Detection of Circulating Pancreas Epithelial Cells in Patients With Pancreatic Cystic Lesions

Rhim, Andrew D.; Thege, Fredrik I.; Santana, Steven M.; Lannin, Timothy B.; Saha, Trisha N.; Tsai, Shannon; Maggs, Lara R.; Kochman, Michael L.; Ginsberg, Gregory G.; Lieb, John G.; Chandrasekhara, Vinay; Drebin, Jeffrey A.; Ahmad, Nuzhat A.; Yang, Yu‐Xiao; Kirby, Brian J.; Stanger, Ben Z.

doi:10.1053/j.gastro.2013.12.007

Cited by 199 publications

(152 citation statements)

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“…The pancreas tumor microenvironment has been studied previously, but new tools [genetically engineered mouse models (GEMs) that faithfully recapitulate the salient features of human PDAC] now allow for a careful dissection of the stroma. Using these models, we showed that generalized inflammation is required for the development of precancerous pancreatic intraepithelial neoplasias (1) and that Hedgehog-dependent stromal elements, including activated myofibroblasts, serve to constrain tumor growth and spread (2). Other cellular components of the pancreatic inflammatory stroma have not been examined, and it is possible they also contribute to the complex balance of inputs, supportive and inhibitory, which underlie tumorigenesis and progression.…”

mentioning

confidence: 99%

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Saloman

Albers

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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271

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro-and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.sensory neuron | pancreatic ductal adenocarcinoma | tumorigenesis | inflammation | PanIN P ancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a median survival of ∼6 mo from diagnosis (National Cancer Institute). A number of unique features distinguish PDAC from other carcinomas, but the most striking is the exuberant desmoplastic infiltrate within tumors. This compartment exhibits an array of cell types, including activated myofibroblasts and myeloid-derived cells. Indeed, this inflammatory infiltrate is present at the inception of neoplasia and accumulates at a near exponential rate during progression to carcinoma and tumor formation. It provides a complex balance of pro-and antitumorigenic signals to neoplastic cells (and also to each other) that is a focus of intense investigation. The pancreas tumor microenvironment has been studied previously, but new tools [genetically engineered mouse models (GEMs) that faithfully recapitulate the salient features of human PDAC] now allow for a careful dissection of the stroma. Using these models, we showed that generalized inflammation is required for the development of precancerous pancreatic intraepithelial neoplasias (1) and that Hedgehog-dependent stromal elements, including activated myofibroblasts, serve to constrain tumor growth and spread (2). Other cellular components of the pancreatic inflammatory str...

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mentioning

confidence: 99%

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Saloman

Albers

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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271

243

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“…1 These cells originate from tumors and a subpopulation has been shown to be pre-cursors to metastasis. 2 In addition to this putative role, it is well known that these circulating tumor cells correlate with disease progression, 3 that they can be captured even in early disease, 4 and that they can be used to gauge functional cell responses to pharmaceuticals 5 or the genetic character of the cancer. 6 This information from captured CTCs is valuable to both clinicians and researchers particularly in the context of pancreatic cancer, in which the presence of circulating pancreatic cells precedes a) Author to whom correspondence should be addressed.…”

Section: Introductionmentioning

confidence: 99%

“…2 Furthermore, circulating pancreatic cells exist in a subset of patients without cancer but with potentially cancerous pancreatic cystic lesions. 4 To obtain this information, CTCs have been successfully captured from blood samples through mechanical, 7 electromechanical 8 and immunoaffinity methods, 9-11 the last being the most common. However, challenges exist capturing subsets of CTCs that have reduced antigen expression, often associated with the epithelial to mesenchymal transition (EMT) 12 or acquired resistance to chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Automated electrorotation shows electrokinetic separation of pancreatic cancer cells is robust to acquired chemotherapy resistance, serum starvation, and EMT

