Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the epidermal growth factor (EGF) was analyzed in six human hepatocellular carcinoma-derived and one human hepatoblastoma-derived cell line, each of which retained the differentiated phenotype and functions of the parenchymal hepatocyte. The level of receptor expression of each hepatoma cell line was similar to that of the normal human fibroblast, approximately 10(5) molecules per cell. However, NPLC/PRF/5, a subline of the PLC/PRF/5 cell line obtained following reestablishment of a xenograft tumor in vitro, was found to express 4 x 10(6) high-affinity EGF receptor molecules per cell. Proliferation of the NPLC/PRF/5 cell line was inhibited in the presence of nanomolar quantities of ligand. Receptor overexpression was found to result from EGF receptor gene amplification without apparent rearrangement of the EGF receptor coding sequences. Although cell-specific variability in posttranslational processing of EGF receptor N-linked oligosaccharides in the hepatoma cell lines was found, no difference between the receptors in PLC/PRF/5 and NPLC/PRF/5 was observed and no aberrant receptor-related species were detected. EGF receptor gene amplification in the NPLC/PRF/5 cell line is probably a reflection of genome instability and selection of variants with augmented growth potential in limiting concentrations of EGF in vivo. When viewed in this light, EGF receptor overexpression could represent a manifestation of tumor progression in the EGF-responsive hepatocyte.
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PMID:Expression and biosynthetic variation of the epidermal growth factor receptor in human hepatocellular carcinoma-derived cell lines. 282 3

Inactivation of the p53 tumor suppressor gene appears to be an important event in the progression of many types of human neoplasms; however its role in rodent experimental tumorigenesis is controversial. Previous studies have shown that a wide array of chemically induced and spontaneous mouse liver tumors lack p53 mutations within the evolutionarily conserved regions of exons 5-8. However, since p53 inactivation in human neoplasms occurs relatively late in tumor progression, it is possible that the mouse liver tumors evaluated previously were not suitably advanced to incur p53 aberrations. In the present study, we examined an end-stage, highly malignant embryonal mouse liver tumor known as the hepatoblastoma (HB) for p53 mutations utilizing the highly sensitive 'cold' single-strand conformation polymorphism (SSCP) technique. In addition, several of the HBs were examined by direct nucleotide sequencing. No aberrations of the p53 gene were detected within exons 5-8 of any of the 16 HBs examined. These results confirm that the p53 gene plays a minimal role in the development or malignant progression of hepatocellular tumors in mice.
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PMID:Lack of p53 point mutations in chemically induced mouse hepatoblastomas: an end-stage, highly malignant hepatocellular tumor. 765 27

Recent evidence suggests that the expression of estrogen receptor (ER) variants in breast cancer may interfere with wild-type (wt) ER function and be related to tumor progression and resistance to hormone treatment. One of these variants, ER delta E5, lacking that part of the hormone-binding domain encoded by exon 5, has previously been identified in breast tumors with the unusual estrogen receptor negative (ER-) and progesterone receptor positive (PgR+) phenotype and found to possess constitutive and hormone-independent transcriptional activity. Using a ribonuclease protection assay, we analyzed 27 breast tumors and 4 breast cell lines for the presence of this variant. We found the ER delta E5 variant to be expressed, not only in all of three ER-/PgR+ tumors but also in 19 of 20 ER+/PgR+ or ER+/PgR- tumors. Moreover, the variant was always coexpressed with and often in excess of wtER. ER delta E5 was also found in three breast cancer cell lines (MCF7, T47D, and ZR75-1), although to a lesser extent than wtER. A complete absence of both ER delta E5 and wtER was noted in four ER-/PgR- tumors and one normal breast cell line (HBL-100). Thus, our data suggest that the occurrence of ER delta E5 in breast cancer may represent a critical stage in tumor progression to autonomy.
