Blocking the hedgehog pathway inhibits hepatoblastoma growth #

Eichenmüller, Melanie; Gruner, Ivonne; Hagl, Beate; Häberle, Beate; Müller‐Höcker, Josef; Schweinitz, Dietrich von; Kappler, Roland

doi:10.1002/hep.22649

Cited by 100 publications

(87 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(28) It has been shown that blocking Gli1 inhibits heptoblastoma growth. (31) Cytotoxic therapies currently used for cancer treatment largely depend on activation of cancer cell apoptosis. Consequently, it is likely that IMD increases HCC cell growth by preventing tumor cells from undergoing apoptotic pathways through regulation of the Hedgehog pathway, which transcriptionally controls Bcl2 expression.…”

Section: Discussionmentioning

confidence: 99%

Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival

et al. 2012

View full text Add to dashboard Cite

Angiogenesis is one of the hallmarks of tumor growth and metastasis. Identification of tumor angiogenic factors has been a critical component in understanding cancer biology and treatment. Intermedin (IMD) has been reported to promote angiogenesis in a rat ischemic model and human umbilical vascular endothelial cells. Our study sought to determine the role of IMD in human hepatocellular carcinoma tumor progression. High IMD mRNA expression levels were observed in human hepatocellular carcinoma tumors, even in early stage disease, by real-time RT-PCR. Immunohistochemical analysis of hepatocellular carcinoma clinical samples demonstrated that the tumor regions were significantly more immunoreactive for IMD than adjacent benign liver. Inhibition of IMD expression using RNA interference reduced cell proliferation in SK-Hep-1 and SNU-398 cells. Blockage of IMD signaling using either an antagonist peptide or a neutralizing antibody inhibited growth in a dose-dependent manner with concomitant induction of apoptosis, causing cleavage of caspase-8 and downregulation of Gli1 and Bcl2. Conversely, addition of IMD active peptide increased the phosphorylation level of extracellular signal-regulated kinase. Thus, IMD might play an important role in cell proliferation and survival of hepatocellular carcinoma. Our data suggests that IMD is a potential biomarker and therapeutic target for hepatocellular carcinoma. (Cancer Sci 2012; 103: 1474-1480 H epatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and the third leading cause of cancer death.(1) The majority (>80%) of liver cancers are HCC.Conventional chemotherapy and hormonal therapies have minimal response rates. (3) Therapeutic agents targeting angiogenesis, which is required for tumor growth and metastasis, are currently in development. (4,5) Of the known angiogenic factors, vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic factor and is secreted by nearly all solid cancers.(5) Sorafenib, an inhibitor targeting the VEGF and platelet-derived growth factor receptors, is the standard of care in patients with advanced HCC.(6) Promising novel inhibitors are under investigation.(7) The key to targeting angiogenesis successfully in the future may be to use a combination of multiple inhibitors against multiple targets. Intermedin (IMD, adrenomedullin-2), is a secreted peptide that belongs to the calcitonin/calcitonin gene-related peptide family.(9) IMD regulates diverse physiological processes. For example, IMD is required for rat normal fetoplacental growth, (10) functions as a vasodilator and reduces blood pressure in both normal and hypertensive rats.(11) IMD is expressed in every endocrine organ of the hypothalamo-pituitary-adrenal axis together with its receptor, calcitonin receptor-like receptor (CRLR). (12) The signaling of IMD is mediated by the interaction of CRLR in association with receptor activity modifying protein 3 (RAMP3).(13) IMD is expressed by endothelial cells, smooth muscle cells and cardiomyocytes at a basal leve...

show abstract

Section: Discussionmentioning

confidence: 99%

Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival

et al. 2012

View full text Add to dashboard Cite

show abstract

“…RNA extraction, complementary (c)DNA synthesis and quantitative polymerase chain reaction (qPCR) analysis were performed as previously described (26). Briefly, total RNA was isolated from all the samples using TRIzol ® reagent (Invitrogen Life Technologies, Carlsbad, CA, USA) and dissolved in RNase-free water.…”

Section: Methodsmentioning

confidence: 99%

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

et al. 2015

Self Cite

View full text Add to dashboard Cite

Abstract. The substance P (SP; also known as TAC1)/neurokinin-1 receptor (NK1R; also known as TACR1) complex is a critical part in the development of cancer. Therefore, NK1R antagonists, such as the clinical drug aprepitant, are currently under investigation as future anticancer agents. In a previous study, NK1R (TACR1) was identified as a potent anticancer target in hepatoblastoma (HB). However, little is known regarding the exact distribution of this target among HB subsets and whether it correlates with clinical features and prognosis. In the present study, mRNA was isolated from 47 children with HB, and reverse transcription-quantitative polymerase chain reaction was performed on the samples to analyze the expression of full-length-TACR1 (fl-TACR1) and truncated-TACR1 (tr-TACR1). These data were correlated with data obtained from 9 tumor-free controls, as well as with the presence of metastasis, PRETEXT, vascular invasion, histology, age of diagnosis, multifocality, CTNNB1 mutation, gender and overall survival. Additionally, the present study investigated a recently described 16-gene signature characteri zing HB known to correlate with prognosis. Compared with tumor-free liver tissue, tumorous tissue expressed TACR1 significantly higher for the truncated version (P=0.0301), and by trend also for the full-length version. Accordingly, the expression of fl-TACR1 correlated with the expression of the truncated version (P=0.0074). Furthermore, a low expression of fl-TACR1 correlated with characteristics of the 16-gene signature known to predict prognosis (P=0.0222). However, there was no correlation between tr-TACR1 and the tumor characteristics investigated, including outcome, although a clear trend was observed for some tumor characteristics. The current results reinforced the previously described findings that in HB, tr-TACR1 is overexpressed compared with tumor-free liver tissue. Furthermore, to the best of our knowledge, the present study demonstrated for the first time that tr-TACR1 is expressed ubiquitously among the different subsets of HB. Therefore, NK1R may serve as a potent anticancer target in a large variety of patients with HB, independent of tumor biology and clinical stage.

show abstract

Section: Other Molecular Alterations Described In Hepatoblastomamentioning

confidence: 99%

“…In particular, one study reported an overexpression of hedgehog members GLI1 and PTCH1 in tumors compared to normal liver tissues (54). More impressively, inhibiting this pathway with cyclopamine induced a striking growth inhibition of hepatoblastoma cells (54). On the other hand, when analysing Notch signaling by immunohistochemistry, Litten et al revealed an overexpression of the NOTCH2 receptor in 92% of the tumors compared to normal liver tissues (55).…”

Section: Other Molecular Alterations Described In Hepatoblastomamentioning

confidence: 99%