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1
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Guo C, Xue H, Guo T, Zhang W, Xuan WQ, Ren YT, Wang D, Chen YH, Meng YH, Gao HL, Zhao P. Recombinant human lactoferrin attenuates the progression of hepatosteatosis and hepatocellular death by regulating iron and lipid homeostasis in ob/ob mice. Food Funct 2020; 11:7183-7196. [PMID: 32756704 DOI: 10.1039/d0fo00910e] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Lactoferrin (Lf), an iron-binding glycoprotein, has been shown to possess antioxidant and anti-inflammatory properties and exert modulatory effects on lipid homeostasis and non-alcoholic fatty liver disease (NAFLD), but our understanding of its regulatory mechanisms is limited and inconsistent. We used leptin-deficient (ob/ob) mice as the rodent model of NAFLD, and administered recombinant human Lf (4 mg per kg body weight) or control vehicle by intraperitoneal injection to evaluate the hepatoprotective effects of Lf. After 40 days of treatment with Lf, insulin sensitivity and hepatic steatosis in ob/ob mice were significantly improved with the down-regulation of sterol regulatory element binding protein-2 (SREBP2), indicating an improvement in hepatic lipid metabolism and function. We further explored the mechanism, and found that Lf may increase the hepatocellular iron output by targeting the hepcidin-ferroportin (FPn) axis, and then maintains the liver oxidative balance through a nonenzymatic antioxidant system, ultimately suppressing the death of hepatocytes. In addition, the cytoprotective role of Lf may be associated with the inhibition of endoplasmic reticulum (ER) stress and inflammation, promotion of autophagy of damaged hepatocytes and induction of up-regulation of hypoxia inducible factor-1α/vascular endothelial growth factor (HIF-lα/VEGF) to facilitate liver function recovery. These findings suggest that recombinant human Lf might be a potential therapeutic agent for mitigating or delaying the pathological process of NAFLD.
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Affiliation(s)
- Chuang Guo
- College of Life and Health Sciences, Northeastern University, No. 195, Chuangxin Road, Hunnan District, Shenyang, 110169, China.
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Yang X, Wang Z, Kai J, Wang F, Jia Y, Wang S, Tan S, Shen X, Chen A, Shao J, Zhang F, Zhang Z, Zheng S. Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis-PROX1-HIF-1α in liver fibrosis. Cell Prolif 2020; 53:e12762. [PMID: 32119185 PMCID: PMC7106966 DOI: 10.1111/cpr.12762] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/13/2019] [Accepted: 12/21/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Hepatic sinusoidal angiogenesis owing to dysfunctional liver sinusoidal endothelial cells (LSECs) accompanied by an abnormal angioarchitecture is a symbol related to liver fibrogenesis, which indicates a potential target for therapeutic interventions. However, there are few researches connecting angiogenesis with liver fibrosis, and the deeper mechanism remains to be explored. MATERIALS AND METHODS Cell angiogenesis and angiogenic protein were examined in primary LSECs of rats, and multifarious cellular and molecular assays revealed the efficiency of curcumol intervention in fibrotic mice. RESULTS We found that curcumol inhibited angiogenic properties through regulating their upstream mediator hypoxia-inducible factor-1α (HIF-1α). The transcription activation of HIF-1α was regulated by hedgehog signalling on the one hand, and the protein stabilization of HIF-1α was under the control of Prospero-related homeobox 1 (PROX1) on the other. A deubiquitinase called USP19 could be recruited by PROX1 and involved in ubiquitin-dependent degradation of HIF-1α. Furthermore, our researches revealed that hedgehog signalling participated in the activation of PROX1 transcription probably in vitro. Besides, curcumol was found to ameliorate liver fibrosis and sinusoid angiogenesis via hedgehog pathway in carbon tetrachloride (CCl4 ) induced liver fibrotic mice. The protein expression of key regulatory factors, PROX1 and HIF-1α, was consistent with the Smo, the marker protein of Hh signalling pathway. CONCLUSIONS In this article, we evidenced that curcumol controlling LSEC-mediated angiogenesis could be a promising therapeutic approach for liver fibrosis.
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Affiliation(s)
- Xiang Yang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Zhimin Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Jun Kai
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Feixia Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Yan Jia
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Shijun Wang
- Shandong University of Traditional Chinese MedicineJinanChina
| | - Shanzhong Tan
- Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjingChina
| | - Xikun Shen
- Suzhou Hospital of Traditional Chinese MedicineSuzhouChina
| | - Anping Chen
- Department of PathologySchool of MedicineSaint Louis UniversitySt. LouisMOUSA
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
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Haldrup D, Heebøll S, Thomsen KL, Andersen KJ, Meier M, Mortensen FV, Nyengaard JR, Hamilton-Dutoit S, Grønbæk H. Preserved liver regeneration capacity after partial hepatectomy in rats with non-alcoholic steatohepatitis. World J Hepatol 2018; 10:8-21. [PMID: 29399274 PMCID: PMC5787687 DOI: 10.4254/wjh.v10.i1.8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 11/20/2017] [Accepted: 12/06/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the liver regeneration capacity (LRC) after partial hepatectomy (PH) in experimental non-alcoholic steatohepatitis (NASH).
METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet (HFCD, 65% fat, 1% cholesterol) or standard diet (STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d post-PH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio (RPR), prothrombin-proconvertin ratio (PP), and mRNA expression of genes related to regeneration.
RESULTS The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline (P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH (P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline, (P < 0.0001), day 2 after PH (P = 0.06) and day 5 after PH (P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes (e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups (P < 0.05).
CONCLUSION NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.
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Affiliation(s)
- David Haldrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
- Department of Internal Medicine, Randers Regional Hospital, Randers NØ DK-8930, Denmark
| | - Sara Heebøll
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | | | - Michelle Meier
- Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | - Frank Viborg Mortensen
- Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | - Jens Randel Nyengaard
- Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | | | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
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Alizai PH, Bertram L, Kroy D, Kummer J, Andert A, Neumann UP, Ulmer TF, Fragoulis A. Expression of VEGFR-2 during Liver Regeneration after Partial Hepatectomy in a Bioluminescence Mouse Model. Eur Surg Res 2017; 58:330-340. [PMID: 29073598 DOI: 10.1159/000479628] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 07/19/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver regeneration requires the formation of new blood vessels. Endothelial cell proliferation is stimulated by vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2. The aim of this study was to investigate VEGFR-2 expression in vivo during liver regeneration after partial hepatectomy (PHx). METHODS Transgenic VEGFR-2-luc mice were used in which the luciferase reporter gene was under control of the VEGFR-2 promoter. Following 2/3 PHx, the mice underwent in vivo bioluminescence imaging until the 14th postoperative day. Additionally, liver tissue was analyzed by immunohistochemistry, in vitro luminescence assays, and quantitative RT-PCR. RESULTS In vivo bioluminescence imaging showed a significant increase in VEGFR-2 promoter activity after PHx. Maximum signal was recorded on the 3rd day; 8 days postoperatively the signal intensity decreased significantly. On the 14th day, bioluminescence signal reached almost baseline levels. Immunohistochemistry, quantitative RT-PCR, and in vitro luminescence confirmed a significant increase on the 3rd day following resection. The mRNA expression of VEGFR-2 was significantly higher on day 3 than preoperatively as well as on day 8. CONCLUSION In vivo bioluminescence imaging with transgenic VEGFR-2-luc mice is feasible and provides a convenient model for noninvasively studying VEGFR-2 expression during liver regeneration. This may facilitate further experiments with modulation of angiogenesis by different substances.
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Affiliation(s)
- Patrick Hamid Alizai
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Lea Bertram
- Department of Surgery, Luisenhospital Aachen, Aachen, Germany.,Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, Aachen, Germany
| | - Daniela Kroy
- Department of Gastroenterology and Metabolic Disorders, RWTH Aachen University Hospital, Aachen, Germany
| | - Julia Kummer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.,Department of Gynaecology and Obstetrics, Vivantes Clinic Berlin, Berlin, Germany
| | - Anne Andert
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Tom Florian Ulmer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Athanassious Fragoulis
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.,Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, Aachen, Germany
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5
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Detection of piRNAs in whitespotted bamboo shark liver. Gene 2016; 590:51-6. [PMID: 27267405 DOI: 10.1016/j.gene.2016.06.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 05/20/2016] [Accepted: 06/03/2016] [Indexed: 01/12/2023]
Abstract
Piwi-interacting RNAs (piRNAs) are 26 to 31-nt small non-coding RNAs that have been reported mostly in germ-line cells and cancer cells. However, the presence of piRNAs in the whitespotted bamboo shark liver has not yet been reported. In a previous study of microRNAs in shark liver, some piRNAs were detected from small RNAs sequenced by Solexa technology. A total of 4857 piRNAs were predicted and found in shark liver. We further selected 17 piRNAs with high and significantly differential expression between normal and regenerative liver tissues for subsequent verification by Northern blotting. Ten piRNAs were further identified, and six of these were matched to known piRNAs in piRNABank. The actual expression of six known and four novel piRNAs was validated by qRT-PCR. In addition, a total of 401 target genes of the 10 piRNAs were predicted by miRanda. Through GO and pathway function analyses, only five piRNAs could be annotated with eighteen GO annotations. The results indicated that the identified piRNAs are involved in many important biological responses, including immune inflammation, cell-specific differentiation and development, and angiogenesis. This manuscript provides the first identification of piRNAs in the liver of whitespotted bamboo shark using Solexa technology as well as further elucidation of the regulatory role of piRNAs in whitespotted bamboo shark liver. These findings may provide a useful resource and may facilitate the development of therapeutic strategies against liver damage.
