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Tomita K, Saito Y, Suzuki T, Imbaby S, Hattori K, Matsuda N, Hattori Y. Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2020; 393:2365-2374. [PMID: 32696151 PMCID: PMC7371837 DOI: 10.1007/s00210-020-01947-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 07/13/2020] [Indexed: 12/26/2022]
Abstract
Vascular endothelial growth factor (VEGF) is a prime regulator of vascular permeability. Acute lung injury (ALI) is characterized by high-permeability pulmonary edema in addition to refractory hypoxemia and diffuse pulmonary infiltrates. In this study, we examined whether VEGF can be implicated as a pulmonary vascular permeability factor in sepsis-associated ALI. We found that a great increase in lung vascular leak occurred in mice instilled intranasally with lipopolysaccharide (LPS), as assessed by IgM levels in bronchoalveolar lavage fluid. Treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced this hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. However, this was not solely attributable to excessive levels of intrapulmonary VEGF. Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Furthermore, a significant rise in plasma VEGF levels was observed in CLP-induced septic mice. The increase in VEGF released from HPMECs after LPS/IFN-γ challenge was completely blocked by either specific inhibitor of mitogen-activated protein kinase (MAPK) subgroups. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways.
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Affiliation(s)
- Kengo Tomita
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
- Medical Environment Engineering Group, Center for Environmental Engineering, Shimizu Corporation, Institute of Technology, Tokyo, 135-0044, Japan
| | - Yuna Saito
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
- Center for Clinical Training, Juntendo University Urayasu Hospital, Urayasu, 279-0021, Japan
| | - Tokiko Suzuki
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
- J-Pharma Co., Ltd., Yokohama, 230-0046, Japan
| | - Samar Imbaby
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Kohshi Hattori
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, 113-8655, Japan
| | - Naoyuki Matsuda
- Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Yuichi Hattori
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.
- Advanced Research Promotion Center, Health Sciences University of Hokkaido, Tobetsu, 061-0293, Japan.
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Kumagai Y, Tachikawa T, Higashi M, Sobajima J, Takahashi A, Amano K, Ishibashi KI, Mochiki E, Yakabi K, Tamaru JI, Ishida H. Chondromodulin-1 and vascular endothelial growth factor-A expression in esophageal squamous cell carcinoma: accelerator and brake theory for angiogenesis at the early stage of cancer progression. Esophagus 2020; 17:159-167. [PMID: 31595395 DOI: 10.1007/s10388-019-00695-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 10/01/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Magnifying endoscopy has demonstrated dramatic morphologic changes in the surface microvasculature of superficial esophageal squamous cell carcinoma (ESCC) according to the depth of invasion. We investigated the mechanism of angiogenesis in early-stage ESCC by examining the expression of vascular endothelial growth factor (VEGF)-A and chondromodulin (ChM)-1. METHODS Using 41 samples of superficial esophageal cancer (EP and LPM 19 cases, MM or deeper 22 cases) and 7 samples of regenerative squamous epithelium, the expression of VEGF-A and ChM-1 was examined in relation to the histological grade or morphology of the surface microvasculature demonstrated by magnifying endoscopy (types A, B, and C correspond to types A, B1, and B2 and B3 of the magnifying endoscopic classification of the Japan Esophageal Society, respectively). We also investigated the correlation between CD31-positive microvessel density (MVD) and VEGF-A or ChM-1 expression. RESULTS In normal squamous epithelium, regenerative squamous epithelium, EP and LPM cancer, and MM or deeper cancer, the positivity rates for VEGF-A and ChM-1 were 0%, 85.7%, 52.6% and 90.9%, respectively, and 48.5%, 71.4%, 73.7% and 23.8%, respectively. The VEGF-A and ChM-1 positivity rates in type B or type C vasculature were 70.0% and 76.2%, respectively, and 75.0% and 19.0%, respectively. The expression of neither VEGF-A nor ChM-1 in cancer cells was correlated with MVD (P = 0.19 and 0.68, respectively), whereas that of VEGF-A in stromal mononuclear cells (SMCs) was significantly correlated with MVD (P = 0.04). CONCLUSION Angiogenesis at the early stage of ESCC progression is configured by the balance between accelerator (angiogenic factors from both cancer cells and SMCs) and brake (angiogenic inhibitor) factors.