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PMID:An exon 5 deletion variant of the estrogen receptor frequently coexpressed with wild-type estrogen receptor in human breast cancer. 826 97

The human insulin receptor substrate-1 (hIRS-1) is a key intracellular protein involved in various cytokine signaling pathways associated with cell growth. We have previously demonstrated that stable transfection and overexpression of hIRS-1 in human hepatoblastoma cells in vitro leads to the constitutive activation of the mitogen-activated protein kinase (MAPK) cascade. In this setting, hIRS-1 acts as a dominant oncogene and will induce neoplastic transformation of NIH 3T3 cells. In the present study, the biologic effects of hIRS-1 overexpression in the liver was analyzed using both clinical tumor samples and a newly developed transgenic mouse model. We have found that approximately 40% of 22 human hepatocellular carcinoma (HCC) tumors had enhanced (>200%) hIRS-1 gene expression compared with adjacent non-involved liver tissue. There was a significant relationship between the level of hIRS-1 overexpression and the tumor size; this finding suggests a possible role for hIRS-1 in tumor progression. To determine if downstream signal transduction cascades were activated by overexpression of hIRS-1 in hepatocytes, we established a transgenic mouse model using an hIRS-1 construct driven by an albumin promoter/enhancer element to direct liver specific expression. The overexpressed hIRS-1 protein was found to be tyrosyl phosphorylated and interacted with downstream SH2-containing molecules such as the p85 subunit of phosphatidylinositol-3 kinase (PI3K), Grb2 adaptor, and SHP2 phosphatase proteins. The functional consequences of hIRS-1 overexpression were reflected by constitutive activation of both the MAPK and PI3K signal transduction cascades. More important, overexpression of hIRS-1 in the transgenic liver led to increased hepatocyte DNA synthesis. Our findings indicate that hIRS-1 overexpression induces downstream signaling molecules associated with hepatocyte growth and may potentially enhance tumor progression of HCC.
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PMID:Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. 930 88

Aberrant cell proliferation is one of the hallmarks of carcinogenesis, and cholesterol is thought to play an important role during cell proliferation and cancer progression. In the present study we examined the pathways that could contribute to enhanced proliferation rates of HBL-100 cells in the presence of apolipoprotein E-depleted high-density lipoprotein subclass 3 (HDL(3)). When HBL-100 cells were cultivated in the presence of HDL(3) (up to 200 microg/ml HDL(3) protein), the growth rates and cellular cholesterol content were directly related to the concentrations of HDL(3) in the culture medium. In principle, two pathways can contribute to cholesterol/cholesteryl ester (CE) uptake from HDL(3), (i) holoparticle- and (ii) scavenger-receptor BI (SR-BI)-mediated selective uptake of HDL(3)-associated CEs. Northern- and Western-blot analyses revealed the expression of CLA-1 (CD-36 and LIMPII analogous 1), the human homologue of the rodent HDL receptor SR-BI. In line with CLA-1 expression, selective uptake of HDL(3)-CEs exceeded HDL(3)-holoparticle uptake between 12- and 58-fold. Competition experiments demonstrated that CLA-1 ligands (oxidized HDL, oxidized and acetylated low-density lipoprotein and phosphatidylserine) inhibited selective HDL(3)-CE uptake. In line with the ligand-binding specificity of CLA-1, phosphatidylcholine did not compete for selective HDL(3)-CE uptake. Selective uptake was regulated by the availability of exogenous cholesterol and PMA, but not by adrenocorticotropic hormone. HPLC analysis revealed that a substantial part of HDL(3)-CE, which was taken up selectively, was subjected to intracellular hydrolysis. A potential candidate facilitating extralysosomal hydrolysis of HDL(3)-CE is hormone-sensitive lipase, an enzyme which was identified in HBL-100 cells by Western blots. Our findings demonstrate that HBL-100 cells are able to acquire HDL-CEs via selective uptake. Subsequent partial hydrolysis by hormone-sensitive lipase could provide 'free' cholesterol that is available for the synthesis of cellular membranes during proliferation of cancer cells.
