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Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer 2021; 21:541-557. [PMID: 34326518 DOI: 10.1038/s41568-021-00383-9] [Citation(s) in RCA: 304] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.
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Affiliation(s)
- Xin Li
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominik Pfister
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marco Seehawer
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Lars Zender
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
- German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Wang D, Hou S, Zhang L, Wang X, Liu B, Zhang Z. iMAP: integration of multiple single-cell datasets by adversarial paired transfer networks. Genome Biol 2021; 22:63. [PMID: 33602306 PMCID: PMC7891139 DOI: 10.1186/s13059-021-02280-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 01/27/2021] [Indexed: 01/28/2023] Open
Abstract
The integration of single-cell RNA-sequencing datasets from multiple sources is critical for deciphering cell-to-cell heterogeneities and interactions in complex biological systems. We present a novel unsupervised batch effect removal framework, called iMAP, based on both deep autoencoders and generative adversarial networks. Compared with current methods, iMAP shows superior, robust, and scalable performance in terms of both reliably detecting the batch-specific cells and effectively mixing distributions of the batch-shared cell types. Applying iMAP to tumor microenvironment datasets from two platforms, Smart-seq2 and 10x Genomics, we find that iMAP can leverage the powers of both platforms to discover novel cell-cell interactions.
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Affiliation(s)
- Dongfang Wang
- BIOPIC and School of Life Sciences, Peking University, Beijing, China
| | - Siyu Hou
- MOE Key Laboratory for Bioinformatics, BNRIST Bioinformatics Division, Department of Automation, Tsinghua University, Beijing, China
| | - Lei Zhang
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China
| | | | - Baolin Liu
- BIOPIC and School of Life Sciences, Peking University, Beijing, China
- Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Zemin Zhang
- BIOPIC and School of Life Sciences, Peking University, Beijing, China
- Analytical Biosciences Limited, Beijing, China
- Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
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Kuczynski EA, Vermeulen PB, Pezzella F, Kerbel RS, Reynolds AR. Vessel co-option in cancer. Nat Rev Clin Oncol 2019; 16:469-493. [PMID: 30816337 DOI: 10.1038/s41571-019-0181-9] [Citation(s) in RCA: 289] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
All solid tumours require a vascular supply in order to progress. Although the ability to induce angiogenesis (new blood vessel growth) has long been regarded as essential to this purpose, thus far, anti-angiogenic therapies have shown only modest efficacy in patients. Importantly, overshadowed by the literature on tumour angiogenesis is a long-standing, but continually emerging, body of research indicating that tumours can grow instead by hijacking pre-existing blood vessels of the surrounding nonmalignant tissue. This process, termed vessel co-option, is a frequently overlooked mechanism of tumour vascularization that can influence disease progression, metastasis and response to treatment. In this Review, we describe the evidence that tumours located at numerous anatomical sites can exploit vessel co-option. We also discuss the proposed molecular mechanisms involved and the multifaceted implications of vessel co-option for patient outcomes.
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Affiliation(s)
- Elizabeth A Kuczynski
- Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. .,Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
| | - Peter B Vermeulen
- HistoGeneX, Antwerp, Belgium.,Translational Cancer Research Unit, GZA Hospitals St Augustinus, University of Antwerp, Wilrijk-Antwerp, Belgium.,Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Francesco Pezzella
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Robert S Kerbel
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK. .,Oncology Translational Medicine Unit, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
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Receptor-Mediated Endocytosis of VEGF-A in Rat Liver Sinusoidal Endothelial Cells. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5496197. [PMID: 31583245 PMCID: PMC6754870 DOI: 10.1155/2019/5496197] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/21/2019] [Accepted: 07/02/2019] [Indexed: 12/25/2022]
Abstract
Background and Aims Vascular endothelial growth factor (VEGF) receptors (VEGFR1 and VEGFR2) bind VEGF-A with high affinity. This study sought to determine the relative contributions of these two receptors to receptor-mediated endocytosis of VEGF-A and to clarify their endocytic itineraries in rat liver sinusoidal endothelial cells (LSECs). Methods Isolated LSECs and radiolabeled VEGF-A were used to examine surface binding and receptor-mediated endocytosis. Quantitative real time RT-PCR (Q-RT-PCR) and Western blotting were applied to demonstrate receptor expression. Results Q-RT-PCR analysis showed that VEGFR1 and VEGFR2 mRNA were expressed in LSECs. Ligand saturation analysis at 4°C indicated two different classes of [125I]-VEGFA binding sites on LSECs with apparent dissociation constants of 8 and 210 pM. At 37°C, LSECs efficiently took up and degraded [125I]-VEGF-A for at least 2 hours. Uptake of [125I]-VEGF-A by LSECs was blocked by dynasore that inhibits dynamin-dependent internalization, whereas inhibition of cysteine proteases by leupeptin inhibited degradation without affecting the uptake of [125I]-VEGF-A, suggesting that it is degraded following transport to lysosomes. Incubation of LSECs in the continued presence of a saturating concentration of unlabeled VEGF-A at 37°C was associated with a loss of as much as 75% of the total VEGFR2 within 30 min as shown by Western blot analysis, whereas there was no appreciable decrease in protein levels for VEGFR1 after 120 min incubation, suggesting that VEGF-A stimulation downregulates VEGFR2, but not VEGFR1, in LSECs. This possibility was supported by the observation that a hexapeptide that specifically blocks VEGF-A binding to VEGFR1 caused a marked reduction in the uptake of [125I]-VEGF-A, whereas a control peptide had no effect. Finally, live cell imaging studies using a fluorescently labeled anti-VEGFR2 antibody showed that VEGFR2 was transported via early and late endosomes to reach endolysosomes where degradation of the VEGFR2 takes place. Conclusion Our studies suggest that, subsequent to VEGF-A binding and internalization, the unoccupied VEGFR1 may recycle to the cell surface allowing its reutilization, whereas the majority of the internalized VEGFR2 is targeted for degradation.
