Molecular analysis of metastasis in a polyomavirus middle T mouse model: the role of osteopontin.
BACKGROUND
In order to study metastatic disease, we employed the use of two related polyomavirus middle T transgenic mouse tumor transplant models of mammary carcinoma (termed Met and Db) that display significant differences in metastatic potential.


METHODS
Through suppression subtractive hybridization coupled to the microarray, we found osteopontin (OPN) to be a highly expressed gene in the tumors of the metastatic mouse model, and a lowly expressed gene in the tumors of the lowly metastatic mouse model. We further analyzed the role of OPN in this model by examining sense and antisense constructs using in vitro and in vivo methods.


RESULTS
With in vivo metastasis assays, the antisense Met cells showed no metastatic tumor formation to the lungs of recipient mice, while wild-type Met cells, with higher levels of OPN, showed significant amounts of metastasis. The Db cells showed a significantly reduced metastasis rate in the in vivo metastasis assay as compared with the Met cells. Db cells with enforced overexpression of OPN showed elevated levels of OPN but did not demonstrate an increase in the rate of metastasis compared with the wild-type Db cells.


CONCLUSIONS
We conclude that OPN is an essential regulator of the metastatic phenotype seen in polyomavirus middle T-induced mammary tumors. Yet OPN expression alone is not sufficient to cause metastasis. These data suggest a link between metastasis and phosphatidylinositol-3-kinase-mediated transcriptional upregulation of OPN, but additional phosphatidylinositol-3-kinase-regulated genes may be essential in precipitating the metastasis phenotype in the polyomavirus middle T model.
Jessen
Katayoun Alavi
KA
Department of Pathology, University of California, Davis, School of Medicine, Sacramento, California, USA.
Liu
Stephenie Y
SY
Tepper
Clifford G
CG
Karrim
Juliana
J
McGoldrick
Erik T
ET
Rosner
Andrea
A
Munn
Robert J
RJ
Young
Lawrence J T
LJ
Borowsky
Alexander D
AD
Cardiff
Robert D
RD
Gregg
Jeffrey P
JP
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D009368:Neoplasm Transplantation; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D018075:RNA, Complementary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012795:Sialoglycoproteins / Q000235:genetics / Q000502:physiology*; D013382:Subtraction Technique; D014162:Transfection
D000952:Antigens, Polyomavirus Transforming; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D018075:RNA, Complementary; D011993:Recombinant Fusion Proteins; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases