PURPOSE: Neurotrophins (NTs) can stimulate cell proliferation and differentiation in various cell types, and play a role in certain human cancers. In this study we analyzed the expression and localization of NTs and their receptors in microdissected pancreatic cancer tissue samples, and studied their ability to stimulate cell growth. EXPERIMENTAL DESIGN: The expression of nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT-4/5, and the receptors tropomyosin receptor kinase A, B, and C, and P75 was studied in pancreatic cancer cell lines, and normal and pancreatic ductal adenocarcinoma (PDAC) tissue samples by quantitative reverse transcription-PCR. Laser capture microdissection was performed in 21 PDAC samples, and mRNA levels were determined in cancer cells, acinar cells, desmoplastic stroma areas, and nerve fibers. Cell growth assays with NTs and in coculture with dorsal root ganglia were performed. RESULTS: NT receptors were differentially expressed in the cancer cell lines, whereas tropomyosin receptor kinase C was not detectable. NTs modulated pancreatic cancer cell growth. Analysis of nonmicrodissected samples revealed that all of the receptors and tested ligands were overexpressed in PDAC when compared with normal pancreas. Analysis of laser captured samples revealed that NTs and their receptors were expressed in the cancer cells but were especially abundant in the intratumoral nerves. Coculture of dorsal root ganglia with T3M4 cells significantly enhanced the proliferation of this cell line. CONCLUSION: The abundance of NTs in the intratumoral nerves in PDAC and the presence of NT receptors in the cancer cells, in conjunction with the ability of NTs to modulate pancreatic cancer cell growth, point to potential paracrine and autocrine effects of NTs in PDAC. Thus, our findings provide additional evidence that blocking NT actions may have a therapeutic potential in PDAC.
PURPOSE: Neurotrophins (NTs) can stimulate cell proliferation and differentiation in various cell types, and play a role in certain humancancers. In this study we analyzed the expression and localization of NTs and their receptors in microdissected pancreatic cancer tissue samples, and studied their ability to stimulate cell growth. EXPERIMENTAL DESIGN: The expression of nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT-4/5, and the receptors tropomyosin receptor kinase A, B, and C, and P75 was studied in pancreatic cancer cell lines, and normal and pancreatic ductal adenocarcinoma (PDAC) tissue samples by quantitative reverse transcription-PCR. Laser capture microdissection was performed in 21 PDAC samples, and mRNA levels were determined in cancer cells, acinar cells, desmoplastic stroma areas, and nerve fibers. Cell growth assays with NTs and in coculture with dorsal root ganglia were performed. RESULTS: NT receptors were differentially expressed in the cancer cell lines, whereas tropomyosin receptor kinase C was not detectable. NTs modulated pancreatic cancer cell growth. Analysis of nonmicrodissected samples revealed that all of the receptors and tested ligands were overexpressed in PDAC when compared with normal pancreas. Analysis of laser captured samples revealed that NTs and their receptors were expressed in the cancer cells but were especially abundant in the intratumoral nerves. Coculture of dorsal root ganglia with T3M4 cells significantly enhanced the proliferation of this cell line. CONCLUSION: The abundance of NTs in the intratumoral nerves in PDAC and the presence of NT receptors in the cancer cells, in conjunction with the ability of NTs to modulate pancreatic cancer cell growth, point to potential paracrine and autocrine effects of NTs in PDAC. Thus, our findings provide additional evidence that blocking NT actions may have a therapeutic potential in PDAC.
Authors: Glen J Weiss; Manuel Hidalgo; Mitesh J Borad; Daniel Laheru; Raoul Tibes; Ramesh K Ramanathan; Lisa Blaydorn; Gayle Jameson; Antonio Jimeno; Jeffrey D Isaacs; Angela Scaburri; Maria Adele Pacciarini; Francesco Fiorentini; Marina Ciomei; Daniel D Von Hoff Journal: Invest New Drugs Date: 2011-12-09 Impact factor: 3.850
Authors: Ha-Soon Choi; Paul V Rucker; Zhicheng Wang; Yi Fan; Pamela Albaugh; Greg Chopiuk; Francois Gessier; Fangxian Sun; Francisco Adrian; Guoxun Liu; Tami Hood; Nanxin Li; Yong Jia; Jianwei Che; Susan McCormack; Allen Li; Jie Li; Auzon Steffy; AnneMarie Culazzo; Celine Tompkins; Van Phung; Andreas Kreusch; Min Lu; Bin Hu; Apurva Chaudhary; Mahavir Prashad; Tove Tuntland; Bo Liu; Jennifer Harris; H Martin Seidel; Jon Loren; Valentina Molteni Journal: ACS Med Chem Lett Date: 2015-03-16 Impact factor: 4.345