Fine-Needle Aspirates v2.0 — The Molecular Era

Tissue biopsies are required for diagnosis, prognosis, and to measure individual drug response markers for patient management. For pancreatic adenocarcinoma, surgically harvested tissues are often used to collect data and perform genomic analysis to identify driver oncogenes and specific mutations, or to quantify a handpick of (micro)RNAs and proteins biomarkers. However, such strategy raises many concerns not only because 80% of patients diagnosed with pancreatic adenocarcinoma are not eligible for surgery, meaning that biopsies are not collected, but also because repeated core biopsies are related to higher risk of morbidity, are expensive and logistics can be limiting. Alternative sample collection methods include fine-needle aspirates (FNA) collected under endoscopic ultrasound (EUS). In this chapter, we will describe how EUS-FNA material can be a wealthy source of biomarkers for pancreatic cancer patient management. In greater details, we will review how DNA, micro(RNA), or protein analysis can help stratify pancreatic adenocarcinoma patients, from single events analysis, to cutting-edge, high-throughput studies

Expression and Function of Kruppel Like-Factors (KLF) in Carcinogenesis

Krüppel-like factor (KLF) family members share a three C2H2 zinc finger DNA binding domain, and are involved in cell proliferation and differentiation control in normal as in pathological situations. Studies over the past several years support a significant role for this family of transcription factors in carcinogenesis. KLFs can both activate and repress genes that participate in cell-cycle regulation. Among them, many up-regulated genes are inhibitors of proliferation, whereas genes that promote cell proliferation are repressed. However, several studies do present KLFs as positive regulator of cell proliferation. KLFs can be deregulated in multiple cancers either by loss of heterozygosity (LOH), somatic mutation or transcriptional silencing by promoter hypermethylation. Accordingly, KLF expression was shown to mediate growth inhibition when ectopically expressed in multiple cancer-derived cell lines through the inhibition of a number of key oncogenic signaling pathways, and to revert the tumorogenic phenotype in vivo. Taken together, these observations suggest that KLFs act as tumor suppressor. However, in some occasion, KLFs could act as tumor promoters, depending on “cellular context”. Thus, this review will discuss the roles and the functions of KLF family members in carcinogenesis, with a special focus on cancers from epithelial origin

The activation of neuronal NO synthase is mediated by Gâ protein βγ subunit and the tyrosine phosphatase SHPâ 2

In CHO cells we had found that CCK positively regulated cell proliferation via the activation of a soluble guanylate cyclase. Here we demonstrate that CCK stimulated a nitric oxide synthase (NOS) activity. The production of NO was involved in the proliferative response elicited by CCK regarding the inhibitory effect of NOS inhibitors Lâ NAME and αâ guanidinoglutaric acid. We identified the NOS activated by the peptide as the neuronal isoform: the expression of the C415A neuronal NOS mutant inhibited both CCKâ induced stimulation of NOS activity and cell proliferation. These two effects were also inhibited after expression of the C459S tyrosine phosphatase SHPâ 2 mutant and the βARKl (495â 689) sequestrant peptide, indicating the requirement of activated SHPâ 2 and Gâ βγ subunit. Kinetic analysis (Western blot after coimmunoprecipitation and specific SHPâ 2 activity) revealed that in response to CCKâ treatment, SHPâ 2 associated to Gâ β1 subunit, became activated, and then dephosphorylated the neuronal NOS through a direct association. These data demonstrate that the neuronal NOS is implicated in proliferative effect evoked by CCK. A novel growth signaling pathway is described, involving the activation of neuronal NOS by dephosphorylation of tyrosyl residues.â Cordelier, P., Estève, J.â P., Rivard, N., Marletta, M., Vaysse, N., Susini, C., Buscail, L. The activation of neuronal no synthase is mediated by Gâ protein βγ subunit and the tyrosine phosphatase SHPâ 2. FASEB J. 13, 2037â 2050 (1999)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154447/1/fsb2fasebj13142037.pd

Genetic and Epigenetic Alterations in Pancreatic Carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Despite significant progresses in the last decades, the origin of this cancer remains unclear and no efficient therapy exists. PDAC does not arise de novo: three remarkable different types of pancreatic lesions can evolve towards pancreatic cancer. These precursor lesions include: Pancreatic intraepithelial neoplasia (PanIN) that are microscopic lesions of the pancreas, Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) that are both macroscopic lesions. However, the cellular origin of these lesions is still a matter of debate

Adult Stromal Cells Derived from Human Adipose Tissue Provoke Pancreatic Cancer Cell Death both In Vitro and In Vivo

