Explore the vast range of titles available.

Gastrointestinal (GI) cancer is a major cause of morbidity and mortality worldwide [...]

Background Gastric cancer (GC) patients frequently develop peritoneal metastasis; however, the underlying mechanism remains unknown. We hypothesised that omental adipocytes (OmAd) trigger GC cells towards malignant activity to induce peritoneal metastasis. Methods We analysed interactions among human GC cells, endothelial cells and OmAd using a 3D co-culture system. We also employed a multipronged animal study, including subcutaneous and orthotopic tumours, and humanised omental adipose tissue models. Urinary levels of CXCL2 were analysed in human GC patients with and without peritoneal metastasis. Results Conditioned media derived from OmAd (OmAd-CM) promoted the proliferation, migration and capacity to induce angiogenesis of GC cells through AKT phosphorylation and VEGFA overexpression, whereas silencing CXCL2 in OmAd cancelled OmAd-induced effects. In an orthotopic tumour model using SCID mice, omentectomy suppressed GC growth and peritoneal dissemination, and reduced serum levels of CXCL2. OmAd promoted GC growth in a humanised omental adipose tissue model using NSG mice, but silencing CXCL2 in OmAd cancelled OmAd-induced tumour growth. Finally, urinary levels of CXCL2 were significantly higher in GC patients with peritoneal metastasis than in those without. Conclusion Omental adipocytes trigger GC cells to an aggressive phenotype through CXCL2 secretion, which induces angiogenesis followed by cell growth and peritoneal metastasis.

Background Photodynamic therapy (PDT) is an effective tumor treatment that involves the administration of a photosensitizer to generate cytotoxic 1 O 2 [reactive oxygen species (ROS)] from molecular oxygen that is produced from energy absorption following tumor irradiation at specific wavelengths. Ferroptosis is induced by the disruption of the glutathione peroxidase 4 (GPX4) antioxidant system, leading to lipid peroxidation. We hypothesized that talaporfin sodium-photodynamic therapy (TS-PDT)-generated ROS would lead to ferroptosis via accumulation of lipid peroxidation. Methods Cell viability assay in TS-PDT-treated cells in combination with a ferroptosis inhibitor (ferrostatin-1: Fer-1) or ferroptosis inducers (imidazole ketone erastin: IKE, Ras-selective lethal 3: RSL3) was performed. Accumulation of lipid peroxidation, GPX4 antioxidant system and cystine/glutamate antiporter (system xc − ) activity in TS-PDT-treated cells was investigated. In xenograft mice, the antitumor effect of TS-PDT in combination with ferroptosis inducers (IKE or sorafenib) was examined. Results TS-PDT-induced cell death was partly suppressed by Fer-1 and accompanied by lipid peroxidation. TS-PDT combined with IKE or RSL3 enhanced the induction of cell death. TS-PDT inhibited cystine uptake activity via system xc − . In vivo, the combination of TS-PDT and ferroptosis inducers (IKE or sorafenib) reduced tumor volume. Conclusion This study found that the mechanism underlying TS-PDT-induced ferroptosis constitutes direct lipid peroxidation by the generated ROS, and the inhibition of system xc − , and that the combination of a ferroptosis inducer with TS-PDT enhances the antitumor effect of TS-PDT. Our findings suggest that ferroptosis-inducing therapies combined with PDT may benefit cancer patients.

Background With the goal of discovering non-invasive biomarkers for early diagnosis of GC, we conducted a case-control study utilising urine samples from individuals with predominantly early GC vs. healthy control (HC). Methods Among urine samples from 372 patients, age- and sex-matched 282 patients were randomly divided into three groups: 18 patients in a discovery cohort; 176 patients in a training cohort and 88 patients in a validation cohort. Results Among urinary proteins identified in the comprehensive quantitative proteomics analysis, urinary levels of TFF1 (uTFF1) and ADAM12 (uADAM12) were significantly independent diagnostic biomarkers for GC, in addition to Helicobacter pylori status. A urinary biomarker panel combining uTFF1, uADAM12 and H. pylori significantly distinguished between HC and GC patients in both training and validation cohorts. On the analysis for sex-specific biomarkers, this combination panel demonstrated a good AUC of 0.858 for male GC, whereas another combination panel of uTFF1, uBARD1 and H. pylori also provided a good AUC of 0.893 for female GC. Notably, each panel could distinguish even stage I GC patients from HC patients (AUC = 0.850 for males; AUC = 0.845 for females). Conclusions Novel urinary protein biomarker panels represent promising non-invasive biomarkers for GC, including early-stage disease.

Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm of solid tumors. To date, many ongoing studies of ADC combinations with a variety of anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical studies and clinical trial settings. Nevertheless, combination therapy does not always guarantee a synergistic or additive effect and may entail overlapping toxicity risks. Therefore, understanding the current status and underlying mechanisms of ADC combination therapy is urgently required. This comprehensive review analyzes existing evidence concerning the additive or synergistic effect of ADCs with other classes of oncology medicines. Here, we discuss the biological mechanisms of different ADC combination therapy strategies, provide prominent examples, and assess their benefits and challenges. Finally, we discuss future opportunities for ADC combination therapy in clinical practice.