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PMID:The human breast carcinoma cell line HBL-100 acquires exogenous cholesterol from high-density lipoprotein via CLA-1 (CD-36 and LIMPII analogous 1)-mediated selective cholesteryl ester uptake. 1088 Mar 55

1-Amino-2,4-dibromoanthraquinone is an anthraquinone-derived vat dye, a member of a class of insoluble dyes that are impregnated into textile fibers. Five anthraquinone-derived dyes with representative and diverse structures, as well as the parent chemical, anthraquinone, were selected for NTP Toxicology and Carcinogenesis evaluation. Similar to the benzidine dye initiative, the rationale for selecting these vat dyes was to generate sufficient toxicologic data to permit more reliable predictions of carcinogenicity to be made on other chemicals in this class, thereby eliminating or reducing the need to study every anthraquinone dye. 1-Amino-2,4-dibromoanthraquinone is the last anthraquinone-derived dye in this group to be studied. Groups of male and female F344/N rats and B6C3F1 mice were exposed to 1-amino-2,4-dibromoanthraquinone (87% to 97% pure) for 13 weeks or for 9, 15, or 24 months. Because 1-amino-2,4-dibromoanthraquinone was predicted to be carcinogenic, these studies were designed to evaluate the potential for tumor progression and regression. Absorption and excretion studies were carried out in male F344/N rats. Genetic toxicity was determined in vitro using Salmonella typhimurium and cultured Chinese hamster ovary cells. Extensive chemical analyses were performed to identify and characterize impurities of the 1-amino-2,4-dibromoanthraquinone used in these studies. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were given 0, 2,500, 5,000, 10,000, 25,000, or 50,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 13 weeks. These levels correspond to approximately 150 to 3,200 mg 1-amino-2,4-dibromoanthraquinone/kg body weight per day for males and to approximately 170 to 3,200 mg/kg for females. Chemical-related mortality was limited to one male and one female in the 50,000 ppm groups. Final mean body weights and body weight gains of all exposed groups of rats were significantly lower than those of the controls. Feed consumption by all exposed groups was less than that by the controls throughout the study and generally decreased with increasing exposure concentration. Pink-red staining of the fur and tail was observed in all exposed groups. Absolute and relative liver weights of all exposed groups were generally significantly greater than those of the controls. Chemical-related lesions were present in the liver, kidney, and spleen of male and female rats. Nonneoplastic lesions in the liver included foci of hepatocellular alteration, diffuse hepatocellular hypertrophy (cytomegaly), hepatocellular cytoplasmic vacuolation, bile duct hyperplasia, inflammation, and pigmentation. These differences were observed primarily in the 25,000 and 50,000 ppm groups of males and females; the spectrum of proliferative lesions of the bile ducts (hyperplasia, fibrosis, and necrotizing cholangitis) in the 25,000 and 50,000 ppm groups was morphologically consistent with the lesion described as cholangiofibrosis. Pigmentation was present in the renal tubule epithelium of all groups of exposed rats; nuclear enlargement (karyomegaly) was also present in the renal tubule epithelium in some of the exposed rats. Accumulation of hyaline droplets in the cytoplasm of the renal tubule epithelium and tubule lumina was present in 2,500, 5,000, 10,000, and 25,000 ppm males. Incidences of hematopoiesis of the spleen in exposed groups of males and females were increased compared to those in the controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were given 0, 2,500, 5,000, 10,000, 25,000, or 50,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 13 weeks. These levels correspond to approximately 500 to 10,600 mg 1-amino-2,4-dibromoanthraquinone/kg body weight per day for males and approximately 660 to 11,700 mg/kg per day for females. There was no chemical-related mortality. Feed consumption and final mean body weights of exposed groups were similar to those of the controls. Red staining of the fur was observed in all exposed groups. Absolute and relative liver weights of the exposed groups were greater than those er than those of the controls except for the absolute liver weight of 2,500 ppm males. Absolute and relative kidney weights of 25,000 and 50,000 ppm males were lower than those of the controls. Chemical-related lesions were limited to the livers of males and consisted of pigmentation of hepatocytes at all exposure concentrations and centrilobular hepatocellular hypertrophy at 10,000, 25,000, and 50,000 ppm. Minimal pigment was present in the liver of one female in the 25,000 ppm group and in one female in the 50,000 ppm group. 