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Clinical Investigations |
University of Nottingham Laboratory of Molecular Oncology, Cancer Research Campaign Department of Clinical Oncology [J. D. W., P. W. H, D. K., J. C., J. C. M.] and Department of Histopathology [T. M.], Nottingham City Hospital, Nottingham NG5 1PB, United Kingdom, and Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, SF-00014 Helsinki, Finland [B. C. E.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the human, VEGF-D activates VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4) receptor tyrosine kinases (2 , 11) , both of which are essential for vascular development (1 , 12) . VEGFR-2, the main receptor through which VEGF-A signals in endothelial cells, is up-regulated in tumor angiogenesis (1) . Although VEGFR-3 expression becomes restricted mainly to lymphatic and fenestrated endothelium in the adult (1 , 6 , 12) , it may also play a critical role in the maintenance of the integrity of the endothelial lining during tumor angiogenesis (13) . VEGFR-3 expression is up-regulated in breast cancer and a number of other tumor types (14, 15, 16) .
Angiogenesis, as indicated by increased MVD and changes in expression of VEGF and its cognate receptors, has been shown in some studies to have prognostic significance in CRC (17, 18, 19, 20, 21) , whereas lymphatic invasion and lymph node involvement are also recognized as important prognostic factors (22) . VEGF-D has been functionally implicated in both angiogenesis and lymphatic development; however its exact biological role remains poorly understood. We have examined the expression of VEGF-D and VEGFR-3 in relation to MVD in archival samples of normal adjacent bowel mucosa, premalignant lesions, and CRC by immunohistochemistry to determine the distribution of this novel member of the VEGF family, its receptor VEGFR-3, and their relationship to known prognostic markers for CRC.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunohistochemistry.
Formalin-fixed, paraffin-embedded serial sections (4 µm) mounted on 3-aminopropyltriethoxysilane-coated slides (Sigma Chemical Co., Poole, United Kingdom) were deparaffinized in Histolene (Cellpath, Herts, United Kingdom) and 1:1 Histolene/ethanol, and rehydrated. Antigen retrieval was performed in 0.1 M citrate buffer (pH 6) in an 800 W microwave for 15 min. Endogenous peroxidase activity was blocked with 0.3% hydrogen peroxide in 100% methanol for 30 min. Sections were washed in Dulbecco’s calcium- and magnesium-free PBS (PBS/A), and blocked with either 1.5% normal rabbit serum or 10% horse serum and 0.3% BSA in PBS/A for 20 min (see Table 1
). Primary antibodies were diluted as indicated in Table 1
in 0.3% BSA in PBS/A and incubated on the sections overnight at 4°C. After three washes in PBS/A (5 min), 1:200 dilutions of secondary antirabbit or antimouse biotinylated antibodies (Vector Laboratories Inc, Burlingame, CA) were added to the sections for 30 min. Antibody binding was visualized using the Avidin Biotin Complex (ABC) Elite Kit and 3,3-diaminobenzidine according to the manufacturer’s instructions (Vector Laboratories). Sections were counterstained with Gill’s hematoxylin and, after dehydration through graded ethanol solutions, mounted in DPX (BDH Lab Supplies, Poole, United Kingdom). For general negative controls, the primary antibody was replaced with PBS/A. In addition, sections stained with primary antibody incubated overnight at 4°C in the presence of 5-fold excess (by weight) of blocking peptide (sc7602; Santa Cruz Biotechnology) were used as negative controls for VEGF-D staining. Sections of normal heart were stained as positive controls for VEGFR-3 expression.
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Statistical Analysis.
