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Assessment of vascular endothelial growth factor in formalin fixed, paraffin embedded colon cancer specimens by means of a well-based reverse phase protein array. Proteome Sci 2014; 12:27. [PMID: 24883046 PMCID: PMC4039052 DOI: 10.1186/1477-5956-12-27] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 05/02/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) is a critical pro-angiogenic factor, found in a number of cancers, and a target of therapy. It is typically assessed by immunohistochemistry (IHC) in clinical research. However, IHC is not a quantitative assay and is rarely reproducible. We compared VEGF levels in colon cancer by IHC and a quantitative immunoassay on proteins isolated from formalin fixed, paraffin embedded tissues. RESULTS VEGF expression was studied by means of a well-based reverse phase protein array (RPPA) and immunohistochemistry in 69 colon cancer cases, and compared with various clinicopathologic factors. Protein lysates derived from formalin fixed, paraffin embedded tissue contained measurable immunoreactive VEGF molecules. The VEGF expression level of well differentiated colon cancer was significantly higher than those with moderately and poorly differentiated carcinomas by immunohistochemistry (P = 0.04) and well-based RPPA (P = 0.04). VEGF quantification by well-based RPPA also demonstrated an association with nodal metastasis status (P = 0.05). In addition, the normalized VEGF value by well-based RPPA correlated (r = 0.283, P = 0.018). Furthermore, subgroup analysis by histologic type revealed that adenocarcinoma cases showed significant correlation (r = 0.315, P = 0.031) between well-based RPPA and IHC. CONCLUSIONS The well-based RPPA method is a high throughput and sensitive approach, is an excellent tool for quantification of marker proteins. Notably, this method may be helpful for more objective evaluation of protein expression in cancer patients.
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Hepatic ischemia-reperfusion increases circulating bone marrow-derived progenitor cells and tumor growth in a mouse model of colorectal liver metastases. J Surg Res 2013; 184:888-97. [PMID: 23726239 DOI: 10.1016/j.jss.2013.04.069] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 04/09/2013] [Accepted: 04/26/2013] [Indexed: 01/22/2023]
Abstract
BACKGROUND Hepatic pedicle clamping is often required to reduce blood loss and transfusion during liver resection. However, the question remains whether use of hepatic pedicle clamping promotes tumor growth. Endothelial progenitor cells (EPCs) are mobilized from bone marrow in response to tissue ischemia, which allows neovascularization of ischemic tissue. It has been suggested that EPCs are involved in tumor progression. We hypothesized that hepatic ischemia reperfusion (I/R)-induced mobilization of EPCs could enhance growth of microscopic tumor, therefore promoting liver metastasis in a mouse model of colorectal cancer. MATERIALS AND METHODS We used mouse models of hepatic I/R and hind limb ischemia. For comparison, we studied mice that underwent limb ischemia as positive controls of EPC mobilization. At day 0, we divided 40 mice into four groups: hepatic I/R, hind limb ischemia, combined hepatic I/R and hind limb ischemia, and control (sham midline incision laparotomy). At day 2, we induced liver metastasis in all mice by injecting CT-26 cells into the spleen. Time-dependent circulating EPCs were determined by flow cytometry. We evaluated liver metastasis and microvascular density on day 21. RESULTS The number of circulating progenitor cells increased rapidly in the ischemic groups compared with the control group. Hepatic I/R significantly increased tumor outgrowth compared with the control group. Increased tumor growth was associated with enhanced CD31-positive microvascular density in liver tissue. CONCLUSIONS Hepatic I/R leads to mobilization of bone marrow-derived EPCs and enhanced intra-hepatic angiogenesis, which is associated with increased tumor burden in an animal model of colorectal liver metastasis.