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Affiliation(s)
- Youichi Kumagai
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan.
| | - Tetsuhiko Tachikawa
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Morihiro Higashi
- Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Jun Sobajima
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
| | - Akemi Takahashi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Kunihiko Amano
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
| | - Kei-Ichiro Ishibashi
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
| | - Erito Mochiki
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
| | - Koji Yakabi
- Department of Internal Medicine, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Jun-Ichi Tamaru
- Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
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Park HS, Ashour D, Elsharoud A, Chugh RM, Ismail N, El Andaloussi A, Al-Hendy A. Towards Cell free Therapy of Premature Ovarian Insufficiency: Human Bone Marrow Mesenchymal Stem Cells Secretome Enhances Angiogenesis in Human Ovarian Microvascular Endothelial Cells. ACTA ACUST UNITED AC 2019; 5. [PMID: 32494757 PMCID: PMC7269190 DOI: 10.24966/srdt-2060/100019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Primary Ovarian Insufficiency (POI) refers to an ovarian loss of function in women under the age of 40. Unfortunately, currently, there is no effective treatment available for POI-related infertility. Alternatives such as the use of egg donations are culturally and ethically unacceptable to many couples. Human Bone marrow-derived Mesenchymal Stem Cells (MSCs) are known for their ability to differentiate into other cell types, once primed by the organ microenvironment. Importantly MSCs produce a vast array of bioactive factors many of them have been shown to enhance neovascularization in various tissues. Recently, preliminary data from our ongoing clinical trial revealed encouraging preliminary data after autologous MSC engraftment into the ovaries of 2 POI patients with durable elevation in serum estrogen levels and increase in size of treated ovaries sustained up to one-year post cell therapy. In this study, we investigated the action of the mechanisms of MSCs treatment on a POI ovary. We designed an in vitro study using MSC secretome and Human Ovarian Endothelial Cells (HOVECs) to understand the molecular mechanisms by which MSC mediates their angiogenic properties and regenerative effects. Human primary HOVECs were treatment with MSC secretome and examined by FACS for the expression of angiogenesis markers such as Endoglin, Tie-2, and VEGF. The formation of vessels was evaluated by using a 3D Matrigel tubulogenesis assay. We observed that the expression of proliferation marker Ki67 was significantly increased under treatment with MSC secretome in HOVEC cells (P4). MSCs secretome treatment also induced significantly higher expression of several angiogenic markers such as VEGFR2, Tie2/Tek, VE-Cadherin, Endoglin, and VEGF compared to matched control (P4). Furthermore, MSC secretome significantly increased the number of branching points in tubulogenesis assay (P4). Our study suggests that MSC secretome likely contains bioactive factors that can enhance ovarian angiogenesis. Further characterization of these factors can lead to novel therapeutic options for women with premature ovarian insufficiency and other related causes of female infertility.
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Affiliation(s)
- Hang-Soo Park
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Dalia Ashour
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA.,Department of Pathology, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Amro Elsharoud
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Rishi Man Chugh
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Nahed Ismail
- Department of Pathology, University at Illinois at Chicago, Medical College, Chicago, USA
| | | | - Ayman Al-Hendy
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
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Bronckaers A, Gago F, Balzarini J, Liekens S. The dual role of thymidine phosphorylase in cancer development and chemotherapy. Med Res Rev 2009; 29:903-53. [PMID: 19434693 PMCID: PMC7168469 DOI: 10.1002/med.20159] [Citation(s) in RCA: 152] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Thymidine phosphorylase (TP), also known as "platelet-derived endothelial cell growth factor" (PD-ECGF), is an enzyme, which is upregulated in a wide variety of solid tumors including breast and colorectal cancers. TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors are synthesized in an attempt to prevent tumor angiogenesis and metastasis. TP is also indispensable for the activation of the extensively used 5-fluorouracil prodrug capecitabine, which is clinically used for the treatment of colon and breast cancer. Clinical trials that combine capecitabine with TP-inducing therapies (such as taxanes or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in cancer development and therapy: on the one hand, TP inhibitors can abrogate the tumorigenic and metastatic properties of TP; on the other, TP activity is necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine-based chemotherapy.
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Affiliation(s)
| | - Federico Gago
- Departamento de Farmacología, Universidad de Alcalá, 28871 Alcalá de Henares, Spain
| | - Jan Balzarini
- Rega Institute for Medical Research, K.U.Leuven, B‐3000 Leuven, Belgium
| | - Sandra Liekens
- Rega Institute for Medical Research, K.U.Leuven, B‐3000 Leuven, Belgium
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Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, Cheng Z, Shah SV, Wang GJ, Zhang L, Grizzle WE, Mobley J, Zhang HG. Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer 2009; 124:2621-33. [PMID: 19235923 DOI: 10.1002/ijc.24249] [Citation(s) in RCA: 458] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) promote tumor progression. The mechanisms of MDSC development during tumor growth remain unknown. Tumor exosomes (T-exosomes) have been implicated to play a role in immune regulation, however the role of exosomes in the induction of MDSCs is unclear. Our previous work demonstrated that exosomes isolated from tumor cells are taken up by bone marrow myeloid cells. Here, we extend those findings showing that exosomes isolated from T-exosomes switch the differentiation pathway of these myeloid cells to the MDSC pathway (CD11b(+)Gr-1(+)). The resulting cells exhibit MDSC phenotypic and functional characteristics including promotion of tumor growth. Furthermore, we demonstrated that in vivo MDSC mediated promotion of tumor progression is dependent on T-exosome prostaglandin E2 (PGE2) and TGF-beta molecules. T-exosomes can induce the accumulation of MDSCs expressing Cox2, IL-6, VEGF, and arginase-1. Antibodies against exosomal PGE2 and TGF-beta block the activity of these exosomes on MDSC induction and therefore attenuate MDSC-mediated tumor-promoting ability. Exosomal PGE2 and TGF-beta are enriched in T-exosomes when compared with exosomes isolated from the supernatants of cultured tumor cells (C-exosomes). The tumor microenvironment has an effect on the potency of T-exosome mediated induction of MDSCs by regulating the sorting and the amount of exosomal PGE2 and TGF-beta available. Together, these findings lend themselves to developing specific targetable therapeutic strategies to reduce or eliminate MDSC-induced immunosuppression and hence enhance host antitumor immunotherapy efficacy.
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Affiliation(s)
- Xiaoyu Xiang
- Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA
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Inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation on tumor-associated endothelial cells leads to treatment of orthotopic human colon cancer in nude mice. Neoplasia 2008; 9:1066-77. [PMID: 18084614 DOI: 10.1593/neo.07667] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2007] [Revised: 09/27/2007] [Accepted: 09/30/2007] [Indexed: 11/18/2022]
Abstract
The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-alpha) and vascular endothelial growth factor (VEGF) but were negative for EGFR, human epidermal growth factor receptor 2 (HER2), and VEGFR. Double immunofluorescence staining revealed that tumor-associated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR), and phosphorylated VEGFR (pVEGFR). Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase) or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01); this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001). AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, and increased the level of apoptosis in both tumor-associated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer.
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7
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Yuan A, Liu J, Liu Y, Cui G. Chromogranin A-positive tumor cells in human esophageal squamous cell carcinomas. Pathol Oncol Res 2007; 13:321-5. [PMID: 18158567 DOI: 10.1007/bf02940311] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2007] [Accepted: 10/20/2007] [Indexed: 10/21/2022]
Abstract
Gastrointestinal cancers have frequently shown neuroendocrine (NE) differentiation, but whether NE differentiation occurs in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, tissue sections obtained from 43 patients with ESCC from a high-incidence area of Northern China were used for the assessing of NE differentiation by immunohistochemistry using antibody against chromogranin A (CGA). In addition, the malignant characteristics and proliferation capacity of CGA-positive cells were also examined by immunohistochemistry. The clinicopathological significance of these CGA-positive tumor cells in ESCC was assessed. Of 43 ESCC samples, CGAimmunoreactive tumor cells were detected in 10 cases (23.26%). However, the CGA-positive tumor cells were scattered at a very low number among non-immunoreactive tumor cells and were rarely constituted a major part of cancer cell nests. Only 4.65% (2/43) cases showed a high density (>10 cells but <1% of total tumor cell mass) of CGA-positive tumor cells. P53 immunoreactivity was frequently shown, while Ki67 was hard to detect in these CGApositive cells. In addition, no relationship between CGA positivity rate and clinicopathological parameters was found. Thus, we concluded that lowdensity CGA-positive tumor cells can be detected in ESCC, supporting the notion that heterogeneous NE differentiation also exists in tumors that lack neuroendocrine cells in their normal epithelial counterparts.
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Affiliation(s)
- Aping Yuan
- Department of Medicine, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Dreilich M, Wagenius G, Bergström S, Brattström D, Larsson A, Hesselius P, Bergqvist M. The role of cystatin C and the angiogenic cytokines VEGF and bFGF in patients with esophageal carcinoma. Med Oncol 2005; 22:29-38. [PMID: 15750194 DOI: 10.1385/mo:22:1:029] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2004] [Accepted: 08/07/2004] [Indexed: 11/11/2022]
Abstract
Angiogenesis is the formation of new blood vessels out of the existing vascular bed. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are potent circulating angiogenic factors, whereas cystatin C is one of the most important extracellular inhibitors of several cysteine proteinases. Because proteases degrade interstitial connective tissue and basement membranes during tumor growth and metastasis, an association between cystatin C and the angiogenic factors seems plausible. The primary aim of the present study was to investigate if such a correlation exists between these serum markers. The secondary aim was to determine the prognostic value of these circulating cytokines and cystatin C, collected prior to therapy, in patients with esophageal carcinoma.A total of 42 patients with esophageal carcinoma donated serum samples prior to therapy. VEGF and bFGF were correlated to platelet and leukocyte counts and VEGF was correlated to tumor volume (p = 0.04), whereas bFGF was not (p = 0.08). VEGF was significantly correlated with cystatin C (p = 0.027). Survival analysis showed that VEGF regarded as a continuous variable was associated with a significantly poorer survival in the univariate analysis (p = 0.023); however, this was not found for bFGF (p = 0.46). Neither of the angiogenic factors were associated with survival in the multivariate analysis. In the univariate analysis, cystatin c was correlated with survival (p = 0.01), but this was not found in the multivariate analysis (p = 0.28). In conclusion, VEGF was correlated with cystatin C, possible explanations being discussed in the present article. Results of the present study indicate that use of the angiogenic factors as prognostic factors, prior to therapy in patients with esophageal carcinoma, appears limited.
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Affiliation(s)
- Martin Dreilich
- Department of Oncology, University Hospital, Uppsala, Sweden
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Zhi YH, Liu RS, Song MM, Tian Y, Long J, Tu W, Guo RX. Cyclooxygenase-2 promotes angiogenesis by increasing vascular endothelial growth factor and predicts prognosis in gallbladder carcinoma. World J Gastroenterol 2005; 11:3724-8. [PMID: 15968728 PMCID: PMC4316024 DOI: 10.3748/wjg.v11.i24.3724] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationships between the expression of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and the degree of vascularization, clinicopathologic feature, survival time of patients with gallbladder carcinomas.
METHODS: Sixty-four gallbladder carcinoma specimens were evaluated for COX-2, VEGF expression by immunohi-stochemical methods. Microvessel counts (MVC) were determined using CD34. The relationships between COX-2, VEGF expression, CD34-stained MVC, clinicopathologic features and survival time were analyzed. The correlations between COX-2 and VEGF expression, CD34-stained MVC were also investigated.
RESULTS: COX-2, VEGF immunoreactivity were observed in 71.9% (46/64) and 54.7% (35/64) specimens, respectively. The average MVC in 64 cases of gallbladder carcinoma was 57±14 per high power vision field. The status of MVC was closely correlated with Nevin staging, tumor differentiation and lymph node metastasis (P<0.01, 0.002, and 0.003, 0.000, respectively). Increased VEGF expression was significantly correlated with tumor differentiation (poorly and moderately>well differentiated, P<0.05, P = 0.016). Clinical stages had no relation with the expression of VEGF (P>0.05, P = 0.612). There was a positive correlation between COX-2 expression and clinical stages. The positive rate of COX-2 was higher in cases of Nevin stages S4-S5 (81.8%) than in those of Nevin stages S1-S3 (50.0%) with a statistical significance (P<0.01, P = 0.009). The expression of COX-2 did not vary with differentiation (P>0.05, P = 0.067). Statistically significant differences were also observed according to lymph node metastasis, COX-2 expression and VEGF expression (P<0.01, 0.000, and 0.001, respectively). There was no relation between VEGF, COX-2 expression, MVC and the age and sex of patients. MVC and VEGF positive rate in the COX-2 positive gallbladder carcinoma tissue was higher than that in the COX-2 negative tissue (P<0.05, 0.000, and 0.032, respectively). Patients with VEGF, COX-2 positive tumors had a significantly shorter survival time than those with negative tumors (P<0.05, 0.004, 0.01, respectively).
CONCLUSION: Augmented tumor neovascularization induced by VEGF may be one of the several effects of COX-2 responsible for poor prognosis of human gallbladder carcinoma. COX-2 inhibitor, either in combination therapy with other agents, or for chemoprevention, may be effective via suppression of angiogenesis in this fatal disease.
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Affiliation(s)
- Ying-Hui Zhi
- Department of General Surgery, Affiliated Beijing Tiantan Hospital, Capital University of Medical Sciences, Beijing 100050, China.
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Yokoi K, Thaker PH, Yazici S, Rebhun RR, Nam DH, He J, Kim SJ, Abbruzzese JL, Hamilton SR, Fidler IJ. Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. Cancer Res 2005; 65:3716-25. [PMID: 15867367 DOI: 10.1158/0008-5472.can-04-3700] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
We studied growth factors and their receptors in tumor cells and tumor-associated endothelial cells as the therapeutic targets in colon cancer. Immunohistochemical analysis of 13 surgical specimens of human colon adenocarcinoma revealed that both tumor cells and tumor-associated endothelial cells in 11 of the 13 specimens expressed the epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and phosphorylated VEGFR (pVEGFR). HT29 human colon cancer cells growing orthotopically in the cecum of nude mice expressed a high level of EGF, EGFR, pEGFR, VEGF, VEGFR, and pVEGFR. Double-immunofluorescence staining found that tumor-associated mouse endothelial cells also expressed pEGFR and pVEGFR. Tumors in mice treated for 5 weeks with oral AEE788 (an inhibitor of EGFR and VEGFR tyrosine kinase) as a single agent or with CPT-11 alone were smaller (>50%) than those in control mice. Mice treated with the combination of AEE788 and CPT-11 had significantly smaller tumors (P < 0.01) and complete inhibition of lymph node metastasis. AEE788 alone or in combination with CPT-11 inhibited pEGFR, pVEGFR, and phosphorylated Akt expression on tumor-associated endothelial cells as well as on tumor cells. The combination therapy also significantly decreased microvessel density and tumor cell proliferation and increased the level of apoptosis in both tumor cells and tumor-associated endothelial cells. Collectively, these data suggest that the dual inhibition of EGFR and VEGFR signaling pathways in tumor cells and tumor-associated endothelial cells in combination with chemotherapy can provide a new approach to the treatment of colon cancer.
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Affiliation(s)
- Kenji Yokoi
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1429, USA
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Zhao ZS, Zhou JL, Yao GY, Ru GQ, Ma J, Ruan J. Correlative studies on bFGF mRNA and MMP-9 mRNA expressions with microvascular density, progression, and prognosis of gastric carcinomas. World J Gastroenterol 2005; 11:3227-33. [PMID: 15929172 PMCID: PMC4316053 DOI: 10.3748/wjg.v11.i21.3227] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mRNA expressions of bFGF and MMP-9 in gastric carcinomas so as to reveal their correlations with tumor microvascular density (MVD), invasion, metastasis, and prognosis.
