White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and ...promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that αSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression.
Development of minimally invasive biomarker assays for early detection and effective clinical management of pancreatic cancer is urgently needed to reduce high morbidity and mortality associated with ...this malignancy. We hypothesized that if aberrantly expressing microRNAs (miRNA) in pancreatic adenocarcinoma tissues are detected in blood plasma, then plasma profiling of these miRNAs might serve as a minimally invasive early detection biomarker assay for this malignancy. By using a modified protocol to isolate and quantify plasma miRNAs from heparin-treated blood, we show that miRNA profiling in plasma can differentiate pancreatic adenocarcinoma patients from healthy controls. We have profiled four miRNAs, miR-21, miR-210, miR-155, and miR-196a, all implicated in the development of pancreatic cancer with either proven or predicted target genes involved in critical cancer-associated cellular pathways. Of these, miR-155 has recently been identified as a candidate biomarker of early pancreatic neoplasia, whereas elevated expression of miR196a has been shown to parallel progression of disease. The results revealed a sensitivity of 64% and a specificity of 89% with the analyses of plasma levels for this panel of four miRNAs. The area under the receiver operating characteristic curve were estimated at 0.82 and 0.78 without and with leave-one-out cross-validation scheme, respectively. These observations, although a "proof of principle" finding at this time, show the feasibility of developing plasma miRNA profiling as a sensitive and specific blood-based biomarker assay for pancreatic cancer that has the potential of translation to the clinic with additional improvements in the future.
Abstract Intraductal papillary mucinous neoplasm (IPMN) is a precursor cystic lesion to pancreatic cancer. With the goal of classifying IPMN cases by risk of progression to pancreatic cancer, we ...undertook an exploratory next generation sequencing (NGS) based profiling study of miRNAs (miRNome) in the cyst fluids from low grade-benign and high grade-invasive pancreatic cystic lesions. Thirteen miRNAs (miR-138, miR-195, miR-204, miR-216a, miR-217, miR-218, miR-802, miR-155, miR-214, miR-26a, miR-30b, miR-31, and miR-125) were enriched and two miRNAs (miR-451a and miR-4284) were depleted in the cyst fluids derived from invasive carcinomas. Quantitative real-time polymerase chain reaction analysis confirmed that the relative abundance of tumor suppressor miR-216a and miR-217 varied significantly in these cyst fluid samples. Ingenuity Pathway Analysis (IPA) analysis indicated that the genes targeted by the differentially enriched cyst fluid miRNAs are involved in five canonical signaling pathways, including molecular mechanisms of cancer and signaling pathways implicated in colorectal, ovarian and prostate cancers. Our findings make a compelling case for undertaking in-depth analyses of cyst fluid miRNomes for developing informative early detection biomarkers of pancreatic cancer developing from pancreatic cystic lesions.
FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress ...caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury.
In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases.
We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects.
FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The validation of candidate biomarkers often is hampered by the lack of a reliable means of assessing and comparing performance. We present here a reference set of serum and plasma samples to ...facilitate the validation of biomarkers for resectable pancreatic cancer. The reference set includes a large cohort of stage I-II pancreatic cancer patients, recruited from 5 different institutions, and relevant control groups. We characterized the performance of the current best serological biomarker for pancreatic cancer, CA 19-9, using plasma samples from the reference set to provide a benchmark for future biomarker studies and to further our knowledge of CA 19-9 in early-stage pancreatic cancer and the control groups. CA 19-9 distinguished pancreatic cancers from the healthy and chronic pancreatitis groups with an average sensitivity and specificity of 70-74%, similar to previous studies using all stages of pancreatic cancer. Chronic pancreatitis patients did not show CA 19-9 elevations, but patients with benign biliary obstruction had elevations nearly as high as the cancer patients. We gained additional information about the biomarker by comparing two distinct assays. The two CA 9-9 assays agreed well in overall performance but diverged in measurements of individual samples, potentially due to subtle differences in antibody specificity as revealed by glycan array analysis. Thus, the reference set promises be a valuable resource for biomarker validation and comparison, and the CA 19-9 data presented here will be useful for benchmarking and for exploring relationships to CA 19-9.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Development of sensitive and specific biomarkers, preferably those circulating in body fluids is critical for early diagnosis of cancer. This study performed profiling of microRNAs (miRNAs) in ...exocrine pancreatic secretions (pancreatic juice) by microarray analysis utilizing pancreatic juice from 6 pancreatic ductal adenocarcinoma (PDAC) patients and two pooled samples from 6 non-pancreatic, non-healthy (NPNH) as controls. Differentially circulating miRNAs were subsequently validated in 88 pancreatic juice samples from 50 PDAC, 19 chronic pancreatitis (CP) patients and 19 NPNH controls. A marked difference in the profiles of four circulating miRNAs (miR-205, miR-210, miR-492, and miR-1427) was observed in pancreatic juice collected from patients with PDAC and those without pancreatic disease. Elevated levels of the four miRNAs together predicted PDAC with a specificity of 88% and sensitivity of 87%. Inclusion of serum CA19-9 level increased the sensitivity to 91% and the specificity to 100%. Enrichment of the four miRNAs in pancreatic juice was associated with decreased OS, as was the combination of miR-205 and miR-210. Higher contents of miR-205 and miR-210 were also associated with lymph node metastasis. Elevated levels of circulating miR-205, miR-210, miR-492, and miR-1247 in pancreatic juice are, therefore, promising candidate biomarkers of disease and poor prognosis in patients with PDAC.
