Open Access

Pediatric sarcomas (Review)

Retraction in: /10.3892/ol.2018.7943

  • Authors:
    • Junhua Cao
    • Qi An
    • Lei Wang
  • View Affiliations

  • Published online on: November 21, 2017     https://doi.org/10.3892/ol.2017.7467
  • Pages:1397-1402
  • Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sarcomas arise from primitive mesenchymal cells, which are classified, into two main groups: Bone and soft tissue sarcomas. We have searched all-important electronic databases including Google scholar and PubMed for the collection of latest literature pertaining to pediatric sarcomas. Latest literature confirmed that these tumors are relatively rare and represent only 1% of all malignancies but they have higher incidence in children. Pediatric sarcomas comprise about 13% of all pediatric malignancies and are ranked third in childhood cancers. The highest incidence rates are reported among rhabdomyosarcoma, osteosarcoma and Ewing's sarcomas in children. All of these neoplasms often display highly aggressive behavior with tendency to form metastases. Important globally used management avenues include surgery with systemic chemotherapy and have success rate of 70% at 5-years. Furthermore, in the cases of advanced stages, the prognosis is poor, chances of treatment failure and recurrence are quite high. Utilization of cancer stem cells is the latest approach with great potential in management of above pathological state. The present review article discuss all-important aspects of commonly found pediatric sarcomas throughout the world.

Introduction

Osteosarcoma is one of the commonest tumors of the bone among pediatric sarcomas and is malignant in nature (1,2). It is histologically characterized by the presence of osteoid-producing neoplastic osteoblasts. Moreover, the reported incidence is 4.8 per million per year (3). The common sites of incidence of primary osteosarcomas typically occur in the metaphysis of long bones (Fig. 1A). The general nature, as discussed earlier, is highly aggressive leading to early systemic metastasis (4). The use of cytotoxic chemo-therapeutic protocols with various chemotherapeutics having diverse range resulted in 60–70% success rate (5). Furthermore, it is a common observation during diagnosis of many cases of pediatric sarcoma that patients confirm macroscopic signs of metastasis to lungs or rarely to lymph nodes. Also, in present scenario, 90% of the cases of metastasis remain undetected due to presence of micro-metastatic disease. Despite utilization of intensive chemotherapy with surgical and radiation approaches, the prognosis is still poor. Also, chances of recurrent osteosarcoma are high. The confirmed presence of cancer stem cells (CSC) in the cases of osteosarcoma was reported initially in 2005 (6). The observation revealed that osteosarcoma cell lines have self-renewing cells. In their study, Gibbs et al (6) showed that about 1 in 100–1,000 osteosarcoma cells were capable of growth in vitro under anchorage-independent and growth-constraining conditions to form spherical colonies, termed sarcospheres. Cells within these sarcospheres showed elevated presence of stem cell markers. Moreover, single cells repeatedly generated spheres during serial re-cloning.

Later, Tsuchida et al (7) showed that treatment of osteosarcoma HOS cell line with cisplatin caused elevation in the side-population (SP) cells. Exposure of HOS cells to cisplatin resulted in the increase of colony-forming and migratory abilities of these cells in vitro. Moreover, SP in cisplatin-treated cells was enriched for cells with CSC properties but this population did not define CSCs absolutely. Similarly, another group revealed stem-like osteosarcoma cell line 3AB-OS by long-term treatment of MG-63 cells with 3-aminobenzamide (8).

Earlier studies confirmed utilization of CD133 as a marker for CSCs in several human malignancies but previously it was explored in cases of osteosarcoma (9). Further, experiments on osteosarcoma cell lines revealed the presence of subpopulation of CD133+ cells with self-renewal characteristics. In the same year, another research group confirmed the presence of CD133 and nestin in osteosarcoma cell lines (10). The identification of CD133+/nestin+ cells suggested the possible occurrence of a cell population with a stem-like phenotype. However, the aforementioned studies did not verify the CSC phenotype of CD133+ and nestin+ populations through the in vivo tumorigenicity assays. Surprisingly, when the tumorigenicity of osteosarcoma cells was tested, two cell lines that were shown to express CD133 did not form tumors after injection into NOD/SCID mice (11). Another study did not find any difference in expression of CD133 between SP cells that were enriched in tumorigenic cells and non-SP cells (12). All these observations finally reached a conclusion that expression of CD133 is a confirmed indicator of lung metastasis in osteosarcoma patients. Although CD133 seems to be of importance in osteosarcoma progression, its role in osteosarcoma CSCs remains controversial.

