Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Noh, Kyung Hee; Kim, Bo Wook; Song, Kwon Ho; Cho, Hanbyoul; Lee, Young Ho; Kim, Jin Hee; Chung, Joon‐Yong; Kim, Jae-Hoon; Hewitt, Stephen M.; Seong, Seung Yong; Mao, Chih Ping; Wu, T. C.; Kim, Tae Woo

doi:10.1172/jci64057

Cited by 175 publications

(233 citation statements)

References 43 publications

(39 reference statements)

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“…Cancer cells are highly heterogeneous and a small fraction of cancer cells with stem cell properties, known as tumor-initiating cells, or cancer stem cells (CSC), may be responsible for tumorigenesis (2), angiogenesis (3) and metastasis (4). Recently, selection by adaptive immunity has been shown to generate or enrich cancer cells with stemness (5)(6)(7)(8)(9), suggesting the presence of intimate interaction between CSCs and the skewed adaptive immunity in patients with cancer. However, the role of innate immunity in affecting CSCs and their metastasis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

et al. 2014

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Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer. Cancer Res; 74(20); 5746-57. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

et al. 2014

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“…It has been suggested that immunoevasion is restricted to CSCs, enabling them to survive in the host (13)(14)(15). Recently, ABCB5 þ malignant melanoma-initiating cells were found to modulate antitumor immunity by preferentially inhibiting IL2-dependent T-cell activation and promoting induction of regulatory T cells (14,16).…”

Section: Introductionmentioning

confidence: 99%

Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

Cheung

Yip

Wong

et al. 2014

Cancer Immunology Research

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Immunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin-epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain-related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n ¼ 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P ¼ 0.089) expression was observed when compared with those in nontumor (n ¼ 80) and normal livers (n ¼ 10). Serum GEP (P ¼ 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n ¼ 80) than in healthy individuals (n ¼ 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P ¼ 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy.

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“…Oct4 and Nanog are expressed mainly in embryonic stem cells and only in very low levels in normal adult tissues (42)(43)(44). However, an increasing number of studies demonstrate that both Oct4 and Nanog are aberrantly overexpressed in different types of cancer, contributing to the stem-cell phenotype of tumor cells (45,46). Consistently, it has been demonstrated that overexpression of Oct4 and Nanog in epithelial cells promotes tumorigenesis and metastasis (47,48).…”

Section: Discussionmentioning

confidence: 92%

MACC1 Induces Tumor Progression in Transgenic Mice and Colorectal Cancer Patients via Increased Pluripotency Markers Nanog and Oct4

Lemos

Hardt

Juneja

et al. 2016

Clinical Cancer Research

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Purpose: We have previously identified the gene MACC1 as a strong prognostic biomarker for colorectal cancer metastasis and patient survival. Here, we report for the first time the generation of transgenic mouse models for MACC1.Experimental Design: We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with Apc Min mice (vil-MACC1/Apc Min ). Results: vil-MACC1/ApcMin mice significantly increased the total number of tumors (P ¼ 0.0056). This was particularly apparent in large tumors (!3-mm diameter; P ¼ 0.0024). A detailed histopathologic analysis of these lesions demonstrated that the tumors from the vil-MACC1/Apc Min mice had a more invasive phenotype and, consequently, showed a significantly reduced survival time than Apc Min mice (P ¼ 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/Apc Min mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors compared with Apc Min controls. Finally, we could also validate that Oct4 and Nanog are regulated by MACC1 in vitro and strongly correlate with MACC1 levels in a cohort of 60 tumors of colorectal cancer patients (r ¼ 0.7005 and r ¼ 0.6808, respectively; P > 0.0001 and P > 0.0002, respectively).Conclusions: We provide proof of principle that MACC1-induced tumor progression in colorectal cancer acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis. These findings might have important implications for the design of novel therapeutic intervention strategies to restrict tumor progression.

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Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Cited by 175 publications

References 43 publications

Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

MACC1 Induces Tumor Progression in Transgenic Mice and Colorectal Cancer Patients via Increased Pluripotency Markers Nanog and Oct4

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