Blood-based biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are urgently needed. Current biomarkers lack high sensitivity and specificity for population screening. The ...gold-standard biomarker, CA 19-9, also fails to demonstrate the predictive value necessary for early detection.
To validate a functional genomics-based plasma migration signature biomarker panel, plasma tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FN III-C), and CA 19-9 levels were measured by enzyme-linked immunosorbent assays in three early-stage PDAC plasma cohorts, including two independent blinded validation cohorts containing a total of 43 stage I, 163 stage II, 86 chronic pancreatitis, 31 acute biliary obstruction, and 108 controls. Logistic regression models developed classification rules combining TFPI and/or TNC-FN III-C with CA 19-9 for patient cases and control subjects, with or without adjustment for age and diabetes status. Model classification performance was evaluated and analyses repeated among subpopulations without diabetes and pancreatitis history. Two-sided P values were calculated using bootstrap method.
The TFPI/TNC-FN III-C/CA 19-9 panel improved CA 19-9 performance in all early-stage cohorts, including discriminating stage IA/IB/IIA, stage IIB, and all early-stage cancer from healthy controls. Statistical significance was reached for a number of subcohorts, including for all early-stage cancer vs healthy controls (cohort 1 AUC = 0.92, 95% CI = 0.86 to 0.96, P = .04; cohort 3 AUC = 0.83, 95% CI = 0.76 to 0.89, P = .045). Among subcohorts without diabetes and pancreatitis history, the panel approaches potential clinical utility for early detection to discriminate early-stage PDAC from healthy controls including an area under the curve (AUC) of 0.87 (95% CI = 0.77 to 0.95) for stage I/IIA, an AUC of 0.93 (95% CI = 0.87 to 0.98) for stage IIB, and a statistically significant AUC of 0.89 (95% CI = 0.82 to 0.95) for all early-stage cancer ( P = .03).
TFPI/TNC-FN III-C migration signature adds statistically significantly to CA 19-9's predictive power to detect early-stage PDAC and may have clinical utility for early detection of surgically resectable PDAC, as well as for enhanced survival from this routinely lethal cancer.
Background
Pancreatic cancer is the fourth leading cause of cancer death in the United States. The high mortality rate of patients with pancreatic cancer is primarily due to the difficulty of early ...diagnosis and a lack of effective therapies. There is an urgent need to discover novel molecular targets for early diagnosis and new therapeutic approaches to improve the clinical outcome of this deadly disease.
Aim
We utilized the reverse-phase protein assay (RPPA) to identify differentially expressed biomarker proteins in tumors and matched adjacent, normal-appearing tissue samples from 15 pancreatic cancer patients.
Methods
The antibody panel used for the RPPA included 130 key proteins involved in various cancer-related pathways. The paired
t
test was used to determine the significant differences between matched pairs, and the false discovery rate-adjusted
p
values were calculated to take into account the effect of multiple comparisons.
Results
After correcting for multiple comparisons, we found 19 proteins that had statistically significant differences in expression between matched pairs. However, only four (AKT, β-catenin, GAB2, and PAI-1) of them met the conservative criteria (both a
q
value <0.05 and a fold-change of ≥3/2 or ≤2/3) to be considered differentially expressed. Overexpression of AKT, β-catenin, and GAB2 in pancreatic cancer tissues identified by RPPA has also been further confirmed by western blot analysis. Further analysis identified several significantly associated canonical pathways and overrepresented network functions.
Conclusion
GAB2, a newly identified protein in pancreatic cancer, may provide additional insight into this cancer’s pathogenesis. Future studies in a larger population are warranted to further confirm our results.
We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, ...human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
