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Roda N, Blandano G, Pelicci PG. Blood Vessels and Peripheral Nerves as Key Players in Cancer Progression and Therapy Resistance. Cancers (Basel) 2021; 13:cancers13174471. [PMID: 34503281 PMCID: PMC8431382 DOI: 10.3390/cancers13174471] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The interactions between cancer cells and the surrounding blood vessels and peripheral nerves are critical in all the phases of tumor development. Accordingly, therapies that specifically target vessels and nerves represent promising anticancer approaches. The first aim of this review is to document the importance of blood vessels and peripheral nerves in both cancer onset and local or distant growth of tumoral cells. We then focus on the state-of-the-art therapies that limit cancer progression through the impairment of blood vessels and peripheral nerves. The mentioned literature is helpful for the scientific community to appreciate the recent advances in these two fundamental components of tumors. Abstract Cancer cells continuously interact with the tumor microenvironment (TME), a heterogeneous milieu that surrounds the tumor mass and impinges on its phenotype. Among the components of the TME, blood vessels and peripheral nerves have been extensively studied in recent years for their prominent role in tumor development from tumor initiation. Cancer cells were shown to actively promote their own vascularization and innervation through the processes of angiogenesis and axonogenesis. Indeed, sprouting vessels and axons deliver several factors needed by cancer cells to survive and proliferate, including nutrients, oxygen, and growth signals, to the expanding tumor mass. Nerves and vessels are also fundamental for the process of metastatic spreading, as they provide both the pro-metastatic signals to the tumor and the scaffold through which cancer cells can reach distant organs. Not surprisingly, continuously growing attention is devoted to the development of therapies specifically targeting these structures, with promising initial results. In this review, we summarize the latest evidence that supports the importance of blood vessels and peripheral nerves in cancer pathogenesis, therapy resistance, and innovative treatments.
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Affiliation(s)
- Niccolò Roda
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
| | - Giada Blandano
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
| | - Pier Giuseppe Pelicci
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
- Correspondence:
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Sasaki H, Morohashi S, Toba T, Seino H, Yoshizawa T, Hirai H, Haga T, Wu Y, Kijima H. Neoangiogenesis of gastric submucosa-invasive adenocarcinoma. Oncol Lett 2018; 16:3895-3900. [PMID: 30128004 PMCID: PMC6096252 DOI: 10.3892/ol.2018.9116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 02/07/2017] [Indexed: 02/01/2023] Open
Abstract
Early gastric cancer may be defined as mucosal or submucosal invasive carcinoma, and exhibits a good prognosis: 90% of patients survive >10 years. Early gastric cancer infrequently exhibits lymph node metastasis, although submucosal invasion, the presence of vascular invasion and/or lymphatic permeation are independent risk factors for lymph node metastasis in early gastric cancer. The analysis of tumor lymphangiogenesis and angiogenesis are important to determine the extent of invasive progression and metastasis in patients. Previously, the presence of vessels expressing the D2-40 antibody and the factor-VIII protein has been identified immunohistochemically. The vessels that are immunoreactive for D2-40 and factor-VIII are morphologically similar to lymphatic vessels or small-size veins, also termed venules. In the present study, the association between tumor invasion and neoangiogenesis in early gastric cancer was examined. The D2-40/factor-VIII double-stained vessel (DSV) density was analyzed, in addition to lymphatic and blood vessel (vein and artery) density, using 46 submucosa-invasive and 50 mucosal carcinomas, and 20 non-neoplastic gastric tissues. The lymphatic density and DSV density of submucosa beneath the carcinoma and submucosa of the surrounding region in submucosa-invasive carcinoma were significantly increased (P<0.001) in comparison with those in mucosal carcinoma or non-neoplastic gastric tissue. No significant difference was observed in blood vessel density between non-neoplastic gastric, mucosal carcinoma and submucosa-invasive carcinoma tissues other than that of mucosa. The present study suggests the potential for the presence of D2-40/factor-VIII DSV and the importance of this vessel for neoangiogenesis in early gastric cancer.
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Affiliation(s)
- Hanae Sasaki
- School of Medicine, Hirosaki University, Hirosaki, Aomori, 036-8560, Japan
| | - Satoko Morohashi
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takahito Toba
- Department of Internal Medicine, Toho University Ohmori Medical Center, Ohta, Tokyo 143-8541, Japan
| | - Hiroko Seino
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.,Department of Radiology and Radiation Oncology Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Tadashi Yoshizawa
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Hideaki Hirai
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Toshihiro Haga
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Yunyan Wu
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Hiroshi Kijima
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
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Zygoń J, Szajewski M, Kruszewski WJ, Rzepko R. VEGF, Flt-1, and microvessel density in primary tumors as predictive factors of colorectal cancer prognosis. Mol Clin Oncol 2016; 6:243-248. [PMID: 28357103 DOI: 10.3892/mco.2016.1121] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 11/23/2016] [Indexed: 01/13/2023] Open
Abstract
Angiogenesis in the primary tumor is known to be necessary for tumor progression in adenocarcinomas of the colon. However, whether angiogenesis in the primary tumors of patients with colorectal cancer affects their prognosis has yet to be fully elucidated. The aim of the present study was to assess the association between selected pathoclinical parameters and overall survival of resectable colorectal cancer patients with the expression of angiogenesis-promoting factors, including vascular endothelial growth factor (VEGF) and Fms-like tyrosine kinase receptor (Flt-1), and microvessel density (MVD) in the primary tumor. VEGF and Flt-1 expression were assessed, as well as MVD (with anti-CD34) by immunohistochemistry in 139 archived primary colorectal cancer tissue samples. These results were compared with the overall survival of the patients and potential prognostic pathoclinical parameters. A higher MVD in the tumors expressing Flt-1 (P=0.04) was identified. However, there was no correlation between the pathoclinical parameters of colon cancer and Flt-1 expression, VEGF expression, or MVD in the tumor. Furthermore, the intensity of VEGF expression, Flt-1 expression and tumor MVD did not correlate with the overall survival of the patients. Therefore, although increased expression of VEGF and Flt-1 was correlated with an increased expression of MVD in the primary tumors of resectable colorectal cancer patients, these factors were not correlated with prognostic pathoclinical factors and overall survival.
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Affiliation(s)
- Justyna Zygoń
- Department of General Surgery, Kościerzyna Hospital Ltd., Kościerzyna 83-400, Poland
| | - Mariusz Szajewski
- Department of Surgical Oncology, Gdynia Oncology Centre, PCK's Maritime Hospital in Gdynia, Gdynia 81-519, Poland; Department of Propaedeutic of Oncology, Faculty of Health Sciences, Medical University of Gdańsk, Gdynia 81-519, Poland
| | - Wiesław Janusz Kruszewski
- Department of Surgical Oncology, Gdynia Oncology Centre, PCK's Maritime Hospital in Gdynia, Gdynia 81-519, Poland; Department of Propaedeutic of Oncology, Faculty of Health Sciences, Medical University of Gdańsk, Gdynia 81-519, Poland
| | - Robert Rzepko
- Department of Pathology, Prabuty Hospital Ltd., Prabuty 82-550, Poland
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Li SY, Huang PT, Xu HS, Liang X, Lv JH, Zhang Y, Cai XJ, Cosgrove D. Enhanced intensity on preoperative double contrast-enhanced sonography as a useful indicator of lymph node metastasis in patients with gastric cancer. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2014; 33:1773-1781. [PMID: 25253823 DOI: 10.7863/ultra.33.10.1773] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
OBJECTIVES The aim of this study was to investigate the predictive value of enhanced intensity on double contrast-enhanced sonography in assessing lymph node metastasis of gastric cancer. METHODS A total of 357 patients with gastric cancer were enrolled in this study. Double contrast-enhanced sonography, in which an oral ultrasound contrast agent is combined with an intravenous contrast agent, was performed preoperatively, and the data were analyzed quantitatively. The predictive ability of enhanced intensity, a quantitative double contrast-enhanced sonographic measure, for lymph node metastasis was evaluated retrospectively. RESULTS Compared to negative lymph node metastasis cases, the presence of thicker lesions, deeper invasion, poorer differentiation, and higher enhanced intensity were found in positive cases (P< .05). An enhanced intensity cutoff value of 16.91 dB was the best point for balancing the sensitivity and specificity (71.50% and 79.30%, respectively) for prediction of lymph node metastasis, with the highest Youden index of 0.508. The area under the receiver operating characteristic curve was 0.828 (P < .001; 95% confidence interval, 0.786-0.870). In cases in which the lesions were hyperenhanced (enhanced intensity >16.91 dB), the lesions were significantly thicker and had deeper invasion, poorer differentiation, and more positive metastasis findings compared to non-hyperenhanced cases (enhanced intensity ≤16.91 dB; P < .05). On logistic regression analysis, the enhanced intensity of primary tumors and the invasion depth were significantly associated with lymph node metastasis. CONCLUSIONS Double contrast-enhanced sonography with quantitative analysis may be considered a novel alternative imaging modality for noninvasive preoperative evaluation of lymph node metastasis with good reliability.
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Affiliation(s)
- Shi-Yan Li
- Department of Diagnostic Ultrasound and Echocardiography (S.L., H.X., J.L.) and Second Department of General Surgery (X.L., X.C.), Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Ultrasonography, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (P.H., Y.Z.); and Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, England (D.C.)
| | - Pin-Tong Huang
- Department of Diagnostic Ultrasound and Echocardiography (S.L., H.X., J.L.) and Second Department of General Surgery (X.L., X.C.), Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Ultrasonography, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (P.H., Y.Z.); and Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, England (D.C.)
| | - Hai-Shan Xu
- Department of Diagnostic Ultrasound and Echocardiography (S.L., H.X., J.L.) and Second Department of General Surgery (X.L., X.C.), Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Ultrasonography, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (P.H., Y.Z.); and Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, England (D.C.)
| | - Xiao Liang
- Department of Diagnostic Ultrasound and Echocardiography (S.L., H.X., J.L.) and Second Department of General Surgery (X.L., X.C.), Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Ultrasonography, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (P.H., Y.Z.); and Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, England (D.C.)
| | - Jiang-Hong Lv
- Department of Diagnostic Ultrasound and Echocardiography (S.L., H.X., J.L.) and Second Department of General Surgery (X.L., X.C.), Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Ultrasonography, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (P.H., Y.Z.); and Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, England (D.C.)
| | - Ying Zhang
- Department of Diagnostic Ultrasound and Echocardiography (S.L., H.X., J.L.) and Second Department of General Surgery (X.L., X.C.), Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Ultrasonography, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (P.H., Y.Z.); and Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, England (D.C.)
| | - Xiu-Jun Cai
- Department of Diagnostic Ultrasound and Echocardiography (S.L., H.X., J.L.) and Second Department of General Surgery (X.L., X.C.), Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Ultrasonography, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (P.H., Y.Z.); and Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, England (D.C.).
| | - David Cosgrove
- Department of Diagnostic Ultrasound and Echocardiography (S.L., H.X., J.L.) and Second Department of General Surgery (X.L., X.C.), Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Ultrasonography, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (P.H., Y.Z.); and Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, England (D.C.)
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Watnick RS, Rodriguez RK, Wang S, Blois AL, Rangarajan A, Ince T, Weinberg RA. Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells. Oncogene 2014; 34:2823-35. [PMID: 25109329 DOI: 10.1038/onc.2014.228] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 06/03/2014] [Accepted: 06/21/2014] [Indexed: 12/27/2022]
Abstract
Tumor-associated angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate here that the critical step in establishing the angiogenic capability of human tumor cells is the repression of a key secreted anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. In transformed epithelial cells, a signaling pathway leading from Ras to Tsp-1 repression induces the sequential activation of PI3 kinase, Rho and ROCK, leading to activation of Myc through phosphorylation, thereby enabling Myc to repress Tsp-1 transcription. In transformed fibroblasts, however, the repression of Tsp-1 can be achieved by an alternative mechanism involving inactivation of both p53 and pRb. We thus describe novel mechanisms by which the activation of oncogenes in epithelial cells and the inactivation of tumor suppressors in fibroblasts permits angiogenesis and, in turn, tumor formation.
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Affiliation(s)
- R S Watnick
- 1] Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA [2] Department of Surgery, Harvard Medical School, Boston, MA, USA [3] Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - R K Rodriguez
- 1] Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA [2] Department of Surgery, Harvard Medical School, Boston, MA, USA [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - S Wang
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
| | - A L Blois
- 1] Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA [2] Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway
| | - A Rangarajan
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - T Ince
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - R A Weinberg
- 1] Whitehead Institute for Biomedical Research, Cambridge, MA, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
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Yazama H, Kitatani K, Fujiwara K, Kato M, Hashimoto-Nishimura M, Kawamoto K, Hasegawa K, Kitano H, Bielawska A, Bielawski J, Okazaki T. Dietary glucosylceramides suppress tumor growth in a mouse xenograft model of head and neck squamous cell carcinoma by the inhibition of angiogenesis through an increase in ceramide. Int J Clin Oncol 2014; 20:438-46. [PMID: 25080062 DOI: 10.1007/s10147-014-0734-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 07/14/2014] [Indexed: 01/22/2023]
Abstract
BACKGROUND We previously reported that dietary glucosylceramides show cancer-prevention activity in a mouse xenograft model of human head and neck cancer cells (SCCKN). However, the mechanism was unclear. Ceramides, metabolites of glucosylceramides, induce apoptotic cell death in various malignancies. Here, we investigated the inhibitory effects of dietary glucosylceramides on tumor growth in vivo and in vitro. METHODS SCCKN were subcutaneously inoculated into the right flanks of NOD/SCID mice. Mice were treated with or without dietary glucosylceramides (300 mg/kg) daily for 14 consecutive days after confirmation of tumor progression. Microvessel areas around the tumor were assessed by hematoxylin-eosin staining and immunohistochemistry of CD31, and, as markers for angiogenesis, protein levels of VEGF, VEGF receptor-2, and HIF-1α were assessed by Western blotting. Mass spectrometry was performed to measure the levels of sphingolipids in mouse serum after treatment with dietary glucosylceramides. RESULTS Oral administration of glucosylceramides significantly decreased SCCKN growth in the xenograft model with inhibition of angioinvasion. In tumor-invasive areas, VEGF and HIF-1α in the tumor cells, and VEGF receptor-2 in endothelial cells decreased after treatment with dietary glucosylceramides. Dietary glucosylceramides increased serum levels of sphingosine-based ceramides as compared to the control. In SCCKN and UV♀2 cells, C6-ceramide suppressed the expressions of VEGF, VEGF receptor-2, and HIF-1α in vitro. CONCLUSION These results suggest that dietary glucosylceramides trigger the de novo pathway of ceramide synthesis, indicating that sphingosine-based ceramide suppresses the growth of head and neck tumors through the inhibition of pro-angiogenic signals such as VEGF, VEGF receptor-2, and HIF-1α.
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Affiliation(s)
- Hiroaki Yazama
- Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, Yonago, 683-8503, Japan
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Hui MKC, Lai KKY, Chan KW, Luk JM, Lee NP, Chung Y, Cheung LCM, Srivastava G, Tsao SW, Tang JC, Law S. Clinical correlation of nuclear survivin in esophageal squamous cell carcinoma. Med Oncol 2012; 29:3009-16. [PMID: 22528514 PMCID: PMC3505527 DOI: 10.1007/s12032-012-0225-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 03/19/2012] [Indexed: 12/20/2022]
Abstract
To examine the correlation of survivin (both total and nuclear survivin) with clinicopathological parameters of esophageal squamous cell carcinoma (ESCC) patients. Tumors and non-tumor tissues near the proximal resection margins were resected from ESCC patients undergone esophagectomy. Quantitative polymerase chain reaction (qPCR) was performed to detect survivin mRNA expression level in the 10 paired tumor and adjacent non-tumor tissues. To confirm with the clinical situation, survivin mRNA and protein expression were measured by qPCR and immunoblot, respectively, in 5 ESCC cell lines and a non-neoplastic esophageal epithelial cell line. Immunohistochemistry was employed to reveal the cellular localization of survivin in tumor tissues isolated from the 64 ESCC patients undergone surgery alone. Up-regulation of survivin mRNA and protein was found in 5 ESCC lines (HKESC-1, HKESC-2, HKESC-3, HKESC-4, and SLMT-1) when compared to a non-neoplastic esophageal epithelial cell line NE-1. In particular, HKESC-3, HKESC-4, and SLMT-1 cells demonstrated ~50-fold increase in survivin mRNA. High level of survivin mRNA in tumor tissues when compared to non-tumor tissues was found in 70 % (7 of 10) of clinical cases. The increase in expression ranged from ~twofold to ~16-fold. Immunohistochemistry results showed that survivin was found at the cell nuclei in all specimens examined. Nuclear expression of survivin was inversely associated with the likelihood of developing nodal metastasis (p = 0.021) and significantly associated with early-stage ESCC (p = 0.039). Nuclear survivin could serve as a marker for indicating disease status in ESCC patients.
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Affiliation(s)
- Marco K. C. Hui
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Kenneth K. Y. Lai
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Kwok Wah Chan
- Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - John M. Luk
- Department of Oncology, Roche R&D Center, pRED China, Shanghai, China
| | - Nikki P. Lee
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Yvonne Chung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Leo C. M. Cheung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Gopesh Srivastava
- Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Sai Wah Tsao
- Department of Anatomy, The University of Hong Kong, Hong Kong, China
| | - Johnny C. Tang
- Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China
| | - Simon Law
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong, China
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Prognostic significance of cyclooxygenase-2, epidermal growth factor receptor 1, and microvascular density in gastric cancer. Med Oncol 2011; 29:1739-47. [PMID: 22048943 DOI: 10.1007/s12032-011-0098-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2011] [Accepted: 10/19/2011] [Indexed: 12/20/2022]
Abstract
Gastric cancer remains a significant global health burden with poor treatment outcome. New treatment modalities that target inflammation, proliferation, and angiogenesis have been used in various cancers, including gastric cancer. We sought to study the pattern of expression of two important proteins, cyclooxygenase-2 and epidermal growth factor receptor, and their association with microvascular density, clinicopathological features, and survival in Arab Omani patients with gastric cancer. Formalin-fixed, paraffin-embedded tumors were studied by immunohistochemistry using monoclonal antibodies to cyclooxygenase-2, epidermal growth factor receptor, and CD34. The immunohistochemical results were correlated with clinicopathological features and survival. In our study population, we found a male/female ratio of 72:43, a median age of 59 years, stage III and IV incidence of 66.9%, and a median follow-up of 96 months. Positive expression rates of cyclooxygenase-2 and epidermal growth factor receptor were 89.6 and 23.5%, respectively. The median microvascular density value was 52.5. When this value was determined as the cut-off point, 50% of patients were found to have high microvascular density. Epidermal growth factor receptor over-expression correlated with high microvascular density values, advanced lymph node involvement (N3), and TNM stage presentation (III and IV). Similarly, lymph node involvement was associated with cyclooxygenase-2 over-expression and high microvascular density. Univariate analysis showed that epidermal growth factor receptor over-expression, pathological T3 and T4 disease, and overall stage III and IV disease were adverse prognostic factors. On multivariate analysis using a Cox regression model, expression of epidermal growth factor receptor, and advanced TNM stage were significant adverse prognostic factors for overall survival. Expression of epidermal growth factor receptor in Arab Omani patients with gastric cancer correlates with aggressive tumor characteristics and is an independent prognostic factor. Further clinical studies are needed to evaluate the utility of epidermal growth factor receptor immunohistochemistry as a tool for gastric cancer treatment.
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Xue N, Huang P, Aronow WS, Wang Z, Nair CK, Zheng Z, Shen X, Yin Y, Huang F, Cosgrove D. Predicting lymph node status in patients with early gastric carcinoma using double contrast-enhanced ultrasonography. Arch Med Sci 2011; 7:457-464. [PMID: 22295029 PMCID: PMC3258739 DOI: 10.5114/aoms.2011.23412] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2010] [Revised: 05/29/2010] [Accepted: 05/31/2010] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION Double contrast-enhanced ultrasonography (DCUS) is a new method we used in predicting lymph node metastasis (LNM) in patients with early gastric cancer. MATERIAL AND METHODS Seventy-six patients with early gastric cancer diagnosed by gastroscope and confirmed by pathology after operation were examined using DCUS preoperatively. Group N1 included 15 patients with LNM and group N0 61 patients without LNM. RESULTS In group N1, 13 patients (87%) had marked hyperenhancement during early arterial phase using DCUS, and 2 patients (13%) were unmarked as hyperenhancement. In group N0, 24 patients (39%) had marked hyperenhancement during early arterial phase using DCUS, and 37 patients (61%) had unmarked hyperenhancement. The sensitivity and specificity of marked hyperenhancement in predicting LNM in patients with early gastric cancer was 86.7% and 60.7% respectively, and the Youden's index was 0.474. The κ value of this method was 0.89. CONCLUSIONS Double contrast-enhanced ultrasonography is a new valuable method to evaluate LNM at an early stage of gastric cancer and prognosis of early gastric cancer preoperatively.
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Affiliation(s)
- Nianyu Xue
- 2 Affiliated Hospital of Wenzhou Medical College, Zhejiang, China
| | - Pintong Huang
- 2 Affiliated Hospital of Wenzhou Medical College, Zhejiang, China
| | | | - Zongmin Wang
- 2 Affiliated Hospital of Wenzhou Medical College, Zhejiang, China
| | | | - Zhiqiang Zheng
- 2 Affiliated Hospital of Wenzhou Medical College, Zhejiang, China
| | - Xuedong Shen
- Cardiac Center of Creighton University, Omaha, NE, USA
| | - Yimei Yin
- 2 Affiliated Hospital of Wenzhou Medical College, Zhejiang, China
| | - Fuguang Huang
- 2 Affiliated Hospital of Wenzhou Medical College, Zhejiang, China
| | - David Cosgrove
- Imaging Sciences Department, Imperial College, Hammersmith Hospital, London, United Kingdom
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Yao J, Yang ZG, Chen TW, Li Y, Yang L. Perfusion changes in gastric adenocarcinoma: evaluation with 64-section MDCT. ABDOMINAL IMAGING 2010; 35:195-202. [PMID: 19259725 DOI: 10.1007/s00261-009-9503-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2008] [Revised: 01/14/2009] [Accepted: 02/08/2009] [Indexed: 02/05/2023]
Abstract
BACKGROUND Perfusion CT has been applied in many clinical areas, but few studies have addressed gastric cancer. This study is to investigate the feasibility of first-pass perfusion CT with volume-based technique to assess microcirculation of gastric adenocarcinoma. METHODS Perfusion CT of gastric adenocarcinoma was performed with 64-section MDCT in 58 patients, which were subdivided into three subgroups according to the location of the tumor. Perfusion, peak enhancement, time to peak, and blood volume were computed in the tumor and in normal gastric wall. Mean values of perfusion parameters were compared between the tumor and normal stomach, between tumors with and without lymph node metastases, and between different stages. RESULTS Blood volume was significantly increased in gastric adenocarcinoma compared with normal stomach (19.75 +/- 14.74 vs. 13.59 +/- 11.46 mL/100 g, in total stomach, P = 0.004). A total of 10.55 mL/100 g of blood volume was employed as the cut-off value to discriminate the microcirculation of the tumor from that of the normal stomach. There were no significant differences of any perfusion parameters between the subgroups with and without lymph node metastases, or between early and advanced cancer. CONCLUSIONS The first-pass perfusion CT with whole tumor acquisition technique is a feasible technique for quantifying tumor vascularity and angiogenesis in gastric adenocarcinoma.
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Affiliation(s)
- Jin Yao
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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11
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Michailidou EZ, Markopoulos AK, Antoniades DZ. Mast cells and angiogenesis in oral malignant and premalignant lesions. Open Dent J 2008; 2:126-32. [PMID: 19444318 PMCID: PMC2606660 DOI: 10.2174/1874210600802010126] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2008] [Revised: 08/08/2008] [Accepted: 10/24/2008] [Indexed: 12/17/2022] Open
Abstract
Mast cell contribution to neoangiogenesis during tumorigenesis in oral squamous cell carcinoma is not determined yet. Objectives: To associate numerical mast cell density (MCD) to numerical microvessel density (MVD) during the progression of oral leukoplakia without dysplasia and leukoplakia with dysplasia to squamous cell carcinoma (OSCC). Materials and methods: MVD was analysed immunohistochemically (mouse monoclonal anti-human CD34) in 49 paraffin-embedded specimens, 35 OSCCs, 9 leukoplakias and 5 normal oral tissues. Toluidine blue counterstaining revealed mast cells. MCD and MVD were assessed at the same optical field. Results: MVD increased between: normal oral mucosa, dysplasia (p=0.004), OSCC (p=0.001), leukoplakia and OSCC (p=0.041). MCD increased between: normal oral mucosa, dysplasia (p=0.003), OSCC (p=0.000), leukoplakia and OSCC (p=0.007). MVD was found to depend on MCD (p=0.000) in a percent 28.3% (power curve fit model). Conclusions: Mast cells are attracted at the lesion site and may turn on an angiogenic switch during tumorigenesis in OSCC.
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Affiliation(s)
- E Z Michailidou
- Department of Oral Medicine and Maxillofacial Pathology, Aristotle University, Thessaloniki, Greece
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12
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Woo SK, Kim S, Kim TU, Lee JW, Kim GH, Choi KU, Jeon TY. Investigation of the association between CT detection of early gastric cancer and ultimate histology. Clin Radiol 2008; 63:1236-1244. [PMID: 18929041 DOI: 10.1016/j.crad.2008.06.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2007] [Revised: 06/01/2008] [Accepted: 06/12/2008] [Indexed: 11/15/2022]
Abstract
AIM To evaluate the association between computed tomography (CT) detection of early gastric cancer (EGC) and various parameters, including the depth of invasion, lesion extent, morpholgical type, location, and histological type. MATERIALS AND METHODS One hundred and ten patients with 114 EGCs were preoperatively examined using multidetector CT (MDCT). All patients received 500 ml water as an oral contrast agent approximately 15 min before the examination and an additional 500 ml immediately prior to the study. Portal venous phase, contrast-enhanced, helical scans with multiplanar reformation were obtained. All patients underwent surgery. For location and size of tumour, the CT findings were compared with the histopathological results. The association between CT detection of EGC and various parameters were assessed. In addition, we performed a stepwise forward logistic regression to identify which variables significantly increased the CT detection rate of EGC. RESULTS The detection rate of all EGCs using MDCT was 36.4%. The detection rate for EGCs confined to the superficial layer (mucosa or SM1) was 14.3%, whereas the detection rate for EGCs that involved the deep layer (SM2 or more than SM2) was 86.5%. All three of the protruded lesions and five of the six excavated lesions were readily detected using CT. Stepwise forward logistic regression showed that the best parameter for CT detection of EGCs was the depth of invasion; more EGCs were detected when the lesion was deep. CONCLUSION MDCT has advantages in acceptable evaluation of the depth invasion of EGCs. EGC that is undetectable using CT suggests an EGC confined to the superficial layer, whereas EGC detectable using CT suggests deep lesions.
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Affiliation(s)
- S K Woo
- Department of Diagnostic Radiology, Pusan National University Hospital, Pusan National University School of Medicine, Pusan National University, Busan 602-739, Republic of Korea
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13
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Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ. Prognostic significance of VEGF immunohistochemical expression and tumor angiogenesis in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 2005; 131:624-30. [PMID: 16044346 DOI: 10.1007/s00432-005-0003-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2004] [Accepted: 04/28/2005] [Indexed: 12/16/2022]
Abstract
PURPOSE Tumor angiogenesis is crucial for both the growth of the primary tumor and the development of metastases. Among the factors causing tumor angiogenesis, vascular endothelial growth factor (VEGF) is considered as a leading candidate. We aimed to assess the prognostic significance of VEGF and tumor angiogenesis in head and neck squamous cell carcinoma (HNSCC). METHODS We performed a retrospective study of 69 patients with HNSCC, in order to investigate whether VEGF immunohistochemical expression and tumor angiogenesis correlate with clinicopathological parameters and outcome. Tumor angiogenesis was estimated by determining microvessel density (MVD), and VEGF expression was assessed quantitatively. RESULTS Vascular endothelial growth factor and MVD correlated statistically significant with the clinical stage, but not with the presence of lymph node metastasis at the time of diagnosis. Tumors located in the oral cavity and larynx more often expressed high VEGF immunostaining compared with tumors located in the lower lip. High VEGF expression was associated with higher clinical stage and worse overall survival in this cohort of patients. CONCLUSIONS Vascular endothelial growth factor expression may have prognostic significance for patients with HNSCC.
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Affiliation(s)
- Panayiotis A Kyzas
- Department of Pathology, Medical School, University of Ioannina, 45110, Ioannina, Greece.
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14
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Fondevila C, Metges JP, Fuster J, Grau JJ, Palacín A, Castells A, Volant A, Pera M. p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 2004; 90:206-15. [PMID: 14710231 PMCID: PMC2395306 DOI: 10.1038/sj.bjc.6601455] [Citation(s) in RCA: 145] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
This study was undertaken to determine the value of tumour microvessel density (MVD) and the expression of p53 and vascular endothelial growth factor (VEGF) as prognostic markers in patients with gastric cancer operated on for cure. In all, 156 patients with curatively resected gastric cancer constituted the basis of this blinded retrospective evaluation. Patients were treated with either surgery alone (n=53) or surgery plus adjuvant chemotherapy (n=103). Tumour MVD, p53 expression, and VEGF expression were assayed using immunohistochemical techniques. After a mean follow-up of 43 months, 64 (41%) patients had died and 55 (35%) patients developed tumour recurrence. Positive correlations between MVD and both p53 (P=0.005) and VEGF (P=0.005) expression were observed. Both MVD >/=100 (P=0.05) and positive VEGF expression (P<0.02) were associated with shorter disease-free survival, and positive VEGF expression (P=0.01) was also associated with shorter overall survival. Multivariate analysis confirmed that, in addition to the pathological tumour stage, lymph node ratio, the extent of lymphadenectomy and perineural invasion, p53 expression, and VEGF expression were independently associated with both disease-free survival (P<0.0005 and 0.02, respectively) and overall survival (P<0.02 and 0.01, respectively). Finally, patients whose tumours did not show p53 expression had a survival benefit compared to those expressing p53 when treated with adjuvant chemotherapy (P=0.01). This investigation demonstrates that p53 expression and VEGF expression are independent prognostic factors for both disease-free survival and overall survival in patients with curatively resected gastric cancer, and that p53 status may also influence response to chemotherapy.
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Affiliation(s)
- C Fondevila
- Services of Gastrointestinal Surgery, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona Medical School, Barcelona, Spain
| | - J P Metges
- Departments of Pathology and Medical Oncology, Centre Hospitalier Universitaire Cavale Blanche and Morvan, Brest, France
| | - J Fuster
- Services of Gastrointestinal Surgery, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona Medical School, Barcelona, Spain
| | - J J Grau
- Department of Medical Oncology, Hospital Clínic, IDIBAPS, University of Barcelona Medical School, Barcelona, Spain
| | - A Palacín
- Department of Pathology, Hospital Clínic, IDIBAPS, University of Barcelona Medical School, Barcelona, Spain
| | - A Castells
- Services of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona Medical School, Barcelona, Spain
| | - A Volant
- Departments of Pathology and Medical Oncology, Centre Hospitalier Universitaire Cavale Blanche and Morvan, Brest, France
| | - M Pera
- Services of Gastrointestinal Surgery, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona Medical School, Barcelona, Spain
- Services of Gastrointestinal Surgery, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona Medical School, Barcelona, Spain. E-mail:
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Dong WG, Sun XM, Yu BP, Luo HS, Yu JP. Role of VEGF and CD44v6 in differentiating benign from malignant ascites. World J Gastroenterol 2003; 9:2596-600. [PMID: 14606105 PMCID: PMC4656549 DOI: 10.3748/wjg.v9.i11.2596] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [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 detect the vascular endothelial growth factor (VEGF) and soluble splice variant 6 of CD44 (sCD44v6) levels in ascites and to explore their role in differentiating benign from malignant ascites.
METHODS: Cirrhotic ascites (n = 36), tuberculosis ascites (n = 8) and malignant ascites (n = 23) were collected and studied. Concentrations of soluble VEGF and sCD44v6 in various kinds of ascites (n = 67) were measured using a sandwich enzyme-linked immunoadsorbent assay.
RESULTS: VEGF and sCD44v6 levels in malignant ascites were 640.74 ± 264.81 pg/mL and 89.22 ± 38.20 ng/mL, respectively, both of which were significantly higher than those in cirrhotic ascites and tuberculous ascites (q = 18.98, 11.89 and q = 8.92, 5.09; P < 0.01). However, the levels of VEGF and sCD44v6 in cirrhotic and tuberculous ascites had no significant difference (q = 0.48, 0.75; P > 0.05). Furthermore, VEGF levels in malignant ascites in patients with ovarian cancer were higher than those with gastric and colon cancer (q = 5.03, 6.79; P < 0.01, respectively). But differences of VEGF levels between gastric and colon cancer were not significant (q = 1.90, P > 0.05). Whereas, sCD44v6 levels in malignant ascites from patients with ovarian, gastric and colon cancer had no significant difference (q = 0.06, 0.91, 0.35; P > 0.05, respectirely). In comparison with cirrhotic and tuberculous ascites, when the upper limit of its VEGF mean levels 119.44 pg/mL (70.90 ± 48.54) and sCD44v6 mean levels 63.59 ng/mL (44.42 ± 19.17) was taken as the minimum cutoff limit, the sensitivity and specificity of VEGF and sCD44v6 of this assay to the diagnos is of malignant ascites were 91.3%, 90.9% and 73.9%, 88.7% respectively.
CONCLUSION: Elevated levels of VEGF and sCD44v6 may be useful in differential diagnosis of benign and malignant ascites.
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Affiliation(s)
- Wei-Guo Dong
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan 430060, Hubei Province, China.
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16
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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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18
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Li HX, Chang XM, Song ZJ, He SX. Correlation between expression of cyclooxygenase-2 and angiogenesis in human gastric adenocarcinoma. World J Gastroenterol 2003; 9:674-7. [PMID: 12679908 PMCID: PMC4611426 DOI: 10.3748/wjg.v9.i4.674] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [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 evaluate the expression of cyclooxygenase (COX-2) and the relationship with tumor angiogenesis and advancement in gastric adenocarcinoma.
METHODS: Immunohistochemical stain was used for detecting the expression of COX-2 in 45 resected specimens of gastric adenocarcinoma; the monoclonal antibody against CD34 was used for displaying vascular endothelial cells, and microvascular density (MVD) was detected by counting of CD34-positive vascular endothelial cells. Paracancerous tissues were examined as control.
RESULTS: Immunohistological staining with COX-2-specific polyclonal antibody showed cytoplasmic staining in the cancer cells, some atypical hyperplasia and intestinal metaplasia, as well as angiogenic vasculature present within the tumors and prexisting vasculature adjacent to cancer lesions. The rate of expression of COX-2 and MVD index in gastric cancers were significantly increased, compared with those in the paracancerous tissues (77.78 vs 33.33%, 58.13 ± 19.99 vs 24.02 ± 10.28, P < 0.01, P < 0.05, respectively). In 36 gastric carcinoma specimens with lymph node metastasis, the rate of COX-2 expression and MVD were higher than those in the specimens without metostasis (86.11 vs 44.44%, 58.60 ± 18.24 vs 43.54 ± 15.05, P < 0.05, P < 0.05, respectively). The rate of COX-2 expression and MVD in the specimens with invasive serosa were significantly higher than those in the specimens without invasion to serosa (87.88 vs 50.0%, 57.01 ± 18.79 vs 42.35 ± 14.65, P < 0.05, P < 0.05). Moreover, MVD in COX-2-positive specimens was higher than that in COX-2-negative specimens (61.29 ± 14.31 vs 45.38 ± 12.42, P < 0.05). COX-2 expression was positively correlated with MVD (r = 0.63, P < 0.05).
CONCLUSION: COX-2 expression might correlate with the occurance and advancement of gastric carcinoma and is involved in tumor angiogenesis in gastric carcinoma. It is likely that COX-2 by inducing angiogenesis can be one of mechanisms which promotes invasion and metastasis of gastric carcinoma. It may become a new therapeutic target for anti-angiogenesis.
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Affiliation(s)
- Hong-Xia Li
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China. hx1105sina.com
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Schechter NR, Yang DJ, Azhdarinia A, Kohanim S, Wendt R, Oh CS, Hu M, Yu DF, Bryant J, Ang KK, Forster KM, Kim EE, Podoloff DA. Assessment of epidermal growth factor receptor with 99mTc-ethylenedicysteine-C225 monoclonal antibody. Anticancer Drugs 2003; 14:49-56. [PMID: 12544258 DOI: 10.1097/00001813-200301000-00007] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Epidermal growth factor receptor (EGFR) plays an important role in cell division and cancer progression, as well as angiogenesis and metastasis. Since many tumor cells exhibit the EGFR on their surface, functional imaging of EGFR provides not only a non-invasive, reproducible, quantifiable alternative to biopsies, but it also greatly complements pharmacokinetic studies by correlating clinical responses with biological effects. Moreover, molecular endpoints of anti-EGFR therapy could be assessed effectively. C225 is a chimeric monoclonal antibody that targets the human extracellular EGFR and inhibits the growth of EGFR-expressing tumor cells. Also, it has been demonstrated that C225, in combination with chemotherapeutic drugs or radiotherapy, is effective in eradicating well-established tumors in nude mice. We have developed 99mTc-labeled C225 using ethylenedicysteine (EC) as a chelator. This study aimed at measuring uptake of 99mTc-EC-C225 in EGFR+ tumor-bearing animal models and preliminary feasibility of imaging patients with head and neck carcinomas. In vitro Western blot analysis and cytotoxicity assays were used to examine the integrity of EC-C225. Tissue distribution studies of 99mTc-EC-C225 were evaluated in tumor-bearing rodents at 0.5-4 h. In vivo biodistribution of 99mTc-EC-C225 in tumor-bearing rodents showed increased tumor-to-tissue ratios as a function of time. In vitro and biodistribution studies demonstrated the possibility of using 99mTc-EC-C225 to assess EGFR expression. SPECT images confirmed that the tumors could be visualized with 99mTc-EC-C225 from 0.5 to 4 h in tumor bearing rodents. We conclude that 99mTc-EC-C225 may be useful to assess tumor EGFR expression. This may be useful in the future for selecting patients for treatment with C225.
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Affiliation(s)
- Naomi R Schechter
- Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston 77030, USA
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Siemann DW, Shi W. Targeting the tumor blood vessel network to enhance the efficacy of radiation therapy. Semin Radiat Oncol 2003; 13:53-61. [PMID: 12520464 DOI: 10.1053/srao.2003.50005] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
It has been well established that the vascularization of solid tumors is a prerequisite if a clinically relevant size is to be reached. For progressive tumor growth, the vessel network must continuously expand to satisfy the neoplastic cells' nutritional needs and waste product removal requirements. This utter reliance of the tumor on its vasculature provides a logical target for new approaches to cancer therapy. Indeed, there currently exists a great deal of enthusiasm for the development of interventions that compromise the growth and/or function of the tumor neovasculature. Two primary directions are being pursued. Inhibitors of angiogenesis seek to interrupt the angiogenic process to prevent new vessel formation. Antivascular approaches aim to cause direct damage to the tumor endothelium and thus lead to extensive secondary neoplastic cell death. The application of such strategies as adjuvants to conventional radiation treatments offers unique opportunities to develop more effective cancer therapies.
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Affiliation(s)
- Dietmar W Siemann
- Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA
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21
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Song ZJ, Gong P, Wu YE. Relationship between the expression of iNOS, VEGF, tumor angiogenesis and gastric cancer. World J Gastroenterol 2002; 8:591-5. [PMID: 12174362 PMCID: PMC4656304 DOI: 10.3748/wjg.v8.i4.591] [Citation(s) in RCA: 111] [Impact Index Per Article: 4.8] [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 investigate the relationship between the expression of inducible nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF), the microvascular density (MVD) and the pathological features and clinical staging of gastric cancer.
METHODS: Immunohistochemical staining was used for detecting the expression of iNOS and VEGF in 46 resected specimens of gastric carcinoma; the monoclonal antibody against CD34 was used for displaying vascular endothelial cells, and MVD was detected by counting of CD34-positive vascular endothelial cells.
RESULTS: Of 46 resected specimens of gastric carcinoma, the rates of expressions of iNOS and VEGF were 58.70% and 76.09%, respectively, and MVD averaged 55.59 ± 19.39. Judged by the standard TNM criteria, the rate of expression of iNOS in stage IV (84.46%) was higher than those in stage I, II, III (Fish exact probabilities test, P = 0.019, 0.023 and 0.033, respectively); the rates of expression of VEGF in stage III, IV (76.0%, 92.31%, respectively) were higher than those in stage I, II (Fish exact probabilities test, P = 0.031, 0.017, 0.022 and 0.019). MVDs in stage III, IV (64.72 ± 14.96, 67.09 ± 18.29, respectively) were higher than those in stage I, II (t = 2.378, 4.015, 2.503 and 2.450, P < 0.05, P < 0.001, P < 0.001, P < 0.05, respectively). In 37 gastric carcinoma specimens with lymph node metastasis, MVD (68.69 ± 18.07) and the rates of expression of iNOS and VEGF (70.27%, 83.78%, respectively) were higher than those in the specimens with absence of metastasis (t = 2.205, χ² = 6.3587, χ² = 6.2584, P < 0.01, P < 0.05, P < 0.05, respectively). MVD and the expressions of iNOS and VEGF were not correlated to the location, size or grade of tumor, nor with the depth of invasion of tumor; MVDs in the positive iNOS and VEGF specimens (59.88 ± 18.02, 58.39 ± 17.73, respectively) were higher than those in the negative iNOS and VEGF specimens (χ² = 6.3587 and 6.1574, P < 0.05, P < 0.05, respectively); thus the expressions of iNOS and VEGF was correlated to MVD, but the expression of iNOS was not correlated to that of VEGF. In addition, of the 46 surviving patients, the 5-year survival rate of patients with positive iNOS or VEGF tumors was significantly less than that of patients with negative iNOS-or VEGF tumors (χ² = 4.3842 and 5.4073, P < 0.05, P < 0.05, respectively).
CONCLUSION: The expressions of iNOS and VEGF are closely related to tumor angiogenesis, and are involved in the advancement and the lymph node metastasis; thus MVD and the expressions of iNOS and VEGF may serve indexes for evaluating staging of gastric carcinoma and forecasting its risk of metastasis, which will help establish a comprehensive therapeutical measure of post-operative patients and provide a new approach to tumor therapy.
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Affiliation(s)
- Zheng-Jun Song
- Department of Gastroenterology,First Affiliated Hospital of Xi'an Jiaotong University,Xi'an 710061, ShaanXi Province,China.
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Hasan J, Byers R, Jayson GC. Intra-tumoural microvessel density in human solid tumours. Br J Cancer 2002; 86:1566-77. [PMID: 12085206 PMCID: PMC2746601 DOI: 10.1038/sj.bjc.6600315] [Citation(s) in RCA: 218] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2002] [Accepted: 03/21/2002] [Indexed: 12/12/2022] Open
Abstract
Over the last decade assessment of angiogenesis has emerged as a potentially useful biological prognostic and predictive factor in human solid tumours. With the development of highly specific endothelial markers that can be assessed in histological archival specimens, several quantitative studies have been performed in various solid tumours. The majority of published studies have shown a positive correlation between intra-tumoural microvessel density, a measure of tumour angiogenesis, and prognosis in solid tumours. A minority of studies have not demonstrated an association and this may be attributed to significant differences in the methodologies employed for sample selection, immunostaining techniques, vessel counting and statistical analysis, although a number of biological differences may account for the discrepancy. In this review we evaluate the quantification of angiogenesis by immunohistochemistry, the relationship between tumour vascularity and metastasis, and the clinicopathological studies correlating intra-tumoral microvessel density with prognosis and response to anti-cancer therapy. In view of the extensive nature of this retrospective body of data, comparative studies are needed to identify the optimum technique and endothelial antigens (activated or pan-endothelial antigens) but subsequently prospective studies that allocate treatment on the basis of microvessel density are required.
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Affiliation(s)
- J Hasan
- Cancer Research UK Department of Medical Oncology, Christie Hospital, Wilmslow Road, Withington, Manchester M20 4BX, UK
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23
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Yang DJ, Kim KD, Schechter NR, Yu DF, Wu P, Azhdarinia A, Roach JS, Kalimi SK, Ozaki K, Fogler WE, Bryant JL, Herbst R, Abbruzzes J, Kim EE, Podoloff DA. Assessment of antiangiogenic effect using 99mTc-EC-endostatin. Cancer Biother Radiopharm 2002; 17:233-45. [PMID: 12030117 DOI: 10.1089/108497802753773856] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
PURPOSE Tumor vascular density may provide a prognostic indicator of metastatic potential or survival. The purpose of this study was to develop 99mTc-ethylenedicysteine-endostatin (99mTc-EC-endostatin) for the evaluation of anti-angiogenesis therapy. METHOD 99mTc-EC-endostatin was prepared by conjugating ethylenedicysteine (EC) to endostatin, followed by adding pertechnetate and tin chloride. Radiochemical purity was > 95%. In vitro cell viability, affinity and TUNEL assays were performed. Tissue distribution and planar imaging of radiolabeled endostatin were determined in tumor-bearing rats. To assess anti-angiogenic treatment response, rats were treated with endostatin, paclitaxel and saline, followed by imaging with 99mTc-EC-endostatin. Tumor response to endostatin therapy in tumor-bearing animal models was assessed by correlating tumor uptake dose with microvessel density, VEGF, bFGF and IL-8 expression during endostatin therapy. RESULTS In vitro cell viability and TUNEL assays indicated no marked difference between EC-endostatin and endostatin. Cellular uptake assay suggests that endostatin binds to endostatin receptor. Biodistribution of 99mTc-EC-endostatin in tumor-bearing rats showed increased tumor-to-tissue count density ratios as a function of time. Tumor uptake (%ID/g) of 99mTc-EC-endostatin was 0.2-0.5. Planar images confirmed that the tumors could be visualized clearly with 99mTc-EC-endostatin. The optimal time for imaging using radiolabeled endostatin was 2 hrs. 99mTc-EC-endostatin could assess treatment response. There was a correlation between tumor uptake and cellular targets expression. CONCLUSION The results indicate that it is feasible to use 99mTc-EC-endostatin to assess efficiency of anti-angiogenesis therapy.
