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Pancreatic Neoplasms: HELP
Articles by Ziv Gil
Based on 14 articles published since 2010
(Why 14 articles?)
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Between 2010 and 2020, Z. Gil wrote the following 14 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Editorial Exosomal transmission between macrophages and cancer cells: new insights to stroma-mediated drug resistance. 2018

Gil, Ziv. ·Ziv Gil: Department of Otolaryngology Head and Neck Surgery, The Laboratory for Applied Cancer Research, The Head and Neck Center, Haifa, Israel; Technion Integrated Cancer Center, Rappaport Institute of Medicine and Research, Technion, Israel Institute of Technology, Haifa, Israel. ·Oncotarget · Pubmed #30647866.

ABSTRACT: -- No abstract --

2 Review Gemcitabine resistance in pancreatic ductal adenocarcinoma. 2015

Binenbaum, Yoav / Na'ara, Shorook / Gil, Ziv. ·Clinical Research Institute at Rambam, Haifa, Israel. · Clinical Research Institute at Rambam, Haifa, Israel; Department of Otolaryngology Head and Neck Surgery, Rambam Healthcare Campus, Haifa, Israel. · Clinical Research Institute at Rambam, Haifa, Israel; Department of Otolaryngology Head and Neck Surgery, Rambam Healthcare Campus, Haifa, Israel; Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: ziv@baseofskull.org. ·Drug Resist Updat · Pubmed #26690340.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) ranks fourth among cancer related deaths. The disappointing 5-year survival rate of below 5% stems from drug resistance to all known therapies, as well as from disease presentation at a late stage when PDA is already metastatic. Gemcitabine has been the cornerstone of PDA treatment in all stages of the disease for the last two decades, but gemcitabine resistance develops within weeks of chemotherapy initiation. From a mechanistic perspective, gemcitabine resistance may result from alterations in drug metabolism until the point that the cytidine analog is incorporated into the DNA, or from mitigation of gemcitabine-induced apoptosis. Both of these drug resistance modalities can be either intrinsic to the cancer cell, or influenced by the cancer microenvironment. Mechanisms of intrinsic gemcitabine resistance are difficult to tackle, as many of the genes that drive the carcinogenic process itself also interfere with gemcitabine-induced apoptosis. In this regard, recent understanding of the involvement of microRNAs in gemcitabine resistance may offer new opportunities to overcome intrinsic gemcitabine resistance. The characteristically fibrotic and immune infiltrated stroma of PDA that accompanies tumor inception and expansion is a lush ground for treatments aimed at targeting tumor microenvironment-mediated drug resistance. In the last couple of years, drugs interfering with tumor microenvironment have matured to clinical trials. Although drugs inducing 'stromal depletion' have yet failed to improve survival, they have greatly increased our understanding of tumor microenvironment-mediated drug resistance. In this review we summarize the current knowledge on intrinsic and environment-mediated gemcitabine resistance, and discuss the impact of these pathways on patient screening, and on future treatments aimed to potentiate gemcitabine activity.

3 Article Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors. 2019

Zinger, Assaf / Koren, Lilach / Adir, Omer / Poley, Maria / Alyan, Mohammed / Yaari, Zvi / Noor, Nadav / Krinsky, Nitzan / Simon, Assaf / Gibori, Hadas / Krayem, Majd / Mumblat, Yelena / Kasten, Shira / Ofir, Sivan / Fridman, Eran / Milman, Neta / Lübtow, Michael M / Liba, Lior / Shklover, Jeny / Shainsky-Roitman, Janna / Binenbaum, Yoav / Hershkovitz, Dov / Gil, Ziv / Dvir, Tal / Luxenhofer, Robert / Satchi-Fainaro, Ronit / Schroeder, Avi. ·Laboratory for Targeted Drug Delivery and Personalized Medicine Technologies, Department of Chemical Engineering , Technion-Israel Institute of Technology , Haifa 3200003 , Israel. · The School for Molecular Cell Biology and Biotechnology and the Department of Materials Science and Engineering , Tel Aviv University , Tel Aviv 6997800 , Israel. · Department of Physiology and Pharmacology, Sackler Faculty of Medicine , Tel Aviv University , Tel Aviv 6997800 , Israel. · Department of Otolaryngology Head and Neck Surgery , Rambam Healthcare Campus, Technion-Israel Institute of Technology , Haifa 3200000 , Israel. · Functional Polymer Materials, Lehrstuhl für Chemische Technologie der Materialsynthese , Julius-Maximilians-Universität Würzburg , Röntgenring 11 , Würzburg 97070 , Germany. · The Ruth and Bruce Rappaport Faculty of Medicine , Technion-Israel Institute of Technology , Haifa 3200003 , Israel. · Department of Pathology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine , Tel-Aviv University , Tel Aviv 6997800 , Israel. ·ACS Nano · Pubmed #31503443.

