Aims:The lymphatic system is involved in fluid homeostasis of the cardiac interstitium, but lymphangiogenesis in myocardial remodelling has not previously been examined histopathologically. The aim was to investigate by D2-40 immunohistochemistry the sequential changes in lymphatic distribution in the process of myocardial remodelling after myocardial infarction (MI). Methods and results: Myocardial tissues in various phases of healing after MI were obtained from 40 autopsied hearts. D2-40+ lymphatic vessel density (LD) and CD34+ blood vessel density (BD) in the lesion were determined. BD decreased with advance of myocardial necrosis, subsequently increased at the early stage of granulation and thereafter decreased with the progression of scar formation. In contrast, lymphatic vessels were not detected in lesions with coagulation necrosis, and newly formed lymphatics first appeared in the early stages of granulation. A subsequent increase in LD was demonstrated in the late stages of granulation, and lymphatics remained up to the scar phase. Vascular endothelial growth factor-C was consistently expressed in viable cardiomyocytes around the lesion in all of these stages. Conclusion: In myocardial remodelling after MI, lymphangiogenesis lags behind blood vessel angiogenesis; newly formed lymphatics may be involved mainly in the maturation of fibrosis and scar formation through the drainage of excessive proteins and fluid.
BACKGROUND. Early colorectal cancer (ECC) is curable by endoscopic local resection; however, 10% of patients with ECC exhibit lymph node (LN) metastasis. In the current study, accurate predictors for LN metastasis in patients with ECC were examined by using immunohistochemistry with the lymphatic endothelial hyaluronan receptor 1 (LYVE‐1) antibody to discriminate between lymphatics and blood vessels. METHODS. Colorectal tissue specimens obtained from 71 patients with ECC, including 28 patients with regional LN metastasis, were immunostained with antibodies against LYVE‐1, β‐catenin, claudin‐3, claudin‐4, and cytokeratin. The significance of the histopathologic variables for LN metastasis in ECC was investigated on the basis of specific histopathologic parameters. RESULTS. Lymphatic invasion confirmed by LYVE‐1 immunohistochemistry was observed mainly in the submucosal area around the primary tumor and rarely was observed in the tumor. Expression patterns of β‐catenin, claudin‐3, and claudin‐4 in cancer cells at the invasive front were irrelevant to LN status. Tumor size, depth of invasion, histologic tumor type, budding formation, and lymphatic invasion were statistically significant to LN status in univariate analysis; however, only 2 factors—lymphatic invasion and budding formation at the invasive front—were independent predictors of LN metastasis in ECC. CONCLUSIONS. LYVE‐1 immunohistochemistry appeared to be a useful method for detecting lymphatics invaded by cancer cells, and detailed examination of the submucosa around the tumor may be important for predicting LN metastasis. When lymphatic invasion and budding formation are observed histopathologically in patients with ECC, additional therapy, such as adjuvant chemotherapy or a curative resection of the regional LN, may be required. Cancer 2008. © 2008 American Cancer Society.
Objective: The microenvironment of cancer plays a critical role in its progression. However, the molecular features of cancer-associated fibroblasts (CAFs) are less well understood than those of cancer cells. We investigated the clinicopathological significance of podoplanin expression in stromal fibroblasts in patients with colorectal cancer (CRC). Methods: We selected podoplanin as an upregulated marker in CAF from a DNA microarray experiment. Consequently, podoplanin was identified as an upregulated gene. Immunohistochemical podoplanin expression was investigated at the National Cancer Center Hospital, Tokyo, Japan, in 120 patients with advanced CRC, and its clinicopathological significance was examined. The biological function of podoplanin expression was also assessed by a coculture invasion assay with CRC cell lines such as HCT116 and HCT15. Results: Podoplanin expression was exclusively confined to stromal fibroblasts and absent in tumor cells. Podoplanin is absent in normal stroma except for lymphatic vessels. Staining was considered positive when over 30% of the cancer stroma was stained. Positive podoplanin expression was significantly correlated with a more distal tumor localization (p = 0.013) and a shallower depth of tumor invasion (p = 0.011). Univariate analysis revealed that negative podoplanin expression in stromal fibroblasts was significantly associated with reduced disease-specific survival (p = 0.0017) and disease-free survival (p < 0.0001). Multivariate analysis revealed that negative podoplanin expression (p = 0.016) and lymph node metastasis (p = 0.027) were significantly associated with disease-free survival. CRC cell invasion was augmented by co-culture with CAFs that were treated with siRNA for podoplanin. Conclusions: Our results suggest that a positive podoplanin expression in stromal fibroblasts could have a protective role against CRC cell invasion and is a significant indicator of a good prognosis in patients with advanced CRC, supported by biological analysis showing that podoplanin expression in CAFs is associated with decreased CRC cell invasion.
The present study investigated the protein expression level of CXCL12 in colorectal cancer and aimed to elucidate its association with prognosis. CXCL12 positivity in 50% or more of tumor cells was defined as high expression and that in less than 50% of the tumor cells as low expression. CXCL12+ tumor budding at the invasive front was divided into 2 grades: high with 10 or more budding foci per x200 field of view and low grade with fewer than 10 budding foci. Patients with high expression (72.7%) and high grade CXCL12+ tumor budding (43.0%) had significantly shorter survival than patients with low expression (P = .014) and low grade (P = .003), respectively. Patients with a combination of high expression and high grade had the worst outcome (P < .001). Our study demonstrated that CXCL12 expression in colorectal cancer cells and at sites of budding were significant prognostic factors. Furthermore, together with lymph node metastasis, a combination of both expression patterns was a more powerful independent prognostic factor.
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