Response to Stress in Early Tumor Colonization Modulates Switching of CD133-Positive and CD133-Negative Subpopulations in a Human Metastatic Colon Cancer Cell Line, SW620

Abstract

According to the cancer stem cell (CSC) model, higher CD133 expression in tumor tissue is associated with metastasis and poor prognosis in colon cancer. As such, the CD133-positive (CD133+) subpopulation of cancer cells is believed to play a central role in tumor development and metastatic progression. Although CD133+ cells are believed to display more CSC-like behavior and be solely responsible for tumor colonization, recent research indicates that CD133− cells from metastatic colon tumors not only also possess colonization capacity but also promote the growth of larger tumors in a mouse model than CD133+ cells, suggesting that an alternative mechanism of metastasis exists. This study investigated this possibility by examining the cell viability, tumorigenicity, and proliferation and growth capacity of the CD133+ and CD133− subpopulations of the SW620 cell line, a human metastatic colon cancer cell line, in both an in vitro cell model and an in vivo mouse model. While both SW620 CD133− and SW620CD133+ cells were found to engage in bidirectional cell-type switching in reaction to exposure to environmental stressors, including hypoxia, a cell adhesion-free environment, and extracellular matrix stimulation, both in vitro and in vivo, CD133− cells were found to have a growth advantage during early colonization due to their greater resistance to proliferation inhibition. Based on these findings, a hypothetical model in which colon cancer cells engage in cell-type switching in reaction to exposure to environmental stressors is proposed. Such switching may provide a survival advantage during early colonization, as well as that explain previous conflicting observations.

In�vitro analysis of putative cancer stem cell populations and chemosensitivity in the SW480 and SW620 colon cancer metastasis model

“…If the proportion of CSC is correlated with tumourigenic potential, then these data were unexpected as SW620 cells have demonstrated a greater tumorigenic potential than the SW480 cell line in vivo ( 32 ). The CD133 + marker has been used to identify drug-resistant CSC populations in colon cancer, although, there is some indication that both CD133 + and CD133 − populations in colorectal cancer can regenerate the growth of a tumour with in vitro serum-free culture ( 36 , 37 ). We originally hypothesised that if there were a link between CSC and metastasis, as suggested in the literature ( 3 – 5 ), then the SW620 cell line might be enriched in cells bearing CSC expression markers and/or CSC properties.…”

Surface expression marker profile in colon cancer cell lines and sphere-derived cells suggests complexity in CD26+cancer stem cells subsets

“…Several studies linked CD133 high expression with a high risk of metastasis in CRC patients (LaBarge and Bissell, 2008; Kojima et al, 2008; Horst et al, 2008; Ong et al, 2010; Gallmeier et al, 2011), but the effective value of CD133 as a CSC biomarker is unclear, because, as observed in the SW620 colon cell line, sorted CD133 + and CD133 − subsets can undergo conversion between the two subsets (Hsu et al, 2013; LaBarge and Bissell, 2008; Kojima et al, 2008).…”

“…EpCAM (CD326) overexpression is an early event during cancer progression in some types of tumors such as prostate and lung cancer, as well as in CRC (Miranda-Lorenzo et al, 2014; Pitule et al, 2014; Rowehl et al, 2014; Liu et al, 2014a,b). EpCAM appears in 85% of colorectal carcinomas, it can inhibit differentiation and promote proliferation (Hsu et al, 2013), and it is used to isolate CTCs in liquid biopsies (Dotse and Bian, 2016).…”

“…Although the presence of EpCAM high /CD44 + cells correlated with the degree of differentiation, depth of invasion, clinical stage and metastatic status in CRC (Liu et al, 2014a,b) and gastric cancers (Han et al, 2011), because of the plasticity and the not completely known role of their isoforms, CD44 expression does not seem to be an appropriate marker of MetSCs (Hsu et al, 2013; Pitule et al, 2014; Rowehl et al, 2014; Qiu et al, 2015; Nagano and Saya, 2004). However, in E-cadherin expressing cells, we observed that the frequency of the CD26 + /CD44 + subset increased independently of the expression of CD133.…”

“…In colorectal cancer (CRC), MetSCs are already present in the primary tumor (de Sousa e Melo et al, 2017; Varela-Calviño and Cordero, 2015). Candidate markers for CRC MetSC characterization include CD166, CD29, CD24, LGR5, EpCAM (CD326), ALDH1, CDCP1, CXCR4, CC188 (Hsu et al, 2013; Pitule et al, 2014) and ephrin type B receptor 2 (EphB2) (Rowehl et al, 2014), although many of these markers are also expressed in normal colonic stem cells (i.e. LGR5, ALDH1, or CD29), complicating the distinction between CSCs and normal stem cells.…”