Differentiation Therapy: Targeting Human Renal Cancer Stem Cells with Interleukin 15

Azzi, Sandy; Bruno, Stefania; Giron‐Michel, Julien; Clay, Denis; Devocelle, Aurore; Croce, Michela; Ferrini, Silvano; Chouaı̈b, Salem; Vázquez, Aimé; Charpentier, B; Camussi, Giovanni; Azzarone, Bruno; Eid, Pierre

doi:10.1093/jnci/djr451

Cited by 70 publications

(73 citation statements)

References 44 publications

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“…In order to be able to monitor the efficiency of such therapies, CSCs must be reliably identified using suitable markers. Although surface expression of CD105 has been used to enrich for tumor-initiating cells in RCC [19,24], this marker was not suitable for use in all RCC cell lines to identify CSC ( [23] and this work).…”

Section: Discussionmentioning

confidence: 99%

“…Efficient therapies therefore must include elimination of CSCs as well as of their proliferating daughter cells. In a number of preclinical studies, various therapeutic approaches to kill CSCs have been tested, such as blockade of CSC maintenance pathways and induction of cell differentiation [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…These showed expression of stemness genes, tumor sphere formation, and enhanced tumorigenicity in severe combined immunodeficiency (SCID) mice [24]. Interestingly, CD105-expressing CSCs from renal carcinomas were amenable to differentiation into nontumorigenic cells with epithelial characteristics using interleukin 15, which might have therapeutic relevance [19].…”

Section: Introductionmentioning

confidence: 99%

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CXC Chemokine Receptor 4 is Essential for Maintenance of Renal cell Carcinoma-Initiating Cells and Predicts Metastasis

et al. 2013

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In many solid tumors, cancer stem cells (CSC) represent a population with tumor-initiating, self-renewal, and differentiation potential, which can be identified by surface protein markers. No generally applicable markers are yet known for renal cell carcinoma (RCC). Two RCC cell lines (RCC-26, RCC-53) were found to differ widely in their capacity to form spheres in vitro and to establish tumors in mice, potentially reflecting differences in CSC content. A subpopulation expressing the CXC chemokine receptor 4 (CXCR4) was present only in the more tumorigenic cell line RCC-53. When grown as spheres, most of the RCC-53 cells were CXCR4-positive, expressed stem cell-associated transcription factor genes at elevated levels, and were more resistant toward the tyrosine kinase inhibitors sunitinib, sorafenib, and pazopanib. Sorted CXCR4-positive cells exhibited greater capacity for sphere formation and tumor growthinducing potential in vivo than CXCR4-negative cells. Significantly, higher CXCR4 mRNA levels in primary RCC tumors from patients with localized but not disseminated disease predicted shorter survival. Downregulation of CXCR4 expression by small interfering RNA (siRNA) or pharmacological inhibition by AMD3100 compromised tumor sphere formation, viability of CXCR4-positive cells, and increased their responsiveness toward tyrosine kinase inhibitors. In conclusion, CXCR4 identifies a subpopulation of tumor-initiating cells in RCC cell lines and plays a role in their maintenance. The relative insensitivity of such cells to tyrosine kinase inhibitors might contribute to the development of therapy resistance in RCC patients. Future therapies therefore could combine blockade of the CXCR4 signaling pathway with standard therapies for more effective treatments of metastatic RCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CXC Chemokine Receptor 4 is Essential for Maintenance of Renal cell Carcinoma-Initiating Cells and Predicts Metastasis

et al. 2013

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“…The treatment strategy should transit to the induction of tumor cell normalization (41)(42)(43)(44). Because embryonic development process has the ability to coordinate the synchronism of cell maturation, we questioned whether developmental stage-specific hepatocytes induce the maturation of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Liu

