title: Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis.
abstract: Elevated levels of TGFβ are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result, the TGFβ pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGFβ remains challenging because TGFβ has tumor suppressor functions in many epithelial malignancies, including pancreatic cancer. In fact, direct neutralization of TGFβ promotes tumor progression of genetic murine models of pancreatic cancer. Here, we report that neutralizing the activity of murine TGFβ receptor 2 using a monoclonal antibody (2G8) has potent antimetastatic activity in orthotopic human tumor xenografts, syngeneic tumors, and a genetic model of pancreatic cancer. 2G8 reduced activated fibroblasts, collagen deposition, microvessel density, and vascular function. These stromal-specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGFβ signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGFβ-dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors. Cancer Res; 74(18); 4996-5007. ©2014 AACR.
authors: Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Katherine T
authors: KT
authors: Ostapoff
authors: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Bercin Kutluk
authors: BK
authors: Cenik
authors: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Miao
authors: M
authors: Wang
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Risheng
authors: R
authors: Ye
authors: Imclone Systems (a wholly owned subsidiary of Eli Lilly and Company), New York, New York.
authors: Xiaohong
authors: X
authors: Xu
authors: Imclone Systems (a wholly owned subsidiary of Eli Lilly and Company), New York, New York.
authors: Desiree
authors: D
authors: Nugent
authors: Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Moriah M
authors: MM
authors: Hagopian
authors: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Mary
authors: M
authors: Topalovski
authors: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Lee B
authors: LB
authors: Rivera
authors: Imclone Systems (a wholly owned subsidiary of Eli Lilly and Company), New York, New York.
authors: Kyla D
authors: KD
authors: Carroll
authors: Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas. Rolf.Brekken@utsouthwestern.edu.
authors: Rolf A
authors: RA
authors: Brekken
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011897:Random Allocation; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D003841:Deoxycytidine; D000093542:Gemcitabine