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Nakamura T. Changes in Expression of Bile Canalicular CD10 and Sinusoidal CD105 (Endoglin) in Peritumoral Hepatic Tissue. TUMORI JOURNAL 2018; 95:495-500. [DOI: 10.1177/030089160909500415] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Aims and background Hepatic tissues, including bile canaliculi and sinusoids, around primary or metastatic tumors are destructed and regenerate associated with tumor growth, and may show some phenotypic changes. The present study was undertaken to examine the expression of CD10 in bile canaliculi [CD10(BC)] and CD105 (endoglin) along hepatic sinusoids [CD105(HS)] in peritumoral hepatic tissue (PTH). Methods Fifty samples of resected liver bearing hepatocellular carcinoma (HCC) or metastatic carcinoma were immunostained for CD10 and CD105. The immunoreactivity for CD10(BC) and CD105(HS) in the background hepatic tissue of tumors and PTH was scored separately. Results CD10(BC) was moderately or markedly expressed in the background hepatic tissue without chronic hepatitis or cirrhosis in most of the cases, and was significantly downregulated in chronic hepatitis and cirrhosis. CD105(HS) was negative or minimally positive in most of the cases of hepatic tissue bearing metastatic carcinoma, and showed a significant increase in chronic hepatitis and cirrhosis. Compared with the background, PTH revealed significantly decreased CD10(BC) staining irrespective of HCC or metastatic carcinoma, and showed belt-like CD105(HS) expression in 66.7% of the cases of metastatic carcinoma and in 88.6% of those with HCC. Conclusions These data indicate that the expression patterns of CD10(BC) and CD105(HS) in PTH are similar to those in chronic hepatitis and cirrhosis, which may be caused by persistent injury and resultant regeneration of hepatic tissue.
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Peng Y, Li SM, Li GY, Ma J, Zhao TJ. Overview on isolation, cultivation and identification of liver sinusoidal endothelial cells. Shijie Huaren Xiaohua Zazhi 2015; 23:728-734. [DOI: 10.11569/wcjd.v23.i5.728] [Citation(s) in RCA: 2] [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] [Indexed: 02/06/2023] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) play an important role in the hepatic physiological and pathological processes, and they have become a hot research topic in recent years. This paper will focus on the isolation, cultivation and identification of LSECs by summarizing and reviewing the latest technologies and methods, with an aim to make a great contribution to the research of LSECs and their roles in the hepatic physiological and pathological processes.
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Varol U, Oktay E, Yildirim M, Surmeli ZG, Dirican A, Meydan N, Karaca B, Karabulut B, Uslu R. Tumor characteristics and metastatic sites may predict bevacizumab efficacy in the first-line treatment of metastatic colorectal cancer. Mol Clin Oncol 2013; 2:166-170. [PMID: 24649328 DOI: 10.3892/mco.2013.212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 11/04/2013] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is among the most frequently diagnosed cancers and a major cause of cancer-related mortality worldwide. The aim of the present study was to determine whether there was an improvement in the time to disease progression (TTP) in patients with metastatic colorectal cancer (mCRC) treated with first-line bevacizumab plus chemotherapy, according to tumor characteristics and metastatic sites. Tumor characteristics and tumor burden were considered to be predictive markers of the therapeutic efficacy of bevacizumab. The medical records of 705 patients with mCRC were retrospectively reviewed in three oncology centers between January, 2005 and September, 2012. A total of 101 patients completed their first-line bevacizumab-containing treatment. The median TTP was 6.93 months [interquartile range (IQR)=4.20-9.80 months] in patients treated with irinotecan, 5-fluorouracil (5-FU) and bevacizumab vs. 7.42 months (IQR=6.08-10.68 months) in those treated with oxaliplatin, 5-FU and bevacizumab (P=0.589). When we compared patients with pulmonary metastases (median TTP, 9.9000 months) or other metastatic patients without pulmonary metastasis (median TTP, 6.9000 months), we observed a statistically significant difference (P=0.046). However, when the efficacy of bevacizumab was compared in terms of other tumor characteristics (tumor grade, size and lymph node involvement) and metastatic sites, the differences were not significant (P>0.05). We concluded that bevacizumab may be effective in all subgroups of patients with mCRC. Furthermore, bevacizumab with combination chemotherapy may be superior to combination chemotherapy only as the first-line treatment of patients with mCRC and pulmonary metastasis.
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Affiliation(s)
- Umut Varol
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
| | - Esin Oktay
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Adnan Menderes University, Aydın
| | - Mustafa Yildirim
- Department of Medical Oncology, Antalya Research and Training Hospital, Antalya
| | - Zeki Gokhan Surmeli
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
| | - Ahmet Dirican
- Department of Medical Oncology, Izmir Ataturk Research and Training Hospital, Bornova, Izmir, Turkey
| | - Nezih Meydan
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Adnan Menderes University, Aydın
| | - Burcak Karaca
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
| | - Bulent Karabulut
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
| | - Ruchan Uslu
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
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Qiu YD, Wang S, Yang Y, Yan XP. Omega-3 polyunsaturated fatty acids promote liver regeneration after 90% hepatectomy in rats. World J Gastroenterol 2012; 18:3288-95. [PMID: 22783054 PMCID: PMC3391767 DOI: 10.3748/wjg.v18.i25.3288] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 01/12/2012] [Accepted: 04/10/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effectiveness of omega-3 polyunsaturated fatty acid (ω-3 PUFA) administration on liver regeneration after 90% partial hepatectomy (PH) in rats.
METHODS: ω-3 PUFAs were intravenously injected in the ω-3 PUFA group before PH surgery. PH, sparing only the caudate lobe, was performed in both the control and the ω-3 PUFA group. Survival rates, liver weight/body weight ratios, liver weights, HE staining, transmission electron microscope imaging, nuclear-associated antigen Ki-67, enzyme-linked immunosorbent assay and signal transduction were evaluated to analyze liver regeneration.
