Cell surface tetraspanin CD9 mediates chemoresistance in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearance of widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial therapy. A theory of cell adhesion-mediated drug resistance is thought to be a principal mechanism in which extracellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found that the tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from three of seven relapsed patients, whereas chemona?ve primary tumors from 16 patients were CD9 negative with only one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisplatin or etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to either of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via β1 integrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of the chemoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreover, selective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering RNA triggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell adhesion-mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC.     

Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma

Purpose

We evaluated the involvement of angiotensin II (AngII)-dependent pathways in melanoma growth, through the pharmacological blockage of AT1 receptor by the anti-hypertensive drug losartan (LOS).

Results

We showed immunolabeling for both AngII and the AT1 receptor within the human melanoma microenvironment. Like human melanomas, we showed that murine melanomas also express the AT1 receptor. Growth of murine melanoma, both locally and at distant sites, was limited in mice treated with LOS. The reduction in tumor growth was accompanied by a twofold decrease in tumor-associated microvessel density and by a decrease in CD31 mRNA levels. While no differences were found in the VEGF expression levels in tumors from treated animals, reduction in the expression of the VEGFR1 (Flt-1) at the mRNA and protein levels was observed. We also showed downregulation of mRNA levels of both Flt-4 and its ligand, VEGF-C.

Conclusions

Together, these results show that blockage of AT1 receptor signaling may be a promising anti-tumor strategy, interfering with angiogenesis by decreasing the expression of angiogenic factor receptors.     

Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group

We evaluated the efficacy and safety of sequential therapy with trastuzumab monotherapy (H-mono) followed by H plus docetaxel (D) after disease progression (H → H + D) versus combination therapy with H + D as first-line therapy. Patients with human epidermal growth factor receptor type 2 (HER2)-positive metastatic breast cancer (MBC) and left ventricular ejection fraction >50% were randomly assigned to either (a) H → H + D [H, once weekly 2 mg/kg (loading dose, 4 mg/kg); D, once every 3 weeks 60 mg/m²] or (b) H + D. Primary endpoints were progression-free survival (PFS) for the H-mono stage of the H → H + D group and H + D group and overall survival (OS) for both groups. Secondary endpoints were overall response rate, time to treatment failure, second PFS and safety. The planned number of patients was 160 patients in total. Of 112 patients enrolled, 107 were eligible. After 112 patients were enrolled, the Independent Data Monitoring Committee recommended stopping enrollment because PFS and OS were greater in the H + D group than the H → H + D group. Median PFS was 445 days in the H + D group versus 114 days for H-mono in the H → H + D group [hazard ratio (HR), 4.24; P < 0.01]. OS was significantly longer in the H + D group (HR, 2.72; P = 0.04). H + D therapy is significantly superior to H → H + D therapy as first-line therapy in patients with HER2-positive MBC, especially in terms of OS.     

Preventive effects of etodolac,a selective cyclooxygenase‐2 inhibitor,on cancer development in extensive metaplastic gastritis,a Helicobacter pylori‐negative precancerous lesion

The present study investigated the preventive effects of etodolac, a selective cyclo‐oxygenase (COX)‐2 inhibitor, on metachronous cancer development after endoscopic resection of early gastric cancer. Among 267 early gastric cancer patients who underwent endoscopic resection, 47 patients with extensive metaplastic gastritis were selected based on endoscopic findings and our previously described criteria of serum pepsinogen (PG) test‐positive and Helicobacter pylori antibody‐negative conditions. Nonrandomized etodolac treatment (300 mg/day) was administered to 26 patients (Group A), while the remaining 21 patients were untreated (Group B). No significant differences in age, sex distribution, lifestyle factors or extent of metaplastic gastritis at baseline were identified between groups. Patients were followed for metachronous cancer development with endoscopy every 6–12 months for up to 5 years. Mean (standard deviation) follow‐up period was 4.2 (0.9) years. In Group B, 5 cancers developed (incidence rate = 6,266/100,000 person‐years), significantly more than the 1 cancer in Group A (incidence rate = 898/100,000 person‐years; p < 0.05). Long‐term etodolac treatment did not influence the extent of metaplastic gastritis as revealed by endoscopic findings or by serum PG levels, but effectively reduced metachronous cancer development in patients with extensive metaplastic gastritis. These results strongly suggest that chemoprevention of cancer in the metaplastic stomach is possible by controlling COX‐2 expression.     

