Losartan slows pancreatic tumor progression and extends survival of SPARC-null mice by abrogating aberrant TGFβ activation

Shanna A. Arnold, Lee B. Rivera, Juliet G. Carbon, Jason E. Toombs, Chi Lun Chang, Amy D. Bradshaw, Rolf A. Brekken

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Pancreatic adenocarcinoma, a desmoplastic disease, is the fourth leading cause of cancer-related death in the Western world due, in large part, to locally invasive primary tumor growth and ensuing metastasis. SPARC is a matricellular protein that governs extracellular matrix (ECM) deposition and maturation during tissue remodeling, particularly, during wound healing and tumorigenesis. In the present study, we sought to determine the mechanism by which lack of host SPARC alters the tumor microenvironment and enhances invasion and metastasis of an orthotopic model of pancreatic cancer. We identified that levels of active TGFβ1 were increased significantly in tumors grown in SPARC-null mice. TGFβ1 contributes to many aspects of tumor development including metastasis, endothelial cell permeability, inflammation and fibrosis, all of which are altered in the absence of stromal-derived SPARC. Given these results, we performed a survival study to assess the contribution of increased TGFβ1 activity to tumor progression in SPARC-null mice using losartan, an angiotensin II type 1 receptor antagonist that diminishes TGFβ1 expression and activation in vivo. Tumors grown in SPARC-null mice progressed more quickly than those grown in wild-type littermates leading to a significant reduction in median survival. However, median survival of SPARC-null animals treated with losartan was extended to that of losartan-treated wild-type controls. In addition, losartan abrogated TGFβ induced gene expression, reduced local invasion and metastasis, decreased vascular permeability and altered the immune profile of tumors grown in SPARC-null mice. These data support the concept that aberrant TGFβ1-activation in the absence of host SPARC contributes significantly to tumor progression and suggests that SPARC, by controlling ECM deposition and maturation, can regulate TGFβ availability and activation.

Original languageEnglish (US)
Article numbere31384
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 14 2012

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Losartan
Tumors
Chemical activation
neoplasms
mice
metastasis
Neoplasms
Neoplasm Metastasis
extracellular matrix
permeability
Angiotensin II Type 1 Receptor Blockers
Western World
Tumor Microenvironment
Extracellular Matrix Proteins
pancreatic neoplasms
Endothelial cells
Capillary Permeability
angiotensin II
Pancreatic Neoplasms
Gene expression

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Losartan slows pancreatic tumor progression and extends survival of SPARC-null mice by abrogating aberrant TGFβ activation. / Arnold, Shanna A.; Rivera, Lee B.; Carbon, Juliet G.; Toombs, Jason E.; Chang, Chi Lun; Bradshaw, Amy D.; Brekken, Rolf A.

In: PLoS One, Vol. 7, No. 2, e31384, 14.02.2012.

Research output: Contribution to journalArticle

Arnold, Shanna A. ; Rivera, Lee B. ; Carbon, Juliet G. ; Toombs, Jason E. ; Chang, Chi Lun ; Bradshaw, Amy D. ; Brekken, Rolf A. / Losartan slows pancreatic tumor progression and extends survival of SPARC-null mice by abrogating aberrant TGFβ activation. In: PLoS One. 2012 ; Vol. 7, No. 2.
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