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.

Therapeutic Approaches for Metastases from Colorectal Cancer and Pancreatic Ductal Carcinoma

“…A recent review by Gonzalez-Villareal in colorectal cancer metastasis emphasized EMT regulation, with members of the miR-200 family upregulated by Ascl2 as key regulators. Moreover, miR-199a downregulation and miR-210 and miR-21 upregulation are also associated with EMT enhancing HIF-1α/VEGF expression [30]. An EMT major driver is hypoxia, which involves HIF1a/b, VEGF, and p53, all of which downregulate miR-107 and miR-145, negatively correlating with p70S6K1 [46].…”

“…Pre-niche is formed by the preconditions in specific organs in terms of nutrients, extracellular matrix, and immune cells necessary to generate fertile soil before the arrival of CTC, which increases the success of metastasis establishment, as shown in Figure 1 [30]. Figure 1.…”

“…Interactions between cancer cells and endothelial cells with an endothelial layer, and the underlying basement membrane VCAM, ICAM, or L1 molecules, expressed by the vascular endothelium, in interaction with α4β1 integrin and αvβ3 integrin, play a central role in leukocyte recruitment to develop this process [28,31]. Other tumor-recruited cells such as cancer-associated fibroblasts (CAFs), stromal myofibroblast, endothelial cells, pericytes, diverse immune cells, mesenchymal stem cells (MSCs), and tumor-associated macrophages (TAMs) contribute to tumor growth and serve as a prerequisite for tumor cell invasion and metastasis [8,30]. For example, during the early stages of tumor development, cytotoxic immune cells such as natural killer (NK) and CD8+ T cells recognize and eliminate the more immunogenic cancer cells.…”

“…IGFBP5 has been shown to regulate cell growth, differentiation, apoptosis, and metastasis. Yet, oxidative phosphorylation, due to hypoxic conditions, remains a preferred energy source [30,53]. Implied in this alternative energy metabolism is creatine kinase brain-type (CKB), necessary to produce phosphocreatine and maintain ATP levels, which are secreted into the microenvironment by the downregulation of miR-483 and miR-551a [54].…”

Diverse expression patterns of mucin 2 in colorectal cancer indicates its mechanism related to the intestinal mucosal barrier

“…The etiological mechanism of CRC tumorigenesis and development is extremely complex, involving a variety of genetic and environmental factors[ 4 ]. Among them, the impairment of intestinal barrier structure and function leads to a series of pathophysiological changes in the intestinal mucosa, which eventually evolves into tumor malignancy.…”