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6
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Xue H, Chen D, Zhong Y, Zhou Z, Fang S, Li M, Guo C. Deferoxamine ameliorates hepatosteatosis via several mechanisms in
ob/ob
mice. Ann N Y Acad Sci 2016; 1375:52-65. [DOI: 10.1111/nyas.13174] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/31/2016] [Accepted: 06/14/2016] [Indexed: 01/12/2023]
Affiliation(s)
- Han Xue
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Di Chen
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Yan‐Ke Zhong
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Zhen‐Diao Zhou
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Shi‐Xin Fang
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Ming‐Yao Li
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Chuang Guo
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
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7
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Impact of Bevacizumab on parenchymal damage and functional recovery of the liver in patients with colorectal liver metastases. BMC Cancer 2016; 16:84. [PMID: 26864935 PMCID: PMC4750178 DOI: 10.1186/s12885-016-2095-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 01/28/2016] [Indexed: 01/04/2023] Open
Abstract
Background Little is known about the safety of the anti-VEGF antibody bevacizumab in patients undergoing resection for colorectal liver metastases (CLM). This meta-analysis evaluates the impact of bevacizumab on parenchymal damage and functional recovery in patients undergoing resection for CLM. Methods The Medline, Embase and Cochrane Library were systematically searched for studies on preoperative chemotherapy with and without bevacizumab prior to resection of CLM. Studies that reported histological and/or clinical outcomes were eligible for inclusion. Meta-analyses were performed using a random effects model. Results A total of 18 studies with a total sample size of 2430 patients (1050 patients with bevacizumab) were found. Meta-analyses showed a significant reduction in sinusoidal obstruction syndrome (SOS) (Odds ratio 0.50 [95 % confidence interval 0.37, 0.67]; p < 0.001; I2 = 0 %) and hepatic fibrosis (0.61 [0.4, 0.86]; p = 0.004; I2 = 7 %) after preoperative chemotherapy with bevacizumab. The reduced incidence of posthepatectomy liver failure in patients with bevacizumab treatment just failed to reach statistical significance (0.61 [0.34, 1.07]; p = 0.08 I2 = 6 %). While there was no difference in perioperative morbidity and mortality, the incidence of wound complications was significantly increased in patients who received bevacizumab (1.81 [1.12, 2.91]; p = 0.02 I2 = 4 %). Conclusions The combination of bevacizumab with cytotoxic chemotherapy is safe but increases the incidence of wound complications after resection of CLM. The reduction of SOS and hepatic fibrosis warrant further investigation and may explain the inverse association of bevacizumab administration and posthepatectomy liver failure. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2095-6) contains supplementary material, which is available to authorized users.
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8
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Zwingenberger AL, Daniel L, Steffey MA, Mayhew PD, Mayhew KN, Culp WTN, Hunt GB. Correlation Between Liver Volume, Portal Vascular Anatomy, and Hepatic Perfusion in Dogs With Congenital Portosystemic Shunt Before and After Placement of Ameroid Constrictors. Vet Surg 2014; 43:926-34. [DOI: 10.1111/j.1532-950x.2014.12193.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2013] [Accepted: 11/01/2013] [Indexed: 12/21/2022]
Affiliation(s)
- Allison L. Zwingenberger
- Department of Surgical and Radiological Sciences; School of Veterinary Medicine; University of California, Davis; Davis California
| | - Leticia Daniel
- Department of Surgical and Radiological Sciences; School of Veterinary Medicine; University of California, Davis; Davis California
| | - Michele A. Steffey
- Department of Surgical and Radiological Sciences; School of Veterinary Medicine; University of California, Davis; Davis California
| | - Philipp D. Mayhew
- Department of Surgical and Radiological Sciences; School of Veterinary Medicine; University of California, Davis; Davis California
| | - Kelli N. Mayhew
- Department of Surgical and Radiological Sciences; School of Veterinary Medicine; University of California, Davis; Davis California
| | - William T. N. Culp
- Department of Surgical and Radiological Sciences; School of Veterinary Medicine; University of California, Davis; Davis California
| | - Geraldine B. Hunt
- Department of Surgical and Radiological Sciences; School of Veterinary Medicine; University of California, Davis; Davis California
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9
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Abstract
Angiogenesis, defined as the formation of new microvasculature from preexisting blood vessels and mature endothelial cells, plays a major role in wound healing and scar formation, and it is associated with inflammatory responses. Angiogenesis can occur in physiological conditions, such as during liver regeneration, and in pathological situations, such as during the progression of fibrosis to cirrhosis and also during tumor angiogenesis. Cellular cross-talk among liver sinusoidal endothelial cells (LSECs), hepatic stellate cells and hepatocytes is believed to play an important role in the angiogenesis process during both liver regeneration and development of cirrhosis. In addition to mature endothelial cells, bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) have been recently identified for their contribution to post-natal vasculogenesis/angiogenesis. In vivo, EPCs are mobilized into the peripheral blood in response to tissue ischemia or traumatic injury, migrate to the sites of injured endothelium and differentiate into mature endothelial cells. In our recent studies, we have explored the role of EPC-mediated angiogenesis in liver regeneration and/or cirrhosis. Results have demonstrated significantly increased endogenous levels of circulating EPCs in cirrhotic patients in comparison to the controls. Also, EPCs from cirrhotic patients have been observed to stimulate substantial angiogenesis by resident LSECs in vitro via paracrine factors such as vascular endothelial growth factor and platelet-derived growth factor. This review gives an overview of the angiogenesis process in liver regeneration and disease and discusses a new mechanism for intrahepatic angiogenesis mediated by BM-derived EPCs.
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Affiliation(s)
- Savneet Kaur
- School of Biotechnology, Gautam Buddha University, Greater Noida, 201312, UP, India.
| | - K Anita
- School of Biotechnology, Gautam Buddha University, Greater Noida, 201312, UP, India
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10
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Volumetric Gain of the Liver after Major Hepatectomy in Obese Patients. Ann Surg 2013; 258:696-702; discussion 702-4. [DOI: 10.1097/sla.0b013e3182a61a22] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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11
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Gelu-Simeon M, Samuel D. Role of cytokine levels in assessment of prognosis and post-treatment outcome in hepatocellular carcinoma. Hepatol Int 2013. [PMID: 26201913 DOI: 10.1007/s12072-013-9441-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Moana Gelu-Simeon
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, 94800, Villejuif, France.
| | - Didier Samuel
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, 94800, Villejuif, France. .,INSERM, U785, 94800, Villejuif, France. .,Faculté de Médecine, Université Paris-Sud, 94270, Le Kremlin-Bicêtre, France.
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12
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Stöppeler S, Palmes D, Fehr M, Hölzen JP, Zibert A, Siaj R, Schmidt HHJ, Spiegel HU, Bahde R. Gender and strain-specific differences in the development of steatosis in rats. Lab Anim 2013; 47:43-52. [PMID: 23467489 DOI: 10.1177/0023677212473717] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common problem with a wide variety of phenotypes. While its pathogenesis is still not fully understood, several risk factors for disease progression have been identified. Therefore, defining adequate animal models may serve to unreveal the pathogenesis in NAFLD. We studied Lewis and Sprague-Dawley rats of both genders (n = 6) fed standard (Std) or high-fat (HF) diet for three weeks. Disease stage was assessed by haematoxylin-eosin, Azan Heidenheim and Oil-Red staining, apoptosis by single-stranded DNA (ssDNA) detection and liver regeneration by Ki-67 staining. Serum markers of liver injury and lipid metabolism including adipocytokines were analysed. Livers of both strains and genders fed with HF diet demonstrated evidence of steatosis. Lewis rats developed microvesicular steatosis whereas Sprague-Dawley rats presented macrovesicular steatosis accompanied by pronounced fibrosis. Female gender of both strains was associated with lower steatosis grade and higher proliferation rate (P < 0.05). Gender-specific differences were most prominent in Lewis rats on a HF diet, where females showed lower alkaline phosphatase, cholesterol, triglyceride and leptin levels and a more favourable low-density lipoprotein/high-density lipoprotein ratio than males (P < 0.05). Reverse transcriptase-polymerase chain reaction analysis was performed to demonstrate changes in expression of various genes important for liver regeneration, fibrosis and steatosis. HF diet induced downregulation of proangiogenic genes such as vascular endothelial growth factor receptor 1 and 2 (P < 0.05) in males was not present in females. In conclusion, strain and gender served major roles in disease progression. These differences should be considered when designing studies and may offer new ways to advance therapeutic strategies.