All statistical calculations were performed using SPSS version 8.0 (SPSS Inc., Chicago, IL). Survival was measured from the date of surgery to the time of event (recurrence or death) or to the last census prior to closure of the study (May 5, 1999) and calculated by the Kaplan-Meier method. Deaths attributable to causes other than CRC were excluded from survival and prognostic analysis. For this analysis, VEGF-D antibody-stained sections were grouped as low (0 and 1) or high grade (2 and 3). The log-rank test was used to compare survival based on VEGF-D grade, VEGFR-3+ vessel densities, and MVD. Differences in VEGF-D expression between groups were estimated using the 
2 test for categorical data and independent-paired Student’s t test for continuous variables. VEGFR-3+ vessel densities or MVD between categorical variables were compared by ANOVA. Comparisons of MVD and VEGFR-3+ vessel densities and their relationship to tumor size were made using the Pearson correlation coefficient. Differences between cases based on VEGFR-3+ vessel densities or MVD above or below the median value were estimated using the 2 test for categorical data and the independent paired Student’s t test for continuous variables. Cox regression analysis was used to estimate the prognostic influence of various factors.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Typical examples of the different intensities of VEGF-D staining observed in CRC are shown in Fig. 1, A and B
. In comparison, VEGF-D staining of adenomas (not shown) and normal adjacent mucosa was generally weaker and less common (Fig. 1C)
. Normal heart, which is known to express VEGF-D, showed a mixture of granular and diffuse staining with this antibody (Fig. 1D)
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. VEGF-D expression was detected in all cases of CRC and in 50% of adenomas examined. Moreover, 74% of CRCs were assessed as high grade, whereas 100% of adenomas and 78% of normal mucosa had either no or low-grade VEGF-D staining. A significant difference in grade of VEGF-D expression was demonstrated between CRCs and adenomas and adjacent normal mucosa (P < 0.001).
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Patients exhibiting high-grade VEGF-D expression had a significantly shorter overall survival compared with those with low-grade expression (median of 343 weeks versus median not reached at 430 weeks; P = 0.0072; Fig. 2A
). The pattern of disease-free survival was similar, with a median survival of 309 weeks for patients with high-grade VEGF-D, whereas the median was not reached at 395 weeks in patients with low-grade expression (P = 0.0041; Fig. 2B
). The significance of the association between shorter overall survival and high-grade VEGF-D expression was maintained when the analysis was restricted to Dukes’ B patients (median overall survival not reached at 401 versus 430 weeks; P = 0.0458). By multivariate analysis, grade of VEGF-D expression was found to be an independent prognostic indicator of both disease-free survival (P = 0.026; hazard ratio, 4.133; 95% confidence interval, 1.181–14.460) and cause-specific overall survival (P = 0.037; hazard ratio, 3.811; 95% confidence interval, 1.087–13.362) in CRC. Dukes’ stage (A to C) and vascular invasion were also identified as independent prognostic factors in this study.
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. Some vessels that stained for VEGFR-3 were also strongly positive for CD31 in consecutive sections (Fig. 3, A and B)
. In CRC, VEGFR-3 was restricted to the endothelium of vessels predominantly at the tumor periphery. Occasional VEGFR-3 staining of the myenteric plexus and platelets within blood vessels was also observed. In a few cases, malignant cells were visible within the lumen of VEGFR-3+ vessels, suggesting lymphatic invasion (Fig. 3C)
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. VEGFR-3 expression was detected in 89.3% of CRCs, with a mean VEGFR-3+ vessel density of 3.9/mm2 (±2.7; median, 3.5/mm2). A significant difference in the mean VEGFR-3+ vessel density was demonstrated between CRCs and either adenomas or normal bowel (P < 0.001; Fig. 4A
). Within the group of malignant lesions, there was no significant difference in the mean VEGFR-3+ vessel density as a function of Dukes’ stages (P = 0.960), tumor differentiation (P = 0.210), or tumor size (P = 0.823). There was a weak association (P = 0.027) between VEGFR-3+ vessel density and MVD (Fig. 4)
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. This difference was not statistically significant. Similarly, in terms of disease-free survival, the median was >424 weeks for patients with high VEGFR-3+ vessel densities compared with 358 weeks for patients with lower values; again, this difference did not achieve statistical significance. There was no increase in overall or disease-free survival demonstrated for individual Dukes’ stages (A to C) on the basis of VEGFR-3+ vessel densities.
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A significant difference in overall survival was demonstrated between those patients with or without inflammatory infiltrates. Median overall survival for patients with inflammatory infiltrates was 361 weeks, compared with 126 weeks for those without (P = 0.007; Fig. 5B
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MVD in Normal Bowel, Premalignant Lesions, and CRC.