RESULTS: All rats in the control group died within 30 h after hepatectomy. Survival rates in the ω-3 PUFA group were 20/20 at 30 h and 4/20 1 wk after PH. Liver weight/body weight ratios and liver weights increased significantly in the ω-3 PUFA group. The structure of sinusoidal endothelial cells and space of Disse was greatly restored in the ω-3 PUFA group compared to the control group after PH. In the ω-3 PUFA group, interleukin (IL)-4 and IL-10 levels were significantly increased whereas IL-6 and tumor necrosis factor-α levels were dramatically decreased. In addition, activation of protein kinase B (Akt) and of signal transducer and activator of transcription 3 signaling pathway were identified at an earlier time after PH in the ω-3 PUFA group.
CONCLUSION: Omega-3 polyunsaturated fatty acids may prevent acute liver failure and promote liver regeneration after 90% hepatectomy in rats.
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Landes U, Robert J, Perneger T, Mentha G, Ott V, Morel P, Gervaz P. Predicting survival after pulmonary metastasectomy for colorectal cancer: previous liver metastases matter. BMC Surg 2010; 10:17. [PMID: 20525275 PMCID: PMC2887792 DOI: 10.1186/1471-2482-10-17] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Accepted: 06/03/2010] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Few patients with lung metastases from colorectal cancer (CRC) are candidates for surgical therapy with a curative intent, and it is currently impossible to identify those who may benefit the most from thoracotomy. The aim of this study was to determine the impact of various parameters on survival after pulmonary metastasectomy for CRC. METHODS We performed a retrospective analysis of 40 consecutive patients (median age 63.5 [range 33-82] years) who underwent resection of pulmonary metastases from CRC in our institution from 1996 to 2009. RESULTS Median follow-up was 33 (range 4-139) months. Twenty-four (60%) patients did not have previous liver metastases before undergoing lung surgery. Median disease-free interval between primary colorectal tumor and development of lung metastases was 32.5 months. 3- and 5-year overall survival after thoracotomy was 70.1% and 43.4%, respectively. In multivariate analysis, the following parameters were correlated with tumor recurrence after thoracotomy; a history of previous liver metastases (HR = 3.8, 95%CI 1.4-9.8); and lung surgery other than wedge resection (HR = 3.0, 95%CI 1.1-7.8). Prior resection of liver metastases was also correlated with an increased risk of death (HR = 5.1, 95% CI 1.1-24.8, p = 0.04). Median survival after thoracotomy was 87 (range 34-139) months in the group of patients without liver metastases versus 40 (range 28-51) months in patients who had undergone prior hepatectomy (p = 0.09). CONCLUSION The main parameter associated with poor outcome after lung resection of CRC metastases is a history of liver metastases.
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Affiliation(s)
- Ulrich Landes
- Department of Surgery, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - John Robert
- Department of Surgery, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Thomas Perneger
- Department of Biostatistics, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Gilles Mentha
- Department of Surgery, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Vincent Ott
- Department of Surgery, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Philippe Morel
- Department of Surgery, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Pascal Gervaz
- Department of Surgery, Geneva University Hospital and Medical School, Geneva, Switzerland
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Jia J, Wang J, Teh M, Sun W, Zhang J, Kee I, Chow PKH, Liang RCMY, Chung MCM, Ge R. Identification of proteins differentially expressed between capillary endothelial cells of hepatocellular carcinoma and normal liver in an orthotopic rat tumor model using 2-D DIGE. Proteomics 2010; 10:224-34. [PMID: 19899081 DOI: 10.1002/pmic.200900607] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers with few treatment options. It is a hypervascular tumor in which angiogenesis plays a critical role in its progression. Tumor capillary endothelial cells (TECs) in HCC are known to originate from liver sinusoid endothelial cells, which then go through a capillarization process to become morphologically as well as functionally different TECs. In this work, we investigated proteins differentially expressed between freshly isolated TECs and sinusoid endothelial cells from well-formed rat HCC using 2-D DIGE coupled with MALDI-TOF/TOF MS. Thirty-eight unique proteins were identified to be differentially expressed more than twofold between the two endothelial cell types. Amongst the differentially expressed proteins, two novel endothelial markers, EH domain-containing protein 3 and galectin-3, were confirmed by Western blot and immunohistochemistry in both rat and human HCC samples. We showed that EH domain-containing protein 3 is significantly down-regulated in TECs, but galectin-3 is up-regulated. We propose possible roles of these two proteins in tumor vessel development in HCC.
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Affiliation(s)
- Jinghui Jia
- Department of Biological Sciences, National University of Singapore, 117543, Singapore
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Connolly MK, Mallen-St Clair J, Bedrosian AS, Malhotra A, Vera V, Ibrahim J, Henning J, Pachter HL, Bar-Sagi D, Frey AB, Miller G. Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor. J Leukoc Biol 2009; 87:713-25. [PMID: 20042467 DOI: 10.1189/jlb.0909607] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The liver is the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune-suppressive cells in the liver of tumor-bearing hosts inhibit anti-tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function of immune-suppressive cells in the liver of tumor-bearing hosts. We found that in mice with intra-abdominal malignancies, two distinct CD11b(+)Gr1(+) populations with divergent phenotypic and functional properties accumulate in the liver, becoming the dominant hepatic leukocytes. Their expansion is contingent on tumor expression of KC. These cells are distinct from CD11b(+)Gr1(+) populations in other tissues of tumor-bearing hosts in terms of cellular phenotype and cytokine and chemokine profile. Liver CD11b(+)Gr1(+) cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs. Moreover, liver myeloid-derived suppressor cells accelerate the development of hepatic metastases by inactivation of cytotoxic T cells. These findings may explain the propensity of patients with intra-abdominal cancers to develop liver metastases and suggest a promising target for experimental therapeutics.