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Affiliation(s)
- S Stöppeler
- Surgical Research, Department of General and Visceral Surgery, Muenster University Hospital, Muenster, Germany
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13
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Bönninghoff R, Schwenke K, Keese M, Magdeburg R, Bitter-Suermann H, Otto M, Hasenberg T, Post S, Sturm J. Effect of different liver resection methods on liver damage and regeneration factors VEGF and FGF-2 in mice. Can J Surg 2013; 55:389-93. [PMID: 22992401 DOI: 10.1503/cjs.007911] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Different approaches to study liver regeneration in murine models have been proposed. We investigated the effect of different liver resection models on liver damage and regeneration parameters in mice. METHODS We compared the technical aspect of the 2 most commonly used techniques of 50% and 70% liver resection. Liver damage, as determined by the change in serum alanine aminotransferase and aspartate aminotransferase, as well as the regeneration parameters VEGF and FGF-2 were analyzed at 6 time points. A postoperative vitality score was introduced. RESULTS Cholestasis was not observed for either technique. Both resection techniques resulted in full weight recovery of the liver after 240 hours, with no significant difference between sham and resection groups. Postoperative animal morbidity and total protein levels did not differ significantly for either method, indicating early and full functional recovery. However, comparing the mitogenic growth factors FGF-2 and VEGF, a significant increase in serum levels and, therefore, increased growth stimulus, was shown in the extended resection group. CONCLUSION Extended resection led to a greater response in growth factor expression. This finding is important since it shows that growth factor response differs acdording to the extent of resection. We have demonstrated the need to standardize murine hepatic resection models to adequately compare the resulting liver damage.
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Affiliation(s)
- Roderich Bönninghoff
- The Department of Surgery, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Heidelberg, Germany
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14
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Role of resident liver cells in the pathogenesis of schistosomiasis. Trends Parasitol 2012; 28:572-9. [PMID: 23099112 DOI: 10.1016/j.pt.2012.09.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2012] [Revised: 09/14/2012] [Accepted: 09/21/2012] [Indexed: 12/12/2022]
Abstract
Pathology in schistosomiasis occurs as a result of eggs deposited in the liver by the schistosome parasite. A granulomatous reaction occurs, resulting in portal hypertension and hepatic fibrosis. Resident non-parenchymal cells within the liver take part in this process, including hepatic stellate cells, which are responsible for collagen production, and Kupffer cells, the liver macrophages involved in both host protection and in pathology. Other cells such as liver sinusoidal endothelial cells or portal fibroblasts may also be involved in this process. This review discusses the possible role of these resident liver cells in the pathology associated with schistosomiasis and provides information which may assist our understanding of the mechanisms associated with chronic liver disease in general.
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15
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Affiliation(s)
- Cristina E Carnovale
- Instituto de Fisiología Experimental-CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570-2000 Rosario, Argentina.
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16
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van der Pool AEM, Marsman HA, Verheij J, Ten Kate FJ, Eggermont AMM, Ijzermans JNM, Verhoef C. Effect of bevacizumab added preoperatively to oxaliplatin on liver injury and complications after resection of colorectal liver metastases. J Surg Oncol 2012; 106:892-7. [PMID: 22552819 DOI: 10.1002/jso.23142] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 04/09/2012] [Indexed: 01/08/2023]
Abstract
BACKGROUND Chemotherapy (CTx) before resection of colorectal liver metastases (CRLM) may cause hepatic injury and postoperative complications. To ascertain whether adding bevacizumab, a monoclonal antibody against VEGF, to oxaliplatin-based CTx has an influence on liver injury and postoperative complications. METHODS Patients with CRLM who received neoadjuvant CTx and underwent resection between 2003 and 2008 were analyzed whether or not they received bevacizumab added to oxaliplatin-based CTx. RESULTS The total study group existed of 104 patients: 53 patients received oxaliplatin-based CTx and 51 patients received oxaliplatin-based CTx and bevacizumab. The overall complication rate (29%) was not significantly different between the two groups. The bevacizumab group exhibited less moderate sinusoidal dilatation (8% vs. 28%, P = 0.01). No difference in complication rate was found between patients given fewer than six cycles of oxaliplatin-based CTx and those given six or more cycles, or between patients with a short (<5 weeks) interval between the last dose of oxaliplatin and resection and those in which the interval was longer. CONCLUSION Bevacizumab added to oxaliplatin-based CTx may protect against moderate sinusoidal dilatation without significantly influencing morbidity. Neither duration of oxaliplatin-based CTx nor the time interval between cessation of oxaliplatin-based CTx and surgery were associated with postoperative complications.
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Affiliation(s)
- Anne E M van der Pool
- Division of Surgical Oncology, Erasmus University MC, Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands
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Dill MT, Rothweiler S, Djonov V, Hlushchuk R, Tornillo L, Terracciano L, Meili-Butz S, Radtke F, Heim MH, Semela D. Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterology 2012; 142:967-977.e2. [PMID: 22245843 DOI: 10.1053/j.gastro.2011.12.052] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Revised: 12/07/2011] [Accepted: 12/29/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Notch signaling mediates embryonic vascular development and normal vascular remodeling; Notch1 knockout mice develop nodular regenerative hyperplasia (NRH). The pathogenesis of NRH is unclear, but has been associated with vascular injury in the liver sinusoids in clinical studies. We investigated the role of Notch1 signaling in liver sinusoidal endothelial cells (LSECs). METHODS We studied MxCre Notch1(lox/lox) mice (conditional knockout mice without tissue-specific disruption of Notch1); mice with hepatocyte-specific knockout were created by crossing Notch1(lox/lox) with AlbCre(+/-) mice. Portal vein pressure was measured; morphology of the hepatic vasculature was assessed by histologic and scanning electron microscopy analyses. We performed functional and expression analyses of isolated liver cells. RESULTS MxCre-induced knockout of Notch1 led to NRH, in the absence of fibrosis, with a persistent increase in proliferation of LSECs. Notch1 deletion led to de-differentiation, vascular remodeling of the hepatic sinusoidal microvasculature, intussusceptive angiogenesis, and dysregulation of ephrinB2/EphB4 and endothelial tyrosine kinase. Time-course experiments revealed that vascular changes preceded node transformation. MxCre Notch1(lox/lox) mice had reduced endothelial fenestrae and developed portal hypertension and hepatic angiosarcoma over time. In contrast, mice with hepatocyte-specific disruption of Notch1 had a normal phenotype. CONCLUSIONS Notch1 signaling is required for vascular homeostasis of hepatic sinusoids; it maintains quiescence and differentiation of LSECs in adult mice. Disruption of Notch1 signaling in LSECs leads to spontaneous formation of angiosarcoma, indicating its role as a tumor suppressor in the liver endothelium.
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Affiliation(s)
- Michael T Dill
- Department of Biomedicine, University Basel, Basel, Switzerland
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18
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Nath B, Szabo G. Hypoxia and hypoxia inducible factors: diverse roles in liver diseases. HEPATOLOGY (BALTIMORE, MD.) 2012. [PMID: 22120903 DOI: 10.1002/hep.25497]] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models.
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Affiliation(s)
- Bharath Nath
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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19
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Abstract
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models.
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Affiliation(s)
- Bharath Nath
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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20
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Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease. J Transl Med 2011; 91:283-93. [PMID: 20956972 DOI: 10.1038/labinvest.2010.166] [Citation(s) in RCA: 154] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an emerging disease with a broad spectrum of liver conditions. The complex molecular pathogenesis of NAFLD is still unclear. In this study, we conducted an analysis of microRNA (miRNA) expression profiles in liver of rats made NAFLD by different diets. To this aim, Sprague-Dawley rats were fed ad libitum for 3 months with different diets: standard diet (SD), diet enriched in fats and low in carbohydrates (HFD), SD with high fructose (SD-HF) and diet with high levels of fats and fructose (HFD-HF). Our results demonstrated that the treatment with different dietetic regimens caused a significant increase of the body weight and the alteration of some metabolic parameters compared with control animals, as well as various liver injuries. The miRNAs analysis showed the significant downregulation of three miRNAs (miR-122, miR-451 and miR-27) and the upregulation of miR-200a, miR-200b and miR-429 in HFD, SD-HF and HFD-HF rats. Besides, miR-21 expression was significantly decreased only in fructose-enriched diets. These miRNAs target molecules involved in the control of lipid and carbohydrate metabolism, signal transduction, cytokine and chemokine-mediated signaling pathway and apoptosis. Western blot analysis of PKCδ, LITAF, ALDOLASE-A, p38MAPK, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 showed a diet-induced deregulation of all these proteins. Interestingly, the expression pattern of LITAF, PTEN, LIPIN1, EPHRIN-A1, EPHA2 and FLT1 might be well explained by the trend of their specific mRNAs, by potentially regulatory miRNAs, or both. In conclusion, we highlight for the first time the potential involvement of novel determinants (miRNAs and proteins) in the molecular pathogenesis of diet-induced NAFLD.
