Cancer stem cells in progression of colorectal cancer

Abstract

Colorectal cancer is one of the most common cancers worldwide with high mortality. Distant metastasis and relapse are major causes of patient death. Cancer stem cells (CSCs) play a critical role in the metastasis and relapse of colorectal cancer. CSCs are a subpopulation of cancer cells with unique properties of self-renewal, infinite division and multi-directional differentiation potential. Colorectal CSCs are defined with a group of cell surface markers, such as CD44, CD133, CD24, EpCAM, LGR5 and ALDH. They are highly tumorigenic, chemoresistant and radioresistant and thus are critical in the metastasis and recurrence of colorectal cancer and disease-free survival. This review article updates the colorectal CSCs with a focus on their role in tumor initiation, progression, drug resistance and tumor relapse.

Keywords: cancer stem cells; colorectal cancer; epithelial mesenchymal transition; metastasis; tumor microenvironment.

Figure 1. Wnt/β-catenin, Notch and Hedgehog signaling pathways and cross-talks in CSC cells

Wnt/β-catenin signaling is transmitted through Frizzled (FZD) receptor and inhibits disheveled (Dvl) and then glycogen synthase kinase-3β (GSK-3β), thereby stabilizing β–catenin. Accumulated β–catenin translocates into the nucleus where it binds to TCF/LEF transcription factors and form a complex of TCF/LEF/β-catenin/Pygo/CBP/BCL-9, regulating expression of target genes. Wnt/β-catenin signaling cross-talks with Notch, MAPK and TGF-β signaling. In Notch signaling, binding of Notch ligands to the receptor results in two proteolytic cleavages to release NICD. The released NICD then translocates into the nucleus where it interacts with the transcription factors, forming the complex of Skip/CSL/NICD/MAML/HAT to activate expression of Wnt, Ptc, BMP, Myc, and P21. Notch signaling cross-talks with the PI3K cascade. In Hedgehog signaling, Hh ligand secreted by Hedgehog secretory cells binds to PTCH1 (Ptc) and generates activated Gli/CBP that translocates into the nucleus and induce the expression of target genes, such as Cyclin D1, Cyclin E, Gli-1 and HIP. These main survival pathways and cross-talks among themselves and with other signaling pathways, i.e., TGF-β, MAPK and PI3K constitute a complex regulatory network for survival and proliferation of cancer stem cells.

Figure 2. Microenvironmental molecules of colorectal CSCs

Microenvironmental molecules of CSCs include two groups: Pro-cancer stem cells (Pro-CSC) molecules and anti-cancer stem cells (anti-CSC) molecules. The Pro-CSC molecules in the tumor microenvironment promote proliferation of CSC while anti-CSC factors promote CSC differentiation, lowering down CSC number. Chemoradiotherapy is scarcely effective in the presence of a Pro-CSC tumor microenvironment and therapeutic molecules that target CSC self-renewal or survival may kill CSCs. HGF, hepatocyte growth factor; PGE2, prostaglandin E2; OPN, osteopontin; SDF1, stromal-cell-derived factor 1; BMP, bone morphogenetic protein; IL, interleukin; and TGF-β, transforming growth factor beta.

Figure 3. Origins and effects of colorectal CSCs on treatment

CSCs with sustained self-renewal, persistent proliferation and tumor initiation originate from mutated adult stem cells, mature cells and differentiated cells. CSCs play a role of pro-tumorigenesis due to the active Wnt, Hedgehog, TGF- beta and Notch signaling pathways. Traditional treatment cannot kill all CSCs, and the survival CSCs lead to the cancer relapse and form migrating cancer stem cells (MCSCs) which form metastatic neoplasms in the distant organs. Primary cancer that accepts therapies targeting CSCs can achieve complete remission.