Colorectal Cancer Stem Cells in the Progression to Liver Metastasis

Abstract

Colorectal carcinoma (CRC) is a leading cause of cancer mortality. Tumorigenesis is a dynamic process wherein cancer stem cells (CSCs) and their microenvironment promote initiation, progression, and metastasis. Metastatic colonization is an inefficient process that is very complex and is poorly understood; however, in most cases, metastatic disease is not curable, and resistance mechanisms tend to develop against conventional treatments. An understanding of the underlying mechanisms and factors that contribute to the development of metastasis in CRC can aid in the search for specific therapeutic targets for improving standard treatments. In this review, we summarize current knowledge regarding tumor biology and the use of stroma cells as prognostic factors and inflammatory inducers associated with the use of tumor microenvironments as a promoter of cancer metastasis. Moreover, we look into the importance of CSC, pericytes, and circulating tumor cells as mechanisms that lead to liver metastasis, and we also focus on the cellular and molecular pathways that modulate and regulate epithelial-mesenchymal transition. Finally, we discuss a novel therapeutic target that can potentially eliminate CSCs as a CRC treatment.

Keywords: cancer stem cells; circulating tumor cells; colorectal cancer; epithelial–mesenchymal transition; liver metastasis; metastasis; pericytes.

Figure 1

Schematic of the signal transduction pathways associated with epithelial–mesenchymal transition (EMT). TGFβ and RTK ligands mediate signaling in liver cells, playing pivotal roles as upstream mediators for inflammation, growth, cytoskeletal rearrangement, proliferation, reducing cell–cell adhesion, and metastasis. TGFβ induces the Smad signaling cascade to block E-cadherin, which is a strong blocker of EMT transition. Additionally, both TGF and RTKs can mediate inflammation by inducing SNAL/SNAG and by activating FOXk1 and Cyr61. Hence, inducing EMT via epigenetic changes results in the activation of α-SMA, N-cadherin, vimentin, and fibronectin. Stem cell signature is also further affected as miR-7 works in concert with Twist to block let-7 and activate miR-10b. Because of inflammatory loopback signaling, HIF-1a, along with IL-8, is no longer induced. Through this response, miR-34 is downregulated and miR-200c is upregulated, leading to the activation of ZEB1 (activator of EMT), which then upregulates SMARC4, setting up the pathway for metastasis. Furthermore, ZEB1 activation is responsible for TGFβ, NOTCH, and Wnt/β-catenin pathway activation, which then leads to proliferation.

Figure 2

Colonocytes (from the primary tumor) undergo EMT. During EMT, initial activation of miR-181a leads, whereas further activity is accomplished by miR-885-50, thereby converting colonocytes to CSC. Macrophages play a key role as they help induce hypoxia and MMP activation, which ultimately leads to ECM removal. CSCs then convert to CTCs and migrate. The primary site for CTC migration is the liver; here, colon CTCs are further assisted by bone marrow stem cells to establish a new metastatic niche after which they invade.

Figure 3

Circulating CSCs in the liver receive inflammatory signals such as VEGF and IL-8 from TAMs and pericytes. Signaling permits the conversion to CTC, which can then migrate and establish a new tumor niche. Assisted by hepatic stellar cells (HSCs) that transition to myofibroblasts, resulting in a fibrotic environment. Hepatic sinusoidal endothelial cells help to establish a new metastatic site.

Figure 4

Roles of key processes in cancer stem cell metabolism during metastasis. Energy production occurs through the enhanced ATP production via glycolysis, amino acid metabolism (greater acetyl-CoA production), and OXPHOS (efficient use of nutrients). Furthermore, energy is also induced by hypoxia as HIF-1a and 2a (elevated GLUT1, ALDH, and PDH) both lead to OXPHOS and glycolysis. Additionally, potential damage to cells is reduced by NADPH as FAO activity and the Warburg effect increases, leading glycolytic intermediates to PPP. As hypoxia increases, the pH levels decrease, leading to MMP and ECM remodeling. Meanwhile, HIF-2a induces CD44 variants and the NOTCH signaling pathway, both activities acting in concert with decreased pH levels, thereby leading CSC to migration, invasion, and EMT.