Most CRC were highly vascular, with hotspots occurring frequently within the mucosal folds of the malignant epithelium (Fig. 3B)
. In addition to endothelium, some inflammatory cells also stained for CD31 but were readily distinguishable on morphological grounds. MVD was determined blind by two independent observers on CD31-stained sections from five selected vascular hotspots under x200 magnification in a graticule area of 0.16 mm2. Chalkley counts (24)
were also examined as an alternative measure of vascularity and were found to correlate well (P < 0.001) with MVD determined in the same vascular hotspots. MVD was also assessed on consecutive sections stained for vWF with good correlation (P = 0.024) to MVD determined using CD31 as a vascular marker.
A summary of MVD data for normal bowel, premalignant lesions, and CRCs is shown in Fig. 4B
. There was no significant difference in MVD between normal mucosa (127.2 ± 53.7/mm2) and premalignant lesions (158.2 ± 44.9/mm2). However, there were highly significant differences between the mean MVD for CRC (237.4 ± 86.4/mm2) and normal mucosa (P < 0.005) or premalignant lesions (P < 0.0001).
MVD was not associated with Dukes’ stage (P = 0.088), tumor differentiation (P = 0.212), or tumor size (r = 0.057; P = 0.611). Patients with a MVD greater than median (218.1/mm2) had a significantly longer overall survival (median, 381 versus 187 weeks; P = 0.030; Fig. 5C
). A difference in disease-free survival was also seen, although this did not achieve statistical significance (median, 424 versus 225 weeks; P = 0.054).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the same population of patients, we examined the expression of VEGFR-3, one of two endothelium-associated tyrosine kinase receptors that bind VEGF-D (1 , 2) . Through the spectrum of disease, VEGFR-3+ vessel densities showed a similar pattern to MVD measurements determined using CD31 as an endothelial cell marker. There was a significant increase in CRC compared with normal bowel and adenomas, but no further increase with tumor stage. Indeed, MVD appeared to decrease slightly with increasing Dukes’ stage. De Waal et al. (26) have reported that lymphatic counts correlate well with MVD in normal skin and early (horizontal) melanomas until the late (vertical) growth phase, which is normally accompanied by an exponential increase in blood vessel number. In contrast, a recent study of breast cancer found no correlation between MVD and VEGFR-3+ vessel densities (27) .
The specificity of the anti-VEGFR-3 monoclonal antibody used has been extensively characterized and found to be restricted to lymphatic endothelium, fenestrated endothelium, and some angiogenic blood vessels (6 , 14 , 15 , 28 , 29) . We detected VEGFR-3 expression on endothelium of both normal and abnormal colorectum. Consistent with lymphatic origin, these vessels were typically thin-walled and devoid of RBCs. In both normal and tumor tissue, only a small proportion of vessels expressed VEGFR-3. A similar pattern of vessel staining in the colon has recently been reported in a study using antibodies against LYVE-1, a CD44 homologue expressed on lymphatic endothelial cells (30) . A proportion of VEGFR-3+ vessels also strongly expressed the endothelial marker CD31, supporting the contention that VEGFR-3 may be expressed on a subset of angiogenic vascular endothelial cells. In a recent study of breast carcinoma, VEGFR-3 was detected in proliferating vascular endothelium as well as in lymphatic vessels (14) . Furthermore, although not associated with tumor stage, VEGFR-3 expression was closely associated with the presence of inflammatory infiltrates in CRC. These findings raise important issues, as yet unresolved, concerning the relationship between the proliferation of vascular and lymphatic endothelium.
In a recent study of malignant mesothelioma, expression of VEGFR-3 (and VEGF-C) was correlated with lymphatic density, although this correlation did not have prognostic significance (31) . Similarly, in gastric carcinoma, VEGFR-3 expression was shown to be spatially associated with VEGF-C, but not related to other clinical parameters (32) . However, in head and neck cancer, high VEGFR-3 expression is a predictor for the presence of lymphatic metastases (33) . We could not demonstrate any difference in survival based on VEGFR-3+ vessel density, which concurs with a recent study of VEGFR-3 expression in breast cancer using the same monoclonal antibody (27) .
