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pancreatic cancer neural invasion

M Amit, S Na'ara, L Leider-Trejo, Y Binenbaum, N Kulish, E Fridman, A Shabtai-Orbach, R J Wong, Z Gil
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...
January 16, 2017: Oncogene
Ihsan Ekin Demir, Kristina Kujundzic, Paulo L Pfitzinger, Ömer Cemil Saricaoglu, Steffen Teller, Timo Kehl, Carmen Mota Reyes, Linda S Ertl, Zhenhua Miao, Thomas J Schall, Elke Tieftrunk, Bernhard Haller, Kalliope Nina Diakopoulos, Magdalena U Kurkowski, Marina Lesina, Achim Krüger, Hana Algül, Helmut Friess, Güralp O Ceyhan
Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
Aditi A Bapat, Ruben M Munoz, Daniel D Von Hoff, Haiyong Han
Perineural invasion (PNI) is thought to be one of the factors responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Signaling via the nerve growth factor (NGF) pathway between pancreatic cancer cells and the surrounding nerves has been implicated in PNI, and increased levels of these proteins have been correlated to poor prognosis. In this study, we examine the molecular mechanism of the NGF signaling pathway in PNI in pancreatic cancer. We show that knocking down NGF or its receptors, TRKA and p75NTR, or treatment with GW441756, a TRKA kinase inhibitor, reduces the proliferation and migration of pancreatic cancer cells in vitro...
2016: PloS One
Alice Nomura, Kaustav Majumder, Bhuwan Giri, Patricia Dauer, Vikas Dudeja, Sabita Roy, Sulagna Banerjee, Ashok K Saluja
NF-κB has an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study, we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids...
December 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
Dhananjaya Sharma, Shuji Isaji
Focused pathological attention to tumor invasion of the retroperitoneal resection margin after pancreaticoduodenectomy for cancer of head of the pancreas led to the knowledge of strong tendency of cancer cells to infiltrate into the retropancreatic tissue and to spread along the peripancreatic neural plexuses as the cause of local recurrence. The term 'mesopancreas' was coined to describe perineural lymphatic layer located dorsally to the pancreas and it was suggested that its complete resection will minimize loco-regional recurrence and improve outcome...
December 2016: Journal of Hepato-biliary-pancreatic Sciences
Shorook Na'ara, Ziv Gil, Moran Amit
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...
April 12, 2016: Journal of Visualized Experiments: JoVE
Dingkong Liang, Si Shi, Jin Xu, Bo Zhang, Yi Qin, Shunrong Ji, Wenyan Xu, Jiang Liu, Liang Liu, Chen Liu, Jiang Long, Quanxing Ni, Xianjun Yu
Pancreatic cancer is one of the most malignant human tumors. Perineural invasion, whereby a cancer cell invades the perineural spaces surrounding nerves, is acknowledged as a gradual contributor to cancer aggressiveness. Furthermore, perineural invasion is considered one of the root causes of the recurrence and metastasis observed after pancreatic resection, and it is also an independent predictor of prognosis. Advanced research has demonstrated that the neural microenvironment is closely associated with perineural invasion in pancreatic cancer...
April 2016: Biochimica et Biophysica Acta
Jun Yao, Wen-Yao Li, She-Gan Gao
Pancreatic cancer is a deadly malignancy associated with rapid progression and poor prognosis. Perineural invasion (PNI) in pancreatic cancer is one of the most common characteristics of this disease, with incidence of nerve invasion between 53.3% and 90%. PNI is also associated with disease recurrence and pain. Despite research efforts, the detailed mechanisms underlying PNI in pancreatic cancer remains unknown. The main factors of PNI in pancreatic cancer will be introduced in the following: 1. The anatomy of the pancreas nerve: The cancer cells along the blood vessels, lymphatic vessels, peripheral nerve gap and perineurium to Invasion...
2015: American Journal of Cancer Research
Elke Tieftrunk, Ihsan Ekin Demir, Helmut Friess, Güralp O Ceyhan
Neural invasion (NI) and severe pain are common features in patients with pancreatic cancer (PCa). Here, we present the case of a 67-year-old patient with PCa whose pre- and postoperative physical situation was clearly dominated by severe pain sensation. The resected pancreas specimen revealed severe and frequent NI by cancer cells. Seven months after R1 resection and additive chemotherapy, the patient presented with severe lumbar back pain. The CT scan showed liver metastasis and local recurrence around the celiac trunk...
2015: Journal of Surgical Case Reports
Ihsan Ekin Demir, Helmut Friess, Güralp O Ceyhan
Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain...
November 2015: Nature Reviews. Gastroenterology & Hepatology
Xuan Wang, Hongwei Zhang, Taihong Wang, Wan Yee Lau, Xin Wang, Jingfeng Sun, Zhenhua Yuan, Yewei Zhang
Pancreatic head cancer is a common but the most lethal cancer of the human digestive system. It is invasive, resulting in early infiltration of adjacent structures and lymph node and distant metastases. Its biological characteristics of neurotropic growth lead to early neural invasion (NI) which is an independent prognostic factor of survival for pancreatic cancer. Radical surgical resection remains the only form of curative treatment. The extent of surgical resection and whether extended resection results in better long-term survival have been controversial...
December 2015: International Journal of Oncology
Jun-Chao Guo, Jian Li, Yu-Pei Zhao, Li Zhou, Quan-Cai Cui, Wei-Xun Zhou, Tai-Ping Zhang, Lei You
It has long been regarded that pancreatic cancer (PC) is a life-threatening malignant tumor. Thus, much attention has been paid for factors, especially relative molecules, predictive for prognosis of PC. However, c-fos expression in PC was less investigated. In addition, its association with clinicopathologic variables and prognosis remains unknown. In the present study, expression of c-fos was detected by tissue microarray-based immunohistochemical staining in cancer and adjacent tissues from 333 patients with PC...
2015: PloS One
Tong Han, Xiao-Ping Yi, Bo Liu, Mu-Jing Ke, Yi-Xiong Li
MicroRNAs (miRNAs) represent a class of small non‑coding RNAs regulating gene expression by inducing the degradation of RNA or interfering with translation. Aberrant miRNA expression has been described in several types of cancer in humans. In the present study, it was demonstrated that miR‑145 is downregulated in pancreatic cancer tissues and the Panc‑1 cell line. Restoration of miR‑145 inhibited cell proliferation, invasion and migration in Panc‑1 cells. Neural precursor cell expressed, developmentally down‑regulated 9 (NEDD9) has been identified as a novel potential miR‑145 target using bioinformatics...
June 2015: Molecular Medicine Reports
Takehito Yamamoto, Shintaro Yagi, Hiromitsu Kinoshita, Yusuke Sakamoto, Kazuyuki Okada, Kenji Uryuhara, Takeshi Morimoto, Satoshi Kaihara, Ryo Hosotani
AIM: To retrospectively analyze factors affecting the long-term survival of patients with pancreatic cancer who underwent pancreatic resection. METHODS: From January 2000 to December 2011, 195 patients underwent pancreatic resection in our hospital. The prognostic factors after pancreatic resection were analyzed in all 195 patients. After excluding the censored cases within an observational period, the clinicopathological characteristics of 20 patients who survived ≥ 5 (n = 20) and < 5 (n = 76) years were compared...
January 7, 2015: World Journal of Gastroenterology: WJG
Florian Liebl, Ihsan Ekin Demir, Katharina Mayer, Tibor Schuster, Jan G DʼHaese, Karen Becker, Rupert Langer, Frank Bergmann, Kun Wang, Robert Rosenberg, Alexander R Novotny, Marcus Feith, Daniel Reim, Helmut Friess, Güralp O Ceyhan
OBJECTIVES: Because neural invasion (NI) is still inconsistently reported and not well characterized within gastrointestinal malignancies (GIMs), our aim was to determine the exact prevalence and severity of NI and to elucidate the true impact of NI on patient's prognosis. BACKGROUND: The union internationale contre le cancer (UICC) recently added NI as a novel parameter in the current TNM classification. However, there are only a few existing studies with specific focus on NI, so that the distinct role of NI in GIMs is still uncertain...
November 2014: Annals of Surgery
Keisuke Taniuchi, Mutsuo Furihata, Kazuhiro Hanazaki, Motoaki Saito, Toshiji Saibara
Pancreatic cancers are aggressive because they are highly invasive and highly metastatic; moreover, effective treatments for aggressive pancreatic cancers are lacking. Here, we report that IGF2BP3 promoted the invasiveness and metastasis of pancreatic cancers through locally translated IGF2BP3-bound transcripts. In neural cells, transcripts sorted into cytoplasmic RNA granules are transported to dendrites and translated in these dendrites, thereby mediating long-term synaptic plasticity; however, such cytoplasmic RNA granules are not known to contribute to the progression of pancreatic cancer...
August 30, 2014: Oncotarget
Ihsan Ekin Demir, Alexandra Boldis, Paulo L Pfitzinger, Steffen Teller, Eva Brunner, Natascha Klose, Timo Kehl, Matthias Maak, Marina Lesina, Melanie Laschinger, Klaus-Peter Janssen, Hana Algül, Helmut Friess, Güralp O Ceyhan
BACKGROUND: In neural invasion (NI), cancer cells are classically assumed to actively invade nerves and to cause local recurrence and pain. However, the opposite possibility, that nerves may reach cancer cells even in their preinvasive stage and thereby promote cancer spread, has not yet been genuinely considered. The present study analyzes the reaction of Schwann cells of peripheral nerves to carcinogenesis in pancreatic cancer and colon cancer. METHODS: Two novel 3D migration and Schwann cell outgrowth assays were developed to monitor the timing and the specificity of Schwann cell migration and cancer invasion toward peripheral neurons through digital-time-lapse microscopy and after blockade of nerve growth factor (NGF) signalling via siRNA or a small-molecule inhibitor of the p75(NTR) receptor...
August 2014: Journal of the National Cancer Institute
L-N Xue, F H Bai, X-Y Wang, M Lin, Y Tan, X-Y Yao, K-Q Xu
We investigated the clinical significance of RUNX3 gene expression in human pancreatic carcinoma. Five samples of pancreatic tissues and 30 samples of pancreatic cancer tissues and paracancerous tissues were collected. RUNX3 expression was detected by real-time PCR and immunohistochemistry. The relationships between clinicopathological findings and the expression of RUNX3 were analyzed. The relative quantification level of RUNX3 mRNA expression in human pancreatic carcinoma tissues and paracancerous tissues was 2...
2014: Genetics and Molecular Research: GMR
Motokazu Sugimoto, Shuichi Mitsunaga, Kiyoshi Yoshikawa, Yuichiro Kato, Naoto Gotohda, Shinichiro Takahashi, Masaru Konishi, Masafumi Ikeda, Motohiro Kojima, Atsushi Ochiai, Hironori Kaneko
BACKGROUND: Neural invasion is a characteristic pattern of invasion and an important prognostic factor for invasive ductal carcinoma (IDC) of the pancreas. M2 macrophages have reportedly been associated with poor prognosis in various cancers. The aim of the present study was to investigate the prognostic impact of M2 macrophages at extrapancreatic nerve plexus invasion (plx-inv) of pancreatic IDC. METHODS: Participants comprised 170 patients who underwent curative pancreaticoduodenectomy for pancreatic IDC...
July 2014: European Journal of Cancer
Jun Yao, Wen-Yao Li, Shuo-Guo Li, Xiao-Shan Feng, She-Gan Gao
AIM: To investigate midkine (MK) and syndecan-3 protein expression in pancreatic cancer by immunohistochemistry, and to analyze their correlation with clinicopathological features, perineural invasion, and prognosis. METHODS: Pancreatic cancer tissues (including adequately sized tumor tissue samples and tissue samples taken from areas less than 2.0 cm around the tumor) were taken from 42 patients who were undergoing a partial duodenopancreatectomy. MK and syndecan-3 proteins were detected by immunohistochemistry using a standardized streptavidin-peroxidase method, and analyzed for their correlation with clinicopathological features, perineural invasion, and prognosis...
March 21, 2014: World Journal of Gastroenterology: WJG
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