To evaluate whether angiogenic factors are of clinical relevance to actual human pancreatic cancers, we studied the intratumoral microvessel density (IMD), and PD-ECGF, VEGF protein expression in 40 pancreatic cancers using immunohistochemistry. We also investigated PD-ECGF and VEGF gene expression using reverse transcriptase-PCR (RT-PCR). Of the 40 pancreatic cancers studied, 30 carcinomas (75.0%) were evaluated to be PD-ECGF -positive and 10 carcinomas (25.0%) were determined to be PD-ECGF -negative. In contrast, 27 carcinomas (67.5%) were evaluated to be VEGF -positive, whereas 13 carcinomas (32.5%) were VEGF -negative. VEGF gene expression was moderately associated with an increase in the IMD ( r 2 = 0.181, P = 0.006), but no significant relationship was found between PD-ECGF gene expression and the IMD ( r 2 = 0.093, P = 0.059). However, tumours with positive expression for both PD-ECGF and VEGF had a higher IMD ( P = 0.027). The results of the immunohistochemistry agreed well with the results of the quantitative RT-PCR. The median survival time of the hypervascular group was significantly shorter than that of the hypovascular group ( P < 0.0001). In comparing the survival according to PD-ECGF and VEGF gene expression, the median survival time of the patients with positive PD-ECGF expression was significantly shorter than those with negative PD-ECGF expression ( P = 0.040). Furthermore, the median survival time of the patients with positive VEGF expression was significantly shorter than those with negative VEGF expression ( P = 0.048). However, the Cox multivariate analysis indicated that the IMD and VEGF expression were independent prognostic factors of the various clinicopathologic variables in pancreatic cancer patients ( P = 0.0021 and P = 0.0443, respectively). © 1999 Cancer Research Campaign

The present study revealed that an overexpression of Wnt5a could produce more aggressive NSCLC, especially in squamous cell carcinomas, during tumor progression.

Immunohistochemical analyses of the effects of hepatocyte growth factor (HGF) and c-Met expression on tumour growth and angiogenesis were performed on 88 patients with non-small-cell lung cancers (NSCLCs). In all, 22 carcinomas (25.0%) were intratumoral HGF-positive, 14 carcinomas (15.9%) were stromal HGF-positive, and 36 carcinomas (40.9%) were intratumoral c-Metpositive. None of the carcinomas were stromal c-Met-positive. Examination of tumour growth revealed that the frequency of tumours with a high Ki-67 index was significantly greater for stromal HGF-positive tumours than for stromal HGF-negative tumours (P ¼ 0.0197). The frequency of tumours with a high Ki-67 index was also significantly greater for intratumoral c-Met-positive tumours than for intratumoral c-Met-negative tumours (P ¼ 0.0301). However, there was no significant difference in tumour vascularity with relation to intratumoral HGF status, stromal HGF status, and intratumoral c-Met status. The survival rate of patients with intratumoral c-Met-positive tumours was significantly lower than for patients with c-Met-negative tumours (P ¼ 0.0095). Furthermore, the survival rate of patients with both intratumoral c-Met-positive and stromal HGF-positive tumours was significantly lower than for patients with either positive tumours, and that of patients with both negative tumours (P ¼ 0.0183 and P ¼ 0.0011, respectively). A univariate analysis revealed that intratumoral c-Met expression was a significant prognostic factor of NSCLC patients (relative risk ¼ 2.642, P ¼ 0.0029). The present study demonstrates that tumour -stromal interaction between tumour cell-derived c-Met and stromal cellderived HGF affects tumour growth and the prognosis of NSCLC patients.

Purpose: We investigated the clinical significance of E2F1gene expression in relation to its target genes, thymidylate synthase (TS) and Survivin, in case of non^small-cell lung cancer (NSCLC). Experimental Design: One hundred twenty-seven cases of resected NSCLC were analyzed. Quantitative reverse transcription-PCR was done to evaluate the gene expression of E2F1, TS, and Survivin. Immunohistochemistry was done to investigate the protein expression of E2F1,TS, and Survivin. The Ki-67 proliferation index and the apoptotic index using the terminal deoxyribonucleotidyl transferase^mediated dUTP nick-end labeling method were also evaluated. Results: E2F1 gene expression significantly correlated with the Ki-67 proliferation index (r = 0.487; P < 0.0001), although no correlation was observed between E2F1 gene expression and the apoptotic index.With regard to E2F1 target genes, E2F1 gene expression significantly correlated withTS gene expression (r = 0.709; P < 0.0001) and Survivin gene expression (r = 0.403; P < 0.0001). The overall survival rate was significantly lower in patients with high-E2F1 tumors than in those with low-E2F1 tumors (P = 0.0027), especially among patients with stage II to III NSCLCs (P = 0.0188). A Cox regression analysis showed that the E2F1 status was a significant prognostic factor for NSCLC patients (hazard ratio, 2.052; P = 0.0261).Conclusions: The present study revealed that E2F1 gene expression correlates with TS and Survivin gene expressions and tumor proliferation. During the progression of NSCLC, E2F1 overexpression could produce more aggressive tumors with a high proliferation rate and chemoresistance.Lung cancer is a major cause of cancer-related deaths, and non -small-cell lung cancer (NSCLC) comprises f75% of all lung cancers (1). It is important to design an optimal therapeutic strategy according to tumor biology to improve the treatment of NSCLC (2). The selection of effective chemotherapies based on the evaluation of biomarkers (i.e., ''tailormade chemotherapy'') can improve the clinical outcome of NSCLC patients (3). For example, 5-fluorouracil (5-FU) -derived agents would be useful for tumors with a low expression of thymidylate synthase (TS; refs. 4,5). Gefitinib and erlotinib would be effective for tumors with epidermal growth factor receptor (EGFR) mutations or increased EGFR gene copy numbers (6). Furthermore, the apoptotic index is also a useful indicator to predict the efficacy of chemotherapy for NSCLC patients (7).The E2F1 transcription factor plays a key role in G 1 -to-S phase transition by attracting numerous upstream signals (8). Experimental studies showed that E2F1 induces various genes encoding S phase -activating proteins, including TS (9, 10). Furthermore, a recent experimental study revealed that E2F1 induced the gene expression of Survivin (11), a member of the inhibitor of apoptosis protein family (12). It is important to clarify the molecular mechanisms of these biomarkers in NSCLCs to develop effective cancer treatments. Therefore, we conducted a...

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