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

Katherine T. Ostapoff, Bercin Kutluk Cenik, Miao Wang, Risheng Ye, Xiaohong Xu, Desiree Nugent, Moriah M. Hagopian, Mary Topalovski, Lee B. Rivera, Kyla D. Carroll, Rolf A. Brekken

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4996-5007
Number of pages12
JournalCancer Research
Volume74
Issue number18
DOIs
StatePublished - Jul 24 2014

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Pancreatic Neoplasms
Neoplasm Metastasis
Phenotype
Neoplasms
Genetic Models
Stromal Cells
Microvessels
Heterografts
Blood Vessels
Cell Differentiation
Collagen
Fibroblasts
Monoclonal Antibodies
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. / Ostapoff, Katherine T.; Cenik, Bercin Kutluk; Wang, Miao; Ye, Risheng; Xu, Xiaohong; Nugent, Desiree; Hagopian, Moriah M.; Topalovski, Mary; Rivera, Lee B.; Carroll, Kyla D.; Brekken, Rolf A.

In: Cancer Research, Vol. 74, No. 18, 24.07.2014, p. 4996-5007.

Research output: Contribution to journalArticle

Ostapoff, KT, Cenik, BK, Wang, M, Ye, R, Xu, X, Nugent, D, Hagopian, MM, Topalovski, M, Rivera, LB, Carroll, KD & Brekken, RA 2014, 'Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis', Cancer Research, vol. 74, no. 18, pp. 4996-5007. https://doi.org/10.1158/0008-5472.CAN-13-1807
Ostapoff, Katherine T. ; Cenik, Bercin Kutluk ; Wang, Miao ; Ye, Risheng ; Xu, Xiaohong ; Nugent, Desiree ; Hagopian, Moriah M. ; Topalovski, Mary ; Rivera, Lee B. ; Carroll, Kyla D. ; Brekken, Rolf A. / Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. In: Cancer Research. 2014 ; Vol. 74, No. 18. pp. 4996-5007.
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