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Affiliation(s)
- Michael K Connolly
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016, USA
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Snipstad K, Fenton CG, Kjaeve J, Cui G, Anderssen E, Paulssen RH. New specific molecular targets for radio-chemotherapy of rectal cancer. Mol Oncol 2009; 4:52-64. [PMID: 19969511 DOI: 10.1016/j.molonc.2009.11.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Revised: 11/10/2009] [Accepted: 11/13/2009] [Indexed: 01/03/2023] Open
Abstract
Patients with locally advanced rectal cancer often receive preoperative radio-chemotherapy (RCT). The mechanisms of tumour response to radiotherapy are not understood. The aim of this study was to identify the effects of RCT on gene expression in rectal tumour and normal rectal tissue. For that purpose tissue samples from 21 patients with resectable adenocarcinomas were collected for use in whole genome-microarray based gene expression analysis. A factorial experimental design allowed us to determine the effect of RCT on tumour tissue alone by removing the effect of radiation on normal tissue. This resulted in 1327 differentially expressed genes in tumour tissue with p<0.05. In addition to known markers for radio-chemotherapy, a Gene Set Enrichment Analysis (GSEA) showed a significant enrichment in gene sets associated with cell adhesion and leukocyte transendothelial migration. The profound change of cell adhesion molecule expression in rectal tumour tissue could either increase the risk of metastasis, or decrease the tumour's invasive potential.
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Affiliation(s)
- Kristin Snipstad
- Laboratory of Molecular Medical Research, Institute of Clinical Medicine, University of Tromsø, N-9037 Tromsø, Norway
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Operative risks of digestive surgery in cirrhotic patients. ACTA ACUST UNITED AC 2009; 33:555-64. [PMID: 19481892 DOI: 10.1016/j.gcb.2009.03.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Accepted: 03/25/2009] [Indexed: 12/13/2022]
Abstract
Digestive surgery in cirrhotic patients has long been limited to the treatment of disorders related to the liver disease (portal hypertension, hepatocellular carcinoma and umbilical hernia). The improvement in cirrhotic patient management has allowed an increase in surgical procedures for extrahepatic indications. The aim of this study was to evaluate the operative risks of such surgical procedures. Extrahepatic surgery in cirrhotic patients is associated with high mortality and morbidity. Emergency surgery, gastrointestinal tract opening (esophagus, stomach and colon), <30 g/L serum albumin, transaminase levels more than three times the upper limit of normal, ascites, and intraoperative transfusions are the main risk factors for postoperative death. In Child A patients, the operative risk of elective surgery is moderate and surgical indications are not altered by the presence of cirrhosis. The laparoscopic approach should be recommended because of the potentially lower morbidity. In Child C patients, operative mortality is often higher than 40%; surgical indications must remain exceptional and non operative management has to be preferred. In Child B patients, preoperative improvement of liver function is mandatory for lower risk surgery.
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Yoneyama S, Okaji Y, Tsuno NH, Kawai K, Yamashita H, Tsuchiya T, Yamada J, Sunami E, Osada T, Kitayama J, Takahashi K, Nagawa H. A study of dendritic and endothelial cell interactions in colon cancer in a cell line and small mammal model. Eur J Surg Oncol 2007; 33:1191-8. [PMID: 17314028 DOI: 10.1016/j.ejso.2007.01.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2006] [Accepted: 01/09/2007] [Indexed: 01/09/2023] Open
Abstract
AIM Historically, cancer therapy directly targeting tumor cells have yielded suboptimal clinical results, and therefore anti-angiogenic therapy that targets tumor cells indirectly through impairing tumor vasculature is now considered to be one of the novel approaches potentially effective against various types of cancer. In this study, we evaluated whether lysates of endothelium could be effectively pulsed in dendritic cells (DCs), to enhance their anti-tumor effects. METHODS For this purpose, we prepared DCs of BALB/c mouse, incubated them with lysates of autologous or xenogeneic endothelium, and tested their anti-tumor effects in two syngeneic models of colon cancer. RESULTS DCs pulsed with the respective endothelium lysates significantly inhibited the growth of subcutaneous tumors as well as pulmonary metastases in mice, and their anti-tumor effect was superior to that of unpulsed DCs. Immunohistopathological analysis showed significant decrease in the mean vascular density of tumors, correlating well with the extent of tumor inhibition. In vitro analysis of splenocytes isolated from immunized mice revealed an induction of cytotoxic T lymphocytes and activation of natural killer cells, with a lytic activity against activated endothelium but not tumor cells. In addition, antibodies reacting with activated endothelium, but not tumor cells, were detected in murine sera by ELISA, and their function was confirmed by complement-dependent cytotoxicity assay. CONCLUSIONS Our present results suggest that lysates of endothelium can be effectively pulsed in DCs and enhance their anti-tumor effects through induction of anti-angiogenesis, and therefore should have important clinical implications for adjuvant cancer therapy.
