Japanese Journal of Clinical Oncology 33:215-220 (2003)
© 2003 Foundation for Promotion of Cancer Research
p73 Overexpression and Angiogenesis in Human Colorectal Carcinoma
1 Center of Laboratory Medicine, Hua Shan Hospital, Fudan University, Shanghai, 2 Department of Gastroenterology, Central Hospital of Changning, Shanghai and 3 Department of Dermatology, Nan Shan Hospital, Shenzhen, China
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Background: Solid tumors requires neovascularization for growth and metastasis. Angiogenesis depends on the local balance between positive and negative effectors, the production of which can be regulated by oncogenes and tumor suppressor genes. The aim of this study was to investigate expression of p73, a gene homologous to the tumor suppressor gene p53, in colorectal cancer and its relationship to angiogenesis.
Methods: p73 expression was examined by immunohistochemistry and western blot analysis on 56 primary colon carcinomas with matched normal mucosas. Vascular endothelial growth factor (VEGF) and microvessels were highlighted using a monoclonal antibody specific to VEGF and von Willebrand factor (vWF).
Results: The immunoexpressions of p73 were significantly higher in the primary colorectal carcinomas than that in the matched normal mucosa (P < 0.001). Western blotting showed that 85% patients have a high level of p73 expression (more than double the normal level). A close association between p73 and VEGF expression level was observed (P = 0.016). Colorectal adenocarcinoma that expressed p73 showed significantly greater vascularity than p73-negative tumors (P = 0.012). However, no association between immunoexpression of p73 and tumor stage or differentiation was observed.
Conclusion: These findings suggest a potential role of p73 in tumor angiogenesis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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In colorectal cancer, the most common tumor in Western countries and the third most common in China (1,2), neovascularization is likely to be an important step in the transition from a latent to a metastatic state that is associated with a poor prognosis. Genetic changes implicated in cancer development and progression include oncogene activation and inactivation of tumor suppressor gene (3–6). It is now known that oncosuppressor genes contribute to the maintenance of the non-angiogenic status of cells by stimulating the production of inhibitors of angiogenesis, while inhibiting the production of angiogenic factors. The tumor suppressor gene p53, often taken as a prototype of these regulators, has been shown to control directly the expression of genes coding for mediators of angiogenesis and therefore its loss, causing an imbalance between angiogenic and antiangiogenic factors, will lead to angiogenic switch in several tumor types (7–9).
p73 maps to chromosome 1p36.33 which frequently undergoes loss of heterozygosity (LOH) in various human cancers (10). The p73 gene encodes a protein that contains two distinct 
- and ß-polypeptides. The structure of p73 protein is highly homologous to p53 and p73 also shares some common functions with p53 protein, such as activating the transcription of other genes and inducing apoptosis, indicating that p73 gene is a p53-like tumor suppressor (11). Although initial reports suggested deletion of p73 associated with tumors, many subsequent studies failed to demonstrate mutational inactivation of p73 in a wide variety of tumors (10,12). Instead, overexpression of wild-type p73 in various tumor types compared with normal tissues has been reported and shown to correlate with a poor prognosis of patients (13–16). Taken together, these data raise the question as to additional activities of p73 in cancer, suggesting that p73 plays some roles in tumorigenesis. Several groups have studied the expression of p73 in colon carcinoma (15,17–19), but so far the association between p73 and tumor angiogenesis is unclear.
In this paper, we report overexpression of p73 in colorectal adenocarcinoma compared with normal tissues and show its correlation with the expression of vascular endothelial growth factor (VEGF) and tumor vascularity.
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METHODS |
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Clinical and Pathological Data
Fifty-six primary tumors of colon adenocarcinoma, and also adjacent normal colonic mucosa counterparts, were obtained at surgery from colorectal cancer patients in Hua Shan Hospital and the Central Hospital of Changning during 2001–02. No patient received preoperative or adjuvant chemotherapy or radiotherapy. Pathological examination of primary tumors was performed at the Department of Pathology in the same hospital. The patient’s gender, age, Duke’s stage and tumor differentiation were obtained from surgical and pathological records. The mean age was 62 years (range, 28–80 years). The expression was classified as negative if less than 5% of tumor cells reacted positively, and as positive if otherwise.
Immunohistochemistry
The following primary monoclonal antibodies were used: anti-p73 (1:50 dilution, p73/ß Ab-2, NeoMarkers), anti-VEGF [1:100 dilution, VEGF (C-1):sc-7269, Santa Cruz Biotechnology] and anti-vWF (1:50 dilution, F8/86, Dako, Glostrup, Denmark). Immunoperoxidase staining of formalin-fixed, paraffin-embedded tissue sections was performed using an ordinary biotin–streptavidin method. Briefly, after sections had been deparaffinized and rehydrated in descending alcohol dilution, they were heated in an 800 W microwave oven at maximum power for 5 min in 10 mmol/l citrate buffer (pH 6.0) and washed with phosphate-buffered saline (PBS, pH 7.3). The sections were then immersed in 0.3% hydrogen peroxide in methanol for 20 min at room temperature to block endogenous peroxidase activity. After non-specific sites had been blocked with 5% normal goat serum in PBS for 1 h, the sections were incubated with anti-p73, anti-VEGF and anti-vWF monoclonal antibodies overnight at 4°C. In subsequent steps, we used a Vectastain ABC kit (Vector, Burlingame, CA) and DAB (diaminobenzidine) as a chromogen. The sections were then counterstained with hematoxylin. In each immunohistochemical staining, we performed additional staining without primary antibody in parallel to ascertain that no staining was seen.
