p53 accumulation in favorable-histology Wilms tumor is associated with angiogenesis and clinically aggressive disease.
OBJECTIVE
Unfavorable histology (UH) in Wilms tumor has been linked to malfunction of the p53 tumor suppressor gene, which regulates (1) the endogenous angiogenesis suppressor thrombospondin-1 (TSP-1) and (2) vascular endothelial growth factor (VEGF). The authors hypothesized that clinically aggressive favorable histology Wilms tumor (FH), like UH, but distinct from standard-risk FH disease, would display altered p53/TSP-1 function and upregulated angiogenesis.


METHODS
Three Wilms tumor specimens manifesting different histology and clinical behavior were obtained: clinically aggressive UH, clinically aggressive FH, and standard-risk FH disease. Xenografts were induced intrarenally in athymic mice. P53, TSP-1, and VEGF status and neovascularity were assessed in tumor tissues. Lungs were evaluated for metastasis.


RESULTS
Clinically aggressive FH Wilms tumor displayed progressive alteration in p53/TSP-1 status and upregulation of VEGF. Such alteration was observed in the UH tumor, but was absent from the standard-risk FH tumor. Xenografts from clinically aggressive tumors displayed brisk neoangiogenesis and yielded lung metastases.


CONCLUSIONS
This is the first report of altered p53/TSP-1 function in association with clinically aggressive behavior in FH Wilms tumor. These characteristics were not observed in parallel studies of a nonaggressive FH tumor. Loss of wild-type p53 function may contribute to disease progression in FH Wilms tumor, in part by upregulation of VEGF.
Huang
Jianzhong
J
Divisions of Pediatric Surgery, Department of Pathology, College of Physicians and Surgeons, Columbia University and Children's Hospital of New York, USA.
Soffer
Samuel Z
SZ
Kim
Eugene S
ES
Yokoi
Akiko
A
Moore
James T
JT
McCrudden
Kimberly W
KW
Manley
Christina
C
Middlesworth
William
W
O'Toole
Kathleen
K
Stolar
Charles
C
Yamashiro
Darrell J
DJ
Kandel
Jessica J
JJ
D000818:Animals; D016228:Endothelial Growth Factors / Q000032:analysis / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000601:surgery; D007680:Kidney Neoplasms / Q000737:chemistry / Q000378:metabolism; D008175:Lung Neoplasms / Q000737:chemistry / Q000556:secondary; D008222:Lymphokines / Q000032:analysis / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology*; D016612:Paraffin Embedding; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D019700:Thrombospondin 1 / Q000032:analysis / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009396:Wilms Tumor / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology
D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors