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Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. Front Oncol 2024; 14:1382183. [PMID: 38947886 PMCID: PMC11211377 DOI: 10.3389/fonc.2024.1382183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/24/2024] [Indexed: 07/02/2024] Open
Abstract
Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.
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Affiliation(s)
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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2
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Goudot G, Berkane Y, de Clermont-Tonnerre E, Guinier C, Filz von Reiterdank I, van Kampen A, Uygun K, Cetrulo CL, Uygun BE, Dua A, Lellouch AG. Microvascular assessment of fascio-cutaneous flaps by ultrasound: A large animal study. Front Physiol 2022; 13:1063240. [PMID: 36589429 PMCID: PMC9797596 DOI: 10.3389/fphys.2022.1063240] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Objectives: Blood perfusion quality of a flap is the main prognostic factor for success. Microvascular evaluation remains mostly inaccessible. We aimed to evaluate the microflow imaging mode, MV-Flow, in assessing flap microvascularization in a pig model of the fascio-cutaneous flap. Methods: On five pigs, bilateral saphenous fascio-cutaneous flaps were procured on the superficial femoral vessels. A conventional ultrasound evaluation in pulsed Doppler and color Doppler was conducted on the ten flaps allowing for the calculation of the saphenous artery flow rate. The MV-Flow mode was then applied: for qualitative analysis, with identification of saphenous artery collaterals; then quantitative, with repeated measurements of the Vascularity Index (VI), percentage of pixels where flow is detected relative to the total ultrasound view area. The measurements were then repeated after increasing arterial flow by clamping the distal femoral artery. Results: The MV-Flow mode allowed a better follow-up of the saphenous artery's collaterals and detected microflows not seen with the color Doppler. The VI was correlated to the saphenous artery flow rate (Spearman rho of 0.64; p = 0.002) and allowed to monitor the flap perfusion variations. Conclusion: Ultrasound imaging of microvascularization by MV-Flow mode and its quantification by VI provides valuable information in evaluating the microvascularization of flaps.
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Affiliation(s)
- Guillaume Goudot
- Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States,Hôpital Européen Georges-Pompidou, Assistance Publique—Hôpitaux de Paris (APHP), Université Paris-Cité, Paris, France,*Correspondence: Guillaume Goudot,
| | - Yanis Berkane
- Hôpital Européen Georges-Pompidou, Assistance Publique—Hôpitaux de Paris (APHP), Université Paris-Cité, Paris, France,Shriners Children’s Boston, Boston, MA, United States,Centre Hospitalier Universitaire de Rennes, Université de Rennes 1, Rennes, France
| | - Eloi de Clermont-Tonnerre
- Shriners Children’s Boston, Boston, MA, United States,Division of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory Center for Transplantation Sciences, Massachusetts General Hospital Harvard Medical School, Boston, MA, United States
| | - Claire Guinier
- Shriners Children’s Boston, Boston, MA, United States,Division of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory Center for Transplantation Sciences, Massachusetts General Hospital Harvard Medical School, Boston, MA, United States
| | - Irina Filz von Reiterdank
- Shriners Children’s Boston, Boston, MA, United States,Division of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory Center for Transplantation Sciences, Massachusetts General Hospital Harvard Medical School, Boston, MA, United States,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Antonia van Kampen
- Division of Cardiac Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States,University Clinic of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany
| | - Korkut Uygun
- Shriners Children’s Boston, Boston, MA, United States,Division of Cardiac Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Curtis L. Cetrulo
- Shriners Children’s Boston, Boston, MA, United States,Division of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory Center for Transplantation Sciences, Massachusetts General Hospital Harvard Medical School, Boston, MA, United States
| | - Basak E. Uygun
- Shriners Children’s Boston, Boston, MA, United States,Division of Cardiac Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Anahita Dua
- Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Alexandre G. Lellouch
- Shriners Children’s Boston, Boston, MA, United States,Division of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory Center for Transplantation Sciences, Massachusetts General Hospital Harvard Medical School, Boston, MA, United States,Department of Plastic, Reconstructive and Aesthetic Surgery, Groupe Almaviva Santé, Clinique de l’Alma, IAOPC, Paris, France
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Hemodynamic Changes in the Masseter and Superior Orbicularis Oris Muscles before and after Exercise Load: A Comparison between Young Adult Women and Middle-Aged to Old Adult Women. Int J Dent 2022; 2022:5340301. [PMID: 36065399 PMCID: PMC9440816 DOI: 10.1155/2022/5340301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 07/29/2022] [Indexed: 11/23/2022] Open
Abstract
Background The vascularity index (VI) is useful for measuring the hemodynamics on ultrasound imaging. However, there are no reports concerning the application of the VI to facial muscles. Objective The aim of this study was (1) to establish a method of measuring the hemodynamics in facial muscles in a constant way and (2) to evaluate the hemodynamic changes in the masseter and superior orbicularis oris muscles (SOOMs) before and after exercise load in two subject groups of females of different ages. Methods (1) The VI in the SOOM was calculated, and the test-retest reliability was assessed in seven healthy adults. (2) The VIs in the left-side masseter and SOOM were calculated in 3 sessions: before exercise loading (T0), immediately after loading (T1), and 5 minutes after T1 (T2) for the young adult group (YAG, n = 20; age range, 20–35 years) and the middle-aged to old group (MOG, n = 20; age range, 50–70 years). Tasks were gum chewing for the masseter muscle and lip sealing for the SOOM. The differences in the mean peak flows between two sessions were examined. Results (1) Significant differences were not noted for the repeatedly measured average volumes of blood flow with good test-retest agreement (intraclass correlation coefficient = 0.81). (2) In both muscles of the YAG, there were a significant increase in T1 compared with T0 and a significant decrease in T2 compared with T1 (all p < 0.05). In both muscles of the MOG, no significant differences were noted in either comparison. Conclusions A method of measuring the hemodynamics in facial muscles was developed and showed good reliability. Changes in the blood flow after exercise load in these muscles may vary with age in women.
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Kang L, Kim M, Lee YM. Expression of ICAM-1 in Blood Vascular Endothelium and Tissues in Human Premalignant Lesion and Gastric/Hepatocellular Carcinomas. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2022; 79:170-176. [PMID: 35473775 DOI: 10.4166/kjg.2022.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 12/16/2022]
Abstract
Background/Aims Angiogenesis is essential for the outgrowth and metastasis of tumors. The structure and characteristics of tumor vasculature differ from those of normal vessels. We compared the characteristics of differentially expressed genes in endothelial cells (ECs) isolated from gastric and normal cells. Methods Previously, we had isolated pure tumor ECs (TECs) and normal ECs (NECs) from advanced gastric cancer (AGC) lesions and normal mucosal tissues, respectively. Using the oligomer chip platform of the Affymetrix GeneChip technology, genes that were expressed more than three-fold with a significance of p≤0.001 were measured. The intercellular adhesion molecule 1 (ICAM-1) was found to be overexpressed in the TECs compared to the normal gastric ECs. In this study, the upregulation of ICAM-1 was confirmed in cultured TECs by immunofluorescence. Results The expression of ICAM-1 was upregulated in the ECs, as well as in the stromal and immune cells, in early human gastric preneoplastic and hepatic fibrotic tissues. Upregulation of ICAM-1 was observed in the TECs, immune cells, and cancer epithelial cells in AGC and hepatocellular carcinoma (HCC). These results suggest that increased ICAM-1 expression in the ECs of the tissue microenvironment progressively contributes to the recruitment of immune cells to promote inflammation, leading to fibrosis and tumorigenesis. Conclusions Therefore, upregulated ICAM-1 in the tissues in premalignant gastric diseases or hepatic fibrosis and their malignant cancers could be a promising target for disease prevention and treatment.
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Affiliation(s)
- Li Kang
- Department of Molecular Pathophysiology, Kyungpook National University College of Pharmacy, Daegu, Korea
| | - Moonsik Kim
- Department of Pathology, Kyungpook National University Chilgok Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - You Mie Lee
- Department of Molecular Pathophysiology, Kyungpook National University College of Pharmacy, Daegu, Korea.,Vessel-Organ Interaction Research Center, VOICE (MRC), Kyungpook National University, Daegu, Korea
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Zhang Y, Zhang J, Yang L, Huang S. A meta-analysis of the utility of transabdominal ultrasound for evaluation of gastric cancer. Medicine (Baltimore) 2021; 100:e26928. [PMID: 34397938 PMCID: PMC8360412 DOI: 10.1097/md.0000000000026928] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 07/27/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Clinical discovery/staging of gastric cancer (GC) is crucial in designing the treatment strategies and largely decides GC patients' survival. Endoscopic ultrasonography (EUS) and computed tomography (CT) are 2 useful GC diagnosis tools. High doses of radiation associated with CT make its use limited, while the process of EUS is stressful, time-consuming, and challenging. Transabdominal ultrasound (TAUS) is a promising candidate to address these shortcomings. This study aimed to meta-analyze the diagnostic accuracy and sensitivity of TAUS in discriminating between advanced and early GCs, as well as compare its utility with other imaging techniques.Methods: Literature searches were conducted using PubMed, Web of Science, Embase, and Cochrane Library databases up to 2019. Data were analyzed using RevMan software (Cochrane Collaboration, Oxford, UK), and pooled estimates of accuracy, sensitivity, and other features were acquired. Seven papers were eventually selected for meta-analysis. RESULTS TAUS had distinct diagnostic efficacies for early and advanced GC patients. The accuracy and sensitivity were significantly higher in the advanced group. A high color Doppler vascularity index and a lesion larger than 1 cm were 2 features of advanced GC. Moreover, TAUS had a comparable (but slightly higher) accuracy than CT and EUS. CONCLUSIONS TAUS is more accurate and sensitive in diagnosing advanced GC compared to early GC. More features of advanced GC are required to improve the recognition ability. At least, TAUS can be considered as a complementary imaging diagnostic tool to CT and EUS.
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Affiliation(s)
- Yuqin Zhang
- Department of Radiology, Second People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Minhou County, China
| | | | - Liu Yang
- Unimed Scientific Inc., Wuxi, China
| | - Songxiong Huang
- Health Management Center, Second People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, No. 282, Wusi Road, Minhou County, China
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Higgins LE, Heazell AEP, Simcox LE, Johnstone ED. Intra-placental arterial Doppler: A marker of fetoplacental vascularity in late-onset placental disease? Acta Obstet Gynecol Scand 2020; 99:865-874. [PMID: 31943128 DOI: 10.1111/aogs.13807] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 11/12/2019] [Accepted: 01/08/2020] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Late-gestation adverse pregnancy outcome is associated with reduced placental villous vascularity but rarely with a frankly abnormal umbilical artery Doppler waveform. The clinical utility of umbilical artery Doppler velocimetry in late gestation is limited by poor understanding of what aspect(s) of placental structure and function the impedance reflects. We hypothesized that placental arterial circulation impedance reflects placental vascularity and arterial function. MATERIAL AND METHODS This was a secondary analysis of data from the FEMINA2 study, a study of pregnancy outcome after reduced fetal movement. Forty-three pregnancies that delivered within 7 days of ultrasound assessment were examined. Impedance was quantified by pulsatility index (PI) from umbilical, chorionic plate arteries, and intra-placental arteries. Site-specific PI was compared with villous vascularity (CD31 immunostaining) and placental arterial function (wire myography) by regression analysis (P < .01) where factor analysis suggested potential co-variance (Eigen value > 2). RESULTS Pulsatility index decreased with proximity to the placental microvasculature (P < .0001). Intra-placental artery PI correlated significantly with vessel number (R2 = 0.40, P = .0007). No significant relations between umbilical or chorionic plate artery PI and villous vascularity were found (P ≥ .11 and P ≥ .042). No significant co-variance was suggested between PI at any Doppler sampling site and ex vivo placental arterial function indices. Measurement reliability (intraclass correlation coefficient) was highest in the umbilical artery (PI 0.75 and 0.50 for intra- and interoperator reliability, respectively) and lowest in the intra-placental arteries (PI 0.55 and 0.41, respectively). Systematic bias in umbilical artery PI was observed between observers, but not at other Doppler sampling sites. CONCLUSIONS More vascular placentas ex vivo are associated with reduced intra-placental artery Doppler impedance in utero. Although umbilical (but not intra-placental) artery Doppler PI is associated with adverse outcome after reduced fetal movement, this predictive ability does not appear to be through assessment of placental vascularity or chorionic plate arterial function. The inferior reliability of intra-placental artery Doppler, although similar to previously published reliability of umbilical artery Doppler, impairs its ability to detect subtle differences in placental vascularity, and must be significantly improved before it could be considered a clinically useful test.
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Affiliation(s)
- Lucy E Higgins
- Maternal and Fetal Health Research Center, Institute of Human Development, University of Manchester, Manchester, UK.,St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Center, Manchester, UK
| | - Alexander E P Heazell
- Maternal and Fetal Health Research Center, Institute of Human Development, University of Manchester, Manchester, UK.,St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Center, Manchester, UK
| | - Louise E Simcox
- Maternal and Fetal Health Research Center, Institute of Human Development, University of Manchester, Manchester, UK.,St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Center, Manchester, UK
| | - Edward D Johnstone
- Maternal and Fetal Health Research Center, Institute of Human Development, University of Manchester, Manchester, UK.,St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Center, Manchester, UK
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7
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Lee JH, Shin HJ, Yoon JH, Kim EK, Moon HJ, Lee HS, Kwon HJ, Kwak JY. Predicting lymph node metastasis in patients with papillary thyroid carcinoma by vascular index on power Doppler ultrasound. Head Neck 2016; 39:334-340. [PMID: 27704649 DOI: 10.1002/hed.24592] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND For patients with papillary thyroid carcinoma (PTC), lymph node metastasis is associated with an increased recurrence rate. The purpose of this study was to investigate whether the vascular endothelial growth factor (VEGF), microvessel density (MVD), and vascular index (VI) can predict lymph node metastasis in patients with PTC. METHODS From January 2011 to October 2011, 202 patients with PTCs underwent preoperative staging ultrasound evaluation. To evaluate vascularity, we measured the VI, VEGF expression, and MVD. RESULTS The VI was significantly correlated with MVD (p = .009). On multivariate analysis, young age showed a significant correlation with lymph node metastasis (p < .001; p < .001; p < .001). However, the other clinicopathologic features, VEGF, MVD, and VI failed to show any significant correlations with lymph node metastasis. CONCLUSION Although the VI showed significant correlation with MVD, it was not significantly correlated to lymph node metastasis. © 2016 Wiley Periodicals, Inc. Head Neck 39: 334-340, 2017.
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Affiliation(s)
- Ji Hye Lee
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Hyun Joo Shin
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Jung Hyun Yoon
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Eun-Kyung Kim
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Hee Jung Moon
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
| | - Hye Sun Lee
- Biostastistics Collaboration Unit, Medical Research Center, Yonsei University, College of Medicine, Seoul, Korea
| | - Hyeong Ju Kwon
- Department of Pathology, Yonsei University, College of Medicine, Seoul, Korea.,Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju, Korea
| | - Jin Young Kwak
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Korea
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Cabreros SS, Jimenez NM, Greer JD, Adebar TK, Okamura AM. Remote Electromagnetic Vibration of Steerable Needles for Imaging in Power Doppler Ultrasound. IEEE INTERNATIONAL CONFERENCE ON ROBOTICS AND AUTOMATION : ICRA : [PROCEEDINGS]. IEEE INTERNATIONAL CONFERENCE ON ROBOTICS AND AUTOMATION 2015; 2015:2244-2249. [PMID: 26413379 DOI: 10.1109/icra.2015.7139496] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Robotic needle steering systems for minimally invasive medical procedures require complementary medical imaging systems to track the needles in real time. Ultrasound is a promising imaging modality because it offers relatively low-cost, real-time imaging of the needle. Previous methods applied vibration to the base of the needle using a voice coil actuator, in order to make the needle visible in power Doppler ultrasound. We propose a new method for needle tip vibration, using electromagnetic actuation of small permanent magnets placed inside the needle to improve needle tip visibility in power Doppler imaging. Robotic needle insertion experiments using artificial tissue and ex vivo porcine liver showed that the electromagnetic tip vibration method can generate a stronger Doppler response compared to the previous base vibration method, resulting in better imaging at greater needle depth in tissue. It also eliminates previous issues with vibration damping along the shaft of the needle.
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Affiliation(s)
- Sarah S Cabreros
- Department of Mechanical Engineering, Stanford University, Stanford, CA 94305 USA
| | - Nina M Jimenez
- Department of Mechanical Engineering, Stanford University, Stanford, CA 94305 USA
| | - Joseph D Greer
- Department of Mechanical Engineering, Stanford University, Stanford, CA 94305 USA
| | - Troy K Adebar
- Department of Mechanical Engineering, Stanford University, Stanford, CA 94305 USA
| | - Allison M Okamura
- Department of Mechanical Engineering, Stanford University, Stanford, CA 94305 USA
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Sun R, Wu J, Chen Y, Lu M, Zhang S, Lu D, Li Y. Down regulation of Thrombospondin2 predicts poor prognosis in patients with gastric cancer. Mol Cancer 2014; 13:225. [PMID: 25262009 PMCID: PMC4189190 DOI: 10.1186/1476-4598-13-225] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 09/22/2014] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Thrombospondins (THBSs) are a family of multidomain and secreted matricellular Ca(2+)-binding glycoproteins which has at least five members encoded by independent genes. As a THBSs family member, Thrombospondin2 (THBS2) has been reported to regulate angiogenesis. Nevertheless, the functions and clinical significance of THBS2 still remains unclear in gastric cancer. METHODS The mRNA and protein expression levels of THBS2 were assessed in 14 paired of gastric cancer specimens and corresponding normal mucosas using quantitative real-time PCR and western blot analysis. Immunohistochemistry of THBS2 and CD34 on population-based tissue microarrays consisting of 129 gastric cancer cases were used to evaluate the prognostic significance of THBS2 and microvessel density (MVD) of each sample. Survival analyses were performed by Kaplan-Meier method and Cox's proportional hazards model. Colony formation assay, endothelial cell tube formation assay, cell migration assay and apoptosis analysis in MKN-45 and SGC-7901 cell lines were carried out to evaluate the effects of THBS2 on gastric cancer in vitro. RESULTS 85.71% (12 of 14) gastric cancer tissues expressed remarkably lower THBS2 in both mRNA and protein levels than the corresponding normal controls. Consistently, tissue microarray (TMA) results showed THBS2 levels were also inhibited in gastric cancer tissues compared with the normal controls. Moreover, we observed that patients with higher levels of THBS2 were significantly correlated with more favourable prognosis while decreased THBS2 expression were associated with poorer histological grades of gastric cancer. Additionally, our in vitro experiments further demonstrated that overexpression of THBS2 could impede both the proliferation rate and the tube formation of Human umbilical vein endothelial cells (HUVECs) in MKN-45 and SGC-7901 cell lines. CONCLUSION Our study suggests THBS2 is aberrantly expressed in gastric cancer and plays a critical role in cancer progression, which can be a potential prognosis predictor of gastric cancer.
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Affiliation(s)
| | | | | | | | | | - Daru Lu
- The Eighth Department of General Surgery, Hefei, China.
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Shin HJ, Kim EK, Moon HJ, Yoon JH, Han KH, Kwak JY. Can increased tumoral vascularity be a quantitative predicting factor of lymph node metastasis in papillary thyroid microcarcinoma? Endocrine 2014; 47:273-82. [PMID: 24366642 DOI: 10.1007/s12020-013-0131-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Accepted: 11/21/2013] [Indexed: 12/15/2022]
Abstract
The aim of the present study was to evaluate the clinical implications of the vascular index (VI) as a predicting factor for central and lateral lymph node metastasis (LNM) in patients with papillary thyroid microcarcinoma (PTMC). From January 2011 to October 2011, 588 patients (495 females, 93 males) who were diagnosed with PTMC were included. Clinicopathologic characteristics of patients and ultrasound (US) features of the lesions including VI were evaluated retrospectively. The VI was measured with QLAB 7.0 quantification software using preoperative Doppler US images. Univariate and multivariate analysis were used to assess predictive factors of LNM. From 588 patients, 140 patients (23.8 %) had central LNM and 26 patients (4.4 %) had lateral LNM on pathologic results. The presence of lateral LNM [odds ratio (OR) 5.46; 95 % confidence interval (CI) = 2.19-13.64], bilaterality (OR 2.16; 95 % CI 1.17-4.01), and increased tumor size (OR 1.15; 95 % CI 1.04-1.28) were significant independent factors for predicting central LNM. The presence of central LNM (OR 5.58; 95 % CI 2.22-14.04), upper third location of malignancy (OR 2.50; 95 % CI 1.01-6.21), and tumor size (OR 1.34; 95 % CI 1.03-1.73) were significant independent factors for predicting lateral LNM. However, the VI was not a significant predicting factor for both central and lateral LNM. Therefore, the VI of PTMC may not be useful for predicting central and lateral LNM in patients with PTMC.
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Affiliation(s)
- Hyun Joo Shin
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemoon-gu, Seoul, 120-752, South Korea
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Chang YC, Huang YH, Huang CS, Chang RF. Vascular morphology and tortuosity analysis of breast tumor inside and outside contour by 3-D power Doppler ultrasound. ULTRASOUND IN MEDICINE & BIOLOGY 2012; 38:1859-69. [PMID: 22975041 DOI: 10.1016/j.ultrasmedbio.2012.06.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Revised: 06/16/2012] [Accepted: 06/26/2012] [Indexed: 05/04/2023]
Abstract
This study aimed to evaluate morphologic and tortuous features of vessels inside and outside the tumor region on three-dimensional power Doppler ultrasonography (PDUS) in 113 breast mass lesions, including 60 benign and 53 malignant tumors. Compared with benign lesions, malignant breast lesions had significantly larger values of vascular morphologic and tortuous features and larger tumor sizes. The receiver operating characteristic curve analysis and Student's t-test were used to estimate the performance of a proposed classification system using 13 vascular features and tumor size selected by the neural network. Accuracy, sensitivity, specificity, positive predictive value, negative predictive value and the A(Z) value of the diagnosis performance based on 14 features were 89.38% (101/113), 84.91% (45/53), 93.33% (56/60), 91.84% (45/49), 87.50% (56/64) and 0.9188, respectively. The three-dimensional PDUS morphologic and tortuous characteristics of blood vessels inside and outside breast mass lesions can be effectively used to classify benign and malignant tumors.
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Affiliation(s)
- Yeun-Chung Chang
- Department of Medical Imaging, National Taiwan Univesity Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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12
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Xi HQ, Wu XS, Wei B, Chen L. Aberrant expression of EphA3 in gastric carcinoma: correlation with tumor angiogenesis and survival. J Gastroenterol 2012; 47:785-94. [PMID: 22350700 DOI: 10.1007/s00535-012-0549-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 01/02/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND EphA3, a member of the Eph receptor tyrosine kinases, plays important roles in tumor angiogenesis and progression. However, the function of EphA3 in solid tumors has not been widely studied. We aimed to explore EphA3 expression in gastric carcinoma and analyze its role as a potential prognostic factor. METHODS Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess EphA3 mRNA in a normal gastric mucosa cell line and carcinoma cell lines. Immunohistochemistry for EphA3 and vascular endothelial growth factor (VEGF) was performed in 318 cases of gastric carcinoma. CD34 immunohistochemical staining was used for microvessel density (MVD) counting. Western blotting was used to analyze EphA3 expression in the cell lines and to determine the expression of EphA3 and VEGF in 75 cases of gastric carcinoma and matched normal mucosa. RESULTS EphA3 mRNA and protein expression was significantly higher in gastric cancer than that in normal mucosa (all P < 0.001). EphA3 was significantly correlated with TNM stage and poor prognosis (all P < 0.001). Multivariate analysis showed that EphA3 had an independent effect on survival (P = 0.037). EphA3 was positively correlated with VEGF (P < 0.001), and MVD (P < 0.001). According to Western blot analysis, both EphA3 and VEGF expression were significantly higher in carcinoma than that in normal mucosa (all P < 0.001). A positive correlation was observed between EphA3 and VEGF expression in cancer (P < 0.001, r = 0.513). CONCLUSIONS EphA3 may play important roles in the angiogenesis and prognosis of gastric carcinoma, and thus may become a useful target for therapeutic intervention and a potential indicator for clinical assessment of tumor prognosis.
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Affiliation(s)
- Hong-Qing Xi
- Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, China
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Yeh FC, Cheng JZ, Chou YH, Tiu CM, Chang YC, Huang CS, Chen CM. Stochastic region competition algorithm for Doppler sonography segmentation. Med Phys 2012; 39:2867-76. [DOI: 10.1118/1.4705350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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Hypoxia, tumour-associated macrophages, microvessel density, VEGF and matrix metalloproteinases in human gastric cancer: interaction and impact on survival. Clin Transl Oncol 2011; 13:133-8. [PMID: 21324802 DOI: 10.1007/s12094-011-0630-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hypoxia is a key feature of the microenvironment of cancer cells actively participating in tumour progression. Our study was aimed to evaluate the impact of hypoxia and hypoxia-associated factors on tumour progression and survival of patients with gastric cancer. MATERIAL AND METHODS One hundred and five resected specimens were used. The level of tumour hypoxia was evaluated using (31)P NMR spectroscopy, CD68 (tumour-associated macrophages), CD34 (microvessel density, MVD) and VEGF expression, immunohistochemistry, MMP-2 and MMP-9 activity, zymography. Statistical analysis was conducted using Pearson's test, Kaplan-Meier survival analysis, log-rank test and Cox proportional hazards model. RESULTS Intratumoral hypoxia level has been significantly correlated with VEGF expression, TAM number and total protease activity. The overall survival rate of patients with strong tumour hypoxia, high level of MVD, VEGF expression, TAM and MMP activity was significantly lower than that of the patients without the mentioned tumour characteristics. CONCLUSIONS The hypoxia-associated signalling that is activated in tumours promotes tumour progression through the recruitment of macrophages, remodelling of extracellular matrix and neoangiogenesis.
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Abstract
A more differentiated therapy regimen for gastric carcinoma requires more precise preoperative staging. In patients with early gastric cancer (EGC), especially in cases with carcinoma confined to mucosa, endoscopic resection (ER) is usually performed to avoid unnecessary surgical procedures. To achieve R0 resection for locally advanced gastric cancer (AGC), neoadjuvant treatments have been investigated. Clinical staging of gastric cancer has been greatly improved by advances in imaging techniques, such as endoscopic ultrasonography (EUS), transabdominal ultrasonography (TAUS), multi-slice spiral CT (MSCT), magnetic resonance imaging (MRI), positron emission tomography (PET), combined PET-CT scans, and laparoscopic staging. This paper aims to summarize the recent advances in preoperative staging of gastric cancer.