2-YEAR STUDY IN RATS: Groups of 70 male and 70 female rats were given 0, 5,000, or 10,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 103 weeks. In addition, groups of 50 male and 50 female rats were given 2,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 104 weeks. These exposure concentrations were approximately equal to 90, 240, or 490 mg 1-amino-2,4-dibromoanthraquinone/kg body weight for males and 110, 285, or 600 mg/kg for females. Ten animals from each group were evaluated for histopathology at 9 months. Additional groups of 10 animals from the 0 and 10,000 ppm groups were evaluated for histopathology at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings In the 2-year study, survival of the 10,000 ppm males and females was significantly lower than that of the controls. Survival of the 2,000 and 5,000 ppm groups was similar to that of the controls. During the last year of the study, the mean body weights of exposed males were 80% to 91% those of controls, and the mean body weights of exposed females were 67% to 84% those of controls. Feed consumption among exposed groups was generally similar, but was less than that by controls. The fur and urine of all exposed male and female groups were discolored. Pathology Findings In the 2-year study, 1-amino-2,4-dibromoanthraquinone was associated with significant chemical-related increases in the incidences of benign and malignant neoplasms in the liver, large intestine, kidney, and urinary bladder of males and females. Chemical-related nonneoplastic proliferative and degenerative lesions occurred in the liver, kidney, urinary bladder, and forestomach of males and females. The incidences of foci of hepatocellular alteration and pigmentation in the liver of males and females were increased at the 9-month interim evaluation, and a hepatocellular adenoma was present in one 5,000 ppm male. At the 15-month interim evaluation, hepatocellular adenoma or carcinoma (combined) occurred in all males and nine females in the 10,000 ppm groups. By the end of the 2-year study, hepatocellular adenoma, carcinoma, cholangioma, or cholangiocarcinoma were observed in males and females in the 5,000 and 10,000 ppm groups. In the 2,000 ppm groups, similar liver neoplasms were present in 63% of the males and in 83% of the females. Of the hepatocellular carcinomas in the 5,000 and 10,000 ppm groups of males and females, 31% to 49% were metastatic to the lungs or other sites. Increases in the incidences of foci of hepatocellular alteration (basophilic, eosinophilic, and clear cell) and pigmentation of the liver were also observed in exposed groups of males and females. Adenomatous polyps (adenoma) of the large intestine were present in six 10,000 ppm males at the 15-month interim evaluation. Incidences of adenomatous polyp (adenoma) and carcinoma of the large intestine were significantly increased in exposed groups of males and females after 2 years; multiple benign and malignant intestinal neoplasms were observed in many of these rats. In the kidney, incidences of renal tubule adenoma and carcinoma were significantly increased in exposed groups of males and females after 2 years. Renal tubule adenomas were present in two 10,000 ppm males at 15 months. There were also chemical-related increases in the incidences and severities of renal tubule epithelial hyperplasia, pigmentation, and transitional cell hyperplasia in the kidney of males and females. Hyaline droplet accumulation was present in all exposed male rats at 9 months. Incidences of transitional cell papilloma and carcinoma of the urinary bladder were increased at 2 years in males and females in the 10,000 ppm groups. Transitional cell hyperplasia was observed in exposed males and females at the 15-month interim evaluation. Other nonneoplastic lesions observed in the urinary bladder at 2 years included metaplasia of the transitional epithelium and submucosal stromal tissue. In the forestomach, the incidences and severities of inflammation, ulceration, hyperkeratosis, and hyperplasia of the squamous mucosa were increased in all exposed groups of males and females at 2 years, but not at the 9- or 15-month interim evaluations. In exposed males and females, the incidences of mononuclear cell leukemia were significantly decreased. The incidences of atrophy of the seminal vesicle were increased in exposed male rats in the 2-year study. Stop-Exposure Evaluation in Rats Groups of 40 male and 40 female rats were given 20,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 9 or 15 months. At 9 months, 10 males and 10 females were evaluated for histopathology (9-month interim evaluation groups). After 9 months of exposure, an additional 10 males and 10 females were fed control diet until the end of the 15-month evaluation (9-month stop-exposure groups), and 20 males and 20 females continued to receive 20,000 ppm 1-amino-2,4-dibromoanthraquinone until the end of the evaluation (15-month exposure groups). The approximate daily consumption of 1-amino-2,4-dibromoanthraquinone was 1,335 mg/kg for males and 1,790 mg/kg for females in the 9-month stop-exposure groups and 1,115 mg/kg for males and 1,435 mg/kg for females in the 15-month exposure groups. Survival was similar among groups except for the females in the 15-month exposure group; the survival of this group was lower than that of the controls. Lower mean body weights were related to increased exposure duration. The mean body weights of exposed males were 76% to 82% that of controls, and the mean body weights of exposed females were 73% to 84% that of controls. For the stop-exposure evaluation, similar chemical-related neoplasms and nonneoplastic lesions were observed in the same sites as in the 2-year study: liver, large