CRCSCs and metastasis

Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

Part II. Cancer stem cells

Many studies have evaluated whether CRCSCs cause metastasis. CD44 has been described as a marker for CRCSCs, but a recent study looked at the role of CD44 variant 6 (CD44v6) in CRC metastasis. Interestingly, CD44v6 was elevated in metastatic lesions as compared to primary tumours, while CD44+ cells were equally present at both sites. Primary orthotopic tumour growth and metastasis were significantly improved when initiated with CD44v6+ CRCSCs as compared to CD44v6 cells. Cancer-associated fibroblasts improved the metastatic potential of CRC cells via secreted cytokines such as hepatocyte growth factor (HGF), osteopontin (OPN) and stromal-derived factor 1a (SDF-1). The cytokines could promote CD44v6 expression and metastasis even with CD44cells. The CD44v6+ population was regulated by the Wnt and PI3K pathway, and CD44v6 or PI3K inhibition prevented CRC metastasis (Todaro et al., 2014). In a similar study, CD26+ CRCSCs were identified as the metastatic CRCSC population. By contrast to CD44v6, CD26+ cells were present in both primary and metastatic tumours, and CD26+ cells in the primary tumour predicted metastasis in CRC patients (Pang et al., 2010).

The epithelial – mesenchymal transition (EMT) is an important determinant of tumour metastasis and enriches the CRCSC population (Hwang et al., 2014). CD44+ CRCSCs have been shown to acquire an EMT phenotype under nonadherent conditions, and CD44 expression to be critical for CRC lung metastasis (Su et al., 2011). Similarly, metastatic CD26+ cells also acquire an EMT phenotype, and reduction of CD26 expression reverses this phenotype (Pang et al., 2010). BCL9/BCL9L protein is a part of the TCF/LEF protein complex, partially regulates β-catenin-mediated transcription and is upregulated in colon cancer. Bcl9/Bcl9l deletion in the mouse intestinal epithelium results in tumours with active Wnt signalling, reduced EMT and CRCSC features (Deka et al., 2010). Thus, BCL9/BCL9L protein potentially links the Wnt pathway and CRCSCs with EMT and metastasis. Further, micro-RNAs (miRs) such as miR-146a and miR-200c serve as a link between EMT and CRCSCs.

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