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Resch T, Pircher A, Kähler CM, Pratschke J, Hilbe W. Endothelial progenitor cells: current issues on characterization and challenging clinical applications. Stem Cell Rev Rep 2012; 8:926-39. [PMID: 22095429 DOI: 10.1007/s12015-011-9332-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Since their discovery about a decade ago, endothelial precursor cells (EPC) have been subjected to intensive investigation. The vision to stimulate respectively suppress a key player of vasculogenesis opened a plethora of clinical applications. However, as research opened deeper insights into EPC biology, the enthusiasm of the pioneer era has been damped in favour of a more critical view. Recent research is focused on three major questions: The fact that the number of EPC in peripheral blood is exceedingly low has consistently raised suspicion whether these cells can plausibly have an impact on physiological or pathophysiological processes. Secondly, whereas the key role of EPC in tumourigenesis has been strongly emphasized by various groups in the past, recent publications are challenging this hypothesis. Thirdly, the lack of consensus on EPC-defining markers and standardized protocols for their detection have repeatedly led to difficulties concerning comparability between papers. In this current review, an overview on recent findings on EPC biology is given, their challenging clinical implications are discussed and the perplexity underlying the current controversial debate is illustrated.
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Affiliation(s)
- Thomas Resch
- Center of Operative Medicine, Department of Visceral, Transplant, and Thoracic Surgery, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
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Hashim AF, Al-Janabi AA, Mahdi LH, Al-Toriahi KM, Yasseen AA. Vascular endothelial growth factor (VEGF) receptor expression correlates with histologic grade and stage of colorectal cancer. Libyan J Med 2010; 5. [PMID: 21483581 PMCID: PMC3071172 DOI: 10.3402/ljm.v5i0.5059] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2009] [Accepted: 02/20/2010] [Indexed: 01/28/2023] Open
Abstract
Background Colorectal carcinoma (CRC) is the seventh-most common malignancy and is the main cause of death in Iraq. The incidence of this cancer has increased sharply after the invasion of Iraq in 2003. Aim To estimate immunohistochemical expression of vascular endothelial growth factor (VEGF) in CRC in relation to other parameters, such as grade and stage of tumour. Methods Formalin fixed, paraffin-embedded blocks from 52 patients (27 male and 25 female) with CRC were included in this study. A group of 22 patients with non-cancerous colonic tissues were included as a control group. Avidin–biotin complex method was employed for immunohistochemical detection of VEGF. Results VEGF immuno-expression was positive in 51.9% of CRC, while it was 18.2% in the normal colonic tissue (p <0.05). VEGF immunostaining was positively correlated with grade of colonic malignancy (p <0.05). Conclusion These findings provide further evidence for the role of VEGF in the carcinogenesis of CRC. However, VEGF could not be well correlated with stage of tumour and hence may be a poor prognostic parameter of state of malignancy of colonic carcinoma.
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Affiliation(s)
- Ali F Hashim
- Department of Pathology and Forensic Medicine, School of Medicine, University of Kufa, Kufa, Iraq
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Alferez D, Wilkinson RW, Watkins J, Poulsom R, Mandir N, Wedge SR, Pyrah IT, Smith NR, Jackson L, Ryan AJ, Goodlad RA. Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in Apc(Min/+) mice. Mol Cancer Ther 2008; 7:590-8. [PMID: 18347145 DOI: 10.1158/1535-7163.mct-07-0433] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Both the epidermal growth factor (EGF) and the vascular endothelial growth factor (VEGF) pathways are associated with intestinal cancer, and therapeutic approaches targeting either EGF receptor (EGFR) or VEGF receptor (VEGFR) signaling have recently been approved for patients with advanced colorectal cancer. The Apc(Min/+) mouse is a well-characterized in vivo model of intestinal tumorigenesis, and animals with this genetic mutation develop macroscopically detectable adenomas from approximately 6 weeks of age. Previous work in the Apc(Min/+) mouse has shown that therapeutic approaches targeting either VEGFR or EGFR signaling affect predominantly the size or number of adenomas, respectively. In this study, we have assessed the effect of inhibiting both these key pathways simultaneously using ZD6474 (Vandetanib, ZACTIMA), a selective inhibitor of VEGFR and EGFR tyrosine kinases. To assess the effects of ZD6474 on early- and later-stage disease, treatment was initiated in 6- and 10-week-old Apc(Min/+) mice for 28 days. ZD6474 markedly reduced both the number and the size of polyps when administered at either an early or a later stage of polyp development. This reduction in both adenoma number and size resulted in a total reduction in tumor burden in the small intestine of nearly 75% in both studies (P < 0.01). The current data build on the concept that EGFR-dependent tumor cell proliferation and VEGF/VEGFR2-dependent angiogenesis and survival are distinct key mechanisms in polyp development. Pharmacologic inhibition of both signaling pathways has significant antitumor effects at both early and late stages of polyp development. Therefore, targeting both VEGFR- and EGFR-dependent signaling may be a beneficial strategy in early intestinal cancer.
