The cancer drug gemcitabine (GEM) is a key drug for treating pancreatic ductal adenocarcinoma (PDAC), but PDAC cells develop chemoresistance after long-term administration. Since the tolerance was immediately spread to every PDAC tissue in a patient, it is assumed that some certain efficient mechanisms underlay in the development of chemoresistance. Changes in the levels of particular microRNAs or alterations in intercellular communication play a dominant role in chemoresistance development, and recent data also suggest that exosomes play an important role in this process. In this study, we revealed that the loop conferred chemoresistance in PDAC cells. The loop was as follows; 1, The long-term exposure of GEM increased miR-155 expression in PDAC cells. 2, The increase of miR-155 induced two different functions; exosome secretion and chemoresistance ability via facilitating the anti-apoptotic activity. 3, Exosome deliver the miR-155 into the other PDAC cells and induce the following function. The target therapy to miR-155 or the exosome secretion effectively attenuated the chemoresistance, and these results were validated with both clinical samples and in vivo experiments. This mechanism represents a novel therapeutic target in GEM treatment to PDAC.
The Wilms' tumor gene, WT1, is a tumor marker for leukemic blast cells. The WT1 expression levels were examined for 57 patients with myelodysplastic syndromes (MDS) (refractory anemia (RA), 35; RA with excess of blasts (RAEB) 14; RAEB in transformation (RAEB-t), six; and MDS with fibrosis, two) and 12 patients with acute myeloid leukemia (AML) evolved from MDS. These levels significantly increased in proportion to the disease progression of MDS from RA to overt AML via RAEB and RAEB-t in both bone marrow (BM) and peripheral blood (PB). WT1 expression levels in PB significantly correlated with the evolution of RAEB or RAEB-t to overt AML within 6 months. Therefore, WT1 expression levels in PB were superior to those in BM for early prediction of the evolution to AML by means of quantitation of the WT1 expression levels. Furthermore, WT1 expression in PB of patients with overt AML evolved from MDS was significantly decreased by effective chemotherapy or allogeneic stem cell transplantation and became undetectable in long-term survivors. These results clearly showed that WT1 expression levels are a tumor marker for preleukemic or leukemic blast cells of MDS and thus reflect the disease progression of MDS. Therefore, monitoring of WT1 expression levels has made continuous assessment of the disease progression of MDS possible, as well as the prediction of the evolution of RAEB or RAEB-t to overt AML within 6 months. The results also showed that quantitation of WT1 expression levels is useful for diagnosis of minimal residual disease of MDS with high sensitivity, thus making it possible to evaluate the efficacy of treatment for MDS.
Biliary tract cancer (BTC) has a generally poor prognosis. Furthermore, it is difficult to distinguish BTC from benign biliary disease (BBD) with commonly used modalities. Therefore, a novel biomarker to facilitate cancer detection is highly desirable. Recent studies have reported the use of circulating microRNAs (miRNAs) as biomarkers for cancers. The purpose of this study was to evaluate whether circulating miRNA-21 (miR-21) could be used as a biomarker for BTC. Plasma samples were obtained from 94 BTC patients, 50 healthy volunteers (HVs), and 23 BBD patients. miR-21 levels in the samples were measured by qRT-PCR. Plasma miR-21 levels in patients with BTC were significantly higher than in HVs or in patients with BBD (P < 0.0001 for both). Receiver-operator curve (ROC) curve analysis in differentiating BTC patients from HVs indicated that area under the curve (AUC), optimal sensitivity and specificity was 0.93, 85.1% and 100%, respectively, and those in differentiating BTC patients from BBD patients was 0.83, 72.3%, 91.3%, respectively. Validation of these results indicated that the negative predictive value, positive predictive value, sensitivity, specificity, and accuracy in differentiating BTC patients from HVs was 76.6%, 98.6%, 84.0%, 98.0%, and 88.9%, respectively, and those in differentiating BTC patients from BBD patients was 42.2%, 93.0%, 71.2%, 82.6%, and 72.6%, respectively. These sets of values were improved by combining miR-21 and CA19-9 measurements. Plasma miR-21 is a novel diagnostic biomarker for BTC, and may be useful in distinguishing between BTC and BBD patients. (Cancer Sci 2013; 104: 1626-1631
BackgroundBone metastasis due to gastric cancer is rare, and the clinical features have not been fully evaluated. We investigated the clinical features, treatment outcomes, and prognostic factors in gastric cancer patients with bone metastasis.MethodsWe retrospectively collected data on 34 consecutive patients who were diagnosed radiologically with bone metastasis due to gastric cancer. We estimated the overall survival after the diagnosis of bone metastasis using the Kaplan-Meier product-limit method and evaluated which clinicopathological factors were associated with prognostic factors for survival using univariate and multivariate Cox proportional hazards regression models.ResultsThe treatment for the primary tumor was surgery in 16 patients (47.1%) and chemotherapy in 18 patients (52.9%). The median serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels at the time of bone metastasis were 375.5 and 249 IU/L, respectively. Ten patients (29.4%) were diagnosed with bone metastasis and gastric cancer at the same time. The 6-month survival rate after the diagnosis of bone metastasis was 63.8%, and the median survival time was 227.5 days. Multivariate analysis revealed that metachronous metastasis (p = 0.035) and extraosseous metastasis (p = 0.028) were significant risk factors for poor survival.ConclusionsThe prognosis of gastric cancer with bone metastasis was poor, and metachronous metastasis and extraosseous metastasis were shown to be poor prognostic factors. Serum ALP, LDH, and tumor markers are not always high, so aggressive diagnosis using appropriate modalities such as bone scan, MRI, or PET-CT may be necessary in routine practice even in asymptomatic patients.
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