We identified the previously undescribed gene MACC1 by a genome-wide search for differentially expressed genes in human colon cancer tissues, metastases and normal tissues. MACC1 plays an important role for metastasis prediction, in particular for early-stage patients. Based on MACC1 mRNA expression in not (yet) metastasized primary colon cancers of stages I, II and III, our negative and positive prediction of the development of metachronous distant metastases was correct to 80% and 74%, respectively. The 5-year-survival for subjects suffering from colon cancer was 80% for MACC1 low expressors, but 15% for individuals with high MACC1 expression in their primary tumors. Moreover, we found MACC1 to act as an inducer of migration, invasion and proliferation in cell culture, and of distant metastases in several xenograft models. MACC1 transcriptionally regulates the receptor tyrosine kinase Met, that activates the HGF/Met signaling pathway resulting in enhanced cell motility, invasion and metastasis. Here we report the reduction of metastasis by using shRNA targeting the metastasis-inducer MACC1 in vivo. MACC1 high expressing human colon cancer cells were transfected with MACC1-shRNA, Met-shRNA, or control-shRNA harboring plasmids, together with luciferase-containing constructs. Cell clones were intrasplenically transplanted into mice. Tumor growth and metastases formation was demonstrated by in vivo imaging. Signals in MACC1-shRNA/luc mice and in Met-shRNA/luc mice originated exclusively from spleen tumors, not from liver metastases, as demonstrated with the isolated organs by luminescence. By contrast, signals in control-shRNA/luc mice originated from spleen tumors and liver metastases. These findings were confirmed by brightfield images, demonstrating reduced tumor growth and metastases development in MACC1-shRNA/luc and Met-shRNA/luc mice compared to control-shRNA/luc mice. In summary, knock down of MACC1 by MACC1-shRNA led to reduction of tumor growth and metastasis in mice, making MACC1-shRNA a useful tool for metastasis intervention of colon cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2258.