Tumor associated macrophages (TAMs) are the most abundant cancer stromal cells educated by tumor microenvironment to acquire trophic functions facilitating angiogenesis, matrix breakdown and cancer cell motility. Tumor associated macrophages have anti-inflammatory properties or "alternatively" activated (M2) phenotype expressing CD204 and ⁄ or CD163. To know the role of TAMs in the growth and progression of esophageal squamous cell carcinomas (ESCCs), we calculated intratumoral CD204, CD163 or CD68 expressing macrophage count (M/C) and CD34-positive microvessel density (MVD) by immunohistochemistry in 70 cases of surgically resected ESCCs and compared them with the clinicopathological factors and prognosis of patients. M/C had positive linear association with MVD. High CD204 + M/C were significantly correlated with more malignant phenotypes including depth of tumor invasion, lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. On the other hand, CD163+ M/C did not associate with these clinicopathological factors with the exception of depth of tumor invasion and blood vessel invasion. Patients with high CD204 + M/C ESCCs showed poor disease-free survival (P = 0.021). Conditioned media of five ESCC cell lines (TE-8, -9, -10, -11 and -15) induced mRNA as well as protein expression of CD204 but not of CD163 with upregulation of vascular endothelial growth factor-A mRNA in TPA treated human acute monocytic leukemia cell line THP-1. These results overall indicate that CD204 is a useful marker for TAMs contributing to the angiogenesis, progression and prognosis of ESCCs whose specific tumor microenvironment may educate macrophages to be CD204
Claudins are transmembrane proteins that seal tight junctions, bind with peripheral protein zonula occludens (ZO)-1, and are known to play an important role in several normal tissues and cancers. However, the role of claudin-1 and claudin-7 expressions in esophageal squamous cell carcinoma remains to be clarified. In the present study, we confirmed the expressions of claudin-1, claudin-7, and ZO-1 in the prickle cell layer of the normal human esophageal squamous epithelium. The expressions of claudin-1 and claudin-7 at the invasive front of the esophageal squamous cell carcinoma were analyzed immunohistochemically to clarify their role in tumor progression. Reduced expression of claudin-7 at the invasive front of the esophageal cancer was significantly associated with the depth of invasion (P = .004), stage (P = .038), lymphatic vessel invasion (P = .001), and lymph node metastasis (P = .014). In contrast, significant association was not detected between claudin-1 expression and clinicopathologic factors except for histologic differentiation of the tumor (P = .0029). Comparison of claudin-7 expression at the invasive front of the primary tumor and its corresponding metastatic lymph nodes revealed significant reduction in claudin-7 expression in the metastatic lymph nodes (P = .007). These results suggest that the reduced expression of claudin-7 at the invasive front of esophageal squamous cell carcinoma may lead to tumor progression and subsequent metastatic events. Thus, claudin-7 can be a novel marker for the prediction of lymph node metastasis.
The essential contribution of the epithelial-mesenchymal transition (EMT) to carcinoma progression is the loss of their epithelial characters, gain of mesenchymal marker expression, acquisition of migration, invasive activity and capability to pass through the basement membrane. In this study, we aimed to clarify the role of EMT regulator Snail, a zinc finger transcription factor, in human oesophageal squamous cell carcinoma (OESCC). Most OESCC cell lines expressed epithelial cell-cell adhesion molecules such as E-cadherin and claudin-1 and -7; however, TE-8 (Snail-positive) cells expressed mesenchymal marker vimentin but not E-cadherin and claudins. Transduction of ectopic Snail in TE-15 (Snail-negative) cells diminished expression of these epithelial adhesion molecules with promotion of cell migration, invasion and proliferation as well as the shift from cobblestone-like appearance to spindle morphology. In OESCC tissue samples, immunohistochemical analyses revealed that the nuclear Snail expression at the invasive front was correlated with the high levels of vimentin expression (p = 0.0061), which was conversely associated with reduced expressions of E-cadherin (p = 0.023), claudin-1 (p = 0.0246) and claudin-7 (p = 0.0161). Interestingly, elevated Snail expression at the invasive front of the OESCC was associated with higher incidence of lymphatic (p = 0.0143) and venous vessels invasion (p = 0.0029), lymph node metastasis (p = 0.0074) and clinicopathological tumour stage (p = 0.0057). According to the expressions of epithelial and mesenchymal markers, the tumours were subclassified into three groups, the epithelial-type OESCC and the complete or incomplete EMT-type OESCCs. Snail-positive tumours were frequently categorized into the complete- or incomplete-type EMT phenotypes. Our present results suggest the significance of Snail-associated EMT in the progression of OESCC. Snail-induced EMT at the invasive front of the OESCC can be a novel marker for the prediction of metastasis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.