Potential Involvement of LOX-1 in Functional Consequences of Endothelial Senescence

Numerous studies have described the process of senescence associated with accumulation of oxidative damage, mutations and decline in proliferative potential. Although the changes observed in senescent cells are likely to result in significant phenotypic alterations, the studies on consequences of endothelial senescence, especially in relation to aging-associated diseases, are scarce. We have analyzed effects of senescence on the functions of endothelial cells relevant to the development of atherosclerosis including angiogenesis, adhesion, apoptosis and inflammation. In the course of progressing through the passages, human umbilical vein endothelial cells (HUVECs) displayed significant increase in size (+36% passage 12 vs. passage 4 , p<0.001) and reduction in both basal and VEGF-stimulated tube formation. The analysis of a scavenger receptor LOX-1, a key molecule implicated in atherogenesis, revealed a significant decline of its message (mRNA) and protein content in senescent endothelial cells (−33%) and in aortas of 50 wk (vs. 5 wk) old mice (all p<0.01). These effects were accompanied by a marked reduction of the basal expression of VCAM-1 and ICAM-1. Compared to early cultures, late passage HUVECs also exhibited nuclear translocation of NF-κB (p65) and reciprocal shifts in BAX and BCL2 protein content resulting in almost 2-fold increase in BAX/BCL2 ratio and 3-fold increase in apoptotic response to TNFα exposure (p<0.04). These changes in senescent endothelial cells are suggestive of aberrant responses to physiological stimuli resulting in a less permissive environment for tissue remodeling and progression of diseases requiring angiogenesis and cell adhesion in elderly, possibly, mediated by LOX-1

Diagnostic utility of snail in metaplastic breast carcinoma

Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer characterized by coexistence of carcinomatous and sarcomatous components. Snail is a nuclear transcription factor incriminated in the transition of epithelial to mesenchymal differentiation of breast cancer. Aberrant Snail expression results in lost expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. We aimed to identify the utility of Snail, and of traditional immunohistochemical markers, in accurate MBC classification and to evaluate clinicopathologic characteristics and outcome

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

Vascular endothelial cell growth factors (VEGF)-A, -C and -D have potent angio and lymphangiogenic functions in experimental models, although their role in the progression of human breast cancer is unclear. The aims of the current study were to examine the relationship between the expression of the aforementioned growth factors with the angio and lymphangiogenic characteristics of breast cancer, and to assess their suitability as potential prognostic factors. Paraffin-embedded sections of 177 primary invasive breast cancer, with complete clinical follow-up information for 10 years, were stained for VEGF-A, -C, -D, podoplanin and CD34 using standard immunohistochemical approaches. The expression of the growth factors was correlated with clinicopathological criteria and patients' survival. Lymph vessel density (LVD) and microvessel density (MVD) were assessed and correlated with expression of the growth factors. Vascular endothelial cell growth factor-A, -C and -D were highly expressed in 40, 37 and 42% of specimens, respectively. High expression of VEGF-A and - C, but not of -D, was associated with a higher LVD (P=0.013 and P=0.014, respectively), a higher MVD (P<0.001 and P=0.002, respectively), the presence of lymph node metastasis (P<0.001 and P<0.001, respectively), distant metastasis (P=0.010 and P=0.008, respectively) and a shorter Overall Survival (P=0.029 and 0.028, respectively). In conclusion, breast cancers that express high levels of VEGF-A and -C are characterised by a poor prognosis, likely through the induction of angio and lymphangiogenesis. Examination of expression of VEGF-A and -C in breast cancer may be beneficial in the identification of a subset of tumours that have a higher probability of recurrence and metastatic spread

Lymphatic Vessel Density Is Significantly Increased in Melanoma

Backgrounds: Melanoma is well known for its ability to involve regional lymph nodes in the early stage. However, the presence of lymphangiogenesis in melanoma is still controversial due to lack of lymphatic-specific markers. The purpose of this study was to determine the intra- and peritumoral lymphatic vessel density (LVD) using a novel lymphatic vessel-specific marker D2-40 and compare it to general vessel density (GVD) as determined by CD31 immunostaining in a series of melanocytic lesions. Methods: The intra- and peritumoral GVD and LVD were examined by immunohistochemistry using D2-40 and CD31 antibodies in a series of melanocytic lesions. Results: We found significantly higher intratumoral LVD in melanomas as compared to either common acquired or dysplastic nevi (p \u3c 0.01). Although peritumoral LVD in melanoma and malignant melanoma in situ was higher compared to nevi, the difference did not reach statistical significance (p = 0.059). There was no significant difference in GVD among the various groups of melanocytic lesions. Conclusions: Our results show that intratumoral LVD is significantly increased in melanomas compared to benign nevi. The higher intratumoral lymphatic density in invasive melanomas suggests that melanoma cells might promote lymphangiogenesis. In addition, assessment of intratumoral LVD may be potentially useful in the differential diagnosis of melanocytic lesions