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Affiliation(s)
- David J Yang
- Department of Nuclear Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
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24
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Giatromanolaki A, Stathopoulos GP, Koukourakis MI, Rigatos S, Vrettou E, Kittas C, Fountzilas G, Sivridis E. Angiogenesis and apoptosis-related protein (p53, bcl-2, and bax) expression versus response of gastric adenocarcinomas to paclitaxel and carboplatin chemotherapy. Am J Clin Oncol 2001; 24:222-6. [PMID: 11404489 DOI: 10.1097/00000421-200106000-00002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The role of angiogenesis and apoptosis-related proteins in defining response to chemotherapy is poorly understood. We examined the microvessel density (MVD) and the expression of p53, bcl-2, and bax proteins in a series of 28 locally advanced gastric adenocarcinomas, treated with paclitaxel and carboplatin. A strong cytoplasmic reactivity in more than 10% of cancer cells was recorded in 25% of cases for p53 protein, and in 14% and 64% of cases for bcl-2 and bax proteins, respectively. Microvessel density was assigned in three categories: low (<35), medium (35-60), and high (>60). Tumors of medium MVD showed a significantly higher response rate compared with those of high or low MVD (p = 0.01 and 0.001, respectively), and prognosis was significantly better in this group of patients with medium MVD tumors (p < 0.02). Loss of bax protein expression was somewhat more frequent in tumors resistant to chemotherapy, but this difference was not of statistical significance. Nuclear p53 reactivity was associated with higher MVD (p = 0.02). The expression of p53 and bcl-2 did not influence the outcome of treatment. The present study suggests that although apoptosis-related proteins may have a role in defining response to taxanes, parameters related to tumors' vasculature, such as drug availability or angiogenic tissue regeneration, may be equally important.
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25
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Eccles SA. Cell biology of lymphatic metastasis. The potential role of c-erbB oncogene signalling. Recent Results Cancer Res 2001; 157:41-54. [PMID: 10857161 DOI: 10.1007/978-3-642-57151-0_5] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Lymphatic metastases are an important indicator of the malignancy of epithelial cancers. Empirical clinical observations associating specific genetic abnormalities with tumour progression, allied with basic laboratory investigations, are providing not only improved prognostic and diagnostic opportunities, but also a detailed understanding of the molecular machinery of metastasis. One such association--between the c-erbB oncogene family and metastasis--has proved particularly instructive. Functional links between over-expression (and occasionally mutational activation) of c-erbB-1 (EGFR) and c-erbB-2 and specific phenotypes of metastatic cells have been elucidated. Activated c-erbB oncogenes potentiate tumour cell adhesion to endothelial cells and upregulate VEGF, potentially facilitating angiogenesis and vascular invasion. In addition, cells over-expressing these oncogenes frequently show aberrant cell-cell and cell-matrix interactions, mediated by changes in integrin and cadherin function. Thirdly, both EGFR and c-erbB-2 signalling can significantly upregulate specific matrix metalloproteinases, key enzymes involved in angiogenesis and invasion. Finally, c-erbB receptors linked to the actin cytoskeleton and highly expressed on invadopodia, are thought to assist cell migration. Taken together, these observations suggest that such receptors can act as "master switches" in metastasis, whose activation co-ordinately controls events normally utilised in development, now subverted by the metastatic cell. As such, they represent ideal targets for therapeutic intervention.
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Affiliation(s)
- S A Eccles
- Section of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK
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26
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Siemann DW, Warrington KH, Horsman MR. Targeting tumor blood vessels: an adjuvant strategy for radiation therapy. Radiother Oncol 2000; 57:5-12. [PMID: 11033183 DOI: 10.1016/s0167-8140(00)00243-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND PURPOSE The neovascularization of tumor cells is a prerequisite if a clinically relevant tumor size is to be reached. A continuously expanding vessel network supplying nutritional requirements and removing waste products is essential for continued tumor development, growth and survival. RESULTS In many tumors, the growing endothelium is unable to fully support the demands of the neoplastic cell population. As a consequence of the inadequacies of the resulting aberrant vasculature, microenvironmental conditions develop in tumors which are not only detrimental to the response of tumors to conventional anticancer treatments, but may lead to or predispose cells to genetic modifications resulting in more aggressive phenotypes and higher metastatic potential. Yet the utter dependence of the tumor on its induced vessel formation for growth, survival and spread has also created a great deal of enthusiasm for developing therapeutic approaches to specifically targeting the tumor microcirculation. CONCLUSIONS The application of such strategies as adjuvants to conventional radiation treatments offers unique opportunities to develop more effective cancer therapies.
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Affiliation(s)
- D W Siemann
- Department of Radiation Oncology, Shands Cancer Center, University of Florida, Box 100385, Gainesville, FL 32610, USA
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27
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Elpek GO, Gelen T, Aksoy NH, Karpuzoglu T, Keles N. Microvessel count, proliferating cell nuclear antigen and Ki-67 indices in gastric adenocarcinoma. Pathol Oncol Res 2000; 6:59-64. [PMID: 10749590 DOI: 10.1007/bf03032660] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The aim of the present study was to immunohistochemically investigate the prognostic value of neovascularization (expressed as microvessel count-MVC) and tumor cell proliferation (expressed as PCNA labeling index PLI and Ki-67 labeling index KLI) in gastric adenocarcinoma. Correlations with clinicopathologic features were also evaluated. Tumor specimens from 74 patients diagnosed as gastric adenocarcinoma were included in this study. Formalin fixed, paraffin embedded tissue sections stained immunohistochemically with F-VIII, PC10 and MIB-1 monoclonal antibodies. By ocular grid subdivided into 100 areas, number of microvessels and PC10, MIB-1 positive and negative cells were counted at x400 magnification. Chi-square test, Kaplan-Meier method and cox regression analysis were used for statistical analysis. The results showed that, MVC and PLI had a significant correlation with invasion and lymph node metastasis. The prognosis was significantly worse in patients with high MVC (>14 ) and with high PLI (>49%). However any relationship was not observed between KLI (38%) and clinicopathologic parameters, so KLI failed to predict the prognosis. Cox model showed that, MVC and PLI were independent prognostic variables. Ki-67 labeling index in gastric carcinomas has no prognostic relevance. However, the evaluation of microvessel count and proliferating cell nuclear antigen index in gastric carcinomas could be reliable indicators of prognosis.
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Affiliation(s)
- G O Elpek
- Akdeniz University, Medical School, Department of Pathology Týp Fakültesi, Patoloji ABD, Yeni Týp, Dekanlýk, Antalya, 07070, Turkey.
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