Zong

et al. 2015

Mol Med

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On the basis of their characteristics, we presume that developmental stage-specific hepatocytes should have the ability to induce maturation of hepatoma cells. A regulatory circuit formed by hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and the upstream stimulatory factor (USF-1) play a key role in the maturation of embryonic hepatocytes; however, it is unclear whether the regulatory circuit mediates the embryonic induction of hepatoma cell maturation. In this study, 12.5-d to 15.5-d mouse embryonic hepatocytes or their medium were used to coculture or treat HepG2 cells, and the induced maturation was evaluated in vitro and in vivo. In the induced HepG2 cells, the components of the regulatory circuit were detected, their cross-regulation was evaluated and HNF-4α RNA interference was performed. We found that 13.5-d to 14.5-d embryonic hepatocytes could induce HepG2 cell maturation, demonstrated by morphological changes, increased maturation markers and decreased c-Myc and α-fetoprotein (AFP) in vitro. The majority of HepG2 tumors were eliminated by 13.5-d embryonic induction in vivo. All components of the regulatory circuit were upregulated and the binding of HNF-4α, HNF-1α, HNF-6 and USF-1 to their target sites was promoted to rebuild the regulatory circuit in the induced HepG2 cells. Moreover, RNA interference targeting HNF-4α, which is the core of the regulatory circuit, attenuated the induced maturation of HepG2 cells with downregulation of the regulatory circuit. These results revealed that developmental stage-specific hepatocytes could induce the maturation of HepG2 cells by rebuilding the regulatory circuit. is believed to be a controller and marker of mature hepatocytes (27,28). As a downstream target of HNF-4α, HNF-1α is also essential for hepatocyte maturation (29,30). USF-1, which competes with the oncogene c-Myc for the E-box regulatory element, is another downstream target of HNF-4α that plays crucial roles in the maturation and formation of functional hepatocytes (31,32). USF-1 can activate HNF-6, which is another important transcription factor for hepatocyte maturation that has been found to regulate 33). Therefore, HNF-4α, HNF-1α, HNF-6 and USF-1 form a positive feedback loop that drives hepatocyte maturation in liver development ( Figure 1A). Because the transcription factor binding sites are generally believed to scatter within 10 kb upstream of the transcriptional start site (34), the 10-kb gene promoters were all analyzed. On the basis of previous reports (25), the predicted binding sites of HNF-4α HNF-1α, HNF-6 and USF-1 were identified, respectively ( Figure 1B). It remains unknown whether developmental stage-specific hepatocytes rebuild the regulatory circuit to induce the maturation of HepG2 cells.In this study, HepG2 cells were cocultured with mouse embryonic hepatocytes at gestation of 12.5-15.5 d, because the mouse hepatocytes differentiated at 12.5 d, and the liver structure became firmly established between 12 and 15 d of gestation (35)(36)(37). The induced maturation of HepG2 cel...

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“…For example, acute promyelocytic leukemia (APL) was nearly universally lethal before the introduction of all-trans-retinoic acid-induced differentiation therapy, which now has cure rates approximating 80% (6). Differentiation therapy in solid tumors has garnered renewed interest over the past decade (7)(8)(9)(10), yet description of these approaches in sarcomas is only now being appreciated. In two studies, peroxisome proliferator-activated receptor γ agonists were able to induce differentiation in a subset of patients with liposarcoma and myxoid liposarcoma, respectively (11,12), suggesting that differentiation therapy will be possible in sarcoma.…”

mentioning

confidence: 99%

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Chen

DeRan

Ignatius

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

127

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Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Selfrenewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress ERMS self-renewal and induce differentiation of TPCs, a large-scale chemical screen was completed. Glycogen synthase kinase 3 (GSK3) inhibitors were identified as potent suppressors of ERMS growth through inhibiting proliferation and inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT/ β-catenin pathway, recombinant WNT3A and stabilized β-catenin also enhanced terminal differentiation of human ERMS cells. Treatment of ERMS-bearing zebrafish with GSK3 inhibitors activated the WNT/ β-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. Activation of the canonical WNT/β-catenin pathway also significantly reduced selfrenewal of human ERMS, indicating a conserved function for this pathway in modulating ERMS self-renewal. In total, we have identified an unconventional tumor suppressive role for the canonical WNT/ β-catenin pathway in regulating self-renewal of ERMS and revealed therapeutic strategies to target differentiation of TPCs in ERMS.

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Differentiation Therapy: Targeting Human Renal Cancer Stem Cells with Interleukin 15

Abstract: IL-15 directs the epithelial differentiation of renal CSCs and meets the criteria for a treatment strategy: CSC pool depletion and generation of differentiated nontumorigenic cells that are sensitive to chemotherapeutic agents.

Cited by 70 publications

References 44 publications

CXC Chemokine Receptor 4 is Essential for Maintenance of Renal cell Carcinoma-Initiating Cells and Predicts Metastasis

CXC Chemokine Receptor 4 is Essential for Maintenance of Renal cell Carcinoma-Initiating Cells and Predicts Metastasis

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

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