNK signaling, while down-regulation of Beclin-1 expression. These pathway modulations collectively contributed to the induction of autophagy and apoptosis.

Conclusion: Isosakuranetin induces apoptosis and autophagy in leukemia cells through the AMPK and PI3K/Akt pathways, as well as through JNK activation, with Beclin-1 playing a critical role in their crosstalk. These results highlight the potential of isosakuranetin as a therapeutic agent for leukemia.

Background/aim: The aim of this study was to investigate locus-specific circulating-tumor DNA (ctDNA) methylation for predicting long-term outcomes of locally-advanced rectal cancer (LARC) after resection.

Materials and methods: In the present study, there were 50 patients without preoperative treatment and 35 patients with preoperative treatment. Methylation analyses for checkpoint with forkhead and ring finger domains (CHFR), sex-determining region Y-box transcription factor 11 (SOX11) and cysteine dioxygenase type 1 (CDO1) used DNA extracted from plasma ctDNA at the time of resection of the primary tumor with curative-intent surgery.

Results: Highly-methylated SOX11 in ctDNA was found to be a biomarker of reduced recurrence-free survival (RFS) in LARC. In multivariate analysis, highly methylated SOX11 was an independent prognostic factor for reduced RFS in the group without preoperative treatment.

Conclusion: The present study demonstrates that elevated ctDNA methylation of the SOX11 gene is a biomarker for reduced RFS after curative-intent resection of LARC. Patients with high ctDNA methylation of the SOX11 gene may not be optimal candidates for LARC resection. A prospective study is necessary to further validate SOX11 ctDNA methylation as a biomarker for RFS of patients with LARC.

Background/aim: The alternative non-surgical treatment approach for large and very large lung cancers (LVL-LC) has rarely been investigated. We describe the outcomes of patients whose LVL-LCs were managed non-operatively with clear intents.

Patients and methods: The effects of definitive (concurrent chemoradiotherapy, 23 patients) or palliative (short course of radiotherapy with chemotherapy, chemotherapy, or radiotherapy alone, 16 patients) treatment for LVL-LC during a 10-year period (2012-2022) were reviewed.

Results: The overall rate of (a) tumor regression, (b) disease progression, and (c) median survival were 82% (32/39), 67% (26/39), and 13 months, respectively. These endpoints in patients with large and very large cancers were (a) 82% (22/27) and 83% (10/12), respectively, p=0.90; (b) 74% (20/27) and 50% (6/12), respectively, p>0.40, and (c) 13.5 months and six months, respectively, p>0.70. In definitively and palliatively treated patients, the outcomes were: (a) 87% (20/23) and 75% (12/16), respectively, p>0.30; (b) 65% (15/23) and 69% (11/16), respectively, p>0.80, and (c) 14 months and 5.5 months, respectively, p>0.70. Low-grade, transient side-effects and imaging-shown lung fibrosis occurred in 65% (15/23) and 26% (10/39) of cases, respectively. On univariate analysis, the prospect of longer survival was suggested for older patients when the upper lobe cancers were not very large and when definitive treatment was administered.

Conclusion: An aggressive management approach seems to be a reasonable treatment strategy for promoting tumor resolution and progression-free survival with acceptable toxicity in LVL-LC.

Background/aim: It remains unclear whether patients with metastatic castration-sensitive prostate cancer (mCSPC) are suitable for upfront docetaxel therapy. Therefore, we retrospectively evaluated patients with metastatic castration-resistant prostate cancer (mCRPC) who could not receive ≥6 cycles of docetaxel for mCRPC.

Patients and methods: This study enrolled 274 patients diagnosed with mCSPC who later developed mCRPC, with data at diagnosis, including blood test results, available from 17 hospitals between 2008 and 2022. Failure to receive ≥6 cycles of docetaxel was defined as receiving ≤5 cycles of docetaxel for mCRPC or dying due to prostate cancer without docetaxel therapy. Factors at mCSPC diagnosis associated with failure to receive ≥6 cycles of docetaxel were evaluated using logistic regression analysis.

Results: Ninety-three patients were not able to receive ≥6 cycles of docetaxel for mCRPC. Multivariate analysis revealed that high lactate dehydrogenase levels and Gleason grade group 5 were significantly associated with failure receive ≥6 cycles of docetaxel for mCRPC. Furthermore, in patients with these factors at mCSPC diagnosis, receiving ≥6 cycles of docetaxel was significantly associated with better overall survival.

Conclusion: Patients with mCSPC who have high lactate dehydrogenase levels and a Gleason grade 5 may be candidates for upfront docetaxel therapy, as they may otherwise miss the chance to receive adequate doses for prostate cancer.

Background/aim: This study aimed to identify mutation profile similarities between tissue and circulating tumor DNA (ctDNA) and to explore driver mutations as potential prognostic or predictive biomarkers or druggable targets in patients with advanced biliary tract cancer (BTC).

Patients and methods: We prospectively enrolled 18 patients with advanced BTC and analyzed next-generation sequencing data from 60 ctDNA samples using AlphaLiquid^® 100. This assay screens up to 118 genes for single-nucleotide variants (SNVs) and insertion or deletions (INDELs), 27 genes for copy number alterations (CNAs), and 10 genes for fusions. We examined the intra-patient tissue-ctDNA concordance and studied the association between ctDNA variant allele frequency (VAF) and survival.

