Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival

Abstract

Thrombomodulin (TM) is an endothelial receptor that exhibits anticoagulant, antifibrinolytic and anti-inflammatory activity by inhibiting thrombin and cellular adhesion. In this study, the expression and significance of TM was examined in primary colorectal cancer and its prognostic implications explored. TM immunostaining was performed on formalin-fixed, paraffin-embedded tissue sections, from primary lesions of 200 patients with colorectal carcinoma. Institutional Ethical approval was granted and clinical data retrieved from patients' records. All normal colonic tissue expressed TM on endothelial cells. TM tumour cell expression was demonstrated in 53 (26.5%) cases and 147 (73.5%) showed no neoplastic cell staining. On univariate and multivariate analysis TM expression on tumour cells correlated significantly with tumour stage, differentiation, Jass score and 5 year survival. TM expression decreases as overall stage and tumour size increase (P ¼ 0.03). In all, 91% TM positive tumours were well differentiated and 85% of TM negative tumours were poorly differentiated (Po0.01). Five year survival rates of patients with positive and negative TM expression were 71 and 41%, respectively. Survival rate was poorer in those patients who were TM negative compared with those who were positive (Po0.01). A total of 101 (50.5%) of the cases were node negative. In this group, 5 year survival rates of patients with positive and negative TM expression were 87.5 and 37.8%, respectively, demonstrating a poorer survival rate for those who are node negative and TM negative at the time of surgery (Po0.001). This study demonstrates that loss of TM is a key indicator in tumour biology and prognosis.

Downregulation of Thrombomodulin, a Novel Target of Snail, Induces Tumorigenesis through Epithelial-Mesenchymal Transition

“…We also found that A2058 cells stably expressing ectopic TM induced closely clustered colonies, reminiscent of mesenchymal-epithelial transition. The effect of TM in promoting epithelial morphogenesis is consistent with the clinical observations that reduced TM expression is associated with poor prognosis for patients with tumor metastases in lung (31), breast (24), and colorectal (16) cancer. These data suggest that TM may play a negative regulatory role in tumorigenesis by modulating the assembly of cell junctions.…”

“…6B). Consistent with the reduced TM expression in metastatic tumors (16,24,31), TM knockdown significantly promoted the invasive ability of cells immunoprecipitated with an antibody to Snail, in the absence of antibody (Input), or with an isotype-matched immunoglobulin (IgG). Isolated DNA was purified and analyzed by PCR using primers to the region of the TM promoter.…”

“…The expression level of TM in the tissues of different carcinomas was inversely correlated with cancer progression and metastasis (16,24,31), suggesting that TM may be one of the endogenous antimetastatic factors and that it has diagnostic and prognostic values for the progression of carcinoma. However, the mechanisms involved in TM downregulation and its relationship to tumorigenesis remain mostly unknown.…”

Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain

“…[3][4][5][12][13][14] TM has been implicated in cancer biology through several studies showing that TM expression within tumor tissue correlates with a better prognosis for multiple cancers. 12,[15][16][17] Other studies have suggested that modifying TM expression by tumor cells can alter important aspects of the transformed phenotype, including tumor cell migration in vitro and tumor cell proliferation. [18][19][20][21] An influence of nonnative, exogenous TM on cancer biology has also been reported in studies showing that administration of soluble TM limits metastasis in mice.…”

Anti-Inflammatory Actions of the Anticoagulant, Activated Protein C

“…Acquired protein C deficiency is observed in cancer patients, especially in patients using certain types of chemotherapy (Feffer, 1989;Mewhort-Buist, 2008;Rogers, 1988;Woodley-Cook, 2006). The loss of expression of thrombomodulin (or increase in its soluble form), a receptor required to convert protein C to APC, on cancer cells correlates with advanced stage and poor prognosis (Hanly, 2006;Hanly & Winter, 2007;Lindahl, 1993). Low levels of thrombomodulin also increase the invasive ability of cancer cells in vitro (Matsushita, 1998) and is significantly correlated with a high relapse rate in breast cancer (Kim, 1997).…”