Adhikari et al (13) reported that double positivity for CD117 (c-kit) and Stro-1 (a marker of osteogenic progenitors in bone marrow) marked CSCs in mouse and human osteosarcoma cell lines. These results suggested CD117 and Stro-1 to be potential therapeutic targets in osteosarcoma. However, no further study has been published to support the utility of CD117 in osteosarcoma. Previously, two independent groups have reported that CD49f may serve in osteosarcoma as another marker that can distinguish CSCs from the cells with limited tumorigenic capacity (14). Nevertheless, these two studies brought contradictory results. Whereas Ying et al (15) initially identified CD49f/CD133+ cells that possessed strong tumorigenic activity, the other study suggested that high levels of CD49f correlate with stemness so, clinical significance of CD49f in identifying CSCs in osteosarcoma is not yet confirmed.

Human ATP-binding cassette (ABC) transporters are considered to cause the resistance of CSCs to chemotherapy and are therefore studied as prospective CSC markers (16). The results concerning expression of ABC transporters in osteosarcoma seem to be partly controversial. Nevertheless, previous study demonstrated that exposure of osteosarcoma cells to chemotherapeutic agents (doxorubicin, cisplatin and methotrexate) induce their stem-like phenotype and result in upregulation of ABC transporters and aldehyde dehydrogenases (ALDH) via Wnt/β-catenin signaling (17).

Examinations of ALDH activity showed the presence of subpopulation of cells with high ALDH activity (ALDH+) in several osteosarcoma cell lines (18). Another study revealed that ALDH+ cells have high cancer inducing capacity (19). ALDH+ cells also showed elevated cell growth rate, clone formation ability, and expression of stem cell marker genes in vitro. However, these results were obtained only when ALDH+ cells were isolated directly from osteosarcoma xenograft tumors but not from the parental cell line. These observations countered the use of ALDH activity as a specific marker for osteosarcoma CSC. Nevertheless, further studies reported that ALDH activity was associated with metastatic potential in murine and human osteosarcomas (20). Previous, Martins-Neves et al (18) provided evidence that ALDH+ cells overexpress Sox2 in osteosarcoma. During the last 5 years, Sox2 has been shown to associate with clinical outcome and/or mediate the maintenance of CSC subpopulation in various types of cancer including osteosarcoma (21). Additionally, Sox2 overexpression enhanced osteosphere formation by murine primary osteoblasts (22). Previous study demonstrated that Sox2 interferes with the tumor-suppressive Hippo pathway to maintain CSCs in osteosarcoma (23). Thus, blocking of Sox2 function might provide a novel therapeutic strategy.

Ewing's sarcoma

Ewing's sarcoma is the second commonest among malignant bone tumors observed both in children and young adults (24). This group of malignancies comprises a spectrum of aggressive tumors, including Ewing's sarcoma or peripheral primitive neuroectodermal tumor. In the diagnosis, these tumors showed the presence of specific fusion oncoproteins as result of chromosomal translocations. Although the exact functions of these fusion oncoproteins are still a matter of research, expression of EWS-Fli-1 has been demonstrated to be essential for the Ewing's sarcoma oncogenesis (25). Tirode et al (26) demonstrated EWS-Fli-1 to block terminal mesenchymal differentiation of mesenchymal stem cells (MSCs) and suggested that these cells may represent the origin of Ewing's sarcoma cells. Thus, MSCs have been recently utilized as a model to investigate and manipulate oncogenesis in Ewing's sarcoma. The most frequent primary sites of Ewing's sarcomas include pelvis and femur; metastatic disease often affects lungs (Fig. 1A). Further, a quarter of patients have detectable metastases at diagnosis and their survival remain at 40% (27).

