Pj. Grippo et Ep. Sandgren, Highly invasive transitional cell carcinoma of the bladder in a simian virus 40 T-antigen transgenic mouse model, AM J PATH, 157(3), 2000, pp. 805-813
Citations number
42
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Transitional cell carcinoma (TCC), a neoplasm of urinary bladder urothelial
cells, generally appears in either of two farms, papillary non-invasive or
invasive TCC, although intermediate forms can occur. Each has a distinctiv
e morphology and clinical course. Altered expression of the p53 and pRb gen
es has been associated with the more serious invasive TCC, suggesting that
the loss of activity of these tumor suppressor proteins may have a causal r
ole in this disease. To test this hypothesis directly, transgenic mice were
developed that expressed the simian virus 40 large T antigen (TAg) in urot
helial cells under the control of the cytokeratin 19 gene (CK19) regulatory
elements. in one CK19-TAg Lineage, all transgenic mice developed highly in
vasive bladder neoplasms that resembled invasive human bladder TCCs. Stages
of disease progression included development of carcinoma in situ stromal i
nvasion, muscle invasion, rapid growth, and, in 20% of affected mice, intra
vascular lung metastasis, Papillary lesions never were observed. Western bl
ot analysis indicated that TAg was bound to both p53 and pRb, which has bee
n shown to cause inactivation of these proteins. Our findings support sugge
stions that (i) inactivation of p53 and/or pRb constitutes a causal step in
the etiology of invasive TCC, (ii) papillary and invasive TCC may have dif
ferent molecular causes, and (iii) carcinoma in situ can represent an early
stage in the progression to invasive TCC.