Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma

Shanna A. Arnold, Lee B. Rivera, Andrew F. Miller, Juliet G. Carbon, Sean P. Dineen, Yang Xie, Diego H. Castrillon, E. Helene Sage, Pauli Puolakkainen, Amy D. Bradshaw, Rolf A. Brekken

Research output: Contribution to journalArticle

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Abstract

Utilizing subcutaneous tumor models, we previously validated SPARC (secreted protein acidic and rich in cysteine) as a key component of the stromal response, where it regulated tumor size, angiogenesis and extracellular matrix deposition. In the present study, we demonstrate that pancreatic tumors grown orthotopically in Sparc-null (Sparc-/-) mice are more metastatic than tumors grown in wild-type (Sparc+/+) littermates. Tumors grown in Sparc-/- mice display reduced deposition of fibrillar collagens I and III, basement membrane collagen IV and the collagen-associated proteoglycan decorin. In addition, microvessel density and pericyte recruitment are reduced in tumors grown in the absence of host SPARC. However, tumors from Sparc -/- mice display increased permeability and perfusion, and a subsequent decrease in hypoxia. Finally, we found that tumors grown in the absence of host SPARC exhibit an increase in alternatively activated macrophages. These results suggest that increased tumor burden in the absence of host SPARC is a consequence of reduced collagen deposition, a disrupted vascular basement membrane, enhanced vascular function and an immune-tolerant, pro-metastatic microenvironment.

Original languageEnglish (US)
Pages (from-to)57-72
Number of pages16
JournalDMM Disease Models and Mechanisms
Volume3
Issue number1-2
DOIs
StatePublished - Jan 2010

Fingerprint

Cysteine
Blood Vessels
Tumors
Neoplasms
Proteins
Collagen
Basement Membrane
Fibrillar Collagens
Decorin
Pericytes
Pancreatic Carcinoma
Proteoglycans
Microvessels
Macrophages
Tumor Burden
Extracellular Matrix
Permeability
Perfusion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

Cite this

Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. / Arnold, Shanna A.; Rivera, Lee B.; Miller, Andrew F.; Carbon, Juliet G.; Dineen, Sean P.; Xie, Yang; Castrillon, Diego H.; Sage, E. Helene; Puolakkainen, Pauli; Bradshaw, Amy D.; Brekken, Rolf A.

In: DMM Disease Models and Mechanisms, Vol. 3, No. 1-2, 01.2010, p. 57-72.

Research output: Contribution to journalArticle

Arnold, Shanna A. ; Rivera, Lee B. ; Miller, Andrew F. ; Carbon, Juliet G. ; Dineen, Sean P. ; Xie, Yang ; Castrillon, Diego H. ; Sage, E. Helene ; Puolakkainen, Pauli ; Bradshaw, Amy D. ; Brekken, Rolf A. / Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. In: DMM Disease Models and Mechanisms. 2010 ; Vol. 3, No. 1-2. pp. 57-72.
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