For the first time, the presence of CSCs in Ewing's sarcoma was reported using isolation CD133+ cells from primary tumors (28). CD133+ cells displayed ability to start and maintain tumor growth via xenotransplantations, The CD133+ cells also expressed elevation in the levels of both OCT4 and NANOG, but not SOX2 or CD133 counterparts. In the subsequent study, the same research group expressed fusion gene EWS-FLI1 in pediatric MSCs (MSCsEWS-FLI-1) and demonstrated that EWS-Fli-1 induced expression of CD133 in 6–10% of these cells (29). Sorted CD133+ MSCsEWS-FLI-1 displayed higher expression levels of OCT4 and NANOG, but did not differ in EWS-FLI1 expression level compared with CD133-fraction. Additionally, unsorted MSCsEWS-FLI-1 were able to form spheres and more importantly these cells expressed significantly reduced expression of miR-145 than wild-type pediatric MSCs. Downregulation of miR-145 indicated its tumor suppressor role in multiple cancers. Indeed, miR-145 expression was found low in self-renewing human ESCs but highly upregulated during differentiation, repressing expression of SOX2, OCT4 and KLF4 (30). Inhibition of miR-145 in dermal skin fibroblasts led to upregulation of pluripotency-associated genes including SOX2, KLF4, OCT4 and MYCC, and increased efficiency of reprogramming these fibroblasts to induced pluripotent stem cells (31). Moreover, the loss of the above miRNA might promote tumorigenesis (Fig. 2). It is not surprising that several studies have demonstrated anti-proliferative and differentiating effects of miR-145 onto CSCs in various cancers (32). In the aforementioned study of pediatric MSCs, repression of miR-145 upon EWS-FLI1 expression resulted in upregulation of SOX2. More importantly, overexpression of miR-145 or depletion of SOX2 in Ewing's sarcoma cell lines led to reduced tumorigenicity of the cells in vivo. Consistent with this study, knockdown of EWS-FLI1 in Ewing's sarcoma cell lines dramatically increased the levels of miR-145, and forced miR-145 expression halted growth of the cells. In the light of these findings, ‘EWS-Fli-1/miR-145/Sox2’ axis may represent the key regulatory pathway in Ewing's sarcoma tumorigenesis reprogramming preneoplastic cells towards the CSC phenotype. In contrast to the first study reporting CD133 as marker of CSCs in Ewing's sarcoma (28), no differences in the tumorigenicity or chemoresistance between CD133+ and CD133 cell fractions in three of four Ewing's sarcoma cell lines tested. Thus, the significance of CD133 as CSC marker in Ewing's sarcoma remains elusive. Further, CD57 is another potential marker proposed to reflect enhanced tumorigenicity in Ewing's sarcoma (33). CD57 high cells were more tumorigenic, formed spheres at higher frequency and had enhanced migratory potential than CD57 low cells. Interestingly, only partial overlap was observed among CD57 high and CD133+ populations of cells, suggesting that CD57 identify different population of Ewing's sarcoma cells with CSC phenotype. Previously, Leuchte et al (34) argued against a role of CD133 and CD57 as markers of CSCs in Ewing's sarcoma.

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is the latest CSC marker in Ewing's sarcoma (35). Lgr5 activation potentiates Wnt/β-catenin signaling, contributing to stem cell proliferation and self-renewal in various tissues (36). In Ewing's sarcoma, expression of LGR5 was identified in both tumor tissues and cell lines, and elevated levels of LGR5 were associated with clinically aggressive tumors. Increased expression of LGR5 also corresponded with CD133 positivity and high ALDH activity in Ewing's sarcoma cell lines. Similarly to osteosarcoma, high ALDH activity was reported to identify stem-like chemotherapy-resistant population in Ewing's sarcoma. More importantly, these cells are highly tumorigenic in vivo. As few as 160 of ALDH high cells were sufficient to initiate tumors in NOD/Shi-scid/IL-2Rγnull (NOG) mice whereas, the same number of CD133+ cells did not result in tumor formation. Furthermore, direct cytotoxicity and loss of clonogenic activity after treatment with YK-4-279 indicated the dependence of the ALDH high cells on EWS-FLI1 oncogene expression. These findings further supported the crucial role of the aforementioned ‘EWS-Fli-1/miR-145/Sox2’ axis for maintenance of CSC phenotype in Ewing's sarcoma.