A pretreatment nomogram predicting recurrence- and progression-free survival for nonmuscle invasive bladder cancer in Japanese patients

Purpose

Our aim was to provide nomograms that allow urologists to easily calculate a nonmuscle invasive bladder cancer patient’s risk of recurrence and progression.

Materials and methods

We retrospectively analyzed 800 nonmuscle invasive bladder cancer patients newly diagnosed between 1991 and 2001 from the Gifu urothelial cancer registry program. We developed the nomogram using the original 500 patients and validated it using the remaining 300 patients. The prognostic factors of recurrence and progression were identified by multivariate analysis in 500 patients.

Results

In the multivariate analysis, tumor number, shape, grade, and intravesical instillation were associated with recurrence-free survival. Tumor shape and grade were associated with progression-free survival. Six factors for recurrence and three factors for progression were used to make the nomogram. Using the original 500 patients who were modeled for the nomogram, the areas under the receiver operating characteristic curves (AUCs) were calculated to be 0.61 for recurrence and 0.71 for progression. To validate nomogram performance, we applied an additional 300 patients to the nomograms. The AUCs were 0.57 for recurrence and 0.67 for progression.

Conclusions

The nomograms that have been developed can be used to predict the probability of recurrence and progression of nonmuscle invasive bladder cancer.     

Wedge tracheobronchoplasty technique for primary pulmonary carcinoma of the right upper bronchus

We describe a novel tracheobronchoplasty procedure for advanced squamous cell carcinoma of the right upper lung. A 78-year-old male was referred for further investigation of an abnormal shadow on a chest x-ray. A conventional right upper sleeve lobectomy was not applicable because of the invasion of lateral wall of the lower trachea. So, we performed a modified tracheobronchoplasty. This report shows that our cutting design for the trachea and bronchus was reasonable and appropriate for a caliber mismatch, with adaptation and suturing of each edge of the wedge-shaped defect of the trachea.     

Preliminary study of early response to neoadjuvant chemotherapy after the first cycle in breast cancer: comparison of <Superscript>1</Superscript>H magnetic resonance spectroscopy with diffusion magnetic resonance imaging

Purpose  

The aim of this study was to assess the efficacy of single-voxel ¹H magnetic resonance spectroscopy (MRS) at 1.5 T to evaluate early responses to neoadjuvant chemotherapy after the first treatment in breast cancer patients and to compare it to measurements of apparent diffusion coefficient (ADC) values derived from diffusion-weighted magnetic resonance imaging (MRI).     

Changes in thioredoxin concentrations: an observation in an ultra-marathon race

Objectives

Changes in plasma thioredoxin (TRX) concentrations before, during, and after a 130-km endurance race were measured with the aim of elucidating the relationship between exercise and oxidative stress (OS).

Methods

Blood samples were taken from 18 runners participating in a 2-day-long 130-km ultra-marathon during the 2 days of the race and for 1 week thereafter. There were six sampling time points: at baseline, after the goal had been reached on the first and second day of the endurance race, respectively, and on 1, 3, and 5/6 days post-endurance race. The samples were analyzed for plasma TRX concentrations, platelet count, and blood lipid profiles.

Results

Concentrations of plasma TRX increased from 17.9 ± 1.2 ng/mL (mean ± standard error of the mean) at baseline to 57.3 ± 5.0 ng/mL after the first day’s goal had been reached and to 70.1 ± 6.9 ng/mL after the second day's goal had been reached; it then returned to the baseline level 1 day after the race. Platelet counts of 21.3 ± 1.2 × 10⁴ cell/μL at baseline increased to 23.9 ± 1.5 × 10⁴ cells/μL on Day 1 and to 26.1 ± 1.0 × 10⁴ cells/μL on Day 2. On Day 7, the platelet counts had fallen to 22.1 ± 1.2 × 10⁴ cell/μL. There was a significant positive correlation between plasma TRX and platelet count.

Conclusions

These data suggest that plasma TRX is an OS marker during physical exercise. Further studies are needed to determine the appropriate level of exercise for the promotion of health.     

A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes

ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to the inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. Here, we detected a de novo heterozygous point mutation of ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamics simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of phospholipids altered cell characteristics, including cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. Matrix-assisted laser desorption ionization–imaging mass spectrometry (MALDI-IMS) showed a marked increase of SM levels in the brains of Q84E-knockin mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.