Dysregulation of growth factor signaling in human hepatocellular carcinoma

Breuhahn, Kai; Longerich, Thomas; Schirmacher, Peter

doi:10.1038/sj.onc.1209556

Cited by 361 publications

(294 citation statements)

References 249 publications

(231 reference statements)

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“…The EGFR signaling pathway may play a role in hepatocarcinogenesis [361]. Expression of transforming growth factor-a, an EGFR ligand, can be induced by hepatitis viral proteins and may act synergistically with viral infection in hepatocarcinogenesis [362][363][364].…”

Section: Anti-egfr Mttmentioning

confidence: 99%

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

et al. 2010

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Introduction The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations. Methods The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements. 123Hepatol Int (2010) 4: 439-474 DOI 10.1007/s12072-010-9165-7 Results Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.

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Section: Anti-egfr Mttmentioning

confidence: 99%

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

et al. 2010

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“…Risk factors for HCC include viral hepatitis B and viral hepatitis C (HCV) infection that activate JAK/ STAT signaling, induce overexpression of insulinlike growth factor-II in 16-40% of HCCs (Breuhahn et al, 2006), and disrupt p53, p55 sen and p21 WAF1/CIP1/SDI1 (Ueda et al, 1995;Feitelson, 1999;Huo et al, 2001). Activation of the Wnt signaling pathway with b-catenin mutations is observed in 17-40% of HCCs and axin-2 inactivation in 3-10% of cases (Taniguchi et al, 2002;Ishizaki et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…While the TGF-b superfamily is composed of more than 40 members, the basic signaling cascade of TGF-b involves type I and type II transmembrane serine/threonine kinase receptors (TBRI and TBRII). Decreases in TBRI and TBRII occur in 50 and 60% of HCCs respectively (Sue et al, 1995;Kiss et al, 1997;Breuhahn et al, 2006). Intracellular signaling occurs through Smads, which are classified into three functional classes: (i) receptoractivated Smads (R-Smads): Smad1, Smad2, Smad3, Smad5 and Smad8; (ii) co-mediator Smads: Smad4; (iii) inhibitory Smads: Smad6 and Smad7 (Derynck et al, 2001;Edamoto et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

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“…26,27 It has been recently shown that the extracellular domain of trimeric TRAIL can be genetically fused by peptide linkers to yield highly active single-chain TRAIL (scTRAIL). This TRAIL version can be further endowed with target-dependent activity by fusion to an Ab derivate recognizing tumor-associated antigens.…”

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confidence: 99%

Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib

et al. 2013

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As the result of an increasing incidence and a prevalent therapy resistance of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis-sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth factor receptor (EGFR) to improve its HCC-targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR-targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR-targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor-free liver tissue, which could even be verified in liver explants from the same individuals. Unlike nontargeted TRAIL, EGFR-targeted TRAIL combined with BZB exerted no toxicity in liver tissues from nonalcoholic fatty liver disease patients. Conclusion: EGFRtargeted TRAIL reveals increased antitumor activity toward HCC without inducing toxicity to tumor-free liver tissue and might therefore represent a promising novel strategy for HCC treatment. (HEPATOLOGY 2013;57:625-636) H epatocellular carcinoma (HCC) is a global health problem with increasing incidence. 1 In western countries, less than 50% of patients are eligible for potential curative treatment, including resection, transplantation, or local ablation. The limited therapeutic options and its resistance to systemic chemotherapy have triggered the search for moleculartargeted therapies for liver cancer. There is evidence of aberrant activation of several signaling cascades, such as the epidermal growth factor receptor (EGFR)/

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Dysregulation of growth factor signaling in human hepatocellular carcinoma

Cited by 361 publications

References 249 publications

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib

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