ABSTRACT: Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, ∼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.

4 Article MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1. 2019

Yang, Ying / Ishak Gabra, Mari B / Hanse, Eric A / Lowman, Xazmin H / Tran, Thai Q / Li, Haiqing / Milman, Neta / Liu, Juan / Reid, Michael A / Locasale, Jason W / Gil, Ziv / Kong, Mei. ·Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA, 92697, USA. · Center for Informatics, City of Hope, Duarte, CA, 91010, USA. · Department of Computational & Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA. · Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Healthcare Campus, The Technion-Israel Institute of Technology, Haifa, 3109601, Israel. · Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27708, USA. · Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA, 92697, USA. meik1@uci.edu. ·Nat Commun · Pubmed #30778058.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.

5 Article RET, a targetable driver of pancreatic adenocarcinoma. 2019

Amit, Moran / Na'ara, Shorook / Fridman, Eran / Vladovski, Euvgeni / Wasserman, Tanya / Milman, Neta / Gil, Ziv. ·Head and Neck Surgery, Houston Methodist Hospital, Houston, TX, USA. · The Laboratory for Applied Cancer Research, The Technion, Israel Institute of Technology, Haifa, Israel. · Department of Otolaryngology Head and Neck Surgery, the Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel. · Department of Pathology, Rambam Healthcare Campus, The Technion, Israel Institute of Technology, Haifa, Israel. · Department of Physiology, Biophysics and Systems Biology, Faculty of Medicine, Technion, Haifa, Israel. ·Int J Cancer · Pubmed #30515799.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease, affecting about 40,000 individuals in the United States annually. We aimed to characterize the role of RET as a co-driver of pancreas tumorigenesis. To assess the role of RET as a co-driver of PDA, we generated a novel triple mutant transgenic mouse based on the cre-activated p53

6 Article L1CAM induces perineural invasion of pancreas cancer cells by upregulation of metalloproteinase expression. 2019

Na'ara, Shorook / Amit, Moran / Gil, Ziv. ·The Laboratory for Applied Cancer Research, Head and Neck Center, Department of Otolaryngology Head and Neck Surgery, Clinical Research Institute at Rambam Healthcare Campus, Haifa, Israel. · The Laboratory for Applied Cancer Research, Head and Neck Center, Department of Otolaryngology Head and Neck Surgery, Clinical Research Institute at Rambam Healthcare Campus, Haifa, Israel. ziv@baseofskull.org. · Technion Integrated Cancer Center, Rappaport Institute of Medicine and Research, Technion, Israel Institute of Technology, Haifa, Israel. ziv@baseofskull.org. ·Oncogene · Pubmed #30171263.

ABSTRACT: Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.