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Hora C, Romanque P, Dufour JFF. Effect of sorafenib on murine liver regeneration. Hepatology 2011; 53:577-86. [PMID: 21274878 DOI: 10.1002/hep.24037] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Accepted: 09/28/2010] [Indexed: 02/05/2023]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is a common cause of cancer-related death. Sorafenib prolongs survival of patients with advanced disease and is approved for the systemic treatment of unresectable HCC. It possesses antiangiogenic and antiproliferative properties by way of inhibition of the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor-beta 1/2 (PDGFR-β) and the kinase RAF. Sorafenib represents a candidate compound for adjuvant therapy in HCC patients. The aim of our study was to investigate whether sorafenib affects liver regeneration. C57BL6 mice received sorafenib orally at 30 mg/kg/day or its vehicle either for 14 days until the day before hepatectomy or starting the day after surgery or both. Animals were sacrificed 24, 72, and 120 hours after hepatectomy. Liver regeneration was calculated as a percent of initial liver weight. Bromodeoxyuridine (BrdU) incorporation and phospho-extracellular signal-regulated kinase (pERK1/2) were determined by immunohistochemistry on liver sections. VEGF-A, PDGF-BB, and hepatocyte growth factor (HGF) levels were measured in liver tissue homogenates. Histological analysis of scar tissue was performed. Treatment stopped 1 day before surgery had no impact on liver regeneration. Continuous sorafenib treatment and treatment started 1 day after surgery had statistically significant effects on liver regeneration at 120 hours compared to vehicle-treated control animals (72% ± 12 versus control 88% ± 15 and 70% ± 13 versus control 86% ± 5 at 120 hours, both P ≤ 0.02). BrdU incorporation showed decreased numbers of positive nuclei in both groups receiving sorafenib after surgery. Phospho-ERK levels were reduced in sorafenib-treated animals. An increase of VEGF-A levels was observed in mice receiving sorafenib. Wound-healing complications were observed in animals receiving sorafenib after surgery and confirmed on histological sections. CONCLUSION This preclinical study shows that sorafenib did not impact on liver regeneration when ceased before surgery; however, administration after hepatectomy affected late liver regeneration.
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Affiliation(s)
- Caroline Hora
- Department of Clinical Research, University of Bern, Switzerland
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22
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Böhm F, Köhler UA, Speicher T, Werner S. Regulation of liver regeneration by growth factors and cytokines. EMBO Mol Med 2010; 2:294-305. [PMID: 20652897 PMCID: PMC3377328 DOI: 10.1002/emmm.201000085] [Citation(s) in RCA: 209] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The capability of the liver to fully regenerate after injury is a unique phenomenon essential for the maintenance of its important functions in the control of metabolism and xenobiotic detoxification. The regeneration process is histologically well described, but the genes that orchestrate liver regeneration have been only partially characterized. Of particular interest are cytokines and growth factors, which control different phases of liver regeneration. Historically, their potential functions in this process were addressed by analyzing their expression in the regenerating liver of rodents. Some of the predicted roles were confirmed using functional studies, including systemic delivery of recombinant growth factors, neutralizing antibodies or siRNAs prior to liver injury or during liver regeneration. In particular, the availability of genetically modified mice and their use in liver regeneration studies has unraveled novel and often unexpected functions of growth factors, cytokines and their downstream signalling targets in liver regeneration. This review summarizes the results obtained by functional studies that have addressed the roles and mechanisms of action of growth factors and cytokines in liver regeneration after acute injury to this organ.
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Affiliation(s)
- Friederike Böhm
- Department of Biology, Institute of Cell Biology, ETH Zurich, Zurich, Switzerland
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23
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Kobayashi A, Miyagawa S. Advances in therapeutics for liver metastasis from colorectal cancer. World J Gastrointest Oncol 2010; 2:380-9. [PMID: 21160889 PMCID: PMC2999674 DOI: 10.4251/wjgo.v2.i10.380] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Revised: 09/15/2010] [Accepted: 09/22/2010] [Indexed: 02/05/2023] Open
Abstract
The evolution of chemotherapeutic regimens that include targeted molecular agents has resulted in a breakthrough in the management of advanced colorectal liver metastasis (CLM), improving the progression-free survival after liver resection, and rendering initially unresectable liver tumors resectable, with reported resection rates ranging from 13% to 51%. In addition, the criteria used for selecting patients for hepatectomy have been expanding because of advances in surgical techniques and improvements in chemotherapy. However, the increasing use of chemotherapy has raised concern about potential hepatotoxicities such as steatosis, chemotherapy-associated steatohepatitis, and sinusoidal obstruction syndrome, and their deleterious effects on postoperative outcome. The present review focuses on the advantages and disadvantages of chemotherapy, strategies for the prevention and diagnosis of chemotherapy-associated liver injury, and the adoption of more aggressive surgical approaches, which have changed the traditional paradigm for CLM.
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Affiliation(s)
- Akira Kobayashi
- Akira Kobayashi, Shinichi Miyagawa, First Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
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24
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Tarantino G, Savastano S, Colao A. Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World J Gastroenterol 2010; 16:4773-4783. [PMID: 20939105 PMCID: PMC2955246 DOI: 10.3748/wjg.v16.i38.4773] [Citation(s) in RCA: 162] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2010] [Revised: 06/15/2010] [Accepted: 06/22/2010] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), a further expression of metabolic syndrome, strictly linked to obesity and diabetes mellitus, is characterized by insulin resistance (IR), elevated serum levels of free fatty acids and fatty infiltration of the liver, which is known as hepatic steatosis. Hepatocyte apoptosis is a key feature of this disease and correlates with its severity. Free-fatty-acid-induced toxicity represents one of mechanisms for the pathogenesis of NAFLD and hormones, growth factors and adipokines influence also play a key role. This review highlights the various pathways that contribute to the development of hepatic steatosis. Circulating concentrations of inflammatory cytokines are reckoned to be the most important factor in causing and maintaining IR. Low-grade chronic inflammation is fundamental in the progression of NAFLD toward higher risk cirrhotic states.
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25
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Shergill U, Das A, Langer D, Adluri R, Maulik N, Shah VH. Inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration. Am J Physiol Regul Integr Comp Physiol 2010; 298:R1279-87. [PMID: 20421635 DOI: 10.1152/ajpregu.00836.2009] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Angiogenesis occurs through a convergence of diverse signaling mechanisms with prominent pathways that include autocrine effects of endothelial nitric oxide (NO) synthase (eNOS)-derived NO and vascular endothelial growth factor (VEGF). However, the redundant and distinct roles of NO and VEGF in angiogenesis remain incompletely defined. Here, we use the partial hepatectomy model in mice genetically deficient in eNOS to ascertain the influence of eNOS-derived NO on the angiogenesis that accompanies liver regeneration. While sinusoidal endothelial cell (SEC) eNOS promotes angiogenesis in vitro, surprisingly the absence of eNOS did not influence the angiogenesis that occurs after partial hepatectomy in vivo. While this observation could not be attributed to induction of alternate NOS isoforms, it was associated with induction of VEGF signaling as evidenced by enhanced levels of VEGF ligand in regenerating livers from mice genetically deficient in eNOS. However, surprisingly, mice that were genetically heterozygous for deficiency in the VEGF receptor, fetal liver kinase-1, also maintained unimpaired capacity for liver regeneration. In summary, inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration, indicating signaling redundancies that allow liver regeneration to continue in the absence of this canonical vascular pathway.
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Affiliation(s)
- U Shergill
- Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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26
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Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration. Hepatol Int 2010; 4:537-47. [PMID: 21063476 DOI: 10.1007/s12072-010-9192-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2010] [Accepted: 07/09/2010] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is naturally resistant to radiotherapy and cytotoxic chemotherapy, leaving surgery as the mainstream therapeutic approach. However, the 5-year recurrence rate after curative resection is as high as 61.5%. The background hepatitis B- or C-induced cirrhosis and the presence of micrometastases at the time of surgery have been regarded as two main causes of recurrence. Recently, accumulating evidence suggests that growth factors and cytokines released during the physiological process of post-surgical liver regeneration could induce the activation of dormant micrometastatic lesions. The establishment of neovasculature to support either liver regeneration or HCC growth involves multiple cell types including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and circulating endothelial progenitors. The crosstalks among these cells are driven by multiple molecules and signaling pathways, including vascular endothelial growth factors and their receptors, platelet-derived growth factor, the angiopoietin/Tie family, hepatocyte growth factor/c-Met signaling, and others. Anti-angiogenic agent targeting liver cancer vasculature has been reported to be able to generate limited survival benefit of the patients. In this review, discussions are focused on various angiogenic mechanisms of HCC and liver regeneration, as well as the prevailing anti-angiogenic strategies.