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Shiyan L, Pintong H, Zongmin W, Fuguang H, Zhiqiang Z, Yan Y, Cosgrove D. The relationship between enhanced intensity and microvessel density of gastric carcinoma using double contrast-enhanced ultrasonography. ULTRASOUND IN MEDICINE & BIOLOGY 2009; 35:1086-1091. [PMID: 19419811 DOI: 10.1016/j.ultrasmedbio.2009.03.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2009] [Revised: 02/24/2009] [Accepted: 03/09/2009] [Indexed: 05/27/2023]
Abstract
The purpose of this study was to assess the value of double contrast-enhanced ultrasound (DCUS), in which intravenous microbubbles are used together with an oral contrast agent as a method to evaluate the microvascular density (MVD) of gastric cancer, and its relationship with the contrast-enhanced intensity (EI) in gastric carcinomas. Sixty-nine patients with gastric cancer were examined preoperatively using DCUS. The arrival time (AT), time-to-peak (TTP), peak (PI) and baseline (pre-injection) intensities (BI) of gastric carcinoma and normal gastric wall were measured. Contrast-enhanced intensity (PI minus BI) was calculated. A monoclonal antibody against CD34 was used to display vascular endothelial cells in the resected gastric carcinoma specimens and in normal gastric mucosal tissues, and MVD was calculated by counting CD34-positive vascular endothelial cells. The differences in AT, TTP, EI and MVD between gastric carcinoma specimens and normal gastric wall tissues were evaluated using Student's t-test. The relationships between EI and MVD in gastric cancer were analyzed by Spearman rank correlation analysis. Both EI and MVD were significantly higher in gastric carcinomas than in normal gastric wall (p<0.001). However, AT and TTP showed no significant differences between gastric carcinoma specimens and normal gastric wall tissues (p>0.05). There was a strong positive linear correlation between EI and MVD in gastric carcinoma (r=0.921, p<0.001). Double contrast-enhanced ultrasound is a useful method for evaluation of the MVD in gastric carcinomas in vivo. Contrast-enhanced intensity has a strong positive linear correlation with MVD and could form a new index for assessing angiogenesis and the biological behavior of gastric carcinomas.
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Affiliation(s)
- Li Shiyan
- Department of Ultrasonography, The 2nd Affiliated Hospital of Wenzhou Medical College, Zhejiang, China
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Chen CN, Lin JJ, Lee H, Cheng YM, Chang KJ, Hsieh FJ, Lai HS, Chang CC, Lee PH. Association between color doppler vascularity index, angiogenesis-related molecules, and clinical outcomes in gastric cancer. J Surg Oncol 2009; 99:402-8. [DOI: 10.1002/jso.21193] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Neuropilin2 expressed in gastric cancer endothelial cells increases the proliferation and migration of endothelial cells in response to VEGF. Exp Cell Res 2009; 315:2154-64. [PMID: 19409892 DOI: 10.1016/j.yexcr.2009.04.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2008] [Revised: 04/03/2009] [Accepted: 04/23/2009] [Indexed: 01/09/2023]
Abstract
The structure and characteristics of the tumor vasculature are known to be different from those of normal vessels. Neuropilin2 (Nrp2), which is expressed in non-endothelial cell types, such as neuronal or cancer cells, functions as a receptor for both semaphorin and vascular endothelial growth factor (VEGF). After isolating tumor and normal endothelial cells from advanced gastric cancer tissue and normal gastric mucosa tissues, respectively, we identified genes that were differentially expressed in gastric tumor endothelial (TEC) and normal endothelial cells (NEC) using DNA oligomer chips. Using reverse transcriptase-PCR, we confirmed the chip results by showing that Nrp2 gene expression is significantly up-regulated in TEC. Genes that were found to be up-regulated in TEC were also observed to be up-regulated in human umbilical vein endothelial cells (HUVECs) that were co-cultured with gastric cancer cells. In addition, HUVECs co-cultured with gastric cancer cells showed an increased reactivity to VEGF-induced proliferation and migration. Moreover, overexpression of Nrp2 in HUVECs significantly enhanced the proliferation and migration induced by VEGF. Observation of an immunohistochemical analysis of various human tumor tissue arrays revealed that Nrp2 is highly expressed in the tumor vessel lining and to a lesser extent in normal tissue microvessels. From these results, we suggest that Nrp2 may function to increase the response to VEGF, which is more significant in TEC than in NEC given the differential expression, leading to gastric TEC with aggressive angiogenesis phenotypes.
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Li Q, Zhang N, Jia Z, Le X, Dai B, Wei D, Huang S, Tan D, Xie K. Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression. Cancer Res 2009; 69:3501-9. [PMID: 19351851 DOI: 10.1158/0008-5472.can-08-3045] [Citation(s) in RCA: 185] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The mammalian forkhead box (Fox) transcription factor FoxM1b is implicated in tumorigenesis. However, the presence of expression and role of FoxM1b in gastric cancer remain unknown. Therefore, we investigated FoxM1b expression in 86 cases of primary gastric cancer and 57 normal gastric tissue specimens. We further investigated the underlying mechanisms of altered FoxM1b expression in and the effect of this altered expression on gastric cancer growth and metastasis using in vitro and animal models of gastric cancer. We found weak expression of FoxM1b protein in the mucous neck region of gastric mucosa, whereas we observed strong staining for FoxM1b in tumor cell nuclei in various gastric tumors and lymph node metastases. A Cox proportional hazards model revealed that FoxM1b expression was an independent prognostic factor in multivariate analysis (P < 0.001). Experimentally, overexpression of FoxM1b by gene transfer significantly promoted the growth and metastasis of gastric cancer cells in orthotopic mouse models, whereas knockdown of FoxM1b expression by small interfering RNA did the opposite. Promotion of gastric tumorigenesis by FoxM1b directly and significantly correlated with transactivation of vascular endothelial growth factor expression and elevation of angiogenesis. Given the importance of FoxM1b to regulation of the expression of genes key to cancer biology overall, dysregulated expression and activation of FoxM1b may play important roles in gastric cancer development and progression.
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Affiliation(s)
- Qiang Li
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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Changes in tumor vascularity depicted by contrast-enhanced ultrasonography as a predictor of chemotherapeutic effect in patients with unresectable pancreatic cancer. Pancreas 2009; 38:30-5. [PMID: 19117085 DOI: 10.1097/mpa.0b013e318183ff73] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
OBJECTIVES This study was conducted to assess changes in tumor vascularity using contrast-enhanced ultrasonography in patients with pancreatic carcinoma under systemic chemotherapy and to examine the correlation among vascular change, clinicopathologic factors, and outcome. METHODS Forty-one consecutive patients with histopathologically confirmed pancreatic carcinoma who had distant metastases and were under systemic chemotherapy were recruited. Contrast-enhanced ultrasonography was performed before and after 1 and 2 cycles of treatment.The vascular signals from the tumor were continuously recorded,and the highest signal intensity was selected and classified into 5 categories by their intensity. RESULTS As for the tumor response determined by dynamic computed tomography after 2 cycles, 6 patients showed a partial response, 25 remained stable, and in 10 patients, the disease progressed. A significant relationship was observed between vascular change after 1 cycle and tumor response (P G 0.001). Progression-free survival and overall survival were significantly short in the case of patients showing increased vascularity after 1 and 2 cycles of chemotherapy, compared with those who did not (P G 0.001). CONCLUSIONS Contrast-enhanced ultrasonography was useful to evaluate tumor vascular changes and thereby the effect of systemic chemotherapy, as well as the prognosis of patients with advanced pancreatic carcinoma.
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Positron Emission Tomography Imaging of Tumor Hypoxia and Angiogenesis. Cancer Imaging 2008. [DOI: 10.1016/b978-012374212-4.50091-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Nakao M, Hata J, Manabe N, Okanobu H, Tanaka S, Haruma K, Chayama K. Evaluation of colon cancer vascularity by flash echo imaging. Scand J Gastroenterol 2008; 43:223-228. [PMID: 17963159 DOI: 10.1080/00365520701676203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Tumor vascularity is strongly related to the prognoses of patients with various malignant primary tumors, including colorectal cancer. The aim of this study was to confirm the usefulness of harmonic flash echo imaging (H-FEI) for the preoperative evaluation of tumor vascularity in colorectal cancer by comparison with CD34 staining of resected specimens. MATERIAL AND METHODS Seventeen patients undergoing surgical resection for advanced colorectal cancer (9 M, 8 F) were enrolled in this study. An ultrasound system transmitting ultrasound pulses at 2.3 MHz and receiving them at 4.6 MHz (second harmonic) was used for H-FEI. After intravenous injection of ultrasonic contrast medium (SHU 508A), intermittent harmonic scanning was carried out for 120 s at intervals of 4 s. On the tumor image of the strongest enhancement in each patient, 5 regions of interest were taken to decide the mean echo intensity of the tumor. Immunohistochemistry using antibodies against CD34 was carried out on resected specimens. The mean microvessel density was decided by counting microvessels on 5 fields (x 400) of CD34-stained specimens. RESULTS The mean value of H-FEI intensity was 5.44+/-1.10, and the mean microvessel count with CD34 staining was 35.0+/-7.95. A significant positive linear correlation was observed between the intensity of H-FEI determined preoperatively and the microvessel count in CD34-stained specimens (r=0.741, p=0.0006). CONCLUSION Vascularity of colon cancer can be evaluated non-invasively using H-FEI.
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Affiliation(s)
- Madoka Nakao
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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Abstract
Angiogenesis plays an important role in the growth and progression of cancer. The regulation of tumor angiogenesis depends on a net balance of angiogenic factors and antiangiogenic factors, which are secreted by both tumor cells and host-infiltrating cells. Numerous studies have indicated that assessment of angiogenic activity by either microvessel density or expression of angiogenic factors in cancer can provide prognostic information independent of conventional clinicopathological factors such as tumor staging. Some studies also suggested that assessment of tumor angiogenesis may predict cancer response to chemotherapy or radiotherapy. However, the most important clinical implication of tumor angiogenesis is the development of a novel strategy of anticancer therapy targeting tumor vessels instead of cancer cells. Antiangiogenic therapy aims to inhibit the growth of tumor, and current evidence suggests that it works best in combination with conventional cytotoxic chemotherapy. Recently, a monoclonal antibody against vascular endothelial growth factor, which is one of the most potent angiogenic factors, has been approved for clinical use in colorectal cancer patients after a clinical trial confirmed that combining the antibody with standard chemotherapy regimen could prolong patient survival. The clinical implications of angiogenesis in cancer are reviewed in this article.
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Affiliation(s)
- Roberta WC Pang
- Department of Medicine, The University of Hong KongPokfulam, Hong Kong, China
| | - Ronnie TP Poon
- Department of Surgery, The University of Hong KongPokfulam, Hong Kong, China
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Ozkol M, Yoleri L, Demir MA, Demireli P, Pabuşçu Y. The significance of venous dominance in color Doppler ultrasound for the diagnosis of primary nodular skin lesions: a new perspective in classification. Clin Imaging 2005; 30:43-7. [PMID: 16377484 DOI: 10.1016/j.clinimag.2005.07.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2005] [Revised: 05/21/2005] [Indexed: 11/19/2022]
Abstract
The aim of this study was to investigate the significance of color Doppler ultrasound (CDUS) findings in the differential diagnosis of suspicious nodular skin lesions and to compare the results according to the Giovagnorio 1999 classification and the modified classification. Forty nodular skin lesions were evaluated with CDUS and US. The number of arteries and veins was recorded in hypervascular lesions. Findings were compared with histopathological results. The specificity and predictivity of the modified classification were higher than those of the Giovagnorio 1999 classification.
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Affiliation(s)
- Mine Ozkol
- Department of Radiology, Celal Bayar University Medical School, 45520 Manisa, Turkey.
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Wang L, Guan X, Gong W, Yao J, Peng Z, Wei D, Wu TT, Huang S, Xie K. Altered expression of transcription factor Sp1 critically impacts the angiogenic phenotype of human gastric cancer. Clin Exp Metastasis 2005; 22:205-13. [PMID: 16158248 DOI: 10.1007/s10585-005-5684-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2005] [Accepted: 04/18/2005] [Indexed: 01/20/2023]
Abstract
Our recent study has shown that transcription factor Sp1 is an independent prognostic factor in gastric cancer. However, it is unclear how Sp1 impacts gastric cancer biology. Since Sp1 regulates multiple genes important to angiogenesis, we sought to evaluate the relationship between Sp1 expression and microvessel density (MVD) as well as their effects on cancer patient survival. The expression of Sp1 and status of MVD was determined using archival tissues of 86 cases of resected human gastric cancer. We found that MVD correlated highly with Sp1 expression (P < 0.001). Patients with strong Sp1 expression were 12 times more likely to have high MVD than were those with negative Sp1 expression. In univariate survival analyses, both elevated Sp1 expression (P = 0.007) and high MVD expression (P = 0.036) were associated with inferior survival. However, when Sp1 expression, MVD expression, disease stage, completeness of resection, Lauren's classification, and patient age were entered into a Cox proportional hazards model, only strong Sp1 expression (P = 0.047) and advanced stage (P < 0.01) were independently prognostic of poor survival. Furthermore, knocking down Sp1 expression significantly impaired the angiogenic potential of tumor cells in vitro and suppressed angiogenesis in vivo animal models. Therefore, we provided both clinical and experimental evidence to indicate that Sp1 might impact gastric cancer development and progression through regulating angiogenesis, a critical aspect of cancer biology.