METHODS: In situ hybridization and immunohistochemical techniques were used to detect the expressions of bFGFmRNA and MMP-9mRNA and the proteins of CD34 in 105 specimens of gastric carcinomas.
RESULTS: In situ hybridization study showed that positive rates of bFGF mRNA and MMP-9mRNA expressions were 60.95% and 59.19%; the mean MVD was 46.09±11.52 and 43.75±13.41, respectively in piece/0.72 mm2 in tumors with bFGFmRNA and MMP-9mRNA positive expressions, which were significantly higher than those with negative expression (29.41±12.47; 33.45±13.92 piece/0.72 mm2, respectively). The positive expression rates of bFGFmRNA and MMP-9mRNA were correlated to the tumor invasion depth (rs = 0.211, P = 0.031; rs = 0.335, P = 0.001), growing pattern (rs = 0.324, P = 0.001; rs = 0.267, P = 0.006), vessel invasion (rs = 0.579, P = 0.001; rs = 0.209, P = 0.032), lymph node metastasis (rs = 0.405, P = 0.001; rs = 0.343, P = 0.001) and distant metastasis (rs = 0.474, P = 0.001; rs = 0.468, P = 0.001), but not correlated to tumor type (rs = 0.134, P = 0.173; rs = 0.103, P = 0.145) and differentiations (rs = 0.096, P = 0.332; rs = 0.102, P = 0.298). The mean MVD was much higher in the tumors with infiltrating growth at stage T3-T4, with vessel invasion, lymph node metastasis and distant metastasis than those with expanding growth type (t = 10.105, P = 0.001) at stage T1-T2 (t = 5.961, P = 0.001), with non-vessel invasion (t = 7.394, P = 0.001), non-lymph node metastasis (t = 3.819, P = 0.01) and non-distant metastasis (t = 10.578, P = 0.001). Positive correlation was observed between MVD and the expressions of bFGFmRNA and MMP-9mRNA (t = 3.207, P = 0.002; t = 7.035, P = 0.001, respectively). The mean survival time and 5-year survival rate were lower in cases with MVD over 39.5 and the positive expressions of bFGFmRNA and MMP-9mRNA than those with MVD less than 39.5 and the negative expressions of bFGFmRNA and MMP-9mRNA.
CONCLUSION: bFGF and MMP-9 promote the angiogenesis of the gastric cancers. Detection of the expressions of bFGF and MMP-9 can serve as a useful index to determine the angiogenesis, invasion, metastasis, and prognosis of gastric cancers.
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Affiliation(s)
- Zhong-Sheng Zhao
- Department of Pathology, Zhejiang Provincial Hospital, Hangzhou 310014, Zhejiang Province, China
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Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 2005; 7:134-53. [PMID: 15831232 PMCID: PMC1871894 DOI: 10.1215/s1152851704001115] [Citation(s) in RCA: 494] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Glioblastomas, like other solid tumors, have extensive areas of hypoxia and necrosis. The importance of hypoxia in driving tumor growth is receiving increased attention. Hypoxia-inducible factor 1 (HIF-1) is one of the master regulators that orchestrate the cellular responses to hypoxia. It is a heterodimeric transcription factor composed of alpha and beta subunits. The alpha subunit is stable in hypoxic conditions but is rapidly degraded in normoxia. The function of HIF-1 is also modulated by several molecular mechanisms that regulate its synthesis, degradation, and transcriptional activity. Upon stabilization or activation, HIF-1 translocates to the nucleus and induces transcription of its downstream target genes. Most important to gliomagenesis, HIF-1 is a potent activator of angiogenesis and invasion through its upregulation of target genes critical for these functions. Activation of the HIF-1 pathway is a common feature of gliomas and may explain the intense vascular hyperplasia often seen in glioblastoma multiforme. Activation of HIF results in the activation of vascular endothelial growth factors, vascular endothelial growth factor receptors, matrix metalloproteinases, plasminogen activator inhibitor, transforming growth factors alpha and beta, angiopoietin and Tie receptors, endothelin-1, inducible nitric oxide synthase, adrenomedullin, and erythropoietin, which all affect glioma angiogenesis. In conclusion, HIF is a critical regulatory factor in the tumor microenvironment because of its central role in promoting proangiogenic and invasive properties. While HIF activation strongly promotes angiogenesis, the emerging vasculature is often abnormal, leading to a vicious cycle that causes further hypoxia and HIF upregulation.