BackgroundGastric cancer (GC) is one of the most common causes of cancer deaths worldwide; however, reliable and non-invasive screening methods for GC are not established. Therefore, we conducted this study to develop a biomarker for GC detection, consisting of urinary microRNAs (miRNAs).MethodsWe matched 306 participants by age and sex [153 pairs consisting of patients with GC and healthy controls (HCs)], then randomly divided them across three groups: (1) the discovery cohort (4 pairs); (2) the training cohort (95 pairs); and (3) the validation cohort (54 pairs).ResultsThere were 22 urinary miRNAs with significantly aberrant expressions between the two groups in the discovery cohort. Upon multivariate analysis of the training cohort, urinary expression levels of miR-6807-5p and miR-6856-5p were significantly independent biomarkers for diagnosis of GC, in addition to Helicobacter pylori (H. pylori) status. A diagnostic panel that combined these 2 miRNAs and H. pylori status distinguished between HC and GC samples with an area under the curve (AUC) = 0.736. In the validation cohort, urinary miR-6807-5p and miR-6856-5p showed significantly higher expression levels in the GC group, and the combination biomarker panel of miR-6807-5p, miR-6856-5p, and H. pylori status also showed excellent performance (AUC = 0.885). In addition, this biomarker panel could distinguish between HC and stage I GC patients with an AUC = 0.748. Urinary expression levels of miR-6807-5p and miR-6856-5p significantly decreased to undetectable level after curative resection of GC.ConclusionsThis novel biomarker panel enables early and non-invasive detection of GC.

Background Currently utilized serum tumor markers and fecal immunochemical tests do not have sufficient diagnostic power for colorectal cancer (CRC) due to their low sensitivities. To establish non-invasive urinary protein biomarkers for early CRC diagnosis, we performed stepwise analyses employing urine samples from CRCs and healthy controls (HCs). Methods Among 474 urine samples, 363 age- and sex-matched participants (188 HCs, 175 stage 0–III CRCs) were randomly divided into discovery (16 HCs, 16 CRCs), training (110 HCs, 110 CRCs), and validation (62 HCs, 49 CRCs) cohorts. Results Of the 23 urinary protein candidates comprehensively identified from mass spectrometry in the discovery cohort, urinary levels of dipeptidase 1 (uDPEP1) and Trefoil factor1 (uTFF1) were the two most significant diagnostic biomarkers for CRC in both training and validation cohorts using enzyme-linked immunosorbent assays. A urinary biomarker panel comprising uDPEP1 and uTFF1 significantly distinguished CRCs from HCs, showing area under the curves of 0.825–0.956 for stage 0–III CRC and 0.792–0.852 for stage 0/I CRC. uDPEP1 and uTFF1 also significantly distinguished colorectal adenoma (CRA) patients from HCs, with uDPEP1 and uTFF1 increasing significantly in the order of HCs, CRA patients, and CRC patients. Moreover, expression levels of DPEP1 and TFF1 were also significantly higher in the serum and tumor tissues of CRC, compared to HCs and normal tissues, respectively. Conclusions This study established a promising and non-invasive urinary protein biomarker panel, which enables the early detection of CRC with high sensitivity.

Esophageal cancer (EC) including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) generally exhibits poor prognosis; hence, a noninvasive biomarker enabling early detection is necessary. Age- and sex-matched 150 healthy controls (HCs) and 43 patients with ESCC were randomly divided into two groups: 9 individuals in the discovery cohort for microarray analysis and 184 individuals in the training/test cohort with cross-validation for qRT-PCR analysis. Using 152 urine samples (144 HCs and 8 EACs), we validated the urinary miRNA biomarkers for EAC diagnosis. Among eight miRNAs selected in the discovery cohort, urinary levels of five miRNAs (miR-1273f, miR-619-5p, miR-150-3p, miR-4327, and miR-3135b) were significantly higher in the ESCC group than in the HC group, in the training/test cohort. Consistently, these five urinary miRNAs were significantly different between HC and ESCC in both training and test sets. Especially, urinary miR-1273f and miR-619-5p showed excellent values of area under the curve (AUC) ≥ 0.80 for diagnosing stage I ESCC. Similarly, the EAC group had significantly higher urinary levels of these five miRNAs than the HC group, with AUC values of approximately 0.80. The present study established novel urinary miRNA biomarkers that can early detect ESCC and EAC.

Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.

BackgroundObstructive colorectal cancer (CRC) is an emergency situation with high morbidity and mortality, but long-term outcomes of stage II/III obstructive CRC remain unclear. The aim of this study was to evaluate prognostic factors, including colorectal obstruction.MethodsData were retrospectively reviewed from consecutive patients with stage II/III CRC who underwent curative surgery between January 2007 and December 2011 at two Japanese institutions. We analyzed overall survival (OS) and relapse-free survival (RFS), according to various prognostic factors including colorectal obstruction.ResultsIn total, 979 patients with stage II/III CRC were identified for this study. Among these 979 patients, 94 patients showed colorectal obstruction (9.6%). In both stage II and stage III CRCs, colorectal obstruction showed significantly poorer OS and RFS compared to non-obstruction (5-year OS, obstruction vs. non-obstruction, stage II: 65.9 vs. 86.5%, P = 0.002; stage III: 55.9 vs. 73.6%, P = 0.007) (5-year RFS, obstruction vs. non-obstruction, stage II: 59.2 vs. 77.8%, P = 0.008; stage III 31.3 vs. 56.3%, P = 0.001). Multivariate analysis demonstrated colorectal obstruction as a significant independent and poor prognostic factor in terms of both OS (hazard ratio (HR) 2.469; 95% CI 1.339–4.545; P = 0.004) and RFS (HR 1.992; 95% CI 1.160–3.425; P = 0.012) for stage II CRC, as well as pT4 stage. On multivariate analysis for stage III CRC, colorectal obstruction was a significant predictor of poor RFS (HR 1.626; 95% CI 1.070–2.469; P = 0.023), but not poor OS.ConclusionsColorectal obstruction is an independent poor prognostic factor for stage II CRC. Adjuvant chemotherapy might be feasible for stage II CRC with colorectal obstruction.