2. Academic Validation
  3. Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis

Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis

  • Cancer Res. 2014 Sep 15;74(18):4996-5007. doi: 10.1158/0008-5472.CAN-13-1807.
Katherine T Ostapoff 1,  Bercin Kutluk Cenik 2,  Miao Wang 2,  Risheng Ye 3,  Xiaohong Xu 4,  Desiree Nugent 4,  Moriah M Hagopian 1,  Mary Topalovski 2,  Lee B Rivera 2,  Kyla D Carroll 4,  Rolf A Brekken 5
Affiliations

Affiliations

  • 1 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.
  • 2 Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 3 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 4 Imclone Systems (a wholly owned subsidiary of Eli Lilly and Company), New York, New York.
  • 5 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. [email protected].
PMID: 25060520 DOI: 10.1158/0008-5472.CAN-13-1807
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.

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