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Affiliation(s)
- Denis Alferez
- Cancer Research UK, Histopathology Unit, London Research Institute, London, UK
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Montero E, Abreu C, Tonino P. Relationship between VEGF and p53 expression and tumor cell proliferation in human gastrointestinal carcinomas. J Cancer Res Clin Oncol 2007; 134:193-201. [PMID: 17636327 DOI: 10.1007/s00432-007-0270-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2007] [Accepted: 06/19/2007] [Indexed: 12/14/2022]
Abstract
PURPOSE The vascular endothelial growth factor (VEGF) and p53 play important roles in the growth of tumor. However, the relationship between the expression of VEGF and p53 and tumor cell proliferation in human gastrointestinal cancer remains unknown. In the present study, therefore, we have examined the relationship between VEGF and p53 expression and tumor cell proliferation in gastrointestinal carcinoma (GITC), as well as the association between these biomarkers and clinicopathological factors. METHODS Surgical specimens from 30 patients with GITC were examined for VEGF, p53, and proliferating cell nuclear antigen (PCNA) expression by immunohistochemical staining. RESULTS We found a predominant VEGF expression of moderate intensity in 16(54.84%) of 30 GITC cases, while p53 expression was mainly high in 13(45.16%) of 30 GITC cases. PCNA expression was high in 20(64.52%) of 30 GITC cases. Tumor size, infiltration, vascular invasion, and gastritis were significantly correlated with VEGF, p53, and PCNA expression. There was a significant correlation between VEGF and p53 expression (P = 0.0001), VEGF and PCNA expression (P = 0.00004), and between p53 expression and PCNA expression (P = 0.0016). When the VEGF and p53 expression, and PCNA expression were considered together, both VEGF and p53 expression were not significantly associated with PCNA. A significant correlation between the PCNA expression and the mitotic index (P = 0.0016) was also found. CONCLUSION These results demonstrate that VEGF and p53 expression are significantly correlated as independent prognostic factors with tumor cell proliferation, and might be associated with relevant events involved in gastrointestinal tumor biology.
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Affiliation(s)
- Elvira Montero
- Centro de Microscopía Electrónica "Dr. Mitsuo Ogura", Facultad de Ciencias, Universidad Central de Venezuela, Apartado 76963, El Marqués 1070, Caracas, Venezuela
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Giannelli G, Azzariti A, Sgarra C, Porcelli L, Antonaci S, Paradiso A. ZD6474 inhibits proliferation and invasion of human hepatocellular carcinoma cells. Biochem Pharmacol 2006; 71:479-85. [PMID: 16332356 DOI: 10.1016/j.bcp.2005.11.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2005] [Revised: 11/02/2005] [Accepted: 11/02/2005] [Indexed: 10/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is characterized by hypervascularization, neoangiogenesis formation and blood vessel invasion. Recently, it has been demonstrated that an inhibitor of the vascular endothelial growth factor (VEGF) receptor, ZD6474, may directly inhibit the growth of tumor cells. ZD6474 effectiveness was investigated on cell growth, apoptosis, adhesion, migration and invasion and related to the drug-dependent modulation of main molecular targets on HCC cells. ZD6474 inhibited HCC cell proliferation, however, such effect was reverted by Laminin-5 (Ln-5) but not by other extracellular matrix proteins (ECM). ZD6474 also inhibited HCC cell adhesion, migration and invasion, whereas the simultaneous treatment with the drug and Ln-5 strongly recovered those effects. Under the same experimental conditions, ZD6474 inhibited the expression of phosphorylated EGFR in all cell lines while the effect on p-Erk1/2 was dependent on cellular invasive characteristics. Nonetheless, co-incubation with Ln-5 completely recovered this effect. Our results support the hypothesis that ZD6474 could represent an interesting therapeutic opportunity for patients with HCC scarcely expressing the ECM protein, Ln-5.