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Affiliation(s)
| | | | | | | | | | - Erwin G. Van Meir
- Address correspondence to Erwin G. Van Meir, Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, NE, Room C5078, Atlanta, GA 30322, USA (
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Covello KL, Simon MC, Keith B. Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Res 2005; 65:2277-86. [PMID: 15781641 DOI: 10.1158/0008-5472.can-04-3246] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hypoxia-inducible factors (HIF) are essential transcriptional regulators that mediate adaptation to hypoxic stress in rapidly growing tissues such as tumors. HIF activity is regulated by hypoxic stabilization of the related HIF-1alpha and HIF-2alpha subunits, which are frequently overexpressed in cancer cells. To assess the relative tumor-promoting functions of HIF-1alpha and HIF-2alpha directly, we replaced HIF-1alpha expression with HIF-2alpha by creating a novel "knock-in" allele at the Hif-1alpha locus through homologous recombination in primary murine embryonic stem cells. Compared with controls, s.c. teratomas derived from knock-in embryonic stem cells were larger and more proliferative, had increased microvessel density, and exhibited increased expression of vascular endothelial growth factor, transforming growth factor-alpha, and cyclin D1. These and other data indicate that HIF-2alpha promotes tumor growth more effectively than HIF-1alpha in multiple contexts.
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Affiliation(s)
- Kelly L Covello
- Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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Clinical significance of angiogenesis in gastrointestinal cancers: a target for novel prognostic and therapeutic approaches. Ann Surg 2003. [PMID: 12832961 DOI: 10.1097/00000658-200307000-00003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To review the current data on the prognostic and therapeutic implications of tumor angiogenesis in gastrointestinal cancers. SUMMARY BACKGROUND DATA Numerous studies have evaluated the prognostic value of tumor angiogenesis and the potential role of antiangiogenic therapy in various gastrointestinal cancers. METHODS A Medline literature search was conducted using "angiogenesis" or the names of various angiogenic factors in combination with the names of gastrointestinal cancers as the key words. RESULTS Several studies have demonstrated a significant prognostic impact of tumor microvessel density and tumor expression of angiogenic factors, in particular vascular endothelial growth factor (VEGF), in various gastrointestinal cancers. A few studies have suggested that circulating VEGF might be a useful prognostic marker. However, results were not consistent across all studies and were limited by the retrospective nature of most studies. Antiangiogenic therapy has been shown to be effective against all common gastrointestinal cancers in preclinical studies, but currently there are few clinical data with regard to antiangiogenic therapy in gastrointestinal cancers. CONCLUSIONS There is mounting evidence to suggest that assessment of tumor angiogenesis might provide a novel approach of prognostication in patients with gastrointestinal cancers. However, current results from retrospective studies need to be validated by prospective studies. Antiangiogenic therapy is a promising strategy of cancer treatment that might be particularly useful in combination therapy for unresectable cancers or as an adjuvant therapy for resectable tumors.
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Poon RTP, Fan ST, Wong J. Clinical significance of angiogenesis in gastrointestinal cancers: a target for novel prognostic and therapeutic approaches. Ann Surg 2003; 238:9-28. [PMID: 12832961 PMCID: PMC1422670 DOI: 10.1097/01.sla.0000075047.47175.35] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To review the current data on the prognostic and therapeutic implications of tumor angiogenesis in gastrointestinal cancers. SUMMARY BACKGROUND DATA Numerous studies have evaluated the prognostic value of tumor angiogenesis and the potential role of antiangiogenic therapy in various gastrointestinal cancers. METHODS A Medline literature search was conducted using "angiogenesis" or the names of various angiogenic factors in combination with the names of gastrointestinal cancers as the key words. RESULTS Several studies have demonstrated a significant prognostic impact of tumor microvessel density and tumor expression of angiogenic factors, in particular vascular endothelial growth factor (VEGF), in various gastrointestinal cancers. A few studies have suggested that circulating VEGF might be a useful prognostic marker. However, results were not consistent across all studies and were limited by the retrospective nature of most studies. Antiangiogenic therapy has been shown to be effective against all common gastrointestinal cancers in preclinical studies, but currently there are few clinical data with regard to antiangiogenic therapy in gastrointestinal cancers. CONCLUSIONS There is mounting evidence to suggest that assessment of tumor angiogenesis might provide a novel approach of prognostication in patients with gastrointestinal cancers. However, current results from retrospective studies need to be validated by prospective studies. Antiangiogenic therapy is a promising strategy of cancer treatment that might be particularly useful in combination therapy for unresectable cancers or as an adjuvant therapy for resectable tumors.