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Affiliation(s)
- S Yoneyama
- Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Liu Y, Matsui O. Changes of Intratumoral Microvessels and Blood Perfusion during Establishment of Hepatic Metastases in Mice. Radiology 2007; 243:386-95. [PMID: 17356176 DOI: 10.1148/radiol.2432060341] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
PURPOSE To prospectively evaluate the stepwise changes that occur in intratumoral microvessels and microcirculation during the establishment of murine colonic hepatic metastases by using in vivo fluorescent microscopy and to compare the changes with tumor angiogenesis evaluated with an immunohistochemical study. MATERIALS AND METHODS This study was approved by the institutional animal care and use committee. Twenty-five mice with hepatic metastases created with injection of murine colonic adenocarcinoma (colon 26) tumor cells into the spleen were examined with in vivo microscopy and immunohistochemical study for CD34, intracellular adhesion molecule (ICAM-1), and alpha smooth muscle actin (alpha-SMA). The tumor size, microcirculation in tumors, intratumoral microvessel density (MVD), afferent MVD, and CD34-positive MVD were evaluated. The data among the tumors that showed different hemodynamic or immunohistochemical patterns were compared with the Kruskal-Wallis test and the Student t test. RESULTS Four stepwise patterns were observed according to the changes in morphology, hemodynamics, and immunohistochemical characteristics of intratumoral microvessels during the establishment of hepatic metastases, as follows: metastases without definite intratumoral blood perfusion or any intratumoral microvessels (mean diameter, approximately 180 microm), metastases with portal perfusion and intratumoral ICAM-1-positive residual hepatic sinusoids (mean diameter, approximately 290 microm), metastases with mixed portal and arterial perfusion and increased CD34-positive microvessels and alpha-SMA-positive arterioles (mean diameter, approximately 520 microm), and metastases with exclusively arterial perfusion and increased CD34-positive microvessels and alpha-SMA-positive arterioles (mean diameter, >2000 microm). The differences among the mean sizes of the tumors that showed these four patterns were statistically significant (P < .01). CONCLUSION Stepwise changes of intratumoral microcirculation were revealed from direct diffusion, to portal perfusion, to mixed portal and arterial perfusion, and finally to arterial perfusion in accordance with stepwise tumor neovascularization during the growth of murine colonic hepatic metastases.
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Affiliation(s)
- Yi Liu
- Department of Radiology, Kanazawa University, Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8641, Japan
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16
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Edwards S, Lalor PF, Tuncer C, Adams DH. Vitronectin in human hepatic tumours contributes to the recruitment of lymphocytes in an alpha v beta3-independent manner. Br J Cancer 2006; 95:1545-54. [PMID: 17088900 PMCID: PMC2360745 DOI: 10.1038/sj.bjc.6603467] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
The degree of lymphocyte infiltration is a prognostic factor in liver cancer, but to date the mechanisms by which lymphocytes infiltrate into and are retained in hepatic tumours are poorly understood. We hypothesised that the extracellular matrix glycoprotein vitronectin, a major component of the stroma of hepatic tumours, might play a role in the recruitment and retention of tumour-infiltrating lymphocytes (TIL). Thus, we investigated the ability of vitronectin to support migration and adhesion of TIL isolated from hepatocellular carcinoma and colorectal hepatic metastases. Soluble vitronectin-induced dose-dependent migration of TIL in in vitro chemotaxis and haptotaxis assays and vitronectin in tissue sections was able to support TIL adhesion to tumour stroma. Neither adhesion nor migration was inhibited by a function blocking mAb against the major vitronectin receptor αvβ3 and we were unable to detect αvβ3 on TIL in vitro or in vivo on tumour tissue. However, TIL did express high levels of urokinase-type plasminogen activator receptor (uPAR) and inhibitory antibodies and amiloride both significantly inhibited TIL adhesion to vitronectin and reduced transendothelial migration of lymphocytes across liver endothelium in vitro. Thus, we provide evidence that vitronectin in liver tumours can support the recruitment and retention of effector lymphocytes by an uPAR-dependent mechanism.
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Affiliation(s)
- S Edwards
- Liver Research Group, Department of Medicine, 5th Floor, Institute of Biomedical Research, Wolfson Drive, The Medical School, University of Birmingham, Birmingham B15 2TT, UK
| | - P F Lalor
- Liver Research Group, Department of Medicine, 5th Floor, Institute of Biomedical Research, Wolfson Drive, The Medical School, University of Birmingham, Birmingham B15 2TT, UK
- E-mail:
| | - C Tuncer
- Liver Research Group, Department of Medicine, 5th Floor, Institute of Biomedical Research, Wolfson Drive, The Medical School, University of Birmingham, Birmingham B15 2TT, UK
| | - D H Adams
- Liver Research Group, Department of Medicine, 5th Floor, Institute of Biomedical Research, Wolfson Drive, The Medical School, University of Birmingham, Birmingham B15 2TT, UK
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17
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Okaji Y, Tsuno NH, Saito S, Yoneyama S, Tanaka M, Nagawa H, Takahashi K. Vaccines targeting tumour angiogenesis--a novel strategy for cancer immunotherapy. Eur J Surg Oncol 2006; 32:363-70. [PMID: 16520018 DOI: 10.1016/j.ejso.2006.01.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2005] [Accepted: 01/26/2006] [Indexed: 01/30/2023] Open
Abstract
AIMS To review the concept of tumour angiogenesis and anti-angiogenic therapy, limitations of recently used anti-angiogenic therapeutics; provide an up-to-date overview of the growing number of reports on vaccines targeting tumour angiogenesis; and finally discuss potential complications and future directions in the development of more potent and specific vaccines. METHODS A literature search was carried out from PubMed for indexed articles. The most important articles were analysed and discussed. FINDINGS The search yielded a large number of important indexed published articles that were reviewed, screened and tracked for other relevant publications. The most relevant articles, including those previously published by authors, were analysed and discussed. CONCLUSIONS Recently, different vaccine strategies have been reported to inhibit tumour growth and metastasis by induction of specific cellular and/or humoral immunity against angiogenesis-associated antigens in pre-clinical models, suggesting effective combination of anti-angiogenesis and cancer immunotherapy. Evaluation of tumour endothelial cells and clinical phase I study of the vaccines are recently ongoing, and should give us better insight into the possibilities of this novel strategy for cancer immunotherapy.