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Affiliation(s)
- Gianluigi Giannelli
- Department of Internal Medicine, Immunology, and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy.
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Roumen RMH, Slooter GD, Croiset van Uchelen FAAM, Huib LV. Preoperative serum vascular endothelial growth factor is not a marker for subsequent recurrence during long-term follow-up of colorectal cancer patients. Dis Colon Rectum 2005; 48:1070-5. [PMID: 15785896 DOI: 10.1007/s10350-004-0870-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Serum vascular endothelial growth factor has been associated with stage of disease in colorectal cancer patients. We investigated whether preoperative serum vascular endothelial growth factor can provide any relevant clinical prognostic information during long-term follow-up of colorectal cancer patients. METHODS Preoperative serum samples of 79 colorectal cancer patients and serum of 28 healthy controls were stored at -80 degrees C until later vascular endothelial growth factor analysis by enzyme-linked immunosorbent assay technique and carcinoembryogenic antigen concentration measurement were performed. There were three patient groups for comparison: 21 patients with overt liver metastases, 18 patients who developed recurrent disease after initial curative surgery, and 40 patients who remained disease-free for at least five years. RESULTS We could not demonstrate any significant difference in serum vascular endothelial growth factor values between the patient groups and controls, nor between the three patient groups (Mann-Whitney U test). There was no relevant correlation between serum vascular endothelial growth factor and carcinoembryogenic antigen concentrations (Pearson r = 0.2; P = 0.07). CONCLUSION Although vascular endothelial growth factor has been shown in previous studies to be a potent inducer of angiogenesis and metastases formation, the present data demonstrate that preoperative serum vascular endothelial growth factor concentration does not provide any relevant individual prognostic information in patients with colorectal cancer.
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Affiliation(s)
- Rudi M H Roumen
- Department of Surgery, Máxima Medisch Centrum, 5500 MB Veldhoven, The Netherlands
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Guba M, Seeliger H, Kleespies A, Jauch KW, Bruns C. Vascular endothelial growth factor in colorectal cancer. Int J Colorectal Dis 2004; 19:510-7. [PMID: 14999511 DOI: 10.1007/s00384-003-0576-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/08/2003] [Indexed: 02/04/2023]
Abstract
Angiogenesis plays an important role in colorectal cancer progression. Evidence from preclinical and clinical studies indicates that vascular endothelial growth factor (VEGF) is the predominant angiogenic factor in human colorectal cancer and is associated with formation of metastases and poor prognosis. Based on these results it was hypothesized that attacking one or more of the VEGF-mediated mechanisms may be promising in the treatment of colorectal cancer. AIMS. This article reviews the role of VEGF in colon cancer and summarizes recent advances in the treatment of colorectal cancer by anti-VEGF strategies.
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Affiliation(s)
- Markus Guba
- Department of Surgery, University Clinic Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany.
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Hilbe W, Dirnhofer S, Oberwasserlechner F, Schmid T, Gunsilius E, Hilbe G, Wöll E, Kähler CM. CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer. J Clin Pathol 2004; 57:965-9. [PMID: 15333659 PMCID: PMC1770433 DOI: 10.1136/jcp.2004.016444] [Citation(s) in RCA: 157] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
AIMS Recent results generated in a mouse model suggest that tumour angiogenesis/vasculogenesis can be initiated and maintained by bone marrow derived endothelial progenitor cells. This present study investigated the distribution and frequency of CD133 positive endothelial progenitor cells in patients with non-small cell lung cancer (NSCLC) (tumour tissue and tumour free lung regions) and healthy controls using fresh frozen specimens. The novel marker CD133 identifies human haemopoetic precursor cells, in addition to human endothelial progenitor cells. METHODS Seventy nine lung cancer specimens and 66 adjacent histologically tumour free tissues of the same patient cohort were analysed; 11 postmortem specimens from control patients who did not suffer from malignant disease served as controls. Cryostat sections were stained for CD133, CD31, vascular endothelial growth factor receptor 2 (VEGFR-2; KDR), p53, and the proliferation marker Ki-67, and the correlations were analysed. RESULTS Forty three of 63 evaluable tumour specimens had increased numbers of CD133 positive cells and in some cases capillary forming CD133 positive structures were detectable. In addition, 30 of 63 specimens had raised expression of KDR and 29 of 63 had increased MVD. Increased CD133 expression marginally correlated with raised KDR expression but not with p53 and Ki-67. CONCLUSION A significant increase in CD133 positive cells was documented in patients with NSCLC, suggesting an involvement of endothelial progenitor cells in tumour vasculogenesis and tumour growth in these patients.
