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, 98 (8), 1389-97

CD133 Expression Is Correlated With Lymph Node Metastasis and Vascular Endothelial Growth factor-C Expression in Pancreatic Cancer

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CD133 Expression Is Correlated With Lymph Node Metastasis and Vascular Endothelial Growth factor-C Expression in Pancreatic Cancer

S Maeda et al. Br J Cancer.

Abstract

Although CD133 has been shown to be a marker for cancer stem cells in various tumours, its expression in pancreatic cancer has not yet been clinically reported. In this study, we investigated the relationship between CD133 expression and clinicopathological factors in pancreatic cancer. Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohistochemically assessed for CD133, vascular endothelial growth factor (VEGF)-C, CXCR4, CD34, Ki-67, and cytokeratin (CK) expressions. Sixty percentage (48/80) of specimens were CD133-positive, with less than 15% cells per specimen expressing the marker. CD133-positive cells were found at the peripheral site of adenocarcinoma glandular structures and were negative for CK. There was a significant correlation between CD133 expression and clinicopathological factors, including histological type, lymphatic invasion, and lymph node metastasis (P=0.0215, 0.0023, and 0.0024, respectively). Vascular endothelial growth factor-C expression was also significantly correlated with CD133 expression (P=0.0002). Consequently, the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P=0.0002) and multivariate analysis revealed that CD133 expression was an independent prognostic factor (P=0.0103). These results suggest that CD133 expression in pancreatic cancer was significantly associated with lymphatic metastasis, VEGF-C expression, and prognosis.

Figures

Figure 1
Figure 1
Immunohistochemical staining for CD133 and CK in invasive ductal adenocarcinoma of the pancreas head. (A) Normal pancreatic ductal epithelium cells were not stained for CD133. (B) The ductal epithelium cells in the consecutive slices of (A) were clearly stained by CK antibody. (C) CD133 expression appeared to be present at the peripheral portions (facing the interstitial space) of the glandular structures of adenocarcinoma. The percentage of immunoreactive cells (arrows) was estimated to be less than 5% of the tumour cells. (D) The CK antibody clearly reacted with the CD133-negative cells of adenocarcinoma, but not with the CD133-positive cells (arrowheads) in the consecutive slices of (C). Scale bars, 100 μm.
Figure 2
Figure 2
(A) CD133 expression (arrows) appeared to be present in the peripheral portions of the glandular structures. The percentage of immunoreactive cells (arrows) was estimated to be more than 5% of the tumour cells. (B) The CK antibody clearly reacted with the CD133-negative cells of adenocarcinoma, but not with the CD133-positive cells (arrowheads) in the consecutive slices of (A). (C) CD133 expression was observed mainly in the cytoplasm of tumour cells (arrows). Shown is a magnified figure described in (A) as a box. (D) CD133-positive cells were unreactive with the CK antibody (arrowheads) in the consecutive slices of (C). Shown is a magnified figure described in (B) as a box. Scale bars, 100 μm (A and B), 20 μm (C and D).
Figure 3
Figure 3
Classification of CD133-positive expression in the invasive ductal adenocarcinoma of the pancreas head samples from 80 patients. Tumour samples were classified into five groups (negative (0%), <5, 5–10, 11–15, and >15%) based on the percentage of stained cells.
Figure 4
Figure 4
Immunohistochemical staining for VEGF-C, CXCR4, Ki-67, and CD34 in invasive ductal adenocarcinoma of the pancreas head. (A) Positive expression of VEGF-C was observed in the cytoplasm of all tumour cells. (B) Positive expression of CXCR4 was seen in all epithelial cells of adenocarcinoma. (C) Ki-67-positive expression was observed in the nuclei of certain CD133-positive cells (arrows). Some CD133-positive cells were negative for staining with Ki-67 (arrowheads). (D) Expression of CD34 was detected in microvessels. The sections shown in (A) and (B) are the consecutive slices of Figure 1C, and those shown in (C) and (D) are the consecutive slices of Figure 2A. Scale bars, 100 μm.
Figure 5
Figure 5
Microvessel density counts after observation of anti-CD34-stained samples (0.785 mm2 per field) under a microscope with × 200 power. The MVD (mean±s.d.) of the CD133-positive specimens was significantly different from that of the CD133-negative specimens (43.64±11.26 vs 38.18±11.71; P=0.0467).
Figure 6
Figure 6
Kaplan–Meier survival curves for patients with more than 5% CD133-positive tumours, less than 5% CD133-positive tumours, and CD133-negative tumours in the pancreatic head carcinomas. There was a significant difference in the 5-year survival rate between patients with tumours that were positive and negative for CD133 expression (P=0.0002), and between patients with more and less than 5% CD133-positive tumours (P=0.0366).
Figure 7
Figure 7
Kaplan–Meier survival curves for patients with CXCR4-positive and CXCR4-negative tumours in the CD133-positive group. There was no significant difference between the patients with tumours that were positive and negative for CXCR4 expression in the CD133-positive group (P=0.2176).

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