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Abstract
AIM Patients with colorectal cancer and liver metastases can benefit from preoperative chemotherapy and liver disease resection. Adjunction of bevacizumab (BV) to chemotherapy improves survival in these patients, but its impact on surgical complications remains to be fully determined. METHODS We reviewed all studies addressing mortality and morbidity following hepatectomy in patients preoperatively treated with a combination of BV and chemotherapy. RESULTS All available data are retrospective. For all patients, the interval between BV and surgery was at least one month. As compared to chemotherapy alone, they demonstrate no significant increase of the incidence of surgical complications, including wound healing delays, hepatocellular insufficiency, infections, and bleeding. CONCLUSION We still recommend managing an interval of at least 6 weeks from discontinuation of bevacizumab to hepatic resection, and at least 4 weeks from surgery to retreatment with bevacizumab. This recommendation is based on retrospective data and small numbers of patients, all indicating that BV use has no deleterious impact on postoperative morbidity and mortality.
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Affiliation(s)
- P Mariani
- Unité de chirurgie digestive, Institut Curie, 26, rue d'Ulm, 75248 Paris cedex 05, France.
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28
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Mahfud M, Breitenstein S, El-Badry AM, Puhan M, Rickenbacher A, Samaras P, Pessaux P, Lopez-Ben S, Jaeck D, Figueras J, Alain-Clavien P. Impact of preoperative bevacizumab on complications after resection of colorectal liver metastases: case-matched control study. World J Surg 2010; 34:92-100. [PMID: 19838754 DOI: 10.1007/s00268-009-0251-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Chemotherapy may increase postoperative morbidity and mortality after liver surgery. Especially bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), could have a detrimental effect. To assess the impact of neoadjuvant bevacizumab on clinical outcome after hepatectomy for colorectal liver metastases (CRLMs) this case-matched control study was initiated. METHODS The multicentric data collection was performed in the Swiss HPB Center of the University Hospital Zurich (CH), the Department of Digestive Surgery and Transplantation Strasbourg (F), and the Division of Hepato-biliary-pancreatic surgery of "Josep Tureta" Hospital Girona (E). Consecutive patients operated onbetween July 2005 and December 2007 due to CRLMs who received neoadjuvant chemotherapy were assessed. Patients were divided in two groups: group A had neoadjuvant chemotherapy with bevacicumab, and group B had it without bevacizumab. RESULTS No differences in overall morbidity (56 vs. 40% in the bevacizumab and control groups, respectively, p = 0.23) or mortality could be documented. Similarly, the incidence of severe postoperative complications was not statistically different between the bevacizumab and control groups (31 and 18%, respectively, p = 0.31). Wound complications were comparable (11% in the bevacizumab group compared and 9% in the control group, p = 1.00). However, bevacizumab was associated with a significantly decreased incidence of postoperative hepatic insufficiency (7 vs. 20%, p = 0.03). CONCLUSIONS No impact on the incidence or severity of complications by bevacizumab could be shown. Bevacizumab may even reduce the incidence of liver failure after liver surgery.
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Affiliation(s)
- Mahfud Mahfud
- Department of Surgery, Swiss HPB (Hepato-Pancreatico-Biliary) Center, University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland
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Hepatic Toxicities Associated with the Use of Preoperative Systemic Therapy in Patients with Metastatic Colorectal Adenocarcinoma to the Liver. Oncologist 2009; 14:1095-105. [DOI: 10.1634/theoncologist.2009-0152] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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30
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How to integrate biologicals in the continuum of care. Eur J Cancer 2009; 45 Suppl 1:57-69. [DOI: 10.1016/s0959-8049(09)70017-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Atta HM, Al-Hendy A, Salama SA, Shaker OG, Hammam OA. Low-dose simultaneous delivery of adenovirus encoding hepatocyte growth factor and vascular endothelial growth factor in dogs enhances liver proliferation without systemic growth factor elevation. Liver Int 2009; 29:1022-30. [PMID: 19515220 DOI: 10.1111/j.1478-3231.2009.02056.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) gene transfer proved to enhance liver regeneration. However, elevation of their plasma levels may induce potentially serious distant effects such as tumorigenesis or proliferative retinopathy. AIMS This study was performed to examine whether simultaneous administration of low-dose adenovirus encoding HGF and VEGF genes in dogs will stimulate liver proliferation but without inducing liver toxicity or systemic elevation of HGF and VEGF levels. METHODS Adult dogs received an intravenous injection of low-dose adenoviral vectors encoding human HGF and VEGF (HGF/VEGF), beta-galactosidase (lacZ) or phosphate-buffered saline (PBS). Liver proliferation was measured using the proliferating cell nuclear antigen (PCNA) immunostaining labelling index. HGF and VEGF plasma concentrations and transaminases were repeatedly measured. Transgene expression was evaluated using reverse-transcription polymerase chain reaction. RESULTS Human HGF and VEGF expressions were detected only in the liver of HGF/VEGF dogs at day 2 after injection but declined at sacrifice (day 7). No expression was detected in the liver of the lacZ or PBS groups. Plasma levels of HGF and VEGF were not statistically different from those in the lacZ group (P=0.81, P=0.22 respectively). The PCNA labelling index was five-fold higher in the HGF/VEGF group compared with the lacZ group (P<0.01). No immunostaining was detected in the PBS group. Transaminases were only elevated (P<0.01) in the lacZ group compared with the other groups. CONCLUSIONS We showed that simultaneous administration of low-dose adenoviral vectors encoding human HGF and VEGF genes can induce transgene expression and liver proliferation without liver toxicity or systemic growth factor elevation.
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Affiliation(s)
- Hussein M Atta
- Department of Surgery, Faculty of Medicine, Minia University, Minia, Egypt.
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Aussilhou B, Dokmak S, Faivre S, Paradis V, Vilgrain V, Belghiti J. Preoperative liver hypertrophy induced by portal flow occlusion before major hepatic resection for colorectal metastases can be impaired by bevacizumab. Ann Surg Oncol 2009; 16:1553-9. [PMID: 19363584 DOI: 10.1245/s10434-009-0447-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Revised: 11/28/2008] [Accepted: 11/29/2008] [Indexed: 12/15/2022]
Abstract
BACKGROUND This prospective study evaluated the effect of bevacizumab on the hypertrophy of the future liver remnant (FLR) after portal vein occlusion (PVO) before major hepatectomy for colorectal liver metastases. METHODS Twenty-seven patients with colorectal liver metastases treated with preoperative FOLFOX/FOLFIRI chemotherapy regimen since 2002 were evaluated for the degree of hypertrophy of the FLR after right PVO. The results were compared with a similar group of 13 patients treated since 2006 with a chemotherapeutic regimen including bevacizumab and PVO. The FLR was measured by volumetric computed tomography 4 weeks before and after PVO. RESULTS Before PVO, the FLR volumes were similar in the 13 patients who received bevacizumab (bev+) (mean +/- standard deviation, 497 +/- 136 cm(3)) and the 27 patients who did not receive bevacizumab (bev-) (511 +/- 222 cm(3), P = NS). After PVO, the increase in the FLR volume was significantly lower in the bev+ group (561 +/- 171 cm(3)) compared with the bev- group (667 +/- 213 cm(3), P < .031). In the bev+ group, patients who had received six or more cycles and were > or =60 years old experienced far lower hypertrophy. A right hepatectomy was performed in 29 patients (72%) without mortality and no clinically important differences in morbidity. CONCLUSIONS Bevacizumab may impair hypertrophy of the FLR after PVO in preparation for major hepatectomy particularly, in patients aged > or =60 years and those who receive six or more cycles of bevacizumab, suggesting that major liver resection should be considered with caution in patients who have received bevacizumab.
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Affiliation(s)
- Béatrice Aussilhou
- Department of HPB Surgery, Beaujon Hospital, University Paris, Clichy, France
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Abstract
Angiogenesis and disruption of liver vascular architecture have been linked to progression to cirrhosis and liver cancer (HCC) in chronic liver diseases, which contributes both to increased hepatic vascular resistance and portal hypertension and to decreased hepatocyte perfusion. On the other hand, recent evidence shows that angiogenesis modulates the formation of portal-systemic collaterals and the increased splanchnic blood flow which are involved in the life threatening complications of cirrhosis. Finally, angiogenesis plays a key role in the growth of tumours, suggesting that interference with angiogenesis may prevent or delay the development of HCC. This review summarizes current knowledge on the molecular mechanisms of liver angiogenesis and on the consequences of angiogenesis in chronic liver disease. On the other hand, it presents the different strategies that have been used in experimental models to counteract excessive angiogenesis and its potential role in preventing transition to cirrhosis, development of portal hypertension and its consequences, and its application in the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Mercedes Fernández
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
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Lai HS, Lin WH, Hsu WM, Chen CN, Chang KJ, Lee PH. Variations in Interferon Gamma Receptor Gene Expression during Liver Regeneration after Partial Hepatectomy in Rats. Am Surg 2009. [DOI: 10.1177/000313480907500111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cell-mediated immunity, which includes interferon gamma (IFN-γ) expression, is activated during the process of liver regeneration; however, the genetic pathway of this activation is still unclear. The present study evaluated variations in the interferon gamma receptor (IFN-γR) gene and its mRNA expression during liver regeneration after partial hepatectomy (PH). Male Wistar rats weighing approximately 200 g were subjected to PH (70 or 40%). IFN-γR gene expression in the remnant liver was measured by cDNA microarray, and mRNA expression was verified by real-time quantitative reverse transcription-polymerase chain reaction (Q-PCR) preoperatively and at 2, 4, 6,12, 24, and 72 hours and 7 days postoperatively. The ratio of remnant liver weight to body weight increased markedly after 70 per cent PH and more gradually after 40 per cent PH. It reached near 90 per cent of the preoperative level at 72 hours after PH in both groups. The scanned spots of the genomic survey on the cDNA microarray chips were uneven and increased irregularly in number and density after PH. IFN-γR gene expression increased markedly in a single peak pattern, up to more than double the preoperative level, at 6 hours after 70 per cent PH. The curve in the 40 per cent PH group was flat and peaked at only 1.6 times the preoperative level. The variations in IFN-γR-related mRNA expression were verified by Q-PCR. Elevations in IFN-γR gene and mRNA expression were shown during the early stage of liver regeneration after PH. The genetic pathway of IFN-γ/IFN-γR expression is activated during liver regeneration.