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Affiliation(s)
- W Hilbe
- Department of Internal Medicine, University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria.
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Ward WK, Quinn MJ, Wood MD, Tiekotter KL, Pidikiti S, Gallagher JA. Vascularizing the tissue surrounding a model biosensor: how localized is the effect of a subcutaneous infusion of vascular endothelial growth factor (VEGF)? Biosens Bioelectron 2004; 19:155-63. [PMID: 14611750 DOI: 10.1016/s0956-5663(03)00180-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Implantable continuous biosensors would improve disease management but long term function of such devices have been limited by a hypovascular foreign body capsule that inhibits influx of analytes. To assess whether capsule vascularity could be increased, we studied the histologic effects of a 28-day continuous infusion of vascular endothelial growth factor (VEGF) (0.45 microg/day) vs. saline from the surface of a model disk biosensor that was implanted subcutaneously in rats. At day 40, tissue was obtained at varying distances from the infusion port and capsular microvessels were counted using two histologic techniques. VEGF treatment led to a marked increase in capillary density. In tissue located 1 mm away from the infusion site, capillary density in VEGF-treated animals was 200-300% higher than in saline controls. Tissue located 13 mm away, but not 25 mm away, also demonstrated neovascularization. Serum obtained from a distant vein during the infusion did not show an elevated concentration of VEGF. These data demonstrate that a subcutaneous infusion of VEGF creates localized neovascularization of the foreign body capsule and suggest that systemic effects of VEGF are avoidable. Vascularization of a foreign body capsule surrounding a subcutaneous biosensor might well extend its useful life.
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Affiliation(s)
- W Kenneth Ward
- Legacy Health System, Legacy Clinical Research and Technology Center, 1225 NE 2nd Avenue, Portland, OR 97232, USA.
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Xiong B, Sun TJ, Yuan HY, Hu MB, Hu WD, Cheng FL. Cyclooxygenase-2 expression and angiogenesis in colorectal cancer. World J Gastroenterol 2003; 9:1237-40. [PMID: 12800231 PMCID: PMC4611791 DOI: 10.3748/wjg.v9.i6.1237] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [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: Cyclooxygenase-2 is involved in a variety of important cellular functions, including cell growth and differentiation, cancer cell motility and invasion, angiogenesis and immune function. However, the role of cyclooxygenase-2 as an angiogenic factor in colorectal cancer tissue is still unclear. We investigated the relationship between cyclooxygenase-2 and angiogenesis by analyzing the expression of cyclooxygenase-2 in colorectal cancer tissue, as well as its association with vascular endothelial growth factor (VEGF) and microvascular density (MVD).
METHODS: The expression of cyclooxygenase-2, VEGF, as well as MVD was detected in 128 cases of colorectal cancer by immunohistochemical staining. The relationship between the cyclooxygenase-2 and VEGF expression and MVD was evaluated. Our objective was to determine the effect of cyclooxygenase-2 on the angiogenesis of colorectal cancer tissue.