Results: A total of seven gallbladder cancer cases, six intrahepatic cholangiocarcinoma cases, and five extrahepatic cholangiocarcinoma cases were observed. Among these cases, tumor tissues were available for 16 patients. Genetic alterations were detected in 88% (14/16) of tissue DNA samples and 89% (16/18) of samples with ctDNA at baseline. The most common genes altered in ctDNA were TP53 (n=11), ERBB3 (n=3), and KRAS (n=3). There was a 29% overlap in somatic SNVs/INDELs and a 60% overlap in CNAs between tissue DNA and ctDNA, while no fusion variant was detected. The sensitivity and positive predictive value of ctDNA for all types of somatic mutations were 47% and 43%, respectively. Among the 14 patients whose serial ctDNA was analyzed, 10 showed changes in ctDNA. A high pre-treatment VAF (>4.0%) was associated with poor overall survival.

Conclusion: ctDNA sequencing can successfully identify molecular genetic alterations in patients with advanced BTC, providing insights into potential biomarkers and therapeutic targets.

Background/aim: Spindle cell carcinoma (SpCC) is a subtype of poorly differentiated squamous cell carcinoma, and comprises a biphasic mixture of epithelial and mesenchymal cells. SpCC is a rare aggressive cancer, with a dismal prognosis. Furthermore, its characteristics remain unclear, complicating treatment for this malignancy. Developing specialized treatment strategies for SpCC that are different from traditional approaches for conventional squamous cell carcinoma is essential for obtaining good clinical outcomes.

Materials and methods: Our previous report documented the presence of platelet-derived growth factor receptor alpha (PDGFRα)-expressing mesenchymal stem/stromal cells (MSCs) in the cancer mass of recurrent SpCC of the tongue. PDGFRα-positive cells identified as cancer-associated fibroblasts are involved in the fate of epithelial-mesenchymal transition in SpCC. In this study, we analyzed the distribution patterns of immunopositive signals for MSC markers including PDGFRα in tissue sections via immunostaining.

Results: Immunohistological analysis showed an expansion of PDGFRα and other MSC marker-positive cells within the cancer fields. MSCs were adjacent to cancer epithelial marker EpCAM-positive cells. Some EpCAM-positive cell populations surrounded by cancer-associated fibroblasts were immunopositive for MSC markers including PDGFRα.

Conclusion: MSC expansion was observed in cancer areas containing EpCAM-positive cells, implying that MSCs, especially PDGFRα-positive MSCs, may serve as cancer niche elements involved in epithelial-mesenchymal transition. Additional studies focusing on PDGFRα pharmacological targeting in SpCC will contribute to understanding of this tumor biology and developing new strategies for treating SpCC.

Background/aim: Elevated fibronectin levels have been observed in various cancers; however, whether they are related to the actual malignancy remains controversial. We herein measured blood levels of sialic acid-fibronectin (S-FN), a type of autocrine cellular fibronectin secreted by breast cancer cells and investigate whether S-FN secretion is associated with the malignancy through epithelial-mesenchymal transition (EMT), as well as recurrent metastasis.

Patients and methods: Blood S-FN was detected in samples from 82 patients with breast carcinoma using ELISA. Vimentin immunostaining was performed in recurrent metastases cases to identify mesenchymal state cancer cells (MCCs) induced by EMT.

Results: Of the 82 patients, twenty- one patients (25.6%) were positive for S-FN. Twelve patients (14.6%) had recurrent metastases, including five with local recurrence (LR) and seven with remote metastasis (RM). Vimentin-positive cancer cells (VPCCs), suggesting the presence of MCCs in the tumor, had 1-10 (1+) in three S-FN-positive patients of LR. However, their histological margins showed remnants of cancer cells. Conversely, two S-FN-negative patients had VPCCs between 11-50 (2+) and did not have residual cancer at the margins, but experienced LR. Of the seven patients with RM, one S-FN-positive patient was VPCCs (1+) and had stable disease (SD). The other six S-FN-negative patients had VPCCs (1+) in two patients, and ≥ (2+) in four patients. One patient with VPCCs (1+) had SD, but four patients with VPCCs ≥ (2+) were treatment-resistant and had progressive disease (PD).

Conclusion: S-FN-negative patients showed treatment resistance and poor prognosis due to the high presence of EMT-induced MCCs in breast cancer.

This review describes the histopathological and molecular features distinguishing high-risk ductal carcinoma in situ (DCIS) from low-risk DCIS and their progression to invasive breast cancer (IBC). We summarize key alterations that occur in various compartments of the breast tissue such as myoepithelial cells, luminal epithelial cells, and the immune environment. Evidence suggests that DCIS and IBC share a largely similar genome, with comparable transcriptomes across various grades of DCIS and IBC. However, some studies report transcriptional up-regulation of multiple genes in luminal epithelial cells of high-risk DCIS. High-risk DCIS is also characterized by loss of genes that are crucial for maintaining the integrity of the myoepithelium, a physical barrier that keeps the cancer cells from invading surrounding tissue. High-grade DCIS is also characterized by global hypomethylation, but hypermethylation of select gene promoters also occurs. Immune environment changes that correlate with high-risk DCIS include overall increased T cell, B cell, and macrophage infiltration. Despite the active immune environment, these immune cells are in suppressed state and are characterized by increased presence of immunosuppressive Tregs, immunosuppressive M2, tumor-associated macrophages (TAMs), an immunophenotypic switch of fibroblasts into cancer-associated fibroblasts (CAFs) and lesser amounts of protective cytotoxic T cells. Several long noncoding RNAs also play a role in driving the premalignant phenotypic changes in normal breast epithelial and DCIS cells. Further validating the ability of these prognostic biomarkers for predicting DCIS progression will help reduce overtreatment while effectively managing the patients with DCIS that are at high risk of progression to IBC.