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Affiliation(s)
- Liwei Wang
- Shanghai East Hospital Cancer Center, Tongji University, Shanghai, The People's Republic of China
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Gong W, Wang L, Yao JC, Ajani JA, Wei D, Aldape KD, Xie K, Sawaya R, Huang S. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res 2005; 11:1386-93. [PMID: 15746037 DOI: 10.1158/1078-0432.ccr-04-0487] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
PURPOSE Angiogenic behavior is a critical aspect of cancer biology and subject to regulation by multiple molecular pathways. Because the signal transducer and activator of transcription 3 (Stat3) transcription factor regulates multiple genes important to angiogenesis, we sought to determine whether Stat3 expression is related to vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in gastric cancer and whether these factors predict survival in gastric cancer patients. EXPERIMENTAL DESIGN The expression of Stat3 and VEGF was determined by immunohistochemistry using archival tissues from 86 cases of resected human gastric cancer and confirmed by Western blot analysis. Angiogenic phenotype was determined by CD34 staining and microvessel counting. RESULTS Stat3 expression correlated with VEGF expression and MVD. In univariate survival analyses, Stat3 expression (P = 0.013) and MVD (P = 0.036) were associated with inferior survival. However, when Stat3 expression, VEGF expression, MVD, stage, completeness of resection, Lauren's histologic classification, and age were entered into a Cox proportional hazards model, only strong Stat3 expression (P = 0.049) and advanced stage (P < 0.01) were independently prognostic of poor survival. Furthermore, genetically enforced alterations of activated Stat3 expression led to altered VEGF expression and angiogenic potential in human gastric cancer cells. CONCLUSION Dysregulated Stat3 activation may play an important role in VEGF overexpression and elevated angiogenic phenotype in gastric cancer and contribute to gastric cancer development and progression.
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Affiliation(s)
- Weida Gong
- Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Hsu C, Chen CN, Chen LT, Wu CY, Hsieh FJ, Cheng AL. Effect of thalidomide in hepatocellular carcinoma: assessment with power doppler US and analysis of circulating angiogenic factors. Radiology 2005; 235:509-16. [PMID: 15858091 DOI: 10.1148/radiol.2352040271] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE To prospectively evaluate the feasibility of using power Doppler ultrasonography (US) and measurement of circulating angiogenic factors to assess the antiangiogenic effect of thalidomide in hepatocellular carcinoma. MATERIALS AND METHODS The Ethics Committee of the National Taiwan University Hospital approved the study, and all patients gave prior written informed consent. Evaluation of response to thalidomide treatment was based on findings at computed tomography (CT) and change in serum alpha-fetoprotein level. Tumor vascularity index was evaluated with power Doppler US in patients with advanced hepatocellular carcinoma treated with 200-300 mg/d thalidomide. Serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and placental growth factor were measured with enzyme-linked immunoassay. The chi(2) test or Fisher exact test was used for categorical variables, and the nonparametric Mann-Whitney test was used for numeric variables. A P value of less than .05 was considered to indicate a statistically significant difference. RESULTS Of 47 patients enrolled in the study who had disease that was bidimensionally assessable on CT scans, 44 were assessable for tumor response. Of the 44 evaluated, five were classified as showing objective response (responders): One each showed a complete and a partial response according to World Health Organization criteria, and three had a decrease in alpha-fetoprotein level by more than 50% and stable disease for 10.4, 5.3, or 3.5 months. The pretreatment vascularity index was significantly higher in responders (median, 7.42; range, 2.99-13.90) than in nonresponders (median, 2.15; range, 0-25.36) (P = .03). Four of five responders had a significant decrease in vascularity index with thalidomide. Serum levels of angiogenic factors did not differ significantly between responders and nonresponders. CONCLUSION Higher vascularity index may be associated with a better chance of response to thalidomide in patients with advanced hepatocellular carcinoma. Serum levels of circulating angiogenic factors do not appear to be clinically useful as an indicator of response.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Angiogenesis Inducing Agents/blood
- Angiogenesis Inhibitors/adverse effects
- Angiogenesis Inhibitors/therapeutic use
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/diagnostic imaging
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Female
- Fibroblast Growth Factor 2/blood
- Follow-Up Studies
- Humans
- Image Processing, Computer-Assisted
- Liver Neoplasms/blood supply
- Liver Neoplasms/diagnostic imaging
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Male
- Middle Aged
- Neoplasm Staging
- Neovascularization, Pathologic/diagnostic imaging
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/pathology
- Placenta Growth Factor
- Pregnancy Proteins/blood
- Prospective Studies
- Thalidomide/adverse effects
- Thalidomide/therapeutic use
- Tomography, X-Ray Computed
- Treatment Outcome
- Ultrasonography, Doppler, Color
- Vascular Endothelial Growth Factor A/blood
- alpha-Fetoproteins/metabolism
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Affiliation(s)
- Chiun Hsu
- Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 100
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N/A, 胡 兵, 冯 亮, 桑 玉. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:1248-1250. [DOI: 10.11569/wcjd.v13.i10.1248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2023] Open
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Li ZP, Meng QF, Sun CH, Xu DS, Fan M, Yang XF, Chen DY. Tumor angiogenesis and dynamic CT in colorectal carcinoma: Radiologic-pathologic correlation. World J Gastroenterol 2005; 11:1287-91. [PMID: 15761965 PMCID: PMC4250674 DOI: 10.3748/wjg.v11.i9.1287] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [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 correlation between microvessel density and spiral CT perfusion imaging in colorectal carcinoma.
METHODS: Thirty-seven patients, with histologically proven colorectal carcinoma, underwent water enema spiral CT scan. The largest axial surface of the primary tumor was searched on unenhanced spiral CT images. At this level, the enhanced dynamic scan series was acquired. Time-density curves (TDC) were created from the region of interest drawn over the tumor, target artery by Toshiba Xpress/SX spiral CT with perfusion functional software. Then the perfusion was calculated. Microvessel density (MVD) was evaluated using immunohistochemical staining of surgical specimens with anti-CD34, and then MVD was correlated with perfusion.
RESULTS: MVD of colorectal carcinomas was 33.11-173.44, mean 87.28, and perfusion was 15.60-64.80 mL/min/ 100 g, mean 39.74 mL/min/100 g. MVD and perfusion were not associated with invasive depth, metastasis and disease stage, and they all decreased with increasing Dukes’ stage, but no significant correlation was found between them (r = 0.18, P = 0.29).