Protein Preparation and Western Blot Analysis
The frozen tissues were dissected and homogenized at 3000 r.p.m. in a solution containing 250 mmol/l sucrose, 1 mmol/l EDTA, 0.1 mmol/l phenylmethylsulfonyl fluoride and 10 mmol/l Tris–HCl buffer, pH 7.6. The homogenate was centrifuged at 1000 g for 15 min to remove whole cells, nuclei and mitochondria. The supernatant was used to measure protein concentration. The supernatants were mixed 1:1 with 2x sample buffer (0.188 mM Tris–HCl, pH 6.8, 3% SDS, 0.0075% bromophenol blue, 30% glycerol and 3% ß-mercaptoethanol) and then an equal amount of protein (30 µg) was loaded on to 10% polyacrylamide gel followed by transfer to a nitrocellulose membrane sheet. The membranes were blocked with 5% skim milk in 0.01M PBS, pH 7.4. After incubation with monoclonal mouse p73 antibody (p73 Ab-1, NeoMarkers), the membranes were washed with PBS for 10 min three times and then incubated with HRP-conjugated second antibody. Signals were detected with an ECL system (Amersham Pharmacia Biotech). Relative protein levels were determined by analyzing the signals of autoradiograms using a transmitter–scanning videodensitometer.
Vascular Density
Anti-vWF monoclonal antibody was used to immunostain vessels in colorectal cancer using the standard immunoperoxidase procedure. After screening the vWF-positive microvessels in the areas with intense neovascularization at low power (x100 field), microvessels in the area with highest number of intratumoral microvessels were assessed at high power (x400 field), because the microvessel density was more precisely observed than at the x100 field. We counted 10–20 fields for each specimen depending on tissue size and the value was expressed as number of vessels per high power field (x400 field). p73, VEGF immunoreactivity and tumor vascularity were analyzed independently by two investigators. When they did not obtain the same results, they were requested to observe them on the TV-captured images and assessed them again. To avoid bias, the tumors were anonymous so that observations were made blind to the original diagnosis.
Statistical Analysis
The chi-squared test or Fisher’s exact test was applied for comparisons between group frequencies. Differences in mean vessel counts among the groups were analyzed by Student’s t-test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Immunostaining Analysis of p73 Expression in Normal Mucosa and Tumors
Fifty-six samples were examined for p73 expression using immunostaining. The antibody that we used for p73 detects both the
and ß forms. The p73 staining was confined to the nuclear area, especially at the invasion front or tumor budding portion. Positive staining frequently showed a heterogeneous distribution and the intensity of staining also varied (Fig. 1). As shown in Table 1, in normal colon, 70% (39/56) was negative and 30% (17/56) showed reactivity. Carcinoma demonstrated a high level of expression: 73% (41/56) exhibited p73 characteristics. The frequencies of p73 immunostaining were increased markedly from normal to tumor tissue (P < 0.001).
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Association of p73 expression in the tumors with patient’s gender, age, Duke’s stage and differentiation is presented in Table 2. We were unable to find a correlation of p73 expression with age (P = 0.14), gender (P = 0.55), Duke’s stage (P = 0.81) and differentiation (P = 0.51).
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Western Blot Analysis of p73 Expression in Normal Mucosas and Tumors
Expression of p73 protein in fresh tissues was analyzed with anti-p73 monoclonal antibody (p73
Ab-1, NeoMarkers), which recognized p73 at about 80 kDa (Fig. 2). Because expression of p73 was found to be variable, ranging from a negligible amount (5-fold lower than the control) to 18-fold higher than the control normal mucosa, we arbitrarily set a 2-fold difference in expression as the cut-off level. Based on this criterion, 82% (46/56) samples were found to have high level of p73 expression (more than double the respective normal level); 14% (8/56) did not show a significant difference in p73 expression; 4% (2/56) of cases even expressed lower than the normal level of the control. The p73 expression detected by western blotting is correlated positively with the its expression previously evaluated by immunostaining (P = 0.016) (Table 3).
