Expression of IGF-I and IGF-II mRNA in breast tissue

Summary Expression of IGF-I and IGF-II was studied in human breast cancer tissues by in situ hybridization. IGF-I mRNA was detected only in stromal cells adjacent to normal breast epithelial cells. Stromal cells associated with the tumor cells did not contain IGF-I, nor did malignant or benign breast epithelial cells. In contrast, IGF-II mRNA was found in both the malignant epithelial cells and their adjacent stromal cells. These data imply that stromal cells associated with breast epithelium may switch expression from IGF-I to IGF-II during breast cancer evolution. This appearance of IGF-II expression may identify cancer-associated stromal cells that have a fetal phenotype.     

Expression of insulin-like growth factor II (IGF–II) in human hepatocellular carcinomas: An immunohistochemical study

Recent results obtained using molecular biology techniques have suggested a possible role for insulin-like growth factor II (IGF-II) in the pathogenesis of hepatocellular carcinoma (HCC). To investigate this phenomenon, a monoclonal anti-body was used against IGF-II to study 54 patients with HCC. The presence of HBsAg was also tested both in serum and liver tissue. A positive immunoreaction was found in 9/15 (60%) of the HCC arising in cirrhotic livers of patients who had serum markers for HBV (HBV+ positive patients). These results provide further evidence that HBV might play a role in the expression of IGF-II. In HCC of patients without any markers of HBV infection (HBV- negative patients), IGF–II was detected in 10/39 (25.6%) of the tumors, and in some benign neoplastic lesions. It was found not only in neoplastic cells but also in some dysplastic nodules. The speculation arises that IGF–II expression may play a role in some steps of hepato-carcinogenesis.     

IGF-II受体基因在IM-9细胞株的表达与调节

利用从人B细胞来源的IM-9淋巴母细胞株为体外模型,通过细胞培养、溶液杂交等方法,研究观察了IGF-Ⅱ受体mRNA水平与细胞增殖的关系,以及GH、IGF-Ⅰ、IL-Ⅰ对其的影响与调节。结果发现,IGF-Ⅱ受体mRNA转录水平与细胞增殖状态有关;GH、IGF-Ⅰ和IL-Ⅰ均能在细胞增殖的一定阶段对IGF-Ⅱ受体基因表达水平产生调节。     

Selective induction of apoptosis in MCF7 cancer-cell by targeted liposomes functionalised with mannose-6-phosphate

Liposomes are versatile platforms to carry anticancer drugs in targeted drug delivery; they can be surface modified by different strategies and, when coupled with targeting ligands, are able to increase cellular internalisation and organelle-specific drug delivery. An interesting strategy of antitumoral therapy could involve the use of lysosomotropic ligand-targeted liposomes loaded with molecules, which can induce lysosomal membrane permeabilization (LMP), leakage of cathepsins into the cytoplasm and subsequent apoptosis. We have previously demonstrated the ability of liposomes functionalised with a mannose-6-phosphate to reach lysosomes; in this research we compare the behaviour of M6P-modified and non-functionalised liposomes in MCF7 tumour cell and in HDF normal cells. With this aim, we first demonstrated by Western blotting the overexpression of mannose-6-phosphate/insulin-like growth factor (M6P/IGF-II) receptor in MCF7. Then, we prepared calcein-loaded liposomes and we revealed the increased uptake of M6P-functionalised liposomes in MCF7 cells respect to HDF cells by flow cytometry analysis. Finally, we loaded functionalised and not functionalised liposomes with N-hexanoyl-d-erythro-sphingosine (C6Cer), able to initiate LMP-induced apoptosis; after having studied the stability of both vesicles in the presence of serum by Dynamic Light Scattering and Spectrophotometric turbidity measurements, we showed that ceramide-loaded M6P-liposomes significantly increased apoptosis in MCF7 with respect to HDF cells.     

Hemangiopericytoma-associated hypoglycemia improved by glucocorticoid therapy: a case report

A 59-year-old man was admitted because of recurrent, severe hypoglycemia. He had multiple metastases from a meningeal hemangiopericytoma, which had been operated on 12 years earlier. The results of laboratory testing at the time of hypoglycemia showed very low serum levels of insulin, C-peptide, and growth hormone, with slightly high levels of insulin-like growth factor-II, and a normal level of insulin-like growth factor-I. The diagnosis of hemangiopericytoma-associated hypoglycemia was proposed. The patient was given corticosteroid therapy, which ameliorated symptoms of hypoglycemia.     

Systemic effects of insulin-like growth factor-II produced and released from Wilms tumour tissue

The concentration of mRNA of insulin-like growth factor-II is (IGF-II) much elevated in some embryonic tumours such as Wilms tumour (nephroblastoma). In order to prove whether or not IGF-II is produced by the tumour tisue, IGF-II was extracted from freshly frozen tissue of Wilms tumour and hepatoblastoma. Normal adjacent tissue of kidney and liver was used as a control. The total IGF-II in Wilms tumour was 548.4±77.4 ng/g (n=7) compared to 112.8±38.2 ng/g (n=5) in kidney. In two hepatoblastomas, it was 96.1±22.8 ng/g compared to 30.1±14,2ng/g in normal liver. Small pieces of fresh primary tissue of several Wilms tumours were successfully transplanted into immunodeficient nude mice. In serum of tumour-bearing mice IGF-II was elevated compared to normal mice. Liver weight of tumour bearing mice was higher than that of control mice (2.29±0.4g and 2.02±0.06 g;P<0.005). This was also found for kidney weight (0.58±0.01 g vs. 0.51±0.01 g in controls,P<0.001). In contrast, serum glucose (9.73±0.29 mmol/l compared to 11.80±0.42 mmol/l in controls,P<0.0005) was decreased. However, there was no significant difference in nose-tail length of tumour-bearing compared to control mice. These results demonstrate that besides the highly increased IGF-II-mRNA, the synthesis of the peptide IGF-II and its release into circulation are also elevated in Wilms tumour transplanted into nude mice. Elevated circulating IGF-II is likely to stimulate growth of some inner organs and has a glucose lowering effect but does no stimulate skeletal growth. This is further evidence for the importance of IGF-II as a growth factor.     

Antagonists of growth hormone-releasing hormone (GH-RH) inhibit IGF-II production and growth of HT-29 human colon cancers

Insulin-like growth factors (IGFs) I and II are implicated in progression of various tumours including colorectal carcinomas. To interfere with the production of IGFs, we treated male nude mice bearing xenografts of HT-29 human colon cancer with various potent growth hormone-releasing hormone (GH-RH) antagonists. Twice daily injections of antagonist MZ-4-71, 10 microg intraperitoneally or 5 microg subcutaneously (s.c.) resulted in a significant 43-45% inhibition of tumour growth. Longer acting GH-RH antagonists, MZ-5-156 and JV-1-36 given once daily at doses of 20 microg s.c. produced a 43-58% decrease in volume and weight of cancers. Histological analyses of HT-29 cancers demonstrated that both a decreased cell proliferation and an increased apoptosis contributed to tumour inhibition. GH-RH antagonists did not change serum IGF-I or IGF-II levels, but significantly decreased IGF-II concentration and reduced mRNA expression for IGF-II in tumours. In vitro studies showed that HT-29 cells produced and secreted IGF-II into the medium, and addition of MZ-5-156 dose-dependently decreased IGF-II production by about 40% as well as proliferation of HT-29 cells. Our studies demonstrate that GH-RH antagonists inhibit growth of HT-29 human colon cancers in vivo and in vitro. The effect of GH-RH antagonists may be mediated through a reduced production and secretion of IGF-II by cancer cells.     

Histopathological diagnosis and prognostic factors in adrenocortical carcinoma

A great majority of adrenocortical tumors are benign, and many adrenocortical carcinomas (ACC) are obviously malignant at presentation. The histopathological diagnosis of ACC is occasionally difficult, particularly with stage I and stage II disease. The prognosis of ACC is generally poor. Surgery is the major treatment, with chemotherapy and radio-therapy being applicable to only restricted patients. The Weiss criteria are useful in diagnosing the common adult type of ACC. Histopathological prognostic factors of ACC have not been fully established because of the rarity of the disease. In this article, we first describe the current histopathological diagnostic and prognostic factors of ACC, highlighting the special types of ACC to which Weiss’s criteria are not fully applicable. These special type tumors include pediatric adrenocortical tumors, oncocytomas, and aldosterone-producing tumors of pure zona glomerulosa type. Then we present three cases with unusual small adrenocortical tumors. One patient had an unequivocal ACC showing metastatic disease. One had a histologically defined ACC with no metastasis or macroscopic invasion. The third was a pediatric patient with a tumor showing a nodule-in-nodule pattern with insulin-like growth factor II expression.