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Affiliation(s)
- Y Okaji
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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18
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Onodera H, Mori A, Nagayama S, Fujimoto A, Tachibana T, Yonenaga Y, Tsuruyama T. Fas/CD95 signaling rather than angiogenesis or proliferative activity is a useful prognostic factor in patients with resected liver metastases from colorectal cancer. Int J Colorectal Dis 2005; 20:477-84. [PMID: 15846499 DOI: 10.1007/s00384-004-0708-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/12/2004] [Indexed: 02/04/2023]
Abstract
BACKGROUND The selection of resective therapy for colorectal hepatic metastases remains controversial. The aim of this study is to investigate the prognostic factors for patients with resected liver metastases from colorectal cancer by analyzing not only clinicopathological factors but also recent immunohistological markers. METHODS Eighty-five patients underwent hepatic resection for metastatic colorectal cancer over the past 20 years. Fas/CD95 expression, microvessel density, and proliferating cell nuclear antigen (PCNA) proliferative activity were assessed with immunohistochemical methods in addition to the clinicopathological factors. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards model, both univariately and multivariately. RESULTS Univariate and multivariate analyses revealed that the number of metastases, Fas/CD95 expression, and postoperative carcinoembryonic antigen doubling time (CEADT) were significant prognostic indicators, whereas the mode of hepatic resection, chemotherapy, and other clinicopathological factors had no influence on survival. Fas/CD95 index correlated with postoperative CEADT (p=0.039), number of metastases (p=0.018), and survival (p=0.023). CONCLUSIONS Our study confirmed the number of metastases and CEADT as prominent prognostic factors after hepatic resection for metastatic colorectal cancer. These two factors reflect the degree of Fas/CD95 signaling rather than angiogenesis or cancer growth rate.
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Affiliation(s)
- Hisashi Onodera
- Department of Surgery and Surgical Basic Science, Kyoto University, 54 Shogoin Kawara cho, Sakyo ku, Kyoto, 606-8507, Japan.
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19
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Pandharipande PV, Krinsky GA, Rusinek H, Lee VS. Perfusion imaging of the liver: current challenges and future goals. Radiology 2005; 234:661-73. [PMID: 15734925 DOI: 10.1148/radiol.2343031362] [Citation(s) in RCA: 243] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Improved therapeutic options for hepatocellular carcinoma and metastatic disease place greater demands on diagnostic and surveillance tests for liver disease. Existing diagnostic imaging techniques provide limited evaluation of tissue characteristics beyond morphology; perfusion imaging of the liver has potential to improve this shortcoming. The ability to resolve hepatic arterial and portal venous components of blood flow on a global and regional basis constitutes the primary goal of liver perfusion imaging. Earlier detection of primary and metastatic hepatic malignancies and cirrhosis may be possible on the basis of relative increases in hepatic arterial blood flow associated with these diseases. To date, liver flow scintigraphy and flow quantification at Doppler ultrasonography have focused on characterization of global abnormalities. Computed tomography (CT) and magnetic resonance (MR) imaging can provide regional and global parameters, a critical goal for tumor surveillance. Several challenges remain: reduced radiation doses associated with CT perfusion imaging, improved spatial and temporal resolution at MR imaging, accurate quantification of tissue contrast material at MR imaging, and validation of parameters obtained from fitting enhancement curves to biokinetic models, applicable to all perfusion methods. Continued progress in this new field of liver imaging may have profound implications for large patient groups at risk for liver disease.
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Affiliation(s)
- Pari V Pandharipande
- MRI-Basement, Schwartz Bldg, NYU Medical Center, 530 First Ave, New York, NY 10016, USA
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20
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Ellis LM. Preclinical data targeting vascular endothelial growth factor in colorectal cancer. Clin Colorectal Cancer 2005; 4 Suppl 2:S55-61. [PMID: 15479480 DOI: 10.3816/ccc.2004.s.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Vascular endothelial growth factor (VEGF) is the driving force behind angiogenesis in most solid malignancies. This also holds true for colorectal cancer (CRC), where increased levels of VEGF in primary cancers are associated with increased microvessel density and poor prognosis. These findings have led to preclinical studies evaluating the efficacy of anti-VEGF therapy in inhibiting the growth of CRC in ectopic and orthotopic locations. In preclinical models, numerous approaches to inhibit VEGF activity led to decreased tumor growth and angiogenesis. These studies led to clinical trials in which, unfortunately, single-agent anti-VEGF therapy was relatively ineffective for patients with metastatic CRC. However, combinations of anti-VEGF therapies with chemotherapy have clearly demonstrated clinical benefit. Understanding the mechanisms of the role of VEGF in CRC angiogenesis and the effect of anti-VEGF therapy on the tumor vasculature will allow oncologists to optimize therapeutic regimens targeting VEGF and its receptors.
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Affiliation(s)
- Lee M Ellis
- Department of Surgical Oncology, Box 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009, USA.
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21
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Yu HK, Kim JS, Lee HJ, Ahn JH, Lee SK, Hong SW, Yoon Y. Suppression of Colorectal Cancer Liver Metastasis and Extension of Survival by Expression of Apolipoprotein(a) Kringles. Cancer Res 2004; 64:7092-8. [PMID: 15466205 DOI: 10.1158/0008-5472.can-04-0364] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The formation of hepatic metastases in colorectal cancer is the main cause of patient death. Current therapies directed at hepatic metastasis of colorectal cancer have had minimal impact on outcome. Therefore, alternative treatment strategies for liver metastasis require development. The present study was performed to evaluate the application of cDNA of LK68 encoding apolipoprotein(a) kringles IV-9, IV-10, and V as possible candidates for gene therapy treatment of this life-threatening disease. The murine colorectal cancer cell line CT26 was transduced ex vivo with LK68 cDNA via retroviral gene transfer, and an experimental model of hepatic metastasis was established by injecting LK68-expressing and control cells into the spleens of BALB/c mice. Expression of LK68 did not affect the growth characteristics and viability of transduced CT26 cells in vitro. LK68 produced from CT26 cells substantially inhibited the migration of endothelial cells in vitro. In vivo, substantial suppression of liver metastasis and prolonged survival were observed in mice bearing LK68-expressing CT26 cells, compared with controls. LK68-expressing liver metastases were restricted to smaller sizes and displayed decreased microvessel density and increased tumor cell apoptosis. Our data collectively indicate that LK68 suppresses angiogenesis-dependent progression of prevascular micrometastases to macroscopic tumors and their growth, which are clinically accessible and biologically relevant therapeutic targets. We propose that antiangiogenic gene therapy with LK68 is a promising strategy for the treatment of colorectal cancer liver metastasis.