7 Article Transfer of miRNA in Macrophage-Derived Exosomes Induces Drug Resistance in Pancreatic Adenocarcinoma. 2018

Binenbaum, Yoav / Fridman, Eran / Yaari, Zvi / Milman, Neta / Schroeder, Avi / Ben David, Gil / Shlomi, Tomer / Gil, Ziv. ·The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Clinical Research Institute at Rambam Healthcare Campus, Haifa, Israel. · Laboratory for Targeted Drug Delivery and Personalized Medicine Technologies, Technion, Israel Institute of Technology, Haifa, Israel. · Departments of Computer Science and Biology, Technion, Israel Institute of Technology, Haifa, Israel. · The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Clinical Research Institute at Rambam Healthcare Campus, Haifa, Israel. G_Ziv@rambam.health.gov.il. · Technion Integrated Cancer Center, Rappaport Institute of Medicine and Research, Technion, Israel Institute of Technology, Haifa, Israel. ·Cancer Res · Pubmed #30042153.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is known for its resistance to gemcitabine, which acts to inhibit cell growth by termination of DNA replication. Tumor-associated macrophages (TAM) were recently shown to contribute to gemcitabine resistance; however, the exact mechanism of this process is still unclear. Using a genetic mouse model of PDAC and electron microscopy analysis, we show that TAM communicate with the tumor microenvironment via secretion of approximately 90 nm vesicles, which are selectively internalized by cancer cells. Transfection of artificial dsDNA (

8 Article Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression. 2017

Bakst, Richard L / Xiong, Huizhong / Chen, Chun-Hao / Deborde, Sylvie / Lyubchik, Anna / Zhou, Yi / He, Shizhi / McNamara, William / Lee, Sei-Young / Olson, Oakley C / Leiner, Ingrid M / Marcadis, Andrea R / Keith, James W / Al-Ahmadie, Hikmat A / Katabi, Nora / Gil, Ziv / Vakiani, Efsevia / Joyce, Johanna A / Pamer, Eric / Wong, Richard J. ·Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York. · Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. · Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Otolaryngology, Rambam Healthcare Campus, The Technion-Israel Institute of Technology, Haifa, Israel. · Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. wongr@mskcc.org. ·Cancer Res · Pubmed #28951461.

ABSTRACT: Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B-mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2-CCR2 signaling or cathepsin B function significantly impaired PNI

9 Article Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma. 2017

Amit, M / Na'ara, S / Leider-Trejo, L / Binenbaum, Y / Kulish, N / Fridman, E / Shabtai-Orbach, A / Wong, R J / Gil, Z. ·Head and Neck Surgery Department, MD Anderson Cancer Center University of Texas, Houston, TX, USA. · The Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel. · Department of Otolaryngology Head and Neck Surgery, The Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, Rambam Medical Center, The Technion, Israel Institute of Technology, Haifa, Israel. · Department of Pathology, Tel Aviv Medical Center, Tel Aviv, Israel. · Department of Surgery Memorial Sloan Kettering Cancer Center, New York, NY, USA. ·Oncogene · Pubmed #28092668.

ABSTRACT: Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes. Immunolabeling of tumors in KPC mice of different ages and analysis of human cancer specimens revealed that RET expression is upregulated during PDAC tumorigenesis. BMT experiments revealed that BM-derived macrophages expressing the RET ligand GDNF are highly abundant around nerves invaded by cancer. Inhibition of perineurial macrophage recruitment, using the CSF-1R antagonist GW2580 or BMT from CCR2-deficient donors, reduced perineurial invasion. Deletion of GDNF expression by perineurial macrophages, or inhibition of RET with shRNA or a small-molecule inhibitor, reduced perineurial invasion in KPC mice with PDAC. Taken together, our findings show that RET is upregulated during pancreas tumorigenesis and its activation induces cancer perineurial invasion. Trafficking of BM-derived macrophages to the perineurial microenvironment and secretion of GDNF are essential for pancreatic cancer neural spread.

10 Article In Vitro Modeling of Cancerous Neural Invasion: The Dorsal Root Ganglion Model. 2016

Na'ara, Shorook / Gil, Ziv / Amit, Moran. ·Otolaryngology, Head and Neck Surgery Department, The Laboratory for Applied Cancer Research, CRIR, Rambam Medical Healthcare Campus. · Otolaryngology, Head and Neck Surgery Department, The Laboratory for Applied Cancer Research, CRIR, Rambam Medical Healthcare Campus; moranamit@gmail.com. ·J Vis Exp · Pubmed #27167037.

