Colorectal cancer-derived tumor spheroids retain the characteristics of original tumors

Lee, Sun-Hwa; Hong, Jun Hwa; Park, Hwan Ki; Park, Jun Seok; Kim, Bokyung; Lee, Jung-Yi; Jeong, Ji Yun; Yoon, Ghil Suk; Inoue, Masahiro; Choi, Gyu–Seog; Lee, Inkyu

doi:10.1016/j.canlet.2015.06.024

Cited by 49 publications

(44 citation statements)

References 31 publications

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“…Based on previously published reports on spheroids isolated from other cancer cell cultures (26,27), we hypothesized that they are composed entirely of CD133+ cancer stem cells and can be used for ACC-CSC purification. In line with this expectation, we demonstrated via immunofluorescent staining on bulk Accx11 cells that spheroids express CD133 and NOTCH1, two ACC-intrinsic stemness markers (FIG.…”

Section: Resultsmentioning

confidence: 99%

MYB fusions and CD markers as tools for authentication and purification of cancer stem cells from salivary adenoid cystic carcinoma

et al. 2017

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Cancer stem cells (CSC) are considered the major cause of aggressive tumor behavior, recurrence, metastases, and resistance to radiation, making them an attractive therapeutic target. However, isolation of CSC from tumor tissue and their characterization are challenging due to uncertainty about their molecular markers and conditions for their propagation. Adenoid cystic carcinoma (ACC), which arises predominantly in the salivary glands, is a slow-growing but relentless tumor that frequently invades nerves and metastasizes. New effective treatment approaches for ACC have not emerged over the last 40 years. Previously, based on a highly conserved SOX10 gene signature that we identified in the majority of ACC tumors, we suggested the existence in ACC of SOX10+ cells with neural stem properties and corroborated this hypothesis via isolation from ACC tissue a novel population of CSC, termed ACC-CSC. These cells co-expressed SOX10 and other ACC-intrinsic neural crest stem cell markers with CD133, a CSC cell surface marker, and activated NOTCH1 signaling suggesting that ACC is driven by a previously uncharacterized population of SOX10+/CD133+ cells with neural stem cell properties. Here, we authenticated ACC identity of our primary cultures by demonstrating that most of them harbor MYB-NFIB fusions, which are found in 86% of ACC. We demonstrated using CyTOF, a novel mass cytometry technology, that these cells express high β-catenin and STAT3 levels and are marked by CD24 and CD44. Finally, to streamline development of ACC cell lines, we developed RT-PCR tests for distinguishing mouse and human cells and used immunomagnetic cell sorting to eliminate mouse cells from long-term cell cultures. Overall, this study describes a new population of CSC that activates signaling pathways associated with poor prognosis, validates their ACC identity, and optimizes approaches that can be used for purification of ACC-CSC and generation of cell lines.

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Section: Resultsmentioning

confidence: 99%

MYB fusions and CD markers as tools for authentication and purification of cancer stem cells from salivary adenoid cystic carcinoma

et al. 2017

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“…Cancer stem cells (CSCs) were first identified in patients with acute myeloid leukemia [32], and subsequently discovered in other malignancies including brain, prostate, lung, breast, colon, melanomas and pancreatic cancers [8, 33–35]. CSCs are a small population of cancer cells, with self-renewal and differentiation potential, and play a distinct role in tumor initiation, progression, metastasis, immune evasion and recurrence [7–8, 36].…”

Section: Discussionmentioning

confidence: 99%

Expression and functional regulation of stemness gene Lgr5 in esophageal squamous cell carcinoma

Zhang

et al. 2017

Oncotarget

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Cancer stem cells (CSCs) are defined as a rare subpopulation of undifferentiated cells with biological characteristics that include the capacity for self-renewal, differentiation into various lineages, and tumor initiation. To explore the mechanism of CSCs in esophageal squamous cell carcinoma (ESCC), we focused on Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), a target gene of the Wnt signaling pathway, which has been identified as a marker of intestinal stem cells and shown to be overexpressed in several human malignancies. Lgr5 expression was significantly correlated with lymph node metastasis, increased depth of invasion, increased tumor size, advanced differentiation, higher AJCC stage and poorer survival. Silencing of Lgr5 expression in the ESCC cell line KYSE450 by small interfering RNA (siRNA) strongly inhibited cell proliferation, migration and invasion ability, the expression of CSCs-related genes and Wnt/β-catenin signaling. In addition, Lgr5 was highly expressed in ESCC spheroid body cells, which were identified by high expression of CSCs-related genes, and high tumorigenicity in vivo. Taken together, these results demonstrate that Lgr5 activation of Wnt/β-catenin signaling is a potential mechanism to promote the progression of ESCC and ESCC stem cell renewal, and Lgr5 may be used as a molecular target for the development of treatments for ESCC.

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“…Because the 3D culture systems of various tissues recapitulate the biological nature of in vivo tissues (34,35), it is expected to play an important role in drug discovery as alternatives to animal experimentations (36). Regarding colorectal cancer, much attention has recently been paid to the patient-derived organoid system (37).…”

Section: Discussionmentioning

confidence: 99%

The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition

Ishida

Koyanagi-Aoi

Oshima

et al. 2017

Molecular Cancer Research

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Cancer stem cells (CSC) are capable of reconstructing cancer tissues, are involved in both recurrence and metastasis, and contribute to therapeutic resistance. Therefore, elucidating the molecular mechanism in CSCs is important to successfully treat unresectable cancers. Previously, we observed that colon cancer stem-like cells can be induced from human colon cancer cell lines by retrovirally introducing OCT3/4, SOX2, and KLF4, and we have designated such cells as induced cancer stem cells (iCSC). In the current study, we used iCSCs to evaluate the molecular mechanism of colon CSCs and developed new methods to control them. The spheres that were derived in vitro from the iCSCs, but not those from parental cells, mimicked human colon cancer tissues in terms of their immunohistologic patterns; therefore, sphere-forming ability was assessed as a measure of the tissuereconstructing ability of iCSCs. Interestingly, the calcineurin inhibitor FK506 enhanced the sphere-forming ability of iCSCs, whereas GSK3 inhibition by RNAi, CHIR99021, and valproic acid (VPA) impeded the sphere-forming ability and expansion of iCSCs. FK506 and GSK3 inhibition showed the opposite effect regarding the NFATc3 localization of iCSCs. These data reveal the crucial role that NFAT localization, as regulated by calcineurin and GSK3, plays in the tissue-reconstructing ability of colon cancer stem cells and the potential of GSK3 inhibitors, such as VPA, in colon cancer stem cell-targeting therapy.

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Colorectal cancer-derived tumor spheroids retain the characteristics of original tumors

Cited by 49 publications

References 31 publications

MYB fusions and CD markers as tools for authentication and purification of cancer stem cells from salivary adenoid cystic carcinoma

MYB fusions and CD markers as tools for authentication and purification of cancer stem cells from salivary adenoid cystic carcinoma

Expression and functional regulation of stemness gene Lgr5 in esophageal squamous cell carcinoma

The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition

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