Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats†

Abstract

Intrahepatic transplantation of ovarian fragments in ovariectomized rats results in morphological abnormalities. The liver acini draining blood from ovarian grafts show alterations resembling chemically induced amphophilic hepatocellular preneoplasias. We investigated the long-term development of these estrogen-induced foci of altered hepatocytes (FAH). We divided 451 Lewis rats into one main group (MG) and 11 (7 female, 4 male) control groups and observed them for up to 30 months. MG animals were ovariectomized and received ovarian transplants into the right liver part. Different combinations of castration, transplantation of ovarian or testicular fragments, and administration of antiestrogenic toremifene were used in controls. In the MG, transplants showed signs of gonadotropic stimulation, and estrogen levels were strongly increased in the downstream liver acini. After 6 and 12 months, O ral contraceptive steroids contribute to the development of hepatocellular adenoma (HCA) in humans, and a recent meta-analysis has also shown an increased incidence of hepatocellular carcinoma (HCC) in women of a low-risk population (low hepatitis B and C prevalence). 1 These observations correspond to findings in animal experiments that have demonstrated an enhancement of hepatocarcinogenesis after administration of various synthetic estrogens such as ethinyl estradiol and diethylstilbestrol. [2][3][4][5][6] Simultaneous administration of tamoxifen inhibited part of the carcinogenic effects of ethinyl estradiol, indicating that they were most likely mediated by the estrogen receptor. 7 These observations suggest that estrogens are not only genotoxic 8,9 but may also act as hepatocarcinogens by altering cell signaling and metabolism, including nuclear and mitochondrial gene expression and cell proliferation. 10,11 Estrogens also interact with other hepatocellular mitogens such as epidermal or hepatocyte growth factor and transforming growth factor ␣ (TGF-␣). [12][13][14] Although the carcinogenic effects of synthetic estrogens on the liver have been extensively studied, little is known about the hepatocarcinogenic potential of endogenous estrogens, although increased levels of circulating estrogens bear a risk for the

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“…Housing of the animals was described in detail previously [14,15,16]. The animal protocols used in this work were evaluated and approved by the Committee for Animal Research (Protocol no.…”

“…FAH can also be induced by hormonal stimuli—after intraportal transplantation of pancreatic islets in diabetic rats (PTx, [14]), ovarian fragments in ovarectomized rats (OTx, [15]) and thyroid follicles in thyroidectomized rats (TTx, [16]). After low-number islet transplantation, insulin related alterations lead to glycogen and fat storing clear cell foci downstream of the islet transplant, which evolve into basophilic foci and progress to HCA and HCC [14].…”

“…After low-number islet transplantation, insulin related alterations lead to glycogen and fat storing clear cell foci downstream of the islet transplant, which evolve into basophilic foci and progress to HCA and HCC [14]. The hepatocytes downstream of the transplanted ovarian fragments are characterized by an amphophilic phenotype driven by estrogens [17], which also evolve to HCA and HCC [15]. Intraportal transplantation of thyroid follicles and the influence of triiodothyronine (T3) lead to hyperproliferative FAH downstream of the transplants, which are amphophilic-tigroid [16].…”

“…Overexpression of TGFα is documented in NNM induced hepatocarcinogenesis [19] and pre-neoplastic lesions of PTx and OTx transplantation models [14,15], but not in T3 induced hepatocellular alterations [16]. …”

Revelation of simple and complex liver acini after portal transplantation of pancreatic islets or thyroid follicles in rats

“…[6][7] Here, we report on our observations made by examining morphologically altered liver acini in animal models that were originally designed to study hormonally induced hepatocarcinogenesis. [14][15][16][17][18][19][20][21][22][23] The altered morphology of the liver acini was induced by local action of hormones [such as insulin and tri-iodothyronine (T3)] on the hepatocellular metabolism after transplantation of endocrine tissues into the rat liver, resulting in considerable changes of the hepatocellular phenotype of the downstream liver acini, such as an excess in glycogen and/or fat storage in the insulin model [14][15][16][17][18][21][22][23] or increased basophilia and loss of glycogen in the T3 model. 20 Therefore, we were able to depict the anatomy of a simple liver acinus for the first time, conclusively proving the correctness of Rappaport's acinus model.…”