E. Santonirugiu et al., EVOLUTION OF NEOPLASTIC DEVELOPMENT IN THE LIVER OF TRANSGENIC MICE CO-EXPRESSING C-MYC AND TRANSFORMING GROWTH-FACTOR-ALPHA, The American journal of pathology, 149(2), 1996, pp. 407-428
We have previously shown that co-expression of c-myc and transforming
growth factor (TGF)-alpha as transgenes in mouse liver results in majo
r enhancement of neoplastic development in this organ as compared with
expression of either of these transgenes alone. In this report we des
cribe in detail the progression from liver cell dysplasia to hepatocel
lular carcinomas (HCCs) occurring in the liver of c-myc/TGF-alpha and
c-myc transgenic mice. Despite morphological similarities in the seque
nce of events between the two transgenic lines, the dramatic accelerat
ion, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice c
learly demonstrated the synergistic effects of this transgenic combina
tion. Although c-myc/TGP-alpha and c-myc females displayed longer late
ncy and lower tumor incidence, the pathological changes were the same
as those seen in the male mice, including the formation of HCCs, which
are absent in TGF-alpha single-transgenic females. Tumors in single-
and double-transgenic mice showed induction of the endogenous c-myc an
d TGF-alpha and, most frequently, unchanged or decreased epidermal gro
wth factor receptor, further indicating the collaborative role of c-my
c and TGF-alpha in providing a selective growth advantage to tumor cel
ls independently of the epidermal growth factor receptor levels. To id
entify Possible tumor precursors, we focused particularly on the dyspl
astic changes Preceding and accompanying the appearance of preneoplast
ic and neoplastic lesions in the double-transgenic mice. Early on, the
se changes were characterized by the appearance of large dysplastic he
patocytes, mostly pericentrally, expressing high levels of TGF-alpha a
nd uPA, as wed as TGF-beta 1, particularly in apoptotic cells. After a
short period of replication and expansion into the liver parenchyma,
as well as penetration into the central veins, these cells underwent a
poptotic cea death while preneoplastic and neoplastic lesions were for
ming. The peritumorous tissues also contained small dysplastic hepatoc
ytes and oval-like cells, similar to those found in the tumors. Transp
lantation of the transgenic liver tissues harboring only dysplasia wit
h or without vascular lesions onto nude mice was able to yield HCCs co
mposed of small diploid cells, suggesting that initiated cells are gen
erated during the early dysplastic phase and can progress to HCC. It i
s therefore likely that large dysplastic hepatocytes undergo apoptosis
, which may be closely associated with the up-regulation of TGF-beta 1
and uPA, whereas other cells evolve into the precursor population for
HCC. Due to the simultaneous presence of c-myc, TGF-alpha, and dyspla
sia in premalignant human liver diseases, our transgenic mouse system
appears to be an appropriate model for studying human hepatocarcinogen
esis.