Tumor Cell-Microenvironment Interaction Models Coupled with Clinical Validation Reveal CCL2 and SNCG as Two Predictors of Colorectal Cancer Hepatic Metastasis

Abstract

Purpose: This study aimed to identify novel biological markers for the prediction of colorectal cancer liver metastasis. Experimental Design: We established two models that mimicked the interactions between colorectal tumor cells and the liver microenvironment. From these models we established subcell lines that had an enhanced ability to metastasize to the liver. Genes that related to hepatic metastasis were screened by microarray. The candidate markers were tested by immunohistochemistry, and their predictive accuracy was assessed by the cross-validation method and an independent test set. Results: Highly metastatic colon cancer cell sublines SW1116p21 and SW1116v3 were established from the tumor cell-microenvironment interaction models. Seven of the upregulated genes in the sublines were selected as candidate markers for predicting metastatic potential. A total of 245 colorectal cancer samples were divided into a training set containing 117 cases and a test set containing 128 cases. In the training set, immunohistochemical analysis showed CCL2 and SNCG expression was higher in the hepatic metastasis group than in the nonmetastasis group, and was correlated with poor survival. Logistic regression analysis revealed that CCL2 and SNCG levels in primary tumors, serum carcinoembryonic antigen level, and lymph node metastasis status were the only significant (P < 0.05) parameters for detecting liver metastasis. In leave-one-out-cross-validation, the two markers, when combined with clinicopathologic features, resulted in 90.5% sensitivity and 90.7% specificity for hepatic metastasis detection. In an independent test set, the combination achieved 87.5% sensitivity and 82% specificity for predicting the future hepatic metastasis of colorectal cancer. Conclusion: Our results suggest that these models are able to mimic the interactions between colorectal cancer cells and the liver microenvironment, and may represent a promising strategy to identify metastasis-related genes. CCL2 and SNCG, combined with clinicopathologic features, may be used as accurate predictors of liver metastasis in colorectal cancer. (Clin Cancer Res 2009;15(17):5485-93) Colorectal carcinoma is one of the major causes of cancer death worldwide (1). Liver is the most common target for metastasis in patients with this disease. It is estimated that approximately 50% of colorectal cancer patients develop liver metastases, with 15% to 25% of synchronous and 20% of heterochronous cases (2). Liver metastasis is the most critical prognostic factor for colorectal cancer. The 5-year overall survival rate of patients with hepatic metastasis is only 25% to 40%

Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer

“…T-box transcription factor 5 in colon cancer J Yu et al and metastasis in human cancers including colon cancer (Liu et al, 2005;Hu et al, 2009). Inhibition of cancer cell migration by TBX5 may result from upregulating MTSS1 and downregulating MTA2.…”

Correlations of Tumor-associated Macrophage Subtypes with Liver Metastases of Colorectal Cancer

“…Therefore, to further study the mechanism of liver metastasis of colorectal cancer, and seek more accurate predictors of liver metastasis are particularly important for establishment of more targeted and individualized prevention, treatment and follow-up measures. Traditional clinical and pathological indicators for prognosis of colorectal cancer include tumor invasion (Wong et al, 2008), vascular invasion (Talbot et al, 1980) and lymphatic metastasis (Adachi et al, 1999), but their ultimate significances are not obvious (Hu et al, 2009). A lot of evidences indicate that, tumor-associated Yun-Long Cui, Hui-Kai Li, Hong-Yuan Zhou, Ti Zhang, Qiang Li* macrophages (TAMs) are related to early metastasis in many primary tumors, and can be used as the evaluation indicators (Leek et al, 1996;Coussens and Werb, 2002).…”

Serum haptoglobin as a novel molecular biomarker predicting colorectal cancer hepatic metastasis

“…2 Thus, early detection of liver metastasis is important for improving patient survival. 3 HP is a secreted glycoprotein, and the elevated concentrations of total serum HP or fucosylated haptoglobin (Fuc-Hpt) was detected in patients with inflammatory diseases and a variety of cancers. [4][5][6][7] In CRC, the levels of Fuc-Hpt were significantly associated with distant metastasis in 77 CRC cases, but the Fuc-Hpt levels were not correlated with those of total serum HP level.…”