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Affiliation(s)
- Hong-Shiee Lai
- From the Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wen-Hsi Lin
- From the Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wen-Ming Hsu
- From the Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chiung-Nien Chen
- From the Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - King-Jen Chang
- From the Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Po-Huang Lee
- From the Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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Kesmodel SB, Ellis LM, Lin E, Chang GJ, Abdalla EK, Kopetz S, Vauthey JN, Rodriguez-Bigas MA, Curley SA, Feig BW. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol 2008; 26:5254-60. [PMID: 18854565 DOI: 10.1200/jco.2008.17.7857] [Citation(s) in RCA: 141] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Although bevacizumab (BV) increases survival rates when used with chemotherapy (CTX) in patients who have metastatic colorectal cancer (CRC), an increase in wound complications has been observed in patients who undergo surgery while receiving BV. We therefore evaluated whether neoadjuvant BV is associated with an increase in postoperative complications in patients undergoing surgery for CRC liver metastases. PATIENTS AND METHODS Two subgroups of patients who received neoadjuvant CTX + BV (n = 81) or CTX alone (n = 44) were identified from a database of patients who underwent surgery for CRC liver metastases. Univariate and multivariate logistic regression models were used to evaluate the association of patient and tumor characteristics, neoadjuvant therapy, and operative factors with postoperative complications. RESULTS Postoperative complications developed in 40 patients (49%) who received CTX + BV and 19 patients (43%) who received CTX. The median time from BV discontinuation to surgery was 58 days (range, 31 to 117 days). No significant associations were identified between BV use and timing of BV discontinuation and postoperative complications. On multivariate analysis, lower serum albumin and concomitant surgical procedures were associated with an increased risk of developing any complication (P = .035 and .023, respectively), and lower serum albumin was associated with hepatobiliary complications (P = .016). CONCLUSION Neither the use of BV nor timing of BV administration was associated with an increase in complication rates. These data suggest that the combination of BV with neoadjuvant CTX in patients who have CRC liver metastases does not increase surgical complications. To determine the optimal timing of surgery in patients receiving neoadjuvant BV, confirmatory prospective studies are required.
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Affiliation(s)
- Susan B Kesmodel
- Department of Surgical Oncology, Cancer Biology, Biostatistics, and Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Ren P, Kang Z, Gu G, Liu Y, Xu W, Tao H, Zhang JH, Sun X, Ji H. Hyperbaric oxygen preconditioning promotes angiogenesis in rat liver after partial hepatectomy. Life Sci 2008; 83:236-41. [PMID: 18644387 DOI: 10.1016/j.lfs.2008.06.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Revised: 05/31/2008] [Accepted: 06/05/2008] [Indexed: 10/21/2022]
Abstract
Hyperbaric oxygen preconditioning (HBO-PC) increases the level of HIF-1alpha (hypoxia inducible factor-1alpha) and its target gene VEGF (vascular endothelial growth factor) which is involved in angiogenesis. Liver regeneration is an angiogenesis-dependent process. We hypothesized that HIF-1alpha and VEGF mediated the angiogenesis effect of HBO-PC on regenerating rat liver. Male Sprague Dawley rats received HBO-PC followed by 70% partial hepatectomy. Proliferation of hepatocytes and endothelial cells was evaluated by BrdU (bromodeoxyuridine) staining. Microvascular density was assessed by immunohistochemistry. mRNA expression of HIF-1alpha was assessed by quantitative RT-PCR and protein levels of HIF-1alpha and VEGF were assessed by western blot. HIF-1alpha DNA-binding activity was determined with an ELISA-based kit. HBO-PC increased the proliferation index of endothelial cells and microvascular density at 48 h after partial hepatectomy. The protein level and DNA-binding activity of HIF-1alpha and the protein level of VEGF were increased by HBO-PC before and after partial hepatectomy. Partial hepatectomy alone also increased proliferation index and the expressions of HIF-1alpha and VEGF. Our results indicated that the angiogenesis effect of HBO-PC on liver after partial hepatectomy could be achieved by increased HIF-1alpha activity and VEGF expression. However, the angiogenic effect of HBO-PC is moderate and HBO-PC failed to produce additional effect on the enhancement of HIF-1alpha and VEGF induced by partial hepatectomy alone.
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Affiliation(s)
- Ping Ren
- Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, PR China
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Abstract
The process of blood vessel proliferation, known as angiogenesis, is essential during embryonic development and organogenesis. In adult life, it participates in normal tissue repair, wound healing, and cyclical growth of the corpus luteum and the endometrium. Crucial as it is, angiogenesis can become pathological, and abnormal angiogenesis contributes to the pathogenesis of inflammatory and neoplasic diseases. The present review highlights the evidence for the role of angiogenesis in HCC (hepatocellular carcinoma) and discusses the increasing importance of inhibitors of angiogenesis in HCC therapy.
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Van Buren G, Yang AD, Dallas NA, Gray MJ, Lim SJ, Xia L, Fan F, Somcio R, Wu Y, Hicklin DJ, Ellis LM. Effect of Molecular Therapeutics on Liver Regeneration in a Murine Model. J Clin Oncol 2008; 26:1836-42. [DOI: 10.1200/jco.2007.11.6566] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Unresectable metastatic colorectal cancer (CRC) can be rendered resectable with systemic chemotherapy in approximately 20% of cases. Most patients with metastatic CRC receive chemotherapy with the addition of targeted therapy with anti–vascular endothelial growth factor (VEGF) or anti–epidermal growth factor receptor (EGFR) antibodies. We sought to determine whether anti-VEGF receptor (VEGFR) or anti-EGFR therapy would impair liver regeneration after partial hepatectomy (PH) in mice. Materials and Methods Mice underwent either 66% PH or sham laparotomy. In the first experiment, mice in the PH group were randomly assigned to receive daily intraperitoneal injections of monoclonal antibodies (MoABs) to murine VEGFR-2 or nonspecific MoABs (control). In the second experiment, mice in the PH group were randomly assigned to receive intraperitoneal injections of antimurine EGFR or nonspecific (control) MoABs. In both experiments, therapy was initiated the day before surgery and continued until the mice were killed on day 5. Livers were collected and processed. Results Anti–VEGFR-2 therapy slightly impaired liver regeneration and hepatic cell proliferation compared with control. Hematoxylin and eosin staining showed no differences in liver morphology. CD105 staining showed decreased levels of activated endothelium in livers in the VEGFR-2 MoAB group. VEGFR-2 MoAB therapy decreased the levels of the cell cycle regulators cyclin D1 and cyclin D3 and the regenerative cytokine interleukin-6. Anti-EGFR therapy had no effect on liver regeneration or cellular proliferation. Conclusion Anti–VEGFR-2 therapy slightly impaired liver regeneration in this murine model, whereas anti-EGFR therapy had no effect on liver regeneration.
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Affiliation(s)
- George Van Buren
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Anthony D. Yang
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Nikolaos A. Dallas
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Michael J. Gray
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Sherry J. Lim
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Ling Xia
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Fan Fan
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Ray Somcio
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Yan Wu
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Daniel J. Hicklin
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
| | - Lee M. Ellis
- From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY
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de Jong KP. Review article: Multimodality treatment of liver metastases increases suitability for surgical treatment. Aliment Pharmacol Ther 2007; 26 Suppl 2:161-9. [PMID: 18081659 DOI: 10.1111/j.1365-2036.2007.03484.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Liver metastases of colorectal cancer occur frequently, but only 10-20% are eligible for liver surgery. Recent new developments changed the concepts of treating patients with colorectal liver metastases. AIM To describe the available modalities that can result in increasing resectability rate. METHODS Potentials and drawbacks of portal vein embolization, radiofrequency ablation (RFA), trans-ablated tumour hepatectomy, neoadjuvant chemotherapy and the approach to patients with extrahepatic metastases are described. RESULTS Portal vein embolization is a well-established technique to increase the volume of the future liver remnant. RFA should be applied if partial liver resection alone cannot make the liver tumour-free. Neoadjuvant chemotherapy in patients with unresectable liver metastases can result in secondary resectability rates of 15-40%. Hepatotoxicity can lead to a higher complication rate after partial liver resection. A limited number of extrahepatic tumour localizations should be resected as well. CONCLUSIONS A more aggressive approach to patients with colorectal liver metastases improves resectability rate and survival. Unfortunately, these new options have not been thoroughly evaluated in randomized controlled trials. For some of these modalities, the currently available results are so promising that it might be difficult to start such trials in the future.