Lannin

Gruber

et al. 2016

Biomicrofluidics

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We used automated electrorotation to measure the cytoplasmic permittivity, cytoplasmic conductivity, and specific membrane capacitance of pancreatic cancer cells under environmental perturbation to evaluate the effects of serum starvation, epithelial-to-mesenchymal transition, and evolution of chemotherapy resistance which may be associated with the development and dissemination of cancer. First, we compared gemcitabine-resistant BxPC3 subclones with gemcitabine-naive parental cells. Second, we serum-starved BxPC3 and PANC-1 cells and compared them to untreated counterparts. Third, we induced the epithelial-to-mesenchymal transition in PANC-1 cells and compared them to untreated PANC-1 cells. We also measured the electrorotation spectra of white blood cells isolated from a healthy donor. The properties from fit electrorotation spectra were used to compute dielectrophoresis (DEP) spectra and crossover frequencies. For all three experiments, the median crossover frequency for both treated and untreated pancreatic cancer cells remained significantly lower than the median crossover frequency for white blood cells. The robustness of the crossover frequency to these treatments indicates that DEP is a promising technique for enhancing capture of circulating cancer cells. Published by AIP Publishing. [http://dx

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“…18 Separately, these obstacle arrays have been used to generate size-dependent collision dynamics, bringing target cells into contact with the antibodies on the obstacle surface, while displacing contaminating cells onto trajectories with infrequent cell-obstacle collisions; this technique has been termed geometrically enhanced differential immunocapture (GEDI). 6,11,27 This work focuses on combining differential DEP response in obstacle arrays with immunocapture, so as to capture target cells on the obstacle surfaces using antibody-antigen binding. Although the ideal DEP-obstacle array system would generate a uniformly high electric field around the obstacles, attracting cells experiencing pDEP to the obstacle capture surface, such a device would require electrodes on the side of each obstacle and would be difficult to fabricate using conventional techniques.…”

Section: Introductionmentioning

confidence: 99%

Enhancing sensitivity and specificity in rare cell capture microdevices with dielectrophoresis

2015

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The capture and subsequent analysis of rare cells, such as circulating tumor cells from a peripheral blood sample, has the potential to advance our understanding and treatment of a wide range of diseases. There is a particular need for high purity (i.e., high specificity) techniques to isolate these cells, reducing the time and cost required for single-cell genetic analyses by decreasing the number of contaminating cells analyzed. Previous work has shown that antibody-based immunocapture can be combined with dielectrophoresis (DEP) to differentially isolate cancer cells from leukocytes in a characterization device. Here, we build on that work by developing numerical simulations that identify microfluidic obstacle array geometries where DEP-immunocapture can be used to maximize the capture of target rare cells, while minimizing the capture of contaminating cells. We consider geometries with electrodes offset from the array and parallel to the fluid flow, maximizing the magnitude of the resulting electric field at the obstacles' leading and trailing edges, and minimizing it at the obstacles' shoulders. This configuration attracts cells with a positive DEP (pDEP) response to the leading edge, where the shear stress is low and residence time is long, resulting in a high capture probability; although these cells are also repelled from the shoulder region, the high local fluid velocity at the shoulder minimizes the impact on the overall transport and capture. Likewise, cells undergoing negative DEP (nDEP) are repelled from regions of high capture probability and attracted to regions where capture is unlikely. These simulations predict that DEP can be used to reduce the probability of capturing contaminating peripheral blood mononuclear cells (using nDEP) from 0.16 to 0.01 while simultaneously increasing the capture of several pancreatic cancer cell lines from 0.03-0.10 to 0.14-0.55, laying the groundwork for the experimental study of hybrid DEP-immunocapture obstacle array microdevices. V C 2015 AIP Publishing LLC.

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Detection of Circulating Pancreas Epithelial Cells in Patients With Pancreatic Cystic Lesions

Cited by 199 publications

References 9 publications

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Automated electrorotation shows electrokinetic separation of pancreatic cancer cells is robust to acquired chemotherapy resistance, serum starvation, and EMT

Enhancing sensitivity and specificity in rare cell capture microdevices with dielectrophoresis

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