intestine, kidney, urinary bladder, and forestomach. After 9 months of dietary exposure to a concentration of 20,000 ppm 1-amino-2,4-dibromoanthraquinone, hepatocellular adenoma and carcinoma occurred in males and females. Nonneoplastic chemical-related lesions in the liver of exposed rats included pigmentation, focal hepatocellular alteration, and bile duct hyperplasia. Neoplasms at other sites in males included one adenomatous polyp (adenoma) in the large intestine and one transitional cell papilloma in the urinary bladder. Hyaline droplet accumulation was present in the kidney of exposed males at 9 months. In the stop-exposure groups examined at 15 months, hepatocellular adenoma and carcinoma were present in most males and females. Adenomatous polyp (adenoma) of the colon, renal tubule cell adenoma, and urinary bladder transitional cell papilloma and carcinoma also occurred in males and females. Nonneoplastic chemical-related lesions included foci of hepatocellular alteration in the liver and hyperplasia of the renal tubule epithelium and urinary bladder transitional epithelium. Hyperplasia, hyperkeratosis, inflammation, and ulceration were observed in the forestomach of some male and female rats continuously exposed for 15 months. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 10,000, or 20,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 104 weeks. The daily compound consumption was approximately 1,690 or 3,470 mg 1-amino-2,4-dibromoanthraquinone/kg body weight for males and 1,950 or 4,350 mg/kg for females. Ten animals from each group were evaluated for histopathology at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings In the 2-year study, survival of exposed males was significantly lower than that of the controls. Survival of exposed females was similar to that of the controls. The final mean body weights of exposed males were 83% to 85% that of controls, and the final mean body weights of exposed females were 81% to 86% that of controls. Feed consumption by exposed groups was generally similar to that by controls. Discoloration of the fur, urine, and feces was observed in all exposed groups. Pathology Findings In the 2-year study, 1-amino-2,4-dibromoanthraquinone was associated with significant chemical-related increases in the incidences of benign and malignant neoplasms in the liver, forestomach, and lung of males and females. Incidences of hepatocellular adenoma and carcinoma were increased in exposed groups at the 15-month interim evaluation and at 2 years. At 2 years, there were significant increases in the incidences of multiple hepatocellular adenoma and carcinoma in males and females and in the incidences of hepatoblastoma in males. Centrilobular hypertrophy of hepatocytes in males and foci of hepatocellular alteration and pigmentation in the liver of males and females were also chemical-related changes. Sqamous cell papilloma of the forestomach mucosa occurred in 10,000 ppm females and 20,000 ppm males and females at the 15-month interim evaluation, and the incidences of squamous cell papilloma and carcinoma were significantly increased in exposed groups of males and females at 2 years. Chemical-related hyperplasia of forestomach epithelium was also present at 15 months and at 2 years. Alveolar/bronchiolar adenomas were present only in the exposed groups of males and females at 15 months, and the incidences of alveolar/bronchiolar adenoma were significantly increased in exposed males and females at 2 years. The incidences of multiple alveolar/bronchiolar adenomas were also increased in exposed males. In the kidney, pigmentation was present in the renal tubules of most mice after 2 years of exposure. DISPOSITION AND METABOLISM STUDIES: Adult male F344/N rats were given [14C]-labeled 1-amino-2,4-dibromoanthraquinone as a single intravenous dose of 0.4 mg/kg body weight or as a single oral dose of 2, 23, 118, 814, or 1,473 mg/kg. A 6-hour bile cannulation study was also performed. From day 0 through day 3 after intravenous administration, about 50% of the 14C was excreted in the feces, 15% in the urine, and 6% in expired air. Unmetabolized 1-amino-2,4-dibromoanthraquinone accounted for less than 3% of the excreted 14C after intravenous administration. For oral doses administered, the amount of the dose that was absorbed fit the equation: absorbed dose = 6.6 x log(dose). After intravenous administration, the metabolites of 1-amino-2,4-dibromoanthraquinone in blood were primarily in the plasma fraction (blood:plasma ratio of approximately 0.5:1). The highest concentrations of 14C in tissues 15 minutes after intravenous dosing were in excretory organs, lung, kidney, small intestine, liver, adipose tissue, and adrenal gland. GENETIC TOXICOLOGY: 1-Amino-2,4-dibromoanthraquinone was mutagenic in Salmonella typhimurium strains TA98 and TA1537 in the absence of S9; with S9, an equivocal response was observed in TA1537. 1-Amino-2,4-dibromoanthraquinone resulted in an equivocal response in TA100 with and without S9, and no mutagenic activity was detected with strain TA1535. In cultured Chinese hamster ovary cells, 1-amino-2,4-dibromoanthraquinone induced sister chromatid exchanges with and without S9; chromosomal aberrations were induced in the absence of S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 1-amino-2,4-dibromoanthraquinone in male and female F344/N rats based on increased incidences of neoplasms in the liver, large intestine, kidney, and urinary bladder. There was clear evidence of carcinogenic activity of 1-amino-2,4-dibromoanthraquinone in male and female B6C3F1 mice based on increased incidences of neoplasms in the liver, forestomach, and lung. Exposure of male and female rats to 1-amino-2,4-dibromoanthraquinone for 2 years was associated with basophilic focus (males only), clear cell focus, eosinophilic focus, and pigmentation in the liver; renal tubule hyperplasia, renal tubule pigmentation, and transitional cell hyperplasia in the kidney; transitional cell hyperplasia, squamous metaplasia, and stromal metaplasia (females only) in the urinary bladder; squamous hyperplasia, hyperkeratosis, ulceration, and inflammation of the forestomach mucosa; and seminal vesicle atrophy. Exposure of male and female mice to 1-amino-2,4-dibromoanthraquinone for 2 years was associated with centrilobular hepatocellular hypertrophy (males only), basophilic focus, clear cell focus (females only), eosinophilic focus, and pigmentation in the liver; pigmentation in the kidney; and hyperplasia, basal cell hyperplasia, hyperkeratosis, and inflammation of the forestomach mucosa. Synonym: ADBAQ
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PMID:NTP Toxicology and Carcinogenesis Studies of 1-Amino-2,4-Dibromoanthraquinone (CAS No. 81-49-2) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1269 53

Liver transplantation for hepatic malignancies has emerged from an exotic and desperate approach to a well-documented and proven treatment modality for these unfortunate patients. However, early unsatisfactory results emphasized that only a highly selected patient population would benefit from transplantation. Currently, <10% of all liver transplants performed are for hepatocellular cancer (HCC). There is no controversy that hepatoblastoma is an excellent indication in pediatric patients with unresectable tumors. Similarly, liver transplantation for HCC in the adult population yields good results for patients whose tumor masses do not exceed the Milan criteria. It remains to be determined whether patients with more extensive tumors can be reliably selected to benefit from the procedure. Adjunctive procedures like radiofrequency ablation, chemoembolization, or cryotherapy might be indicated to limit tumor progression for patients on waiting lists. Epitheloid hemangioendothelioma is also an appropriate indication for liver transplantation, unlike angiosarcoma. Metastatic liver disease is not an indication for liver transplantation, with the exception of cases in which the primary is a neuroendocrine tumor, for which liver transplantation can result in long-term survival and even cure in a number of patients. And finally, while gallbladder cancers are never an indication for liver transplantation, rare cases of cholangiocellular cancer might qualify if aggressive combination therapies, including chemotherapy and radiotherapy followed by OLT, are carried through. Survival in these selected patients can approach that for patients with cholestatic liver disease.
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PMID:Liver transplantation for malignancy. 1582 Dec 47

The aim of this pilot study was to determine VEGF serum levels (S-VEGF) at diagnosis and at restaging in children diagnosed with cancer, and to investigate whether this parameter provides prognostic information for remission after induction therapy and response to treatment. S-VEGF levels of 35 consecutive pediatric patients with various types of cancer were assayed at diagnosis and at restaging. Levels of VEGF were determined using a commercially available ELISA anti-human VEGF immunoassay kit. Thirty-one children went into complete remission or had a very good partial response to first-line therapy; 4 patients developed tumor progression. At diagnosis average S-VEGF level was 495 pg/mL (range, 0.89--2220 pg/mL) and at restaging it decreased to 118.36 pg/mL (range, 7.44--487 pg/mL). (p=.0039). The 4 patients with tumor progression had increased S-VEGF levels at restaging. The comparison between the levels of S-VEGF at diagnosis and at restaging showed a significant difference for the patients who responded to treatment with decreased S-VEGF and the patients who developed tumor progression with increased S-VEGF (p=.0019). One child with metastatic Ewing sarcoma developed progressive disease after several weeks, with significantly progressively higher S-VEGF levels. One child with Hodgkin disease, who had a higher level at first restaging and developed progressive disease, responded to reinduction therapy and had a significantly lower level at the second restaging. The child with metastatic hepatoblastoma responded to first-line chemotherapy with concomitant decrease in S-VEGF and alpha-fetoprotein levels, but developed local recurrence with elevation in both parameters. Changes in S-VEGF levels correlated with response to treatment for most of the children diagnosed with cancer. This provides a rationale for exploring clinical interest in S-VEGF measurements of a larger group of children with malignancies, and using the test for clinical trials of antiangiogenic therapies.
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PMID:Serum vascular endothelial growth factor as a significant marker of treatment response in pediatric malignancies. 1616 18

Hepatoblastoma (HBL), a major childhood malignant neoplasm, represents the most frequent malignant liver tumor in childhood. Recent reports have shown the CTNNB1 coding beta-catenin protein to be frequently mutated or deleted at hot-spot regions involving exon 3 in HBL. We investigated the genetic alterations of the CTNNB1 coding beta-catenin protein and expression of several genes downstream of Wnt signals in 4 benign and 17 malignant pediatric liver tumors (PLTs) consisting of 15 HBL, 1 hepatocellular carcinoma, and 1 hepatic immature sarcoma. Of 17 malignant PLTs, 10 (56%) revealed pathogenic alterations of the CTNNB1 gene, including 4 with missense mutations at codons 28, 32, 34 or 44, and 6 with interstitial deletions that partially or totally affected exon 3. All 6 deletions were in-frame deletions without a frame shift. The high frequency without any correlation to histological type indicates that the CTNNB1 gene alteration is a crucial event in the tumorigenesis of malignant PLTs. The immunohistochemical studies in 17 malignant PLTs demonstrated the nuclear/cytoplasmic accumulation of beta-catenin to be positive in all tumor specimens except for one hepatic sarcoma. A histological examination revealed all HBL cases involving tumors without detectable CTNNB1 gene alterations to show high expression of beta-catenin, thus indicating the accumulation of beta-catenin to be a common event in malignant PLTs, including HBL and hepatocellular carcinoma. Among the Wnt signal genes downstream of beta-catenin, E-cadherin is expressed in all malignant PLTs, while cyclin D1 expression was significantly detected in malignant PLTs with an advanced stage of disease. An immunohistological examination of nuclear accumulation of beta-catenin may thus be useful for diagnosing malignant PLTs. On the other hand, the expression of cyclin D1, a gene downstream of beta-catenin, might play a role in tumor progression.
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PMID:Diagnostic and prognostic impact of beta-catenin alterations in pediatric liver tumors. 1646 11

Galectin-3 is a soluble endogenous lectin in vertebrates and is implicated in a variety of biological functions, including tumor cell adhesion, proliferation, differentiation, apoptosis, cancer progression and metastasis. In the present study, we analyzed the role of galectin-3 in apoptosis in human malignant lymphoma. Galectin-3 induced cell death in the HBL-2 human diffuse large B cell lymphoma cell line. A morphological examination and annexin V assays revealed that galectin-3-induced cell death is consistent with apoptosis and swainsonine, a potent inhibitor of alpha-mannosidase II, which catalyzes the synthesis of complex type N-linked oligosaccharides, inhibited galectin-3-induced apoptosis in HBL-2 cells. These results suggest that galectin-3 induces apoptosis in HBL-2 cells by interacting with cell surface N-linked oligosaccharides. Furthermore, treatment of cells with Vibrio Cholerae neuraminidase enhanced galectin-3-induced apoptosis, suggesting that cell surface sialylation regulates galectin-3-induced apoptosis in human B cell lymphoma. In conclusion, our results indicate that galectin-3-induced apoptosis is regulated by cell surface expression of N-glycans and sialic acid in human diffuse large B cell lymphoma. This mechanism may be involved in the malignant behavior of human lymphoma cells.
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PMID:Cell surface N-glycosylation and sialylation regulate galectin-3-induced apoptosis in human diffuse large B cell lymphoma. 1828 10


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