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MESH Headings
- Animals
- Apolipoproteins/biosynthesis
- Apolipoproteins/genetics
- Apoprotein(a)
- Apoptosis/genetics
- Cell Line, Tumor
- Cell Movement/genetics
- Colorectal Neoplasms/blood supply
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/therapy
- DNA, Complementary/administration & dosage
- DNA, Complementary/genetics
- Disease Models, Animal
- Endothelium, Vascular/pathology
- Genetic Therapy/methods
- Kringles/genetics
- Lipoprotein(a)/biosynthesis
- Lipoprotein(a)/genetics
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/prevention & control
- Liver Neoplasms, Experimental/secondary
- Male
- Mice
- Mice, Inbred BALB C
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/therapy
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Affiliation(s)
- Hyun-Kyung Yu
- Mogam Biotechnology Research Institute, Yongin-city, Kyonggi-do, Republic of Korea
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22
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Tao KS, Dou KF, Wu XA. Expression of angiostatin cDNA in human hepatocellular carcinoma cell line SMMC-7721 and its effect on implanted carcinoma in nude mice. World J Gastroenterol 2004; 10:1421-4. [PMID: 15133846 PMCID: PMC4656277 DOI: 10.3748/wjg.v10.i10.1421] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To transfect murine angiostatin cDNA into human hepatocellular carcinoma cell line SMMC-7721 and to investigate its effects on implanted carcinoma in nude mice.
METHODS: A eukaryotic expression vector of pcDNA3.1-mAST containing murine angiostatin was constructed. Then pcDNA3.1-mAST plasmid was transfected into cell line SMMC-7721 by Lipofectamine. The resistant clone was screened by G418 filtration and identified by RT-PCR and Western blotting. Nude mice were divided into three groups of 10 each. Mice in blank control group were only injected with SMMC-7721 cells. Mice in vector control group were injected with SMMC-7721 cells transfected with pcDNA3.1 (+) vector, whereas mice in angiostatin group were injected with SMMC-7721 cells transfected with pcDNA3.1-mAST plasmid. Volume, mass and microvessel density (MVD) of the tumors in different groups were measured and compared.
RESULTS: Murine angiostatin cDNA was successfully cloned into the eukaryotic expression vector pcDNA3.1 (+). pcDNA3.1-mAST was successfully transfected into SMMC-7721 cell line and showed stable expression in this cell line. No significant difference was observed in the growth speed of SMMC-7721 cells between groups transfected with and without angiostatin cDNA. Tumor volume, mass and MVD in the angiostatin group were significantly lower than those in the blank control group and vector control group (P < 0.01). The inhibitory rate of tumor reached 78.6%. Mass and MVD of the tumors only accounted for 34.6% and 48.9% respectively of those in the blank control group.
CONCLUSION: Angiostatin cDNA could be stably expressed in human hepatocellular carcinoma cell line SMMC-7721 without obvious inhibitory effects on the growth of SMMC-7721 cells. When implanted into nude mice, SMMC-7721 cells transfected with angiostatin cDNA show a decreased tumorigenic capability. It suggests that angiostatin can inhibit tumor growth through its inhibition on angiogenesis in tumors.
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Affiliation(s)
- Kai-Shan Tao
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
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23
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Kobayashi H, Gonda T, Uetake H, Higuchi T, Enomoto M, Sugihara K. JTE-522, a selective COX-2 inhibitor, interferes with the growth of lung metastases from colorectal cancer in rats due to inhibition of neovascularization: A vascular cast model study. Int J Cancer 2004; 112:920-6. [PMID: 15386343 DOI: 10.1002/ijc.20523] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The lung is a frequent site of metastasis from colorectal cancer, but angiogenesis of lung metastases has not been clarified. Some COX-2 inhibitors prevent tumor growth, although the inhibitory mechanism at the metastatic site is obscure. We investigated the microvascular structure of small lung metastases and the effect of JTE-522, a selective COX-2 inhibitor, on the angiogenesis of pulmonary metastases from colorectal cancer in rats. The tail veins of 25 male F344/DuCrj rats, aged 5 weeks, were injected with a tumor suspension containing 5 x 10(6) RCN-9, a rat colon cancer cell line. Three weeks later, pulmonary vascular resin corrosion casts were taken and the vascularity of metastases was studied using stereo and scanning electron microscopes. We investigated the effect of 0, 10 and 30 mg/kg/day of JTE-522 on the angiogenesis of pulmonary metastases in 3 groups of 5 male rats out of 25. JTE-522 reduced the diameter of tumor vessels as well as the number and size of metastatic tumors. The diameter of tumor vessels and the size of lung metastases significantly and positively correlated with neovascularization in the control group, but not in the JTE-522-treated groups. JTE-522 also affected type of vasculature of metastases, which differed depending on their size. JTE-522 interfered with the growth of hematogenous metastatic tumors by disrupting neovascularization. However, JTE-522 may have some important mechanisms other than inhibition of neovascularization. JTE-522 may be one of the therapeutic agents for the treatment of hematogenous metastasis of colorectal cancer.
