Angiogenesis and hepatocellular carcinoma

Semela, David; Dufour, Jean–François

doi:10.1016/j.jhep.2004.09.006

Cited by 334 publications

(288 citation statements)

References 207 publications

(208 reference statements)

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“…Our positive results contrast with those of Newell and colleagues, who found no difference in tumor growth with this combination (14). This disparity is perhaps explained by our propitious choice of an orthotopic syngeneic model, which is a closer representation of HCC than the xenograft model chosen by previous investigators (7,14,15) HCC is a hypervascular tumor, relying on angiogenesis for growth (16). Focal hypoxia is a potent angiogenic stimulus and both everolimus and sorafenib treatment regimens exerted their antitumoral effects within a local environment that was subject to such stimuli, as shown by the increased expression of HIF-1a in all treated tumors (Fig.…”

Section: Discussioncontrasting

confidence: 91%

Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Piguet

Saar

Hlushchuk

et al. 2011

Molecular Cancer Therapeutics

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Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2Â/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib.

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Section: Discussioncontrasting

confidence: 91%

Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Piguet

Saar

Hlushchuk

et al. 2011

Molecular Cancer Therapeutics

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“…Hepatocellular carcinoma (HCC) has a characteristic hypervascularity and depends on angiogenesis for tumor growth. 62 Pharmacological inhibition of the serine-threonine kinase mammalian target of rapamycin (mTOR) with sirolimus impairs tumor growth by an antiangiogenic mechanism. [63][64][65] In a rat model of HCC, animals treated with mTOR inhibitors developed smaller tumors, fewer extrahepatic metastases, less ascites, and had a longer survival.…”

Section: Emerging Therapies For Vascular Diseases Of the Livermentioning

confidence: 99%

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

2008

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Portal hypertension and its complications account for the majority of morbidity and mortality that occurs in patients with cirrhosis. In addition to portal hypertension, a number of other vascular syndromes are also of great importance, especially the ischemia-reperfusion (IR) injury. With the identification of major vascular defects that could account for many of the clinical sequelae of these syndromes, the liver vasculature field has now integrated very closely with the broader vascular biology discipline. In that spirit, the Vascular Cell Signaling Mediated by NO. Endothelial cells (ECs) produce NO through the enzyme endothelial NO synthase (eNOS). NO then regulates important vascular functions, such as vascular tone, angiogenesis, and arterial remodeling. 1 eNOS is regulated in a multiprotein complex (Fig. 1), which includes the activating kinase, Akt1 and putative negative regulator caveolin-1 (Cav-1). Although eNOS Ϫ/Ϫ mice evidence impaired angiogenesis, overexpression of a constitutively active allele of eNOS that mimics the phosphorylated and active state rescues these angiogenic defects. 2 Because eNOS is an EC-specific Akt substrate, ECs from mice lacking the Akt1 isoform also have defects in eNOS phosphorylation, NO production, and angiogenesis which are correspondingly rescued by Akt1 overexpression. 3 One key mechanism by which the Akt-eNOS axis promotes angiogenesis in vivo is through mobilization of endothelial progenitor cells and EC migration to sites of vascular injury. In contradistinction to AKT, Cav-1 is a negative regulator of eNOS. Mice deficient in Cav-1 have defective mechanotransduction, calcium signaling, prostacyclin production, and elevated NO production indicating that endothelial Cav-1 also importantly regulates vascular function by regulating eNOS and other signaling pathways. 4 Upon its generation in ECs, NO also acts on adjacent vascular effector cells to modulate vascular tone, cellular proliferation, apoptosis, migration, and synthesis of extracellular matrix (Fig. 2). NO acts in part by stimulating soluble guanylate cyclase (sGC) to produce intracellular Abbreviations: Cav-

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“…Sorafenib works by inhibiting the serine/threonine kinases Raf-1, B-Raf, the receptor tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3 and platelet-derived growth factor receptor β (PDGFR-β) [14,15] . Cellular signaling pathways mediated by Raf-1 and vascular endothelial growth factor (VEGF) have been implicated in the molecular pathogenesis of HCC [16][17][18][19] , providing a rationale for investigating sorafenib for this indication. In preclinical experiments, sorafenib had antiproliferative activity on liver cancer cell lines, and it reduced tumor angiogenesis and tumor-cell signaling.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation

Tan

Qiu

et al. 2010

Acta Pharmacol Sin

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Aim: To determine the efficacy and toxicities of sorafenib in the treatment of patients with multiple recurrences of hepatocellular carcinoma (HCC) after liver transplantation in a Chinese population. Methods: Twenty patients with multiple recurrences of HCC after liver transplantation were retrospectively studied. They received either transarterial chemoembolization (TACE) or TACE combined with sorafenib. Results: The median survival times (MST) after multiple recurrences was 14 months (TACE+sorafenib group) and 6 months (TACE only group). The difference was significant in MST between the two groups (P=0.005). The TACE + sorafenib group had more stable disease (SD) patients than the TACE group. The most frequent adverse events of sorafenib were hand-foot skin reaction and diarrhea. In the univariate analysis, preoperative bilirubin and CHILD grade are found to be significantly associated with tumor-free survival time, the survival time after multiple recurrences and overall survival time. TACE+sorafenib group showed a better outcome than single TACE treatment group. In the multivariate COX regression modeling, the preoperative high CHILD grade was found to be a risk factor of tumor-free survival time. In addition, the preoperative high bilirubin grade was also found to be a risk factor of survival time after recurrence and overall survival time. Furthermore, survival time after recurrence and overall survival time were also associated with therapeutic schedule, which was indicated by the GROUP. Conclusion: Treatment with TACE and sorafenib is worthy of further study and may have more extensive application prospects.

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Angiogenesis and hepatocellular carcinoma

Cited by 334 publications

References 207 publications

Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation

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