RESULTS: Among 128 cases of colorectal cancer, 87 were positive for cyclooxygenase-2 (67.9%), and 49 for VEGF (38.3%), respectively. The microvessel counts ranged from 23 to 142, with a mean of 51.7 (standard deviation, 19.8). The expression of cyclooxygenase-2 was correlated significantly with the depth of invasion, stage of disease, metastasis (lymph node and liver), VEGF expression and MVD. Patients in T3-T4, stage III-IV and with metastasis had much higher expression of cyclooxygenase-2 than patients in T1-T2, stage I-II and without metastasis (P < 0.05). The positive expression rate of VEGF (81.6%) in the cyclooxygenase-2 positive group was higher than that in the cyclooxygenase-2 negative group (18.4%, P < 0.05). Also, the microvessel count (56 ± 16) in cyclooxygenase-2 positive group was significantly higher than that in cyclooxygenase-2 negative group (43 ± 12, P < 0.05). The microvessel count in tumors with positive cyclooxygenase-2 and VEGF was the highest (60 ± 18, 41-142, P < 0.05), whereas that in tumors with negative cyclooxygenase-2 and VEGF was the lowest (39 ± 16, 23-68, P < 0.05).
CONCLUSION: Cyclooxygenase-2 may be associated with tumor progression by madulating the angiogenesis in colorectal cancer tissue and used as a possible biomarker.
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Affiliation(s)
- Bin Xiong
- Department of Oncology, Affiliated Zhongnan Hospital of Wuhan University,Wuhan 430071, Hubei Province, China.
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Gunsilius E. Evidence from a leukemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 522:17-24. [PMID: 12674207 DOI: 10.1007/978-1-4615-0169-5_3] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
The maintenance of tissues of virtually all organs depends on a sufficient blood supply. During embryogenesis, primitive blood vessels are formed de novo by the aggregation of angioblasts, a process that is termed vasculogenesis. In postnatal life, the development of new blood vessels is restricted to the female reproductive tract (during the ovulatory cycle) and to sites of wound healing, and occurs through a process called angiogenesis, i.e. the sprouting of new vessels from the preexisting vasculature. However, neovascularization can also occur under pathological conditions, e.g. tumor cells can "switch on" angiogenesis. New blood vessels bring in nutrients and proteins, so the tumor mass can expand. In fact, neovascularization appears to be one of the crucial steps in the transition of a tumor from a small cluster of malignant cells to a visible macroscopic tumor capable of spreading to other organs via the vasculature throughout the body. The association of tumor growth with the development of a vascular network was recognized nearly a century ago. Using a leukemia model, chronic myelogenous leukemia (CML), we were able to provide evidence for the existence of a hemangioblastic progenitor cell in the bone marrow of adult humans. Using the pathognomonic BCR-ABL-fusion gene as a genetic marker present in virtually all bone marrow derived cells of patients with CML, we were able to show that endothelial cells belong to the malignant cell clone, since they also contain the BCR-ABL-fusion gene. Our data suggest that CML arises from a hemangioblastic progenitor cell, the progeny of which are malignant blood cells and genotypically clonal endothelial cells. Thus, we provide substantial evidence that indeed a hemangioblast exists in the bone marrow of human adults. In addition, our data imply that normal as well as genotypically malignant bone-marrow-derived endothelial cells can contribute to maintenance angiogenesis in the vascular endothelium, a condition that is consistent with postnatal vasculogenesis. These findings were recently confirmed by other groups and should help in elucidating the pathophysiology of malignant and nonmalignant disorders. The integration of bone-marrow-derived endothelial cells into the vascular endothelium has implications for the development of vascular targeting strategies (e.g., gene therapy) for vascular diseases, inflammatory disorders, and cancer. The characterization of the hemangioblast at a clonal level as well as the translation of these findings into a clinically applicable concept for the delivery of therapeutic genes to malignant tumors is currently in progress in our laboratory.
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MESH Headings
- Animals
- Cell Differentiation/immunology
- Cell Lineage/immunology
- Endothelium, Vascular/cytology
- Endothelium, Vascular/embryology
- Endothelium, Vascular/immunology
- Hematopoietic Stem Cells/cytology
- Hematopoietic Stem Cells/immunology
- Hematopoietic Stem Cells/metabolism
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Models, Biological
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/physiopathology
- Neovascularization, Physiologic/immunology
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Affiliation(s)
- Eberhard Gunsilius
- Tumor-Biology & Angiogenesis Lab., Division of Hematology & Oncology, University Innsbruck, Austria.
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