Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis.
SPARC, a matricellular glycoprotein, modulates cellular interaction with the extracellular matrix (ECM). Tumor growth and metastasis occur in the context of the ECM, the levels and deposition of which are controlled in part by SPARC. Tumor-derived SPARC is reported to stimulate or retard tumor progression depending on the tumor type, whereas the function of host-derived SPARC in tumorigenesis has not been explored fully. To evaluate the function of endogenous SPARC, we have examined the growth of pancreatic tumors in SPARC-null (SP(-/-)) mice and their wild-type (SP(+/+)) counterparts. Mouse pancreatic adenocarcinoma cells injected s.c. grew significantly faster in SP(-/-) mice than cells injected into SP(+/+) animals, with mean tumor weights at sacrifice of 0.415 +/- 0.08 and 0.086 +/- 0.03 g (P < 0.01), respectively. Lack of endogenous SPARC resulted in decreased collagen deposition and fiber formation, alterations in the distribution of tumor-infiltrating macrophages, and decreased tumor cell apoptosis. There was no difference in microvessel density of tumors from SP(-/-) or SP(+/+) mice. However, tumors grown in SP(-/-) had a lower percentage of blood vessels that expressed smooth muscle alpha-actin, a marker of pericytes. These data reflect the importance of ECM deposition in regulating tumor growth and demonstrate that host-derived SPARC is a critical factor in the response of host tissue to tumorigenesis.
Puolakkainen
Pauli A
PA
Department of Vascular Biology, Hope Heart Institute, University of Washington, Seattle, Washington, USA.
Brekken
Rolf A
RA
Muneer
Sabeeha
S
Sage
E Helene
EH
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism*; D017353:Gene Deletion; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D015676:Osteonectin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*
D015676:Osteonectin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases