Syndecan-1, Epithelial-Mesenchymal Transition Markers (E-cadherin/ß-catenin) and Neoangiogenesis-related Proteins (PCAM-1 and Endoglin) in Colorectal Cancer.

The Syndecan-1 protein plays a crucial role in cell proliferation, cell adhesion, cell migration and angiogenesis and, at the same time, its co-expression with E-cadherin is regulated during epithelial-mesenchymal transition (EMT). In colorectal cancer (CRC), the expression of syndecan-1, E-cadherin/ß-catenin complex is frequently disturbed. Angiogenesis is critical for the growth and metastatic spread of tumors. In the present study, we focused on the expression of these biological molecules and their prognostic significance in human CRC. Formalin-fixed paraffin-embedded surgical specimens from 69 patients with CRC were immunostained for syndecan-1, E-cadherin, ß-catenin, endoglin (CD105) and CD31 (platelet cell adhesion molecule (PCAM-1)). A significant association was found between syndecan-1 with E-cadherin (p<0.0001), as well with ß-catenin (p<0.0001). High ß-catenin expression appeared to reduce the risk of poor outcome. Endoglin microvascular density (MVD) count was correlated significantly with Dukes' stage (p<0.0001), vessel invasion (p<0.0001), lymph node metastasis (p=0.039), liver metastasis (p<0.0001), recurrence of disease (p=0.010) and poor survival rate (p<0.0001). Endoglin tumor epithelial cell expression was associated with E-cadherin, ß-catenin and syndecan-1 (p=0.001, p=0.068 and p=0.005, respectively). In conclusion, changes in the pattern of expression of syndecan-1, EMT markers, E-cadherin/ß-catenin, in association with endoglin (CD105), may be involved in tumor progression and prognosis of CRC patients. Further studies are needed to clarify the interaction between these proteins and tumor initiation and progression.

Spinal cord early ischemic preconditioning activates the stabilized fraction of ß-catenin after thoracoabdominal aortic occlusion in pigs.

BACKGROUND: Paraplegia after thoracoabdominal aortic surgery is a devastating complication attributed to motor neurons loss and dysfunction, due to spinal cord ischemia. ß-Catenin is a protein that has been associated with cell survival and healing and many studies have correlated this protein with late ischemic preconditioning (IPC). Herein we investigate the potential contribution of ß-catenin in an early IPC animal model, and its relationship with heat shock protein 70 (Hsp70), suggesting a possible role of this protein as a first window of protection. METHODS: A total of 42 pigs were used in an experimental thoracoabdominal aortic occlusion model. Twelve animals were used for neurologic evaluation and were randomly assigned to 2 groups (A and B). The remaining 30 animals were used in experiments for biologic measurements and innunohistochemical studies, and were randomly assigned to 5 groups (1-5). Western blotting analysis and immunoprecipitations were performed to study the levels of ß-catenin and its binding relationship with Hsp70. The cellular distribution of ß-catenin at various time-points was investigated by immunohistochemical studies. RESULTS: According to neurologic evaluation, the animals in the IPC+ischemia group had significantly better neurologic scores compared with those in the ischemia group, indicating a protective role for IPC. The biologic measurements demonstrated a significant (P=0.03) increase in ß-catenin levels and translocation of the protein in the nucleus at the end of ischemic preconditioning. CONCLUSIONS: Our results suggest a significant role of ß-catenin in early IPC protection of spinal cord after thoracoabdominal occlusion, as IPC seems to trigger the activation of the ß-catenin stabilized fraction and, thus, its survival pathway.

Predictive role of thymidine phosphorylase expression in patients with colorectal cancer and its association with angiogenesis-related proteins and extracellular matrix components.

BACKGROUND: Thymidine phosphorylase (TYMP) is an angiogenic factor that has potent chemotactic activity for endothelial cells and is involved in 5-fluorouracil (5-FU) metabolism. In colorectal cancer (CRC), previous studies evaluating the relationship between TYMP expression and clinicopathological features have yielded inconsistent results. The aim of this study was to investigate the prognostic value of TYMP, its association with other angiogenic factors, proliferation markers and, to our knowledge, for the first time its relationship with extracellular matrix components. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded specimens from 97 patients with CRC were immunostained for TYMP, vascular endothelial growth factor (VEGF), microvascular density (CD34), proliferation marker (Ki-67), proliferating cell nuclear antigen (PCNA), p53 oncoprotein and extracellular matrix components (collagen type IV, fibronectin, tenascin and laminin). Survival curves were calculated with the Kaplan-Meier method. RESULTS: Immunoreactivity was observed in the cytoplasm (cyt) and nucleus (n) of the tumor cells, as well in the stroma (st), endothelium and tumor-associated macrophages. High TYMPcyt expression was observed in 7.2% of the cases, moderate in 22.7% and weak in 59.9%, while 10.3% were negative. High TYMPst expression was observed in 58.8% of the cases. TYMPcyt expression was correlated with the VEGF expression of tumor cells and VEGF expression of vessels (p=0.014 and p=0.022, respectively). TYMPst expression was correlated with VEGF expression and tenascin (p=0.014 and p=0.011, respectively). Patients with higher TYMPcyt expression had a more favorable overall survival (p=0.041) in univariate analysis compared to patients without TYMP expression. CONCLUSION: These findings suggest that TYMP plays an important role in angiogenesis, extracellular matrix remodeling and in the prognosis of patients with CRC, but further studies are needed to clearly define its role in CRC.

Association of syndecan-1 with angiogenesis-related markers, extracellular matrix components, and clinicopathological features in colorectal carcinoma.

Syndecan-1 is a transmembrane heparansulfate proteoglycan, which regulates cell proliferation, migration, angiogenesis, cell-to-cell and cell-to-extracellular matrix adhesion and may influence malignant cell behavior. We investigated the alterations of syndecan-1 expression in colorectal cancer and analyzed the relationship between clinicopathological parameters, proliferation indices, angiogenic markers, and extracellular matrix components. Syndecan-1 protein expression observed in the tumorous epithelium was high in 52/97 (53.6%) of the studied cases, moderate in 20/97 (20.6%), and weak in 5/97 (5.22%) of the cases, and there was strong stromal expression in 34.02% of the tumors. Syndecan-1 expression was statistically correlated to VEGF expression in tumor (p=0.001) and vessels (p=0.007). In addition, there was a borderline correlation between syndecan-1 expression and tenascin (p=0.053). Patients with weak staining reaction had a more unfavorable prognosis (p=0.032) in univariate analysis. These results indicate the implication of syndecan-1 in the remodeling and angiogenesis of colorectal cancer tissue, through interaction with other extracellular matrix components and VEGF, probably influencing the tumor progression and aggressiveness.