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Affiliation(s)
- Ronnie Tung-Ping Poon
- Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China.
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Zheng S, Han MY, Xiao ZX, Peng JP, Dong Q. Clinical significance of vascular endothelial growth factor expression and neovascularization in colorectal carcinoma. World J Gastroenterol 2003; 9:1227-30. [PMID: 12800229 PMCID: PMC4611789 DOI: 10.3748/wjg.v9.i6.1227] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To clarify the association of vascular endothelial growth factor (VEGF) and microvascular density (MVD) expression with the angiogenesis and prognosis of colorectal cancer.
METHODS: A total of 97 cases of colorectal carcinomas were examined by immunohistochemical staining (SP method), using anti-VEGF and anti-factor CD34+ monoclonal antibodies.
RESULTS: VEGF positive staining was obtained in 68 out of 97 cases (70.1%), and observed mainly in the cytoplasm of tumor cells, and also frequently in stromal cells. VEGF expression was more intense in poorly differentiated adenocarcinoma in comparison with others, but there was no significant correlation between VEGF expression and age, sex and stage. A significant correlation was found between the MVD and grades, and there was no significant relationship between the MVD and age, sex, and stage. The MVD in the VEGF positive group (68 cases) was higher than that in the negative group. Upon multivariate analysis, the significant variables were stage, tumor grade and MVD; VEGF expression was not an independent prognostic factor.
CONCLUSION: The expression of VEGF has a significant correlation with MVD; MVD expression has prognostic value but VEGF has not in colon cancer.
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Affiliation(s)
- Shu Zheng
- Cancer Institute, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
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Tao HQ, Zou SC, Wang RN, Lin YZ. Relationship between gastric carcinogenesis and angiogenesis. Shijie Huaren Xiaohua Zazhi 2003; 11:43-46. [DOI: 10.11569/wcjd.v11.i1.43] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the relationship between gastric carcinogenesis and angiogenesis.
METHODS: Experimental model of gastric precancerous lesions and carcinomas was established in rats by chemical carcinogen, N-methyl-N?nitro-soguanidine(MNNG). The specimens were collected in groups at different time points from pre-malignant precursor to gastric carcinoma, the sections were stained by HE and angiogenesis was observed. Tissue sections were also immunohistochemically stained for CD34 antigen, a marker for endothelial cells, and the microvessels were counted.
RESULTS: Only a few microvessels were found in the hyperplastic stage of gastric mucosal glands, but angiogenesis was increased markedly and heterogeneously distributed in the dysplastic stage, especially in specimens with moderate and severe degree of dysplasia as well as in the intra-mucosal carcinoma. Profuse vascularity in the frontier of tumor invasion and tumor stroma was found in the infiltrating carcinoma. Comparison of microvessel counts in low grade lesions(hyperplasia and mild dysplasia) with microvessel counts in moderate(26.3±9.6 vs 17.1±5.6 P < 0.05) and severe dysplasia lesions(32.5±11.7 vs 17.1±5.6 P < 0.01) showed a statistically significant increase in the more advanced lesions, but there was no significant difference in vessel count between moderate and severe degree of dysplasia.
CONCLUSION: Angiogenesis is switched on at the early stage of gastric carcinogenesis, and becomes more pronounced with the progress toward more advanced stage. There is a close relationship between gastric carcinogenesis and angiogenesis.
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