We also found a progressive increase in MVD from normal mucosa through adenomas to CRC, but no further increase with advancing Dukes’ stage or tumor differentiation. In CRC, MVD has been associated with poorer prognosis in some studies (17 , 20) , and in another to be of no prognostic significance (34) . In one study, however, high MVD was associated with longer survival (19) , as we report here. Potential explanations for such differences include the grade of CRC examined, the endothelial cell marker used, and field area/magnification under which the vessels were counted. To confirm our findings we examined consecutive sections for CD31 and vWF expression and found a good correlation between MVD determined with these endothelial markers. MVD determined with anti-CD31 was consistently higher than when anti-vWF was used, probably reflecting the greater sensitivity of this marker for the detection of blood vessels (35) .
This is the first report documenting a significant association between VEGFR-3+ vessels and inflammatory cell infiltrates in tumors. The relationship between VEGFR-3 and inflammation has been noted previously in rodent model systems of wound healing (36)
. Moreover, expression of VEGFR-3 is transient in experimental wounds, but persists at low levels in human inflammatory skin ulcers (36)
. Interestingly, the density of VEGFR-3+ vessels observed in our study is within a range similar to that seen in experimental wound models (36)
. Inflammatory infiltrates predict increased survival in rectal cancer patients, and lymphocytic infiltration around these tumors is associated with a stage-related improvement in prognosis (37)
. The pattern of inflammatory cell infiltrates we observed in CRC is similar to that seen in other studies of tumor angiogenesis (38)
. Associations between increased macrophage count and MVD have been noted in breast and endometrial cancer and lymphoma (39, 40, 41)
. Macrophages are an important source of angiogenic growth factors such as VEGF (42)
and also produce inflammatory cytokines. These cytokines may regulate the expression of VEGF family members and their receptors, e.g., interleukin-1ß and tumor necrosis factor 
, which up-regulate VEGF-A in CRC cell lines and VEGF-C in fibroblasts (43
, 44)
. The same cytokines up-regulate expression of VEGFR-2, but not VEGFR-3, in endothelial cells (44)
. At this time there is no clear candidate molecule that might up-regulate the expression of VEGFR-3.
The mechanistic link between VEGF-D expression and disease outcome in CRC remains unclear: One interpretation of these data is that, in CRC, VEGF-D expression plays a greater role in lymphatic function and trafficking of leukocytes than in neovascularization per se. In agreement with our findings, enhanced VEGF-D expression was recently reported to be associated with lymph node involvement in inflammatory breast carcinomas (9) . Moreover, VEGFR-3 has been shown to be expressed at major sites of hematopoiesis or blood cell trafficking in the sinusoidal endothelium of the liver, spleen, and bone marrow, which may be related to the regulation of hematopoietic cell translocation (6) . Collectively these data suggest an important role for VEGF-D and its receptors at the interface of the immune system and the tumor.
We conclude that expression of VEGF-D, but not that of its receptor VEGFR-3, is associated with poor survival in CRC. Because expression of VEGF-D is not closely correlated with MVD, it appears that VEGF-D may not act primarily as an angiogenic factor in this setting, but rather is implicated in lymphatic development and function, facilitating lymphatic dissemination of disease.
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FOOTNOTES |
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1 This work was supported by the Cancer Research Campaign, United Kingdom. J. D. W. was recipient of a Cancer Research Campaign Clinical Research Fellowship. A preliminary report of this work was presented at the Annual Meeting of the American Society of Clinical Oncology, New Orleans, May 20–23, 2000. 
2 Present address: Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, United Kingdom.
3 These authors contributed equally to this work.
4 Present address: Reproductive and Vascular Biology, S102, West Wing Extension, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.
5 To whom requests for reprints should be addressed, at Nottingham City Hospital, CRC Department of Clinical Oncology, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Fax: 44 115 9628014; E-mail: cliff.murray{at}nottingham.ac.uk
6 The abbreviations used are: VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; MVD, microvessel density; PBS/A, Dulbecco’s calcium- and magnesium-free PBS; vWF, von Willebrand’s factor; CRC, colorectal carcinoma.
Received 1/22/00. Accepted 1/16/02.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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