Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression correlated with tumor angiogenesis and macrophage infiltration in colorectal cancer
Introduction
The initiation and maintenance of tumor angiogenesis depends on the balance of angiogenic inducers and inhibitors [1]. A large effort has been made to identify pro- and anti-angiogenic molecules. Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF) [2], is an enzyme that has been implicated indirectly in tumor angiogenesis 3, 4. TP activity has been reported to be increased considerably in tumor tissues relative to neighboring normal tissues in a variety of malignancies 5, 6, 7. PD-ECGF cDNA-transfected cells exhibited higher angiogenic activity than untransfected cells [3]. Experimental studies have revealed that the expression of PD-ECGF/TP in tumor cells is significantly correlated with intratumor microvessel density (IMVD) 8, 9, 10, 11, 12and hematogenous metastasis 10, 11. Moreover, several papers have reported an association between the expression of PD-ECGF/TP in tumor cells and the overall survival of patients with malignant tumors 9, 10. However, Takahashi et al. [13]showed that PD-ECGF/TP is predominantly expressed in tumor-infiltrating macrophages with only a minority of tumor cells (5%) staining positively in colorectal cancer. Fox et al. [14]reported that macrophages in most of the normal tissues were usually PD-ECGF/TP-positive with no apparent correlation with angiogenesis. As yet it is unknown whether the expression of PD-ECGF/TP in tumor stroma cells has any clinical or prognostic significance. The positive rates of PD-ECGF/TP expression in tumor cells and tumor stroma cells also remain to be investigated. In addition, a recent study showed that macrophage infiltration (MI) in breast carcinoma was correlated with tumor angiogenesis and prognosis [15]. Recent research revealed that PD-ECGF/TP in tumor cells can be upregulated by tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interferon-γ (INF-γ) [16], suggesting that this enzyme is perhaps a mediator of angiogenesis in chronic inflammation and that tumor cells can amplify their own angiogenic activity by recruiting or activating macrophages. Accordingly, it is possible that PD-ECGF/TP expression may correlate with MI in tumor tissue.
To determine the positive rates of PD-ECGF/TP expression in either tumor cells or tumor stroma cells and to clarify whether tumor stromal PD-ECGF/TP expression has an independent or synergistic impact on tumor angiogenesis and patient prognosis, an immunohistochemical study using anti-PD-ECGF/TP antibody and anti-CD34, together with an assessment of macrophage infiltration, was conducted on resected specimens from 148 cases of colorectal cancer. The correlation of PD-ECGF/TP expression with tumor angiogenesis, MI and patient outcome was investigated.
Section snippets
Patients
A total of 148 patients with colorectal carcinomas who underwent surgery at our institution from 1983 to 1993 were studied. Patients had received neither chemotherapy nor radiotherapy before surgery. Pathological classification, including stage, invasion depth, histologic differentiation, lymphatic invasion and venous invasion, was defined in accordance with the General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus by the Japanese Society for Cancer of the
Clinical outcome
Eighty-five (57%) of 148 patients survived with a median survival of 74 months (range 1–147 months), while the other 63 patients died within 2–109 months (median 30 months) after surgery. Hematogenous metastases were observed in 69 (47%) patients, which were diagnosed either at the time of surgery (17 cases) or during follow-up (52 cases).
Histological examination identified 69 (47%) cases with well-differentiated adenocarcinoma, 63 (42%) cases with moderately-differentiated adenocarcinoma,
Discussion
In this study, tumor cell PD-ECGF/TP expression was observed in 53% of patients with colorectal carcinoma. This finding contrasts with other reports using the same antibody. Takahashi et al. [13]reported that only 5% of colon cancer cases were stained positively. In a study on gastric cancer, Maeda et al. [10]reported that 60.8% of cases were positive for PD-ECGF/TP expression. This discrepancy may be explained by the difference in evaluation methods. Takahashi et al. [13]evaluated the
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