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Cited by 118Bone and Dental Protein StudiesConnective Tissue Growth Factor ResearchAngiogenesis and VEGF in Cancer

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

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Arnold, Shanna A., Rivera, Lee B., Miller, Andrew F., Carbon, Juliet G., Dineen, Sean P., Xie, Yang, Castrillon, Diego H., Sage, E. Helene +3 more·2010·Disease Models & Mechanisms
DOI 10.1242/dmm.003228PMC PMC2806901
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Abstract

SUMMARY: 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.

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  • NOS2 and MMR were representative markers for the M1 and M2 activation states, respectively.

    “Nitric oxide synthase 2 (NOS2) and MΦ mannose receptor (MMR) were representative markers for the M1 and M2 activation states, respectively (18–20) (Fig. 4 A–D).”

    From Proangiogenic scaffolds as functional templates for cardiac tissue engineering (2010) · cites this paper as [18]

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Authors
Arnold, S. A., Rivera, L. B., Miller, A. F., Carbon, J. G., Dineen, S. P., Xie, Y., Castrillon, D. H., Sage, E. H., Puolakkainen, P., Bradshaw, A. D., & Brekken, R. A.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • The University of Texas at Dallas (US)
  • Hamon Center for Therapeutic Oncology Research, Departments of Surgery and Pharmacology
  • Center for Biostatistics and Clinical Sciences and
  • Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
  • Benaroya Research Institute (US)
  • Helsinki University Hospital (FI)
  • Medical University of South Carolina (US)
Corresponding author
Brekken, Rolf A.
ORCID
Venue
Disease Models & Mechanisms
Publisher
The Company of Biologists
Published
2010-01-14
Volume
3
Issue
1-2
Pages
57-72
ISSN
  • 1754-8403 (ISSN-L)
  • 1754-8411
DOI
10.1242/dmm.003228
PMC
PMC2806901
OpenAlex
W2146122315
Cited by
118
References
80
Citations by year
2026: 3 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 7 · 2021: 14 · 2020: 7 · 2019: 7 · 2018: 4 · 2017: 7 · 2016: 2 · 2015: 13 · 2014: 9 · 2013: 14 · 2012: 9
FWCI
5.42
Type
journal article
Language
en
Open access
Locations
  • Disease Models & Mechanisms (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • University of Texas Southwestern Medical Center
  • Scheme for Promotion of Academic and Research Collaboration
  • National Cancer Institute (R01CA118240)
  • National Institute of General Medical Sciences (T32GM007062, GM007062, R01-GM 40711, R01GM040711)
  • National Center for Research Resources (K26RR024196)
Topics
  • Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
SPARC, pancreatic cancer, metastasis, orthotopic tumor model, SPARC-null mice, tumor stroma, collagen deposition, basement membrane, decorin, tumor angiogenesis, microvessel density, pericyte recruitment, tumor vascular permeability, tumor hypoxia, M2 macrophages, tumor microenvironment, extracellular matrix
MeSH terms
Animals, Basement Membrane, Cell Movement, Collagen, Disease Models, Animal, Extracellular Matrix, Macrophage Activation, Neoplasm Invasiveness, Neoplasm Metastasis, Neovascularization, Pathologic, Pancreatic Neoplasms, Perfusion, Permeability, Phenotype, Osteonectin, Mice, Knockout, Mice

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