Rationale and Objectives
The purpose of this study was to assess the correlations between the maximum standardized uptake value (SUVmax) of colorectal carcinoma and hepatocyte growth factor (HGF), vascular endothelial growth factor C (VEGF-C), and their respective receptors using 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT).
Methods
Fluorine-18-FDG PET/CT scans were performed on 33 patients with colorectal carcinoma before any treatment. The SUVmax of colorectal carcinoma and the clinicopathologic data associated with lymphatic metastases were analyzed. The expression of glucose transporter 1 (GLUT1), HGF, c-Met, VEGF-C, and vascular endothelial growth factor receptor 3 (VEGFR-3) in tumor tissues was analyzed using immunohistochemical methods. Lymphatic endothelial cells were marked with D2-40, and lymphatic vessel density (LVD) was recorded. The correlations were analyzed among the SUVmax of colorectal carcinoma, LVD, and the expression of GLUT1, HGF, c-Met, VEGF-C, and VEGFR-3 in tumor tissues.
Results
SUVmax and LVD in 15 patients with lymphatic metastases were 13.00 ± 4.51 and 6.25 ± 1.54, respectively, whereas in 18 patients with nonmetastatic nodes, SUVmax and LVD were 9.66 ± 4.82 and 4.54 ± 1.02, respectively. The differences of SUVmax and LVD between metastatic and nonmetastatic patients were statistically significant ( F = 4.153, P = .025, and F = 14.501, P = .001, respectively). There were no statistical differences of SUVmax and LVD in variably differentiated colorectal carcinoma ( F = 0.708, P = .502, and F = 0.311, P = .735, respectively). The expression rates of GLUT1 in neoplastic and normal tissue were 72.7% (24 of 33) and 21.2% (seven of 33), respectively ( P = .001). Moreover, the expression rates of GLUT1 in metastatic and nonmetastatic tissue were 93.33% (14 of 15) and 61.11% (11 of 18), respectively ( P = .038). LVD and the integrated optical density of GLUT1 were 5.31 ± 1.53 and 8.21 × 10 4 ± 4.30 × 10 4 , respectively, in tumor tissue, and there were linear correlations between SUVmax and LVD ( r = 0.373, P = .033) and between SUVmax and expression of GLUT1 ( r = 0.428, P = .013). The differences of SUVmax in HGF, c-Met, and VEGF-C groups with different expressions were statistically significant ( P = .007, P = .009, and P = .030, respectively). No correlation was found between the expression of VEGFR-3 and SUVmax. The expression of GLUT1 and HGF as well as of GLUT1 and VEGF-C was rank correlated ( r = 0.521, P = .002, and r = 0.505, P = .003, respectively). No rank correlations were found between the expression of GLUT1 and c-Met, GLUT1, and VEGFR-3.
Conclusions
The SUVmax of colorectal carcinoma was significantly higher in metastatic patients; the uptake of colorectal carcinoma was associated with LVD and the expression of HGF and VEGF-C but not with the expression of VEGFR-3.
Whole-body positron emission tomography (PET)/computed tomography (CT) with 18 F-fluorodeoxyglucose (FDG), which integrates the functional imaging of PET and the anatomic imaging of CT, can provide some information about the biologic characteristics of tumors. The quantitative index standardized uptake value (SUV) is correlated with malignancy and tumor-node-metastasis staging in many tumors, including colorectal carcinoma .
Neoplastic angiogenesis and lymphangiogenesis play an important role in the origin and development of tumors. Many studies have demonstrated that there are correlations between maximum SUV (SUVmax) and vascular endothelial growth factor A (VEGF-A), as well as between SUVmax and neoplastic microvascular density. Thus, SUVmax may reflect neoplastic angiogenesis to some degree . Similarly to angiogenesis, neoplastic lymphangiogenesis can be induced by many growth factors and cytokines, such as VEGF-A, vascular endothelial growth factor C (VEGF-C), basic fibroblast growth factor 2, angiopoietins, platelet-derived growth factors, hepatocyte growth factor (HGF), and so forth . Some growth factors can promote both angiogenesis and lymphangiogenesis . Moreover, hypoxia in tumor tissue can up-regulate the expression of VEGF-A and VEGF-C, which can resist hypoxia and promote neoplastic angiogenesis and lymphangiogenesis . Thus, we suppose that the uptake of FDG by tumors could reflect, to some extent, neoplastic lymphangiogenesis.