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Affiliation(s)
- Hirotoshi Kobayashi
- Department of Surgical Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
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24
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Okaji Y, Tsuno NH, Kitayama J, Saito S, Takahashi T, Kawai K, Yazawa K, Asakage M, Hori N, Watanabe T, Shibata Y, Takahashi K, Nagawa H. Vaccination with autologous endothelium inhibits angiogenesis and metastasis of colon cancer through autoimmunity. Cancer Sci 2004; 95:85-90. [PMID: 14720332 PMCID: PMC11159040 DOI: 10.1111/j.1349-7006.2004.tb03175.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2003] [Revised: 11/13/2003] [Accepted: 11/17/2003] [Indexed: 12/14/2022] Open
Abstract
Overcoming immune tolerance of tumor angiogenesis should be useful for adjuvant therapy of cancer. We hypothesized that vaccination with autologous endothelium would induce an autoimmune response targeting tumor angiogenesis. To test this concept, we immunized BALB/c mice with a vaccine of glutaraldehyde-fixed murine hepatic sinusoidal endothelial cells (HSEs) in a lung metastasis model of Colon-26 cancer. Vaccination with autologous HSEs induced both preventive and therapeutic anti-tumor immunity that significantly inhibited the development of metastases. ELISA revealed an immunoglobulin response involving IgM and IgG subclasses. These antibodies had a strong affinity for antigens of both murine and human endothelium, and lyzed endothelial cells in the CDC assay. Flow-cytometry and chromium-release cytotoxicity assay revealed a specific CTL response against endothelial cells, which were lyzed in an effector: target ratio-dependent manner. Neither antibodies nor CTLs reacted with Colon-26. The effect of autologous HSEs was more pronounced than that of xenogeneic human umbilical vein endothelial cells (HUVECs), which were tested in the same experimental setting. Our results suggest that vaccination with autologous endothelium can overcome peripheral tolerance of self-angiogenic antigens and therefore should be useful for adjuvant immunotherapy of cancer.
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Affiliation(s)
- Yurai Okaji
- Department of Surgical Oncology, Graduate School of Medical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
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Stoeltzing O, Liu W, Reinmuth N, Parikh A, Ahmad SA, Jung YD, Fan F, Ellis LM. Angiogenesis and antiangiogenic therapy of colon cancer liver metastasis. Ann Surg Oncol 2003; 10:722-33. [PMID: 12900362 DOI: 10.1245/aso.2003.07.019] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The fact that tumor growth and metastatic spread relies on angiogenesis has been widely proven and accepted. The understanding of cancer biology and metastasis formation has led to the development of new therapeutic approaches that target tumor biology. The survival and establishment of metastatic lesions depend on a shift in the normal balance of proangiogenic and antiangiogenic factors that favor angiogenesis. Colorectal cancer is one of the leading cancer deaths worldwide. Angiogenesis has been associated with colon cancer progression and metastatic spread, thereby significantly affecting patient survival. New experimental approaches that inhibit angiogenic processes have demonstrated promising antineoplastic effects on metastatic colorectal cancer and are partially being investigated in clinical trials. This review focuses on angiogenesis in colorectal cancer metastasis formation as a target for antiangiogenic therapy, describing the experience from experimental studies and current clinical trials.
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Affiliation(s)
- Oliver Stoeltzing
- Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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Gervaz P, Pak-art R, Nivatvongs S, Wolff BG, Larson D, Ringel S. Colorectal adenocarcinoma in cirrhotic patients. J Am Coll Surg 2003; 196:874-9. [PMID: 12788423 DOI: 10.1016/s1072-7515(03)00117-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
BACKGROUND Colorectal carcinoma in cirrhotic patients is different from that in patients without the liver disease. The aims of this study were to evaluate the incidence of liver metastasis, postoperative mortality, and the predictors of longterm survival. STUDY DESIGN A retrospective analysis of patients operated on for colorectal adenocarcinoma at the Mayo Clinic, Rochester, MN between 1976 and 2001, with confirmed liver cirrhosis at the time of abdominal exploration. RESULTS Seventy-two patients were available for analysis. They were 43% Child A, 42% Child B, and 15% Child C. The median age was 70 (range 42 to 89) years, and the mean duration of followup was 46 months. Postoperative death was 13%. The risk factors were an elevated bilirubin (p = 0.01) and prolonged prothrombin time (p = 0.009). Seven patients (10%) developed liver metastases. For the whole group 1-, 3-, and 5-year survival rates were 69%, 49%, and 35%, respectively. Child A patients had a significantly better survival rate than the combined group of Child B and C patients (p = 0.008). The risks for longterm survival were decreased albumin (p = 0.002) and prolonged prothrombin time (p < 0.001). TNM stage of the carcinoma provided no prognostic information (p = 0.51). CONCLUSIONS Liver metastases from colorectal adenocarcinoma is infrequent (10%) in cirrhotic patients. The Child's classification, and not the TNM stage of the carcinoma, predicts the risk of postoperative death and longterm survival.
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Affiliation(s)
- Pascal Gervaz
- Division of Colon & Rectal Surgery, Mayo Clinic, Rochester, MN 55905, USA
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Takeda A, Stoeltzing O, Ahmad SA, Reinmuth N, Liu W, Parikh A, Fan F, Akagi M, Ellis LM. Role of angiogenesis in the development and growth of liver metastasis. Ann Surg Oncol 2002; 9:610-6. [PMID: 12167573 DOI: 10.1007/bf02574475] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cancer metastasis is a highly complex process that involves aberrations in gene expression by cancer cells leading to transformation, growth, angiogenesis, invasion, dissemination, survival in the circulation, and subsequent attachment and growth in the organ of metastasis. Angiogenesis facilitates metastasis formation by providing a mechanism to (1) increase the likelihood of tumor cells entering the blood circulation and (2) provide nutrients and oxygen for growth at the metastatic site. The formation and establishment of metastatic lesions depend on the activation of multiple angiogenic pathways at both primary and metastatic sites. A variety of factors involved in the angiogenesis of liver metastasis have been identified and may serve as prognostic markers and targets for therapy. Vascular endothelial growth factor, interleukin-8, and platelet-derived endothelial cell growth factor are all proangiogenic factors that have been associated with liver metastasis from various primary tumor types. Inhibition of the activity of these factors is a promising therapeutic approach for patients with liver metastases. In addition, inhibition of integrins that mediate endothelial cell survival may also serve as a component of therapeutic regimens for liver metastases. This review focuses on the biology of angiogenesis in liver metastasis formation and growth. Because colorectal carcinoma is the most common tumor to metastasize to the liver, this disease will serve as a paradigm for the study of angiogenesis in liver metastases.
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Affiliation(s)
- Akihiko Takeda
- Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
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