CD271 Defines a Stem Cell-Like Population in Hypopharyngeal Cancer

Imai, Takayuki; Tamai, Keiichi; Oizumi, Sayuri; Oyama, Kyoko; Yamaguchi, Kazunori; Sato, Iwao; Satoh, Kennichi; Matsuura, Kazuto; Saijo, Shigeru; Sugamura, Kazuo; Tanaka, Nobuyuki

doi:10.1371/journal.pone.0062002

Cited by 58 publications

(77 citation statements)

References 46 publications

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“…S5). The CCL19 þ CD271 þ tumor cells may be cancer stem cells (CSC) because CD271 is one of the representative markers for CSCs in some cancers (24,25). tative RT-PCR, both ccl19 and cd271 mRNA expressions increased significantly and correlatively with herv-h mRNA expression (P < 0.01; Fig.…”

Section: A Close Connection Between Herv-h/ccl19 Expression In Tumor mentioning

confidence: 95%

Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

et al. 2014

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Human endogenous retroviruses (HERV) are associated with many diseases such as autoimmune diseases and cancer. Although the frequent expression of a variety of HERVs in tumor cells has been demonstrated, their functional contributions in cancer are as yet unclear. Intriguingly, HERVs and other retroviruses include an immunosuppressive domain in their transmembrane envelope proteins, but its mechanism of action and cancer relevance are obscure. In this study, we demonstrate that the human endogenous retrovirus HERV-H has a critical role in tumor metastasis and immune escape. We found that expression of herv-h mRNA was elevated in metastatic tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and in primary tumor tissues from advanced colon cancer. The immunosuppressive peptide H17 derived from HERV-H was sufficient to induce EMT in tumor cells that expressed low levels of HERV-H, and it amplified this event within the tumor microenvironment. H17 also stimulated CCL19 expression in tumor cells, which in turn recruited and expanded a population of pluripotent immunoregulatory CD271 þ cells, which included mesenchymal stem cells and myeloid-derived suppressor cells. In tumor tissues from patients with advanced colon cancer, we confirmed that CD271 þ cells were increased in HERV-H þ CCL19 þ tumor tissues. Notably, RNAi-mediated change of HERV-H or CCL19, or depletion of CD271 þ cells, improved immune responses in vitro and in vivo accompanied by tumor regression. Together, our results argued that HERV-H is a critical determinant of immune escape in cancer, suggesting its candidacy as a promising therapeutic target to treat patients with advanced cancer.

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Section: A Close Connection Between Herv-h/ccl19 Expression In Tumor mentioning

confidence: 95%

Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

et al. 2014

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“…(14) We also reported that CD271 is a marker of CSC in hypopharyngeal cancer and that high levels of CD271 expression in tumor tissues correlate with a poor prognosis. (15) However, little is known about the surface marker of CSC in cholangiocarcinoma. Since CSC initiate the tumor-forming process, they are expected to provide optimal target(s) for therapy.…”

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confidence: 99%

Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma

et al. 2014

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Cholangiocarcinoma is an aggressive malignant tumor originating from intrahepatic or extrahepatic bile ducts. Its malignant phenotypes may be assumed by cancer stem cells (CSC). Here, we demonstrate that CD274 (PD-L1), known as an immunomodulatory ligand, has suppressive effects on CSC-related phenotypes of cholangiocarcinoma. Using two human cholangiocarcinoma cell lines, RBE and HuCCT1, we attempted to isolate the CD274low and CD274high cells from each cell line, and xenografted them into immunodeficient NOD/scid/γcnull (NOG) mice. We found that the CD274low cells isolated from both RBE and HuCCT1 are highly tumorigenic in NOG mice compared with CD274high cells. Furthermore, the CD274low cells possess several CSC-related characteristics, such as high aldehyde dehydrogenase (ALDH) activity, reduced reactive oxygen species production and a dormant state in the cell cycle. Furthermore, depletion of CD274 expression by shRNA in RBE cells enhances their tumorigenicity and increases ALDH activity. These findings are compatible with our observation that clinical cholangiocarcinoma specimens are classified into low and high groups for CD274 expression, and the CD274 low group shows poorer prognosis when compared with the CD274 high group. These results strongly suggest that CD274 has a novel function in the negative regulation of CSC-related phenotypes in human cholangiocarcinoma, which is distinct from its immunomodulatory actions.

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“…NGFR has been identified as a marker of cells with these properties in multiple malignancies, including head and neck squamous cell carcinoma [4, 32]. Here, we report the identification of a novel downstream target gene of NGFR, ESM1 .…”

Section: Discussionmentioning

confidence: 80%

ESM1 mediates NGFR-induced invasion and metastasis in murine oral squamous cell carcinoma

et al. 2016

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Oral squamous cell carcinoma (OSCC) is a highly invasive and metastatic malignancy. The nerve growth factor receptor (NGFR) has been observed to be expressed on a subset of cells in OSCC, and NGFR+ cells have greater tumor-initiating capacity in vivo. Further, inhibition of NGFR reduces tumor growth, indicating a functional role of this receptor; however, the mechanisms by which NGFR confers enhanced tumor formation are not known. Here, we used an established murine model of OSCC and gene expression array analysis to identify ESM1 as a downstream target gene of NGFR, critical for tumor invasion and metastasis. ESM1 encodes a protein called endocan, which has the property of regulating proliferation, differentiation, migration, and adhesion of different cell types. Incubation of NGFR+ murine OSCC cells with nerve growth factor resulted in increased expression of ESM1. Importantly, ESM1 overexpression conferred an enhanced migratory, invasive, and metastatic phenotype, similar to what has been correlated with NGFR expression. Conversely, shRNA knockdown of ESM1 in NGFR overexpressing OSCC cells abrogated the tumor growth kinetics and the invasive and metastatic properties associated with NGFR. Together, our data indicate that NGFR plays an important role in the pathogenesis and progression of OSCC via regulation of ESM1.

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CD271 Defines a Stem Cell-Like Population in Hypopharyngeal Cancer

Cited by 58 publications

References 46 publications

Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma

ESM1 mediates NGFR-induced invasion and metastasis in murine oral squamous cell carcinoma

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