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Affiliation(s)
- K P de Jong
- Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Reddy SK, Morse MA, Hurwitz HI, Bendell JC, Gan TJ, Hill SE, Clary BM. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg 2007; 206:96-106. [PMID: 18155574 DOI: 10.1016/j.jamcollsurg.2007.06.290] [Citation(s) in RCA: 151] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Revised: 06/05/2007] [Accepted: 06/12/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although commonly used in combination with irinotecan or oxaliplatin (iri/oxal) for treatment of colorectal liver metastases before extirpation, the effects of preoperative bevacizumab on surgical outcomes are not established. The objective of this retrospective study was to determine if addition of bevacizumab to iri/oxal preoperative chemotherapy increases morbidity after hepatic resection. STUDY DESIGN We compared demographics, clinicopathologic data, treatments, and postoperative outcomes between patients given preoperative iri/oxal with and without bevacizumab and patients who underwent hepatic resection within and after 8 weeks from the last dose of bevacizumab. RESULTS From 1996 to 2006, 96 patients were treated with preoperative iri/oxal; 39 (40.6%) received concurrent bevacizumab. Preoperative bevacizumab treatment was associated with less blood loss (median 425 mL versus 600 mL, p=0.01) and lower RBC transfusion rates (43.9% versus 23.1%, p=0.06) after partial hepatectomy on univariable analysis. Only age>or=70 years (hazard ratio=8.52, 95% CI [2.00 to 36.45]) and concurrent extrahepatic procedures (hazard ratio=4.12, 95% CI [1.49 to 11.39]) independently predicted RBC transfusion and overall complications, respectively. There were no differences in overall (43.6% versus 38.6%), severe (28.2% versus 24.6%), hepatic (17.9% versus 26.3%), wound (10.3% versus 7%), or thromboembolic or bleeding (2.6% versus 5.3%) complications (all p > 0.05). For patients treated with iri/oxal and bevacizumab, overall complications were more common when resection was performed within 8 weeks after the last bevacizumab dose (62.5% versus 30.4%), but this difference was not statistically significant (p=0.06). CONCLUSIONS If discontinued at least 8 weeks before hepatic resection, addition of bevacizumab to preoperative iri/oxal does not increase morbidity after hepatic resection.
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Affiliation(s)
- Srinevas K Reddy
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
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Shirai M, Yamauchi H, Nakayama H, Doi K, Uetsuka K. Expression of epidermal growth factor receptor protein in the liver of db/db mice after partial hepatectomy. ACTA ACUST UNITED AC 2007; 59:157-62. [PMID: 17826083 DOI: 10.1016/j.etp.2007.06.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2006] [Accepted: 06/08/2007] [Indexed: 11/23/2022]
Abstract
Liver regeneration was impaired after partial hepatectomy (PH) in leptin receptor-deficient db/db mice with severe liver steatosis. In the present study, we analyzed the mode of epidermal growth factor receptor (EGFR) protein expression in the liver of 5- and 10-week-old db/db and age-matched control mice. In 5-week-old db/db mice, neither the expression of EGFR protein in the intact liver nor the rate of liver regeneration after PH was significantly different from that in age-matched control mice. However, in 10-week-old db/db mice, the level of EGFR protein expression was very low and liver regeneration was prominently suppressed. Histopathologically, much severer fatty change was observed in the liver of 10-week-old db/db mice than 5-week-old db/db mice. These results suggest that the down-regulation of EGFR protein expression is associated with an impairment of liver regeneration in db/db mice and that the severity of hepatic steatosis plays an indirect role in the impairment of liver regeneration by modifying EGFR expression.
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Affiliation(s)
- Makoto Shirai
- Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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Ronco MT, Francés D, de Luján Alvarez M, Quiroga A, Monti J, Parody JP, Pisani G, Carrillo MC, Carnovale CE. Vascular endothelial growth factor and nitric oxide in rat liver regeneration. Life Sci 2007; 81:750-5. [PMID: 17706723 DOI: 10.1016/j.lfs.2007.07.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Revised: 06/04/2007] [Accepted: 07/06/2007] [Indexed: 11/27/2022]
Abstract
In this work we investigated the role of nitric oxide (NO) in the angiogenesis mediated by vascular endothelial growth factor (VEGF) during rat liver regeneration after two-thirds partial hepatectomy. Sham operated (Sh) and partially hepatectomized (PH) male Wistar rats were randomized in three experimental groups: control (treated with vehicle); pre-treated with sodium nitroprusside (SNP: 0.25 mg/kg body weight, i.v. at a rate of 1 ml/h) and pre-treated with the preferential iNOS inhibitor, aminoguanidine (AG, 100 mg/kg body weight, i.p.). Animals were killed at 5, 24 and 72 h after surgery. At 5 h post-surgery, NO production was estimated by EPR (Sh-Control: 37.65+/-10.70; PH-Control: 88.13+/-1.60(); Sh-SNP: 90.35+/-3.11(); PH-SNP: 119.5+/-12.10()(#); Sh-AG: 33.27+/-5.23, PH-AG: 36.80+/-3.40(#)) (p<0.05 vs Sh-Control; (#)p<0.05 vs PH-Control). At 24 h after PH, VEGF levels showed no difference between PH-Control and PH-SNP animals. However, after 72 h, VEGF protein levels in PH-SNP animals were found to be increased (above 300%) with respect to PH-Control. On the other hand, aminoguanidine (AG) pre-treatment blocked the rise of inhibition of NO generation and decreased VEGF expression. Our results demonstrated that NO plays a role in modulating VEGF protein expression after hepatectomy in rats.
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Affiliation(s)
- Maria Teresa Ronco
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Argentina
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Baba S, Heike T, Umeda K, Iwasa T, Kaichi S, Hiraumi Y, Doi H, Yoshimoto M, Kanatsu-Shinohara M, Shinohara T, Nakahata T. Generation of cardiac and endothelial cells from neonatal mouse testis-derived multipotent germline stem cells. Stem Cells 2007; 25:1375-83. [PMID: 17322104 DOI: 10.1634/stemcells.2006-0574] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Multipotent germline stem (mGS) cells have been established from neonatal mouse testes. Here, we compared mGS, embryonic stem (ES), and embryonic germ (EG) cells with regard to their ability to differentiate into mesodermal cells, namely, cardiomyocytes and endothelial cells. The in situ morphological appearances of undifferentiated mGS, ES, and EG cells were similar, and 4 days after being induced to differentiate, approximately 30%-40% of each cell type differentiated into Flk1(+) cells. The sorted Flk1(+) cells differentiated efficiently into cardiomyocytes and endothelial cells. By day 10 after differentiation induction, the three cell types generated equal number of endothelial colonies. However, by day 13 after differentiation induction, the Flk1(+) mGS cells generated more contractile colonies than did the Flk1(+) ES cells, whereas the Flk1(+) EG cells generated equivalent numbers as the Flk1(+) mGS cells. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis of differentiation markers such as Rex1, FGF-5, GATA-4, Brachyury, and Flk1 revealed that mGS cells expressed these markers more slowly during days 0-4 after differentiation induction than did ES cells, but that this mGS cell pattern was similar to that of the EG cells. RT-PCR analysis also revealed that the three differentiation cell types expressed various cardiac markers. Moreover, immunohistochemical analysis revealed that the contractile colonies derived from Flk1(+) mGS cells express mature cardiac cell-specific markers. In conclusion, mGS cells are phenotypically similar to ES and EG cells and have a similar potential to differentiate into cardiomyocytes and endothelial cells. Disclosure of potential conflicts of interest is found at the end of this article.
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Affiliation(s)
- Shiro Baba
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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Rupertus K, Kollmar O, Scheuer C, Junker B, Menger MD, Schilling MK. Major but not minor hepatectomy accelerates engraftment of extrahepatic tumor cells. Clin Exp Metastasis 2007; 24:39-48. [PMID: 17260102 DOI: 10.1007/s10585-006-9054-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2006] [Accepted: 12/08/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND The effect of hepatectomy and hepatic regeneration on intra- and extrahepatic tumor growth is still controversially discussed. Herein we studied the effect of minor (30%) or major (70%) hepatectomy on engraftment of extrahepatic tumor cells, and the role of tumor neovascularization and tumor cell migration. METHODS Green fluorescent protein (GFP)-transfected CT26.WT colorectal cancer cells were implanted in dorsal skinfold chambers of syngeneic BALB/c mice. Animals underwent 30% (30%Phx, n = 8) or 70% hepatectomy (70%Phx, n = 8). Sham-operated animals served as controls (n = 8). Angiogenesis and neovascularization as well as tumor cell migration, proliferation and growth were studied over 14 days using intravital fluorescence microscopy, histology and immunohistochemistry. RESULTS After both minor and major hepatectomy tumor proliferating cell nuclear antigen (PCNA) expression increased significantly (P < 0.05) when compared with nonhepatectomized controls. However, only major but not minor hepatectomy accelerated neovascularization (P < 0.05) and tumor cell migration (P < 0.05). This was associated with a significantly (P < 0.05) enhanced tumor growth after 70%Phx when compared with 30%Phx and controls. The rate of apoptotic cell death was not affected by major or minor hepatectomy. CONCLUSION Regeneration after major hepatectomy accelerates extrahepatic tumor cell engraftment, most probably by acceleration of neovascularization and induction of tumor cell migration.
