Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Abstract

Purpose: The aim of this study was to examine the expression and prognostic relevance of thrombospondin-1 (TSP-1) in tumor biopsies taken from a consecutive series of liver resections done at the University Hospitals of Leicester and the Royal Liverpool Hospital. Experimental Design: Patients having undergone a liver resection for colorectal liver metastases at our institutions between 1993 and 1999 inclusive were eligible. Inclusion criteria were curative intent, sufficient tumor biopsy, and patient follow-up data. One hundred eighty-two patients were considered in this study. Standard immunohistochemical techniques were used to study the expression of TSP-1 in 5-Am tumor sections from paraffin-embedded tissue blocks. TSP-1 was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis. Results: One hundred eighty-two patients (male, n = 122 and female, n = 60) ages between 25 and 81 years (mean, 61 years) were included. TSP-1 was expressed around blood vessels (n = 45, 25%) or in the stroma (n = 59, 33%). No expression was detected in the remaining tumors. TSP-1 significantly correlated with poor survival on univariate (P = 0.01 for perivascular expression and P = 0.03 for stromal expression) and multivariate analysis (P = 0.01 for perivascular expression). Conclusion: TSP-1 is a negatively prognostic factor for survival in resected colorectal liver metastases.Thrombospondin-1 (TSP-1) is a multidomain glycoprotein that modulates platelet aggregation, wound healing, protease activity, and cellular functions such as adhesion, motility, and growth (1). However, the precise function of TSP-1 in the growth of tumors is not straightforward. Evidence suggests that different fragments of the large TSP-1 molecule may individually facilitate different and opposing tumor-modulating properties, such as proangiogenic and antiangiogenic activity (2) and promotion/inhibition of tumor cell migration (3).In colorectal cancer, TSP-1 has been shown to have both an antiangiogenic effect (4, 5) and conversely be associated with venous invasion and tumor progression (6). However, expression of TSP-1 has been associated with increased disease-free survival rates: 84% 5-year survival in primary colorectal tumors expressing TSP-1 compared with 55% in TSP-1-negative tumors in one study (4) and 91% survival versus 44% in TSP-1-negative tumors in another study (5). Studies in breast cancer have described reduced TSP-1 levels in association with more aggressive tumors (3). It is noteworthy that these figures pertain to studies carried out in primary tumors. The aim of this study was to examine the expression and prognostic relevance of TSP-1 in resected colorectal liver metastases.

Association Between Thrombospondin-1, Angiogenesis Related Markers, and Extracellular Matrix Components with Colorectal Cancer Outcome

“…It regulates the growth metastasis and angiogenesis in various tumors and is significant in predicting tumor malignancy. Some researches in their studies found that TSP-1 was distributed in the cytoplasm of tumor cells in thyroid cancer [31], breast cancer [32], hepatocellular carcinoma [33], gastric carcinoma [34], and CRC [19]; while others studies showed that TSP-1 was mainly expressed in the ECM in pancreatic cancer [35], CRC [16], esophageal squamous cell carcinoma [36], non-small cell lung cancer [10], ductal in situ carcinoma of the breast [37]. However, others studies reported TSP-1 expression in both cytoplasm and stroma, as well in CRC [9], bladder cancer [13], and breast cancer [38].…”

“…In patients with primary CRC with low TSP-1 expression with or without detection of mp53 gene product are more likely to harbor lymph node metastasis than patients with higher expression [41]. Sutton et al, reported that TSP-1 is expressed differently in liver metastasis when compared with the primary tumor, possibly showing different modes of action such as facilitating tumor invasion rather than acting as antiangiogenic growth factor [16]. Maeda et al, concluded in their work, that patients with TSP-1 negative tumors had a significantly worse prognosis than those with TSP-1 positive tumors and the frequency of hepatic recurrence was significantly higher in patients with tumors that were TSP-1 negative [15].…”

“…Decreased expression of the TSP-1 is correlated with metastatic potential in prostate cancer [10], non-small lung cancer [11], breast cancer [12], and bladder cancer [13]. In CRC, TSP-1 has been shown to have both an angiogenic effect [14,15] and conversely be associated with venous invasion and tumour progression [16].…”

Syndecan‐4 contributes to endothelial tubulogenesis through interactions with two motifs inside the pro‐angiogenic N‐terminal domain of thrombospondin‐1

“…The HBD has been involved in the disassembly of focal contacts and stimulation of endothelial cell migration (Murphy-Ullrich et al, 1993;Vogel et al, 1993). Importantly, a few recent clinical studies suggest that the anti-angiogenic capacity of TSP-1 was decreased in metastatic deposits, as compared with less advanced primary tumors (Sutton et al, 2005) and that its expression by tumor cells was associated with the presence of venous invasion and with VEGF expression (Poon et al, 2004). Moreover, it was shown that some human cancers can bypass the angioinhibitory effects of TSP-1, by an intricate mechanism, which seems to involve the local balance of VEGF and TSP-1-activated transforming growth factor-b (TGF-b) (Filleur et al, 2001;Fontana et al, 2005).…”

Expression of angiogenic markers in the peripheral blood of docetaxel-treated advanced breast cancer patients: A Hellenic Cooperative Oncology Group (HeCOG) study

“…To our knowledge, the prognostic significance of THBS-1 mRNA expression in breast cancer has never been confirmed (40,41). On the contrary, in other tumors several studies reported a favorable prognostic value of THBS-1 expression (42,43), while others suggested a negative impact on survival (44,45). Certain investigators have linked increased blood THBS-1 protein expression with an aggressive phenotype in breast (35) and colon cancer (46).…”