Rhabdomyosarcoma

Rhabdomyosarcoma is the most common malignant mesenchymal tumor encountered in children with the peak of incidence in patients younger than 5 years (37). Previously revised classification of rhabdomyosarcoma distinguishes four subtypes: i) Alveolar rhabdomyosarcoma; ii) embryonal rhabdomyosarcoma; iii) pleomorphic rhabdomyosarcoma; and iv) sclerosing/spindle cell rhabdomyosarcoma. Embryonal subtype represents about 70% of all childhood rhabdomyosarcomas, mainly affecting infants and children under 10-years of age, and is usually associated with a favorable prognosis. Embryonal rhabdomyosarcomas predominantly localize to the head and neck, the genitourinary tract and the retroperitoneum. In contrast, alveolar rhabdomyosarcoma is a high-grade malignancy with 5-year survival of <50% and occurs mostly in adolescents and young adults, usually arising in the extremities and trunk. This subtype of rhabdomyosarcoma typically harbors one of two characteristic chromosomal translocations t(2;13) (q35;q14) or t(1;13) (p36;q14) that juxtapose PAX3 or PAX7 and FOXO1A genes, resulting in Pax3 and Pax7-FKHR fusion proteins (38).

Similarly to Ewing's sarcomas, MSCs were suggested as the cells of origin of alveolar rhabdomyosarcomas. Ren et al (39) showed that Pax3 and Pax7-FKHR induced skeletal myogenesis in murine MSCs, although additional secondary genetic event was needed for their transformation towards alveolar rhabdomyosarcoma and tumor formation in vivo. No characteristic cytogenetic abnormality has been associated with tumorigenesis of embryonal rhabdomyosarcoma. Nevertheless, this rhabdomyosarcoma subtype may probably develop from a whole range of muscle cells, including muscle satellite cells and downstream myogenic progenitors such as maturing myoblasts (40).

Embryonal rhabdomyosarcoma cell lines cultured as spherical colonies (rhabdospheres) that possessed stem cell properties including elevated expression of stem cell markers POU5F1, NANOG, MYCC, SOX2, and PAX3. Rhabdosphere cells were highly tumorigenic compared with adherent cells and showed upregulated CD133 expression both on RNA and protein levels. CD133+ sorted cells formed tumors at lower cell densities than CD133 and unsorted cells, and were more resistant to treatment with the chemotherapy drugs cisplatin and chlorambucil. Furthermore, high expression of CD133 in tumor tissue samples correlated with poor survival of embryonal rhabdomyosarcoma patients. Later, Pressey et al (41) suggested CD133 as a marker of CSCs also in alveolar rhabdomyosarcoma. The authors showed that both alveolar and embryonal rhabdomyosarcoma-derived CD133+ cells have enhanced colony-forming ability and resistance to chemotherapy, and are characterized by a myogenically primitive phenotype. In contrast, no difference in tumorigenicity of CD133+ and CD133 cells was found in a previous study of three embryonal rhabdomyosarcoma cell lines (42). The investigators tested a panel of potential CSC markers and found that only cell fractions positive for fibroblast growth factor receptor 3 (FGFR3) were enriched for CSCs. Previously, ALDH1 has been found to mark population of embryonal rhabdomyosarcoma cells showing higher capacity for self-renewal and tumor formation (43). ALDH high cells were more chemoresistant and expressed higher levels of SOX2 than their ALDH low counterparts. Thus, ALDH1 is a potential marker of CSCs at least in embryonal subtype of rhabdomyosarcoma.

Pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal of all pediatric malignancies. Although its incidence is relatively low, PDAC represents the forth-leading cause of cancer-related deaths in Western countries (44). Despite previous advances in the diagnosis and treatment, the 5-year survival rate does not generally reach 5%. More than 90% of mortality rate has been reported in PDAC patients (45). Distinct subpopulation of CD133+ cells that co-expressed CXCR4 was further identified in the invasive front of the PDAC tumors. These CD133+ CXCR4+ cells were shown to have migratory capacity in vitro and were demonstrated to be essential for metastatic phenotype of the PDAC in vivo. Although CD133+ CXCR4 formed tumors at the same rate, only mice injected with CD133+ CXCR4+ cells developed metastases. In accordance with these results, another study showed that CXCR4 is expressed in pancreatic intraepithelial neoplasias (PanIN) and its expression is increased during PanIN progression towards invasive carcinoma (46; Fig. 3). The possible prognostic significance of CXCR4 in PDAC was further confirmed by a meta-analysis study showing correlation between CXCR4 expression and poor prognosis (47). More importantly, strong association of CXCR4 expression and metastatic disease was found in this study. Consistent with these findings, previous experimental data demonstrated increased proliferation and invasiveness of pancreatic cancer cells after induction of CXCR4 by its ligand CXCL12 (48).