CONCLUSION: There is no significant correlation between MVD and perfusion. Neovascularizaton and perfusion are highly presented in early colorectal carcinoma. CT perfusion imaging may be more suited for assessing tumorigenesis in colorectal carcinoma than histological MVD technique.
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Affiliation(s)
- Zi-Ping Li
- Department of Radiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China.
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Abstract
There is a clear need in cancer treatment for a noninvasive imaging assay that evaluates the oxygenation status and heterogeneity of hypoxia and angiogenesis in individual patients. Such an assay could be used to select alternative treatments and to monitor the effects of treatment. Of the several methods available, each imaging procedure has at least one disadvantage. The limited quantitative potential of single-photon emission CT and MR imaging always limits tracer imaging based on these detection systems. PET imaging with FMISO and Cu-ATSM is ready for coordinated multicenter trials, however, that should move aggressively forward to resolve the debate over the importance of hypoxia in limiting response to cancer therapy. Advances in radiation treatment planning, such as intensity-modulated radiotherapy, provide the ability to customize radiation delivery based on physical conformity. With incorporation of regional biologic information, such as hypoxia and proliferating vascular density in treatment planning, imaging can create a biologic profile of the tumor to direct radiation therapy. Presence of widespread hypoxia in the tumor benefits from a systemic hypoxic cell cytotoxin. Angiogenesis is also an important therapeutic target. Imaging hypoxia and angiogenesis complements the efforts in development of antiangiogenesis and hypoxia-targeted drugs. The complementary use of hypoxia and angiogenesis imaging methods should provide the impetus for development and clinical evaluation of novel drugs targeted at angiogenesis and hypoxia. Hypoxia imaging brings in information different from that of FDG-PET but it will play an important niche role in oncologic imaging in the near future. FMISO, radioiodinated azamycin arabinosides, and Cu-ATSM are all being evaluated in patients. The Cu-ATSM images show the best contrast early after injection but these images are confounded by blood flow and their mechanism of localization is one step removed from the intracellular O2 concentration. FMISO has been criticized as inadequate because of its clearance characteristics, but its uptake after 2 hours is probably the most purely reflective of regional PO2 at the time the radiopharmaceutical is used. The FMISO images show less contrast than those of Cu-ATSM because of the lipophilicity and slower clearance of FMISO but attempts to increase the rate of clearance led to tracers whose distribution is contaminated by blood flow effects. For single-photon emission CT the only option is radioiodinated azamycin arabinosides, because the technetium agents are not yet ready for clinical evaluation. Rather than develop new and improved hypoxia agents, or even quibbling about the pros and cons of alternative agents, the nuclear medicine community needs to convince the oncology community that imaging hypoxia is an important procedure that can lead to improved treatment outcome.
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Affiliation(s)
- Joseph G Rajendran
- Division of Nuclear Medicine, Department of Radiology, Box 356113, University of Washington, Seattle, WA 98195, USA.
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Ohshima T, Yamaguchi T, Ishihara T, Yoshikawa M, Kobayashi A, Sakaue N, Baba T, Yamada S, Saisho H. Evaluation of blood flow in pancreatic ductal carcinoma using contrast-enhanced, wide-band Doppler ultrasonography: correlation with tumor characteristics and vascular endothelial growth factor. Pancreas 2004; 28:335-43. [PMID: 15084983 DOI: 10.1097/00006676-200404000-00024] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS Tumor vascularization has been attracting attention. However, there have been only a few reports on tumor vascularization in pancreatic ductal carcinoma, especially on vascularization depicted by imaging modalities. We investigated the relationship among wide-band Doppler signals, clinicopathological factors, and vascular endothelial growth factor (VEGF) expression. METHODS Sixty-nine patients with pancreatic ductal carcinoma were investigated. The vascular signals from carcinoma lesions were assessed by contrast-enhanced, wide-band Doppler ultrasonography (dynamic flow). VEGF expression was quantitated by enzyme immunoassay for 28 patients. Depending on the intensity of the signals, the patients were classified into type A (definite vascular signal) or type B (almost no vascular signal). RESULTS Type A patients and type B patients accounted for 65% and 35% of patients, respectively. According to multivariate analysis of vascular signal type and clinicopathological factors, liver metastasis occurred significantly more frequently in the type A group. VEGF expression was also significantly higher in the type A group than in the type B group. CONCLUSIONS Dynamic flow has very high sensitivity for detecting the vascular signals from pancreatic ductal carcinoma. The quantity of vascular signals correlated with tumor characteristics and VEGF.
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Affiliation(s)
- Tadashi Ohshima
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
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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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Wu J, Shi YQ, Wu KC, Zhang DX, Yang JH, Fan DM. Angiostatin up-regulation in gastric cancer cell SGC7901 inhibits tumorigenesis in nude mice. World J Gastroenterol 2003; 9:59-64. [PMID: 12508352 PMCID: PMC4728250 DOI: 10.3748/wjg.v9.i1.59] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the influence of angiostatin up-regulation on the biologic behavior of gastric cancer cells in vitro and in vivo, and the potential of angiostatin gene therapy in the treatment of human gastric cancer.
METHODS: Mouse angiostatin cDNA was subcloned into the eukaryotic expression vector pcDNA3.1(+) and identified by restriction endonucleases digestion and sequencing. The recombinant vector pcDNA3.1(+)-angio was transfected into human gastric cancer cells SGC7901 with liposome and paralleled with the vector control and the mock control. Angiostatin transcription and protein expression were examined by RT-PCR and Western blot in the stable cell lines selected by G418. Cell proliferation and growth in vitro of the three groups were observed respectively under microscope, cell number counting and FACS. The cells overexpressing angiostatin, vector transfected and untreated were respectively implanted subcutaneously into nude mice. After 30 days the size of tumors formed was measured, and microvessel density count (MVD) in the tumor tissues was assessed by immunohistochemistry with the primary anti-vWF antibody.
RESULTS: The recombinant vector pcDNA3.1(+)-angio was confirmed with the correct sequence of mouse angiostatin under the promoter CMV. After 30 d of transfection and selection with G418, macroscopic resistant cell clones were formed in the experimental group transfected with pcDNA 3.1(+)-angio and the vector control. But no untreated cells survived in the mock control. Angiostatin mRNA transcription and protein expression were detected in the experimental group. No significant differences were observed among the three groups in cell morphology, cell growth curves and cell cycle phase distributions in vitro. However, in nude mice model, markedly inhibited tumorigenesis and slowed tumor expansion were observed in the experimental group as compared with the controls, which was paralleled with decreased microvessel density in and around tumor tissues (P < 0.05).
CONCLUSION: Angiostatin does not directly inhibit human gastric cancer cell proliferation and growth in vitro, but exerts its anti-tumor functions through antiangiogenesis in a paracrine way in vivo.
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Affiliation(s)
- Jing Wu
- Institute of Gastrointestinal Diseases Research, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shannxi Province, China.
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