Isolation and Propagation of a Human CD133<sup>-</sup> Colon Tumor-Derived Cell Line with Tumorigenic and Angiogenic Properties

Navarro-Alvarez, Nalú; Kondo, Eisaku; Kawamoto, Heizan; Hassan, Wael; Yuasa, Takeshi; Kubota, Yasuhiro; Seita, Masayuki; Nakahara, Hiroyuki; Hayashi, Tetsuo; Nishikawa, Yuriko; Hassan, Reham; Javed, Shahid M.; Noguchi, Hirofumi; Matsumoto, Shinichi; Nakaji, Shuhei; Tanaka, Noriaki; Kobayashi, Naoya; Soto-Gutiérrez, Alejandro

doi:10.3727/096368910x508997

Cited by 30 publications

(24 citation statements)

References 47 publications

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“…In addition to Bmi-1, several other molecules have been proposed as colon CSC markers including CD133, CD44, Lgr-5 and pluripotency genes such as Oct-4, Sox-2 and Nanog [38]. However, recent studies by others have shown that NANK, a human colon tumor cell line with a high level of Bmi-1 expression but negative for CD133, CD44, Oct4, and Nanog, is capable of initiating tumors in mice [39]. This report suggests that Bmi-1 is crucial for the self-renewal and oncogenic potential of colon CSCs.…”

Section: Discussionmentioning

confidence: 99%

IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation

et al. 2012

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BackgroundIL-1β is a pleiotropic pro-inflammatory cytokine and its up-regulation is closely associated with various cancers including gastrointestinal tumors. However, it remains unclear how IL-1β may contribute to the initiation and development of these inflammation-associated cancers. Here we investigated the role of IL-1β in colon cancer stem cell (CSC) development.MethodsUsing self-renewal assay, soft-agar assay, invasion assay, real-time PCR analysis, immunoblot assay and shRNA knockdown, we determined the effects of IL-1β on cancer stem cell development and epithelial-mesenchymal transition (EMT) in human primary colon cancer cells and colon cancer cell line HCT-116.ResultsWe found that IL-1β can increase sphere-forming capability of colon cancer cells in serum-free medium. IL-1β-induced spheres displayed an up-regulation of stemness factor genes (Bmi1 and Nestin) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activator Zeb1 was increased in IL-1β-induced spheres, indicating that there might be a close association between EMT and IL-1β-induced CSC self-renewal. Indeed, IL-1β treatment led to EMT of colon cancer cells with loss of E-cadherin, up-regulation of Zeb1, and gain of the mesenchymal phenotype. Furthermore, shRNA-mediated knockdown of Zeb1 in HCT-116 cells reversed IL-1β-induced EMT and stem cell formation.ConclusionOur findings indicate that IL-1β may promote colon tumor growth and invasion through activation of CSC self-renewal and EMT, and Zeb1 plays a critical role in these two processes. Thus, IL-1β and Zeb1 might be new therapeutic targets against colon cancer stem cells.

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Section: Discussionmentioning

confidence: 99%

IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation

et al. 2012

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“…Indeed, the functional and causal relation between CD133 protein expression and putative cancer stemness and plasticity is still a matter of debate. 6,10,[46][47][48][49][50][51] This prompted us to further investigate the relevance of CD133 expression in CRC cell lines, which are integral to many drug development test platforms.…”

Section: Discussionmentioning

confidence: 99%

Rapid re-expression of CD133 protein in colorectal cancer cell lines in vitro and in vivo

Peickert

Waurig

Dittfeld

et al. 2012

Laboratory Investigation

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Studies related to the cancer stem cell hypothesis are challenging because of the imperfect tools to identify cell populations of interest and controversy on the usefulness of established cancer cell lines. We previously found CD133 to not be selective for a tumor-propagating or radioresistant population in a near-diploid, microsatellite-instable colorectal carcinoma (CRC) cell line. Because of discrepant literature data, we herein systematically analyzed the behavior of microsatellite-stable cell line subpopulations reflecting the more frequent carcinogenesis pathway in spontaneous CRC. CD133 þ and CD133 À /low populations were isolated by fluorescence-activated cell sorting and further processed. HT29 and SW620 cells were studied in detail in monolayer and/or spheroid culture assays and upon subcutaneous injection in NMRI (nu/nu) mice using a limiting dilution approach. CD133À /low HT29 cells showed a significantly lower clonogenic survival and reduced spheroid formation capacity than their CD133 þ counterparts. However, the cell populations neither differed in growth kinetics and response to treatment in vitro nor in tumor formation capacity when injecting as low as 10 cells. CD133 À /low HT29 cells rapidly re-expressed CD133 protein in vitro and in vivo as shown by flow cytometry and/or western blot analyses, and they also showed a particular survival benefit under tissue normoxic conditions. In contrast, CD133 protein in the CD133 þ population was quite stable throughout culturing. The observation of CD133 re-expression and lack of difference in tumor take rate of subpopulations was confirmed in SW620 cells. Here, we found cell density to affect CD133 re-expression in the CD133À -sorted population. And even SW480 cells, classified as a CD133 À cell line, presented some CD133 protein on their surface upon in vivo engraftment. We conclude that (i) CD133 protein expression shows high plasticity in CRC cell lines, and (ii) in vitro CD133 status on the cell surface neither determines tumorigenic potential nor CD133 profile in vivo.

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“…Similar switching was observed in the NANK cell line, a primary colon cancer line. Although NANK is a CD133 − cell line isolated from ovarian metastatic colon cancer tissues, CD133 + cells were found in a NANK-induced tumor [21].…”

Section: Resultsmentioning

confidence: 99%

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

Hsu¹,

Tung²,

Yang

et al. 2013

PLoS ONE

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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.

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Isolation and Propagation of a Human CD133^- Colon Tumor-Derived Cell Line with Tumorigenic and Angiogenic Properties

Cited by 30 publications

References 47 publications

IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation

IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation

Rapid re-expression of CD133 protein in colorectal cancer cell lines in vitro and in vivo

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

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Isolation and Propagation of a Human CD133- Colon Tumor-Derived Cell Line with Tumorigenic and Angiogenic Properties

Cited by 30 publications

References 47 publications

IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation

IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation

Rapid re-expression of CD133 protein in colorectal cancer cell lines in vitro and in vivo

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

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Isolation and Propagation of a Human CD133^- Colon Tumor-Derived Cell Line with Tumorigenic and Angiogenic Properties