Although CD133 was initially suggested as a CSC marker in PDAC, further published studies argued against the usefulness of this protein alone to specifically identify pancreatic CSCs. Immervoll et al (49) showed that CD133 is expressed not only in pancreatic cancer cells but also in normal pancreas. Moreover, no correlation of CD133 and patient survival was found in subsequent studies. Co-expression of CD44 and CD133 was then proposed as more specific phenotype of CSCs and was shown to predict worse survival in PDAC patients (50). However, significance of CD133 expression in PDAC tumorigenesis has been previously supported by two independent studies reporting CD133 as efficient negative prognostic factor (51). Expression of ALDH isoenzymes and their enhanced activity represent another putative marker of CSCs that has been evaluated in PDAC. ALDH1-positive cells were detected in primary tumor tissues, and their presence was associated with shorter survival. Importantly, ALDH1- positivity was found in metastatic lesions of primary PDAC tumors that were ALDH1-negative. Further experiments demonstrated that sorted ALDH-high cells were considerably more clonogenic in vitro and tumorigenic in vivo than ALDH low cells. Interestingly, only minor overlap of ALDH-high and CD44+/CD24+ cell populations was found in PDAC cell lines.

However, these ALDH-high/CD44+/CD24+ cells showed increased tumorigenic potential compared to ALDH-high or CD44+/CD24+ cells only. Contrary to these results, another study reported much higher rates of tumor formation after injection of ALDH-high cells into NOD/SCID mice. In some cases, as few as 100 ALDH-high cells were able to initiate tumor growth in 100% of mice, suggesting that sorting for ALDH-high cells alone is sufficient to enrich for CSCs. Thus it still needs to be determined whether ALDH-high/CD44+/CD24+ cells might represent more primitive cells that give rise to phenotypically distinct but still (to a certain extent) tumorigenic pancreatic cancer cells.

Previously, ALDH1B1 expression was shown to correlate with invasiveness of PDAC tumors and proliferation of PDAC-derived cells (52). In vivo experiments in mice showed that administration of disulfiram in combination with low-dose gemcitabine significantly suppressed tumor growth and reduced ALDH-positivity of xenografted CFPAC-1 cells. Thus targeting ALDH-high therapy-resistant CSCs with specific inhibitors, such as disulfiram, may provide better therapeutic response and reduced toxicity of chemotherapy in PDAC patients.

Conclusions

It was concluded from the above that CSC markers are more informative with regard to clinical outcome or tumor progression. Further, in pediatric sarcomas and PDAC, more selective marker is needed for further investigations of CSCs for better management.

References

1 

van der Graaf WT, Orbach D, Judson IR and Ferrari A: Soft tissue sarcomas in adolescents and young adults: A comparison with their paediatric and adult counterparts. Lancet Oncol. 18:e166–e175. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Kager L, Tamamyan G and Bielack S: Novel insights and therapeutic interventions for pediatric osteosarcoma. Future Oncol. 13:357–368. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Weiss A, Gill J, Goldberg J, Lagmay J, Spraker-Perlman H, Venkatramani R and Reed D: Advances in therapy for pediatric sarcomas. Curr Oncol Rep. 16:3952014. View Article : Google Scholar : PubMed/NCBI

4 

Luetke A, Meyers PA, Lewis I and Juergens H: Osteosarcoma treatment - where do we stand? A state of the art review. Cancer Treat Rev. 40:523–532. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Dela Cruz FS: Cancer stem cells in pediatric sarcomas. Front Oncol. 3:1682013.PubMed/NCBI

6 

Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON, Scott EW, Ghivizzani SC, Ignatova TN and Steindler DA: Stem-like cells in bone sarcomas: Implications for tumorigenesis. Neoplasia. 7:967–976. 2005. View Article : Google Scholar : PubMed/NCBI

