Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma.
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.
Arnold
Shanna A
SA
Hamon Center for Therapeutic Oncology Research, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Rivera
Lee B
LB
Miller
Andrew F
AF
Carbon
Juliet G
JG
Dineen
Sean P
SP
Xie
Yang
Y
Castrillon
Diego H
DH
Sage
E Helene
EH
Puolakkainen
Pauli
P
Bradshaw
Amy D
AD
Brekken
Rolf A
RA
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D008262:Macrophage Activation; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D015676:Osteonectin / Q000172:deficiency / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000503:physiopathology* / Q000648:ultrastructure; D010477:Perfusion; D010539:Permeability; D010641:Phenotype
D015676:Osteonectin; D003094:Collagen