1932-6203 (Electronic) Journal Article Research Support, Non-U.S. Gov'tBACKGROUND: Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. Disrupting this homeostasis can induce aberrant cell proliferation, adhesion, function and migration that might promote malignant behavior. Indeed, aberrant stromal-epithelial interactions contribute to pancreatic ductal adenocarcinoma (PDAC) spread and metastasis, and this raises the possibility that novel stroma-targeted therapies represent additional approaches for combating this malignant disease. The aim of the present study was to determine the effect of human stromal cells derived from adipose tissue (ADSC) on pancreatic tumor cell proliferation. PRINCIPAL FINDINGS: Co-culturing pancreatic tumor cells with ADSC and ADSC-conditioned medium sampled from different donors inhibited cancer cell viability and proliferation. ADSC-mediated inhibitory effect was further extended to other epithelial cancer-derived cell lines (liver, colon, prostate). ADSC conditioned medium induced cancer cell necrosis following G1-phase arrest, without evidence of apoptosis. In vivo, a single intra-tumoral injection of ADSC in a model of pancreatic adenocarcinoma induced a strong and long-lasting inhibition of tumor growth. CONCLUSION: These data indicate that ADSC strongly inhibit PDAC proliferation, both in vitro and in vivo and induce tumor cell death by altering cell cycle progression. Therefore, ADSC may constitute a potential cell-based therapeutic alternative for the treatment of PDAC for which no effective cure is available

Expression and Role of MicroRNAs from the miR-200 Family in the Tumor Formation and Metastatic Propensity of Pancreatic Cancer

MicroRNAs from the miR-200 family are commonly associated with the inhibition of the metastatic potential of cancer cells, following inhibition of ZEB transcription factors expression and epithelial-to-mesenchymal transition. However, previous studies performed in pancreatic adenocarcinoma revealed a more complex picture challenging this canonical model. To gain better insights into the role of miR-200 family members in this disease, we analyzed the expression of miR-200a, miR- 200b, miR-200c, miR-141, miR-429, and miR-205, and ZEB1, ZEB2, and CDH1 in pancreatic tumors and matching normal adjacent parenchyma and patient-derived xenografts. We found that miR-200a, miR-429, and miR-205 are frequently overex- pressed in pancreatic tumors, whereas CDH1 is downregulated, and ZEB1 and ZEB2 levels remain unchanged. Furthermore, we measured a positive correlation between miR-200 family mem- bers and CDH1 expression, and a negative correlation between ZEB1 and miR-200c, miR-141, and miR-205 expression, respec- tively. Interestingly, we identified significant changes in expres- sion of epithelial-to-mesenchymal transition regulators and miR-200 members in patient-derived xenografts. Lastly, func- tional studies revealed that miR-141 and miR-429 inhibit the tumorigenic potential of pancreatic cancer cells. Taken together, this comprehensive analysis strongly suggests that miRNAs from the miR-200 family, and in particular miR-429, may act as a tu- mor suppressor gene in pancreatic cancer

Autocrine regulation of human prostate carcinoma cell proliferation by somatostatin through the modulation of the SH2 domain containing protein tyrosine phosphatase (SHP)-1

The present study was intended to gain additional information on the growth regulation of prostate by somatostatin\ud (SRIF) and the intracellular events involved. The humanprostate adenocarcinoma cell lines PC-3 and LNCaP produce SRIF and express subtypes 2 and 5 of SRIF receptors. The secretion\ud of SRIF is related to the proliferative status of these cells; an inverse relationship exists between cell proliferation and the amount of secreted SRIF. Moreover, the growth of PC-3 cells\ud is inhibited by SRIF overexpression and increased by blockage of endogenous SRIF. Coincident with the increase in SRIF\ud secretion, the activity and levels of theSH2domain containing protein tyrosine phosphatase (SHP)-1, present in PC-3 cells are augmented, but the effect can be partially prevented by neutralization of secreted endogenously SRIF. The activity of SHP-1 is also stimulated by the SRIF analog RC160. Overexpression of SHP-1 induces inhibition of PC-3 cell growth.\ud SHP-1 is also present in normal prostate, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and well differentiated adenocarcinoma. In contrast, no signal is detected in poorly differentiated prostate cancer. These findings demonstrate that SRIF inhibits PC-3 and LNCaP cell proliferation through an autocrine/paracrine SRIF loop. This effect could be mediated by activation of the tyrosine phosphatase SHP-1 detected in these cells as well as in human prostate and prostate cancer.Fundación para la Investigación en UrologíaMinisterio de Asuntos Exteriore

Sedimentation and Fouling of Optical Surfaces at the ANTARES Site

ANTARES is a project leading towards the construction and deployment of a neutrino telescope in the deep Mediterranean Sea. The telescope will use an array of photomultiplier tubes to detect the Cherenkov light emitted by muons resulting from the interaction with matter of high energy neutrinos. In the vicinity of the deployment site the ANTARES collaboration has performed a series of in-situ measurements to study the change in light transmission through glass surfaces during immersions of several months. The average loss of light transmission is estimated to be only ~2% at the equator of a glass sphere one year after deployment. It decreases with increasing zenith angle, and tends to saturate with time. The transmission loss, therefore, is expected to remain small for the several year lifetime of the ANTARES detector whose optical modules are oriented downwards. The measurements were complemented by the analysis of the ^{210}Pb activity profile in sediment cores and the study of biofouling on glass plates. Despite a significant sedimentation rate at the site, in the 0.02 - 0.05 cm.yr^{-1} range, the sediments adhere loosely to the glass surfaces and can be washed off by water currents. Further, fouling by deposits of light-absorbing particulates is only significant for surfaces facing upwards.Comment: 18 pages, 14 figures (pdf), submitted to Astroparticle Physic