7 

Tsuchida R, Das B, Yeger H, Koren G, Shibuya M, Thorner PS, Baruchel S and Malkin D: Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling. Oncogene. 27:3923–3934. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Di Fiore R, Santulli A, Ferrante RD, Giuliano M, De Blasio A, Messina C, Pirozzi G, Tirino V, Tesoriere G and Vento R: Identification and expansion of human osteosarcoma-cancer-stem cells by long-term 3-aminobenzamide treatment. J Cell Physiol. 219:301–313. 2009. View Article : Google Scholar : PubMed/NCBI

9 

Tirino V, Desiderio V, D'Aquino R, de Francesco F, Pirozzi G, Graziano A, Galderisi U, Cavaliere C, de Rosa A, Papaccio G, et al: Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS One. 3:e34692008. View Article : Google Scholar : PubMed/NCBI

10 

Veselska R, Kuglik P, Cejpek P, Svachova H, Neradil J, Loja T and Relichova J: Nestin expression in the cell lines derived from glioblastoma multiforme. BMC Cancer. 6:322006. View Article : Google Scholar : PubMed/NCBI

11 

Tirino V, Desiderio V, Paino F, De Rosa A, Papaccio F, Fazioli F, Pirozzi G and Papaccio G: Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo. FASEB J. 25:2022–2030. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Yang M, Yan M, Zhang R, Li J and Luo Z: Side population cells isolated from human osteosarcoma are enriched with tumor-initiating cells. Cancer Sci. 102:1774–1781. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Adhikari AS, Agarwal N, Wood BM, Porretta C, Ruiz B, Pochampally RR and Iwakuma T: CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res. 70:4602–4612. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Penfornis P, Cai DZ, Harris MR, Walker R, Licini D, Fernandes JD, Orr G, Koganti T, Hicks C, Induru S, et al: High CD49f expression is associated with osteosarcoma tumor progression: A study using patient-derived primary cell cultures. Cancer Med. 3:796–811. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Ying M, Liu G, Shimada H, Ding W, May WA, He Q, Adams GB and Wu L: Human osteosarcoma CD49f(−)CD133(+) cells: Impaired in osteogenic fate while gain of tumorigenicity. Oncogene. 32:4252–4263. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Wilkens S: Structure and mechanism of ABC transporters. F1000 Prime Rep. 7:142015. View Article : Google Scholar

17 

Martins-Neves SR, Paiva-Oliveira DI, Wijers-Koster PM, Abrunhosa AJ, Fontes-Ribeiro C, Bovée JV, Cleton-Jansen AM and Gomes CM: Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/β-catenin signaling. Cancer Lett. 370:286–295. 2016. View Article : Google Scholar : PubMed/NCBI

18 

Martins-Neves SR, Corver WE, Paiva-Oliveira DI, Van Den Akker BE, Briaire-de-Bruijn IH, Bovee JV, Gomes CM and Cleton-Jansen AM: Osteosarcoma stem cells have active Wnt/beta-catenin and Overexpress SOX2 and KLF4. J Cell Physiol. 231:876–886. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Wang L, Park P, Zhang H, La Marca F and Lin CY: Prospective identification of tumorigenic osteosarcoma cancer stem cells in OS99-1 cells based on high aldehyde dehydrogenase activity. Int J Cancer. 128:294–303. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Greco N, Schott T, Mu X, Rothenberg A, Voigt C, McGough RL III, Goodman M, Huard J and Weiss KR: ALDH Activity correlates with metastatic potential in primary sarcomas of bone. J Cancer Ther. 5:331–338. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Weina K and Utikal J: SOX2 and cancer: Current research and its implications in the clinic. Clin Transl Med. 3:192014. View Article : Google Scholar : PubMed/NCBI

22 

Yang C, Hou C, Zhang H, Wang D, Ma Y, Zhang Y, Xu X, Bi Z and Geng S: miR-126 functions as a tumor suppressor in osteosarcoma by targeting Sox2. Int J Mol Sci. 15:423–437. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Basu-Roy U, Bayin NS, Rattanakorn K, Han E, Placantonakis DG, Mansukhani A and Basilico C: Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells. Nat Commun. 6:64112015. View Article : Google Scholar : PubMed/NCBI

