title: Neurogenin 3-directed cre deletion of Tsc1 gene causes pancreatic acinar carcinoma.
abstract: The role of tuberous sclerosis complex (TSC) in the pathogenesis of pancreatic cancers remains largely unknown. The present study shows that neurogenin 3 directed Cre deletion of Tsc1 gene induces the development of pancreatic acinar carcinoma. By cross-breeding the Neurog3-cre mice with Tsc1 (loxp/loxp) mice, we generated the Neurog3-Tsc1-/- transgenic mice in which Tsc1 gene is deleted and mTOR signaling activated in the pancreatic progenitor cells. All Neurog3-Tsc1-/- mice developed notable adenocarcinoma-like lesions in pancreas starting from the age of 100 days old. The tumor lesions are composed of cells with morphological and molecular resemblance to acinar cells. Metastasis of neoplasm to liver and lung was detected in 5% of animals. Inhibition of mTOR signaling by rapamycin significantly attenuated the growth of the neoplasm. Relapse of the neoplasm occurred within 14 days upon cessation of rapamycin treatment. Our studies indicate that activation of mTOR signaling in the pancreatic progenitor cells may trigger the development of acinar carcinoma. Thus, mTOR may serve as a potential target for treatment of pancreatic acinar carcinoma.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China ; Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109-0346.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D018267:Carcinoma, Acinar Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010179:Pancreas / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D000903:Antibiotics, Antineoplastic; D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C407737:Neurog3 protein, mouse; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; C546843:mTOR protein, mouse
keywords: 4EBP-1, 4E binding protein 1; ACC, acinar cell carcinoma; Neurog3, neurogenin 3; PDA, pancreatic ductal adenocarcinoma; S6, ribosomal protein S6; TSC, tuberous sclerosis complex; mTOR, mammlian target of rapamycin