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Materials and methods
Patients and Clinicopathologic Information
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18 F-FDG PET/CT
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FDG PET/CT Image Interpretation
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Preparation of Tissue Microarrays
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Immunohistochemical Stains
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Antigen reparation
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Tissue Microarray Interpretation
Lymphatic vessel count
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LVD count
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HGF, c-Met, VEGF-C, and vascular endothelial growth factor receptor 3 (VEGFR-3) immunohistochemical staining
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Scoring of positive stain intensity
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Scoring of positive cell proportion
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Glucose Transporter 1 (GLUT1) immunohistochemical staining
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Statistical Analysis
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Results
Correlations among SUVmax, Lymphatic Metastases, and LVD for Colorectal Carcinoma
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Correlations between SUVmax and Expression of HGF, c-Met, VEGF-C, and VEGFR-3
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Table 1
Correlations between SUVmax, LVD, and Expression of HGF, c-Met, VEGF-C, and VEGFR-3 in Colorectal Carcinoma
Expression Level_n_ SUVmax_F__P_ LVD_F__P_ HGF − 7 8.60 ± 2.33 4.842 .007 4.47 ± 1.49 4.536 .010 + 5 8.20 ± 2.51 4.53 ± 0.51 ++ 15 11.27 ± 4.61 5.31 ± 1.34 +++ 6 16.44 ± 5.62 6.90 ± 1.50 c-Met − 3 9.83 ± 1.46 4.596 .009 3.83 ± 0.23 3.933 .018 + 7 7.74 ± 1.78 4.17 ± 0.86 ++ 12 10.16 ± 2.35 5.72 ± 1.27 +++ 11 14.84 ± 6.62 5.97 ± 1.74 VEGF-C − 3 7.59 ± 2.53 3.969 .030 4.40 ± 0.55 2.399 .088 + 14 9.50 ± 1.82 4.95 ± 1.22 ++ 14 13.12 ± 5.89 5.81 ± 1.78 +++ 1 7.67 ± 0.00 VEGFR-3 − 3 9.44 ± 1.55 2.420 .086 5.56 ± 1.57 3.866 .019 + 16 9.37 ± 2.45 4.52 ± 1.16 ++ 10 14.12 ± 7.57 6.00 ± 1.54 +++ 4 12.37 ± 1.40 6.58 ± 1.52
HGF, hepatocyte growth factor; LVD, lymphatic vessel density; SUVmax, maximum standardized uptake value; VEGF-C, vascular endothelial growth factor C; VEGFR-3, vascular endothelial growth factor receptor 3.
Data are expressed as mean ± SD.
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Correlations between Expression of GLUT1 and SUVmax and Expression of HGF, c-Met, VEGF-C, and VEGFR-3 for Colorectal Carcinoma
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Table 2
Correlations between Expression of GLUT1 and Expression of HGF and c-Met in 33 Patients with Colorectal Carcinoma
GLUT1 HGF c-Met − + ++ +++ − + ++ +++ + 4 1 3 0 1 2 3 2 ++ 3 3 5 2 2 5 2 4 +++ 0 1 7 4 0 0 7 5
GLUT1, glucose transporter 1; HGF, hepatocyte growth factor.
Table 3
Correlations between Expression of GLUT1 and Expression of VEGF-C and VEGFR-3 in 33 Patients with Colorectal Cancer
GLUT1 VEGF-C VEGFR-3 − + ++ +++ − + ++ +++ + 3 5 0 0 1 5 2 0 ++ 0 6 7 0 2 5 4 2 +++ 1 3 7 1 0 6 4 2
GLUT1, glucose transporter 1; VEGF-C, vascular endothelial growth factor C; VEGFR-3, vascular endothelial growth factor receptor 3.
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Discussion
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Conclusions
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