24 

Balamuth NJ and Womer RB: Ewing's sarcoma. Lancet Oncol. 11:184–192. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Kinsey M, Smith R, Iyer AK, McCabe ER and Lessnick SL: EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing's sarcoma. Cancer Res. 69:9047–9055. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P and Delattre O: Mesenchymal stem cell features of Ewing tumors. Cancer Cell. 11:421–429. 2007. View Article : Google Scholar : PubMed/NCBI

27 

Karski EE, McIlvaine E, Segal MR, Krailo M, Grier HE, Granowetter L, Womer RB, Meyers PA, Felgenhauer J, Marina N, et al: Identification of discrete prognostic groups in Ewing sarcoma. Pediatr Blood Cancer. 63:47–53. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Suvà ML, Riggi N, Stehle JC, Baumer K, Tercier S, Joseph JM, Suvà D, Clément V, Provero P, Cironi L, et al: Identification of cancer stem cells in Ewing's sarcoma. Cancer Res. 69:1776–1781. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Riggi N, Suvà ML, De Vito C, Provero P, Stehle JC, Baumer K, Cironi L, Janiszewska M, Petricevic T, Suvà D, et al: EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells. Genes Dev. 24:916–932. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Xu N, Papagiannakopoulos T, Pan G, Thomson JA and Kosik KS: MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell. 137:647–658. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Barta T, Peskova L, Collin J, Montaner D, Neganova I, Armstrong L and Lako M: Brief Report: Inhibition of miR-145 enhances reprogramming of human dermal fibroblasts to induced pluripotent stem cells. Stem Cells. 34:246–251. 2016. View Article : Google Scholar : PubMed/NCBI

32 

Panza A, Votino C, Gentile A, Valvano MR, Colangelo T, Pancione M, Micale L, Merla G, Andriulli A, Sabatino L, et al: Peroxisome proliferator-activated receptor γ-mediated induction of microRNA-145 opposes tumor phenotype in colorectal cancer. Biochim Biophys Acta. 1843:1225–1236. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Wahl J, Bogatyreva L, Boukamp P, Rojewski M, van Valen F, Fiedler J, Hipp N, Debatin KM and Beltinger C: Ewing's sarcoma cells with CD57-associated increase of tumorigenicity and with neural crest-like differentiation capacity. Int J Cancer. 127:1295–1307. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Leuchte K, Altvater B, Hoffschlag S, Potratz J, Meltzer J, Clemens D, Luecke A, Hardes J, Dirksen U, Juergens H, et al: Anchorage-independent growth of Ewing sarcoma cells under serum-free conditions is not associated with stem-cell like phenotype and function. Oncol Rep. 32:845–852. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Scannell CA, Pedersen EA, Mosher JT, Krook MA, Nicholls LA, Wilky BA, Loeb DM and Lawlor ER: LGR5 is expressed by Ewing sarcoma and potentiates Wnt/β-catenin signaling. Front Oncol. 3:812013. View Article : Google Scholar : PubMed/NCBI

36 

Leushacke M and Barker N: Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer. Oncogene. 31:3009–3022. 2012. View Article : Google Scholar : PubMed/NCBI

37 

Yang L, Takimoto T and Fujimoto J: Prognostic model for predicting overall survival in children and adolescents with rhabdomyosarcoma. BMC Cancer. 14:6542014. View Article : Google Scholar : PubMed/NCBI

38 

Marshall AD and Grosveld GC: Alveolar rhabdomyosarcoma - the molecular drivers of PAX3/7-FOXO1-induced tumorigenesis. Skelet Muscle. 2:252012. View Article : Google Scholar : PubMed/NCBI

39 

Ren YX, Finckenstein FG, Abdueva DA, Shahbazian V, Chung B, Weinberg KI, Triche TJ, Shimada H and Anderson MJ: Mouse mesenchymal stem cells expressing PAX-FKHR form alveolar rhabdomyosarcomas by cooperating with secondary mutations. Cancer Res. 68:6587–6597. 2008. View Article : Google Scholar : PubMed/NCBI