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Affiliation(s)
- Kathrin Rupertus
- Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, 66421 Homburg/Saar, Germany
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Yoo PS, Lopez-Soler RI, Longo WE, Cha CH. Liver resection for metastatic colorectal cancer in the age of neoadjuvant chemotherapy and bevacizumab. Clin Colorectal Cancer 2006; 6:202-7. [PMID: 17026789 DOI: 10.3816/ccc.2006.n.036] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatic metastases from colorectal carcinoma (CRC) were once thought to portend a uniformly grim outcome; however, improvements in chemotherapeutic and surgical approaches have led to significant advances as well as new clinical challenges. Some 60% of the 150,000 patients diagnosed with CRC each year in the United States will develop hepatic metastases. Only a fraction of these metastases are resectable at the time of presentation, but an increasing number of patients are able to undergo resection after neoadjuvant chemotherapy. Additionally, recent trials have demonstrated the efficacy of using chemotherapy with bevacizumab as first-line therapy for metastatic CRC, but how this treatment will affect surgical resection is unknown. Herein, we review the recent literature regarding neoadjuvant chemotherapy for hepatic metastases from CRC, discuss key aspects of the basic science of hepatic regeneration with regard to angiogenic mediators, and outline the key problems to be solved so that a rational strategy can be developed to treat patients with hepatic colorectal metastases in the age of neoadjuvant chemotherapy and antiangiogenic drugs.
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Affiliation(s)
- Peter S Yoo
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520, USA
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Tsuchihashi SI, Ke B, Kaldas F, Flynn E, Busuttil RW, Briscoe DM, Kupiec-Weglinski JW. Vascular endothelial growth factor antagonist modulates leukocyte trafficking and protects mouse livers against ischemia/reperfusion injury. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 168:695-705. [PMID: 16436682 PMCID: PMC1780159 DOI: 10.2353/ajpath.2006.050759] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although hypoxia stimulates the expression of vascular endothelial growth factor (VEGF), little is known of the role or mechanism by which VEGF functions after ischemia and reperfusion (I/R) injury. In this report, we first evaluated the expression of VEGF in a mouse model of liver warm ischemia. We found that the expression of VEGF increased after ischemia but peaked between 2 and 6 hours after reperfusion. Mice were treated with a neutralizing anti-mouse VEGF antiserum (anti-VEGF) or control serum daily from day -1 (1 day before the initiation of ischemia). Treatment with anti-VEGF significantly reduced serum glutaminic pyruvic transaminase levels and reduced histological evidence of hepatocellular damage compared with controls. Anti-VEGF also markedly decreased T-cell, macrophage, and neutrophil accumulation within livers and reduced the frequency of intrahepatic apoptotic terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells. Moreover, there was a reduction in the expression of pro-inflammatory cytokines (tumor necrosis factor-alpha and interferon-gamma), chemokines (interferon-inducible protein-10 and monocyte chemoattractant protein-1) and adhesion molecules (E-selectin) in parallel with enhanced expression of anti-apoptotic genes (Bcl-2/Bcl-xl and heme oxygenase-1) in anti-VEGF-treated animals. In conclusion, hypoxia-inducible VEGF expression by hepatocytes modulates leukocyte trafficking and leukocyte-induced injury in a mouse liver model of warm I/R injury, demonstrating the importance of endogenous VEGF production in the pathophysiology of hepatic I/R injury.
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Larrivée B, Niessen K, Pollet I, Corbel SY, Long M, Rossi FM, Olive PL, Karsan A. Minimal contribution of marrow-derived endothelial precursors to tumor vasculature. THE JOURNAL OF IMMUNOLOGY 2005; 175:2890-9. [PMID: 16116175 DOI: 10.4049/jimmunol.175.5.2890] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
During embryogenesis, vascular and hemopoietic cells originate from a common precursor, the hemangioblast. Recent evidence suggests the existence of endothelial precursors in adult bone marrow cells, but it is unclear whether those precursors have a role in tumor neovascularization. In this report, we demonstrate that murine bone marrow contains endothelial progenitors, which arise from a cell with self-renewing capacity, and can integrate into tumor microvasculature, albeit at a very low frequency. A transgenic double-reporter strategy allowed us to demonstrate definitively that tumor bone marrow-derived endothelial cells arise by transdifferentiation of marrow progenitors rather than by cell fusion. Single cell transplants showed that a common precursor contributes to both the hemopoietic and endothelial lineages, thus demonstrating the presence of an adult hemangioblast. Furthermore, we demonstrate that increased vascular endothelial growth factor (VEGF)-A secretion by tumor cells, as well as activation of VEGF receptor-2 in bone marrow cells does not alter the mobilization and incorporation of marrow-derived endothelial progenitors into tumor vasculature. Finally, in human umbilical cord blood cells, we show that endothelial precursors make up only approximately 1 in 10(7) mononuclear cells but are highly enriched in the CD133+ cell population. By ruling out cell fusion, we clearly demonstrate the existence of an adult hemangioblast, but the differentiation of marrow stem cells toward the endothelial lineage is an extremely rare event. Furthermore, we show that VEGF-A stimulation of hemopoietic cells does not significantly alter this process.
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Affiliation(s)
- Bruno Larrivée
- Department of Medicine, University of British Columbia, Canada
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Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 2005; 23:4853-5. [PMID: 16051943 DOI: 10.1200/jco.2005.23.754] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Lee M Ellis
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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Uetsuka K, Shirai M, Yamauchi H, Nakayama H, Doi K. Impaired proliferation of non-parenchymal cells participates in an impairment of liver regeneration in db/db mice. Exp Mol Pathol 2005; 79:51-8. [PMID: 16005712 DOI: 10.1016/j.yexmp.2005.02.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2005] [Accepted: 02/04/2005] [Indexed: 11/23/2022]
Abstract
In this study, we examined the possibility that impaired proliferation of non-parenchymal cells affects in an impairment of liver regeneration in db/db mice, which are congenitally deficient in receptors for leptin. Liver regeneration after a two thirds partial hepatectomy (2/3 PH) was impaired in 10-week-old female db/db mice. The proliferation of both hepatocytes and non-parenchymal cells estimated from a bromodeoxyuridine (BrdU) labeling index was suppressed, and the protein expression of vascular endothelial growth factor was blocked in db/db mice. Although the extent of fatty change and the level of epidermal growth factor receptor protein expression in the liver were improved in 5-week-old db/db mice, the regeneration of liver was impaired after 2/3 PH in both 5- and 10-week-old db/db mice. These results suggested that suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration in db/db mice. As leptin has also the angiogenic effect, the angiogenic inhibitor FR-118487 was administered to ICR mice to examine liver regeneration after 2/3 PH, and the rate of regeneration was affected. In conclusion, it is suggested that the suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration probably through a disrupted angiogenesis in db/db mice.
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Affiliation(s)
- Koji Uetsuka
- Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-8657 Tokyo, Japan.
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Omori K, Terai S, Ishikawa T, Aoyama K, Sakaida I, Nishina H, Shinoda K, Uchimura S, Hamamoto Y, Okita K. Molecular signature associated with plasticity of bone marrow cell under persistent liver damage by self-organizing-map-based gene expression. FEBS Lett 2004; 578:10-20. [PMID: 15581608 DOI: 10.1016/j.febslet.2004.09.090] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2004] [Revised: 09/03/2004] [Accepted: 09/23/2004] [Indexed: 12/01/2022]
Abstract
The mechanism that regulates the plasticity of bone marrow cells (BMCs) into hepatocytes is poorly understood. We developed a green fluorescent protein/carbon tetrachloride model to find that BMC transplantation recovered liver damage. Serum albumin level and liver fibrosis were recovered by BMC transplantation. To understand the mechanism, we used DNA-chip technology to profile the change of transient gene expression before and after BMC transplantation. On the basis of gene expression with self-organizing map using specific equation, genes were classified into 153 clusters. The information is useful to understand the dramatic gene activation during the process of the plasticity of BMC.
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Affiliation(s)
- Kaoru Omori
- Department of Molecular Science and Applied Medicine (Gastroenterology and Hepatology), Yamaguchi University School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi 755 8505, Japan
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