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p73 Expression in the Primary Tumors in Relation to VEGF Expression and Vascular Density
To examine the relevance of VEGF in the neoplastic transformation of human colon, we analyzed protein expression in 56 primary colorectal carcinomas by immunohistochemistry. Amongst 56 patients, no mucosas expressed VEGF. VEGF expression was observed in 63% (35/56) of tumor tissues (Fig. 3). Association between p73 expression in the primary tumors and the expression of VEGF is presented in Table 4. The expression of the p73 was correlated positively with VEGF expression (P = 0.016). We further investigated if there was a significant difference in the microvessel number between the p73-positive and p73-negative tumors (Fig. 4). Colorectal adenocarcinoma that expressed p73 showed significantly greater vascularity than p73-negative tumors (Table 5) (Student’s t-test, P = 0.012).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Tumor angiogenesis or the formation of new vessels required for tumor growth and malignant behavior is controlled by precise balance of positive and negative effectors (20). Tumor cells become angiogenic at early stages of tumor progression and the switch to angiogenic phenotype is considered to be an important hallmark of malignancy. The angiogenic ability of tumor cells is often the direct consequence of genetic alterations. Oncogenes and tumor suppressor genes can directly modulate the expression of proangiogenic and antiangiogenic factors in an opposite way, determining the overall angiogenic activity of tumor (21,22). In this work, we studied the expression of p73, another member of the p53 family, with the specific aim of correlating it with tumor vascularization.
The present study showed that p73 was overexpressed in patients with primary colorectal tumors compared with matched normal mucosas. We demonstrated a significant correlation between p73 expression and vascularization. p73 expression did not show any significant correlation with Duke’s stage and differentiation. The results showed that the frequency of p73 expression was markedly increased from normal tissue to primary tumor. This suggests that p73 may play an important role in the pathogenesis of colon cancer, especially in angiogenesis.
To date, a significant prevalence of p73 overexpression has been found in dozens of different tumor types, including tumors of the breast (13), neuroblastoma (23), lung (24,25), esophagus (26), stomach (27), colon (28), bladder (29,14), ovaries (30–32), ependymoma (33) and liver (34). Most studies measured overexpression of full-length p73 mRNA by reverse transcription polymerase chain reaction (RT-PCR), but a few also measured overexpression of p73 protein, either by immunoblotting or immunostaining. In a series of 193 patients with hepatocellular carcinoma, 32% of tumors showed high p73 expression by immunocytochemistry and in situ hybridization, whereas all normal tissues exhibited undetectable levels (15). All these results indicated that p73 might be involved in the development of cancers, including metastasis. The activation of a silent allele or overexpression for p73, rather than an impairment of tumor suppressor function, may contribute to tumor development. Recently, Stiewe et al. (35) showed that overexpression of p73 protein resulted in malignant transformation of NIH3T3 cells, supporting the view that p73 possesses oncogenic functions.
However, the mechanism by which p73 exerts its biological effect, if it does, remains to be investigated. Several studies indicated that p73 independently predicted poor prognosis in patients with cancer. Sun (17) found that overexpression of p73 was a valuable prognostic factor to predict poor outcome for patients with colorectal cancer. Tannapfel et al. (15) studied hepatocellular carcinomas and found that patients with p73-positive tumors have a poorer prognosis than those with p73-negative tumors. Since angiogenesis has a great potential as a prognostic indicator for cancer patients, we sought to investigate its relationship with p73. This is the first study reporting the association between tumor vascularity and p73 in colorectal cancer. We hypothesized that p73 acts as an oncogene by being involved in the regulation of angiogenesis factor (VEGF, etc.), participating in the modulation of tumor microvessel formation. Vikhanskaya et al. (36) investigated the production of proangiogenic and antiangiogenic factors in two clones obtained from the human ovarian carcinoma cells in which p73 were overexpressed. They showed that overexpression of p73 increased VEGF production and reduced thrombospondin-1 production. These findings provide strong support for our speculation and implicate a potential role of p73 in tumor angiogenesis. In agreement with their findings, we have shown here that p73 expression is significantly correlated with microvessel density, providing a possible mechanism for the acquisition of angiogenesis.
In addition, we showed from our results on the relationship between p73 expression in the primary tumor and the clinicopathological variables that a patient’s age, gender, tumor stage and differentiation did not correlate with the its expression. These findings are in line with the results from several other groups (15,17,18), who have shown that the p73 expression plays a role in inducing tumor recurrence and the analysis of expression is useful in evaluating the clinical course of colorectal carcinoma post-surgery. Our observations reinforce the interpretation that overexpression of p73 independently predicted poor prognosis in patients with colorectal cancer (17). Considering that there are other variables related to angiogenesis (e.g. other angiogenic factors, p53 status), further studies will be required to establish its direct role in tumor vascularization.
In conclusion, our data demonstrated high expression levels of p73 protein in primary colorectal carcinoma with a close correlation with VEGF expression and tumor vascular density. This supports the view that p73, involved in the regulation of tumor angiogenesis, is a potential biological marker of clinical disease progression.
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FOOTNOTES |
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+ For reprints and all correspondence: Yuan Lu, Center of Laboratory Medicine, Hua Shan Hospital, Fudan University, 12 Central Urumqi Road, Shanghai 200040, China. E-mail: yuanlu{at}mycity.com.cn
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Received January 9, 2003; accepted April 15, 2003
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