ABSTRACT: One way that solid tumors disseminate is through neural invasion. This route is well-known in cancers of the head and neck, prostate, and pancreas. These neurotropic cancer cells have a unique ability to migrate unidirectionally along nerves towards the central nervous system (CNS). The dorsal root ganglia (DRG)/cancer cell model is a three dimensional (3D) in vitro model frequently used for studying the interaction between neural stroma and cancer cells. In this model, mouse or human cancer cell lines are grown in ECM adjacent to preparations of freshly dissociated cultured DRG. In this article, the DRG isolation protocol from mice, and implantation in petri dishes for co-culturing with pancreatic cancer cells are demonstrated. Five days after implantation, the cancer cells made contact with the DRG neurites. Later, these cells formed bridgeheads to facilitate more extensive polarized, neurotropic migration of cancer cells.

11 Article Computer-aided diagnostics in digital pathology: automated evaluation of early-phase pancreatic cancer in mice. 2015

Langer, Leeor / Binenbaum, Yoav / Gugel, Leonid / Amit, Moran / Gil, Ziv / Dekel, Shai. ·School of Mathematical Sciences, Tel Aviv University, 6997801, Tel Aviv, Israel, leeor.langer@gmail.com. ·Int J Comput Assist Radiol Surg · Pubmed #25354901.

ABSTRACT: PURPOSE: Digital pathology diagnostics are often based on subjective qualitative measures. A murine model of early-phase pancreatic ductal adenocarcinoma provides a controlled environment with a priori knowledge of the genetic mutation and stage of the disease. Use of this model enables the application of supervised learning methods to digital pathology. A computerized diagnostics system for histological detection of pancreatic adenocarcinoma was developed and tested. METHODS : Pathological H&E-stained specimens with early pancreatic lesions were identified and evaluated with a system that models cancer detection using a top-down object learning paradigm, mimicking the way a pathologist learns. First, the dominant primitives were identified and segmented in the images, i.e., the ducts, nuclei and tumor stroma. A boost-based machine learning technique was used for duct segmentation, classification and outlier pruning. Second, a set of morphological features traditionally used for cancer diagnosis which provides quantitative image features was employed to quantify subtle findings such as duct deformation and nuclei malformations. Finally, a visually interpretable predictive model was trained to distinguish between normal tissue and premalignant cancer lesions, given ground truth samples. RESULTS : A predictive success rate of 92% was achieved using tenfold cross-validation and 93% on an independent test set. Comparison was made with state-of-the-art classification algorithms that are not interpretable as visible features yielded the contribution of individual primitive features to the prediction outcome. CONCLUSIONS : Quantitative image analysis and classification were successful in preclinical histology diagnosis for early-stage pancreatic adenocarcinoma. The usage of annotated contours coupled with interpretable supervised learning methods and outlier pruning can be adapted to other medical imaging tasks. The usage of interpretable supervised learning techniques may improve the success of CAD in histopathological diagnosis.

12 Article Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. 2014

Weizman, N / Krelin, Y / Shabtay-Orbach, A / Amit, M / Binenbaum, Y / Wong, R J / Gil, Z. ·The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Haifa, Israel. · 1] The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Haifa, Israel [2] Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, The Technion Israel Institute of Technology, Haifa, Israel. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ·Oncogene · Pubmed #23995783.

