title: Biologic effect of neurogenesis in pancreatic cancer.
abstract: Pancreatic cancer (PaCA) is a deadly disease with few systemic therapeutic options. The head of the pancreas is the most innervated part and most common location of cancer. However, little is known about the contribution of the nerve-cancer interaction to facilitate pancreatic progression. To quantify PaCA axonogenesis, we used a 3-dimensional in vitro neurogenesis model. In addition, neurogenesis in human PaCA was analyzed using PGP9.5 immunohistochemistry, deconvolution imaging, and image segmentation and analysis. There was a significant increase of the total area of neurites in the in vitro coculture with dorsal root ganglia group than control. The nerve density in PaCA tissue was significantly higher than normal pancreatic tissue. To study the functional role of nerves in PaCA, male athymic nude (Nu-Nu) mice were divided into 3 groups: (A) animals were coinjected with MIA PaCa-2 cells and 20U/kg weight units of Botulinum toxin (Botox) (n=10); (B) first injected with Botox and 6weeks later MIA PaCa-2 cancer cells (n=4); and (C) control animals were injected with equivalent amounts of saline fluid (n=9). Animals were sacrificed 6weeks later. Tumor size and apoptotic count (terminal deoxynucleotidyl transferase dUTP nick-end labeling) were measured. Tumor size was decreased and apoptotic rate increased in Botox-treated PaCA. Our data indicate that neural microenvironment may play an important role in the progression of PaCA. It may lead to novel nerve-targeted coadjuvant therapies for PaCA.
authors.affiliation: Department of Internal Medicine, Detroit Medical Center, Sinai-Grace Hospital, Wayne State University, Detroit, MI 48235, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77401 USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Manzoni
authors.affiliation: Department of Internal Medicine, Detroit Medical Center, Sinai-Grace Hospital, Wayne State University, Detroit, MI 48235, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Florentin
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, TX, 77401 USA.
authors.forename: William
authors.initials: W
authors.lastname: Fisher
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center Medical School, Houston, TX, 77401 USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, TX 77401.
authors.forename: MinJae
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center Medical School, Houston, TX, 77401 USA. Electronic address: Gustavo.E.Ayala@uth.tmc.edu.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ayala
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D019274:Botulinum Toxins, Type A / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D047368:Tumor Burden; D059016:Tumor Microenvironment; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase; D019274:Botulinum Toxins, Type A
keywords: Axonogenesis; Nerve density; Neurogenesis; PGP9.5; Pancreatic cancer