40 

Rubin BP, Nishijo K, Chen HI, Yi X, Schuetze DP, Pal R, Prajapati SI, Abraham J, Arenkiel BR, Chen QR, et al: Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. Cancer Cell. 19:177–191. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Pressey JG, Haas MC, Pressey CS, Kelly VM, Parker JN, Gillespie GY and Friedman GK: CD133 marks a myogenically primitive subpopulation in rhabdomyosarcoma cell lines that are relatively chemoresistant but sensitive to mutant HSV. Pediatr Blood Cancer. 60:45–52. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Hirotsu M, Setoguchi T, Matsunoshita Y, Sasaki H, Nagao H, Gao H, Sugimura K and Komiya S: Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells. Br J Cancer. 101:2030–2037. 2009. View Article : Google Scholar : PubMed/NCBI

43 

Nakahata K, Uehara S, Nishikawa S, Kawatsu M, Zenitani M, Oue T and Okuyama H: Aldehyde dehydrogenase 1 (ALDH1) is a potential marker for cancer stem cells in embryonal rhabdomyosarcoma. PLoS One. 10:e01254542015. View Article : Google Scholar : PubMed/NCBI

44 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI

45 

Ryan DP, Hong TS and Bardeesy N: Pancreatic adenocarcinoma. N Engl J Med. 371:1039–1049. 2014. View Article : Google Scholar : PubMed/NCBI

46 

Thomas RM, Kim J, Revelo-Penafiel MP, Angel R, Dawson DW and Lowy AM: The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia. Gut. 57:1555–1560. 2008. View Article : Google Scholar : PubMed/NCBI

47 

Krieg A, Riemer JC, Telan LA, Gabbert HE and Knoefel WT: CXCR4 A prognostic and clinicopathological biomarker for pancreatic ductal adenocarcinoma: A meta-analysis. PLoS One. 10:e01301922015. View Article : Google Scholar : PubMed/NCBI

48 

Shen B, Zheng MQ, Lu JW, Jiang Q, Wang TH and Huang XE: CXCL12 CXCR4 promotes proliferation and invasion of pancreatic cancer cells. Asian Pac J Cancer Prev. 14:5403–5408. 2013. View Article : Google Scholar : PubMed/NCBI

49 

Immervoll H, Hoem D, Steffensen OJ, Miletic H and Molven A: Visualization of CD44 and CD133 in normal pancreas and pancreatic ductal adenocarcinomas: Non-overlapping membrane expression in cell populations positive for both markers. J Histochem Cytochem. 59:441–455. 2011. View Article : Google Scholar : PubMed/NCBI

50 

Hou YC, Chao YJ, Tung HL, Wang HC and Shan YS: Coexpression of CD44-positive/CD133-positive cancer stem cells and CD204-positive tumor-associated macrophages is a predictor of survival in pancreatic ductal adenocarcinoma. Cancer. 120:2766–2777. 2014. View Article : Google Scholar : PubMed/NCBI

51 

Li X, Zhao H, Gu J and Zheng L: Prognostic value of cancer stem cell marker CD133 expression in pancreatic ductal adenocarcinoma (PDAC): A systematic review and meta-analysis. Int J Clin Exp Pathol. 8:12084–12092. 2015.PubMed/NCBI

52 

Singh S, Arcaroli JJ, Orlicky DJ, Chen Y, Messersmith WA, Bagby S, Purkey A, Quackenbush KS, Thompson DC and Vasiliou V: Aldehyde dehydrogenase 1B1 as a modulator of pancreatic adenocarcinoma. Pancreas. 45:117–122. 2016. View Article : Google Scholar : PubMed/NCBI

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February 2018
Volume 15 Issue 2

Print ISSN: 1792-1074
Online ISSN:1792-1082

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APA
Cao, J., An, Q., & Wang, L. (2018). Pediatric sarcomas (Review) Retraction in /10.3892/ol.2018.7943. Oncology Letters, 15, 1397-1402. https://doi.org/10.3892/ol.2017.7467
MLA
Cao, J., An, Q., Wang, L."Pediatric sarcomas (Review) Retraction in /10.3892/ol.2018.7943". Oncology Letters 15.2 (2018): 1397-1402.
Chicago
Cao, J., An, Q., Wang, L."Pediatric sarcomas (Review) Retraction in /10.3892/ol.2018.7943". Oncology Letters 15, no. 2 (2018): 1397-1402. https://doi.org/10.3892/ol.2017.7467