ABSTRACT: Resistance to pharmacologic agents used in chemotherapy is common in most human carcinomas, including pancreatic ductal adenocarcinoma (PDA), which is resistant to almost all drugs, including gemcitabine, a nucleoside analog used as a first-line treatment. Poor survival rates of PDA patients have, therefore, not changed much over 4 decades. Recent data indicated that tumor-associated macrophages (TAMs), which are abundant in the microenvironment of several tumors, including PDA, secrete pro-tumorigenic factors that contribute to cancer progression and dissemination. In this study, we show for the first time that TAMs can also induce chemoresistance of PDA by reducing gemcitabine-induced apoptosis. Macrophages co-cultured with cancer cells or TAM-conditioned medium significantly reduced apoptosis and activation of the caspase-3 pathway during gemcitabine treatment. In vivo PDA models of mice, which have reduced macrophage recruitment and activation, demonstrated improved response to gemcitabine compared with controls. Similarly, inhibition of monocytes/macrophages trafficking by a CSF1-receptor antagonist GW2580 augmented the effect of gemcitabine in a transgenic mouse PDA model that was resistant to gemcitabine alone. Analysis of multiple proteins involved in gemcitabine delivery and metabolism revealed that TAMs induced upregulation of cytidine deaminase (CDA), the enzyme that metabolizes the drug following its transport into the cell. Decreasing CDA expression by PDA cells blocked the protective effect of TAMs against gemcitabine. These results provide the first evidence of a paracrine effect of TAMs, which mediates acquired resistance of cancer cells to chemotherapy. Modulation of macrophage trafficking or inhibition of CDA may offer a new strategy for augmenting the response of PDA to chemotherapy.

13 Article Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. 2012

Cavel, Oren / Shomron, Olga / Shabtay, Ayelet / Vital, Joseph / Trejo-Leider, Leonor / Weizman, Noam / Krelin, Yakov / Fong, Yuman / Wong, Richard J / Amit, Moran / Gil, Ziv. ·The Laboratory for Applied Cancer Research, Department of Pathology, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel. ·Cancer Res · Pubmed #22971345.

ABSTRACT: Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDA), prostate, or head and neck cancers. These patients undergo palliative rather than curative treatment due to dissemination of cancer along nerves, well beyond the extent of any local invasion. Although CPNI is a common source of distant tumor spread and a cause of significant morbidity, its exact mechanism is undefined. Immunohistochemical analysis of specimens excised from patients with PDAs showed a significant increase in the number of endoneurial macrophages (EMΦ) that lie around nerves invaded by cancer compared with normal nerves. Video microscopy and time-lapse analysis revealed that EMΦs are recruited by the tumor cells in response to colony-stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumor-activated EMΦs (tEMΦ) induced a 5-fold increase in migration of PDA cells compared with controls. Compared with resting EMΦs, tEMΦs secreted higher levels of glial-derived neurotrophic factor (GDNF), inducing phosphorylation of RET and downstream activation of extracellular signal-regulated kinases (ERK) in PDA cells. Genetic and pharmacologic inhibition of the GDNF receptors GFRA1 and RET abrogated the migratory effect of EMΦ-CM and reduced ERK phosphorylation. In an in vivo CPNI model, CCR2-deficient mice that have reduced macrophage recruitment and activation showed minimal nerve invasion, whereas wild-type mice developed complete sciatic nerve paralysis due to massive CPNI. Taken together, our results identify a paracrine response between EMΦs and PDA cells that orchestrates the formation of cancer nerve invasion.

14 Article Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. 2010

Gil, Ziv / Cavel, Oren / Kelly, Kaitlyn / Brader, Peter / Rein, Avigail / Gao, Sizhi P / Carlson, Diane L / Shah, Jatin P / Fong, Yuman / Wong, Richard J. ·Department of Otolaryngology, Head and Neck Surgery, Tel Aviv Sourasky Medical Center, 6 Weizmann St, Tel Aviv, 64239, Israel. gilz@tasmc.health.gov.il ·J Natl Cancer Inst · Pubmed #20068194.

ABSTRACT: BACKGROUND: The ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown. METHODS: We used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function. RESULTS: Nerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean = 187.1 microm, 95% confidence interval [CI] = 148 to 226 microm vs 14.4 microm, 95% CI = 9.58 to 19.22 microm, difference = 143 microm; P < .001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras-mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/-, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P < .001; n = 60-66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFalpha1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice. CONCLUSION: These data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer.