Redundancy of autocrine loops in human osteosarcoma cells

Benini, Stefania; Baldini, Nicola; Manara, Maria Cristina; Chano, Tokuhiro; Serra, Massimo; Rizzi, Simona; Lollini, Pier Luigi; Picci, Piero; Scotlandi, Katia

doi:10.1002/(sici)1097-0215(19990209)80:4<581::aid-ijc16>3.0.co;2-o

Cited by 79 publications

(37 citation statements)

References 15 publications

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“…Among the underexpressed genes, p16 ( CDKN2A ) exhibited the greatest downregulation (145-fold decrease), which confirmed that the loss of p16 expression is correlated with osteosarcoma development [40]. Moreover, we confirmed reports in the literature describing over-expression of PDGFB [41]. …”

Section: Resultssupporting

confidence: 85%

In vitro biosafety profile evaluation of multipotent mesenchymal stem cells derived from the bone marrow of sarcoma patients

et al. 2014

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BackgroundIn osteosarcoma (OS) and most Ewing sarcoma (EWS) patients, the primary tumor originates in the bone. Although tumor resection surgery is commonly used to treat these diseases, it frequently leaves massive bone defects that are particularly difficult to be treated. Due to the therapeutic potential of mesenchymal stem cells (MSCs), OS and EWS patients could benefit from an autologous MSCs-based bone reconstruction. However, safety concerns regarding the in vitro expansion of bone marrow-derived MSCs have been raised. To investigate the possible oncogenic potential of MSCs from OS or EWS patients (MSC-SAR) after expansion, this study focused on a biosafety assessment of MSC-SAR obtained after short- and long-term cultivation compared with MSCs from healthy donors (MSC-CTRL).MethodsWe initially characterized the morphology, immunophenotype, and differentiation multipotency of isolated MSC-SAR. MSC-SAR and MSC-CTRL were subsequently expanded under identical culture conditions. Cells at the early (P3/P4) and late (P10) passages were collected for the in vitro analyses including: sequencing of genes frequently mutated in OS and EWS, evaluation of telomerase activity, assessment of the gene expression profile and activity of major cancer pathways, cytogenetic analysis on synchronous MSCs, and molecular karyotyping using a comparative genomic hybridization (CGH) array.ResultsMSC-SAR displayed comparable morphology, immunophenotype, proliferation rate, differentiation potential, and telomerase activity to MSC-CTRL. Both cell types displayed signs of senescence in the late stages of culture with no relevant changes in cancer gene expression. However, cytogenetic analysis detected chromosomal anomalies in the early and late stages of MSC-SAR and MSC-CTRL after culture.ConclusionsOur results demonstrated that the in vitro expansion of MSCs does not influence or favor malignant transformation since MSC-SAR were not more prone than MSC-CTRL to deleterious changes during culture. However, the presence of chromosomal aberrations supports rigorous phenotypic, functional and genetic evaluation of the biosafety of MSCs, which is important for clinical applications.

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Section: Resultssupporting

confidence: 85%

In vitro biosafety profile evaluation of multipotent mesenchymal stem cells derived from the bone marrow of sarcoma patients

et al. 2014

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“…U-2OS, Saos-2, HOS (CRL-1543) and MG-63 cell lines were obtained from the American Type Culture Collection (ATCC, Rockville, MD). IOR/OS9, IOR/OS10, IOR/OS14, IOR/OS18, and SARG human OS cell lines were established from bioptic clinical specimens obtained from OS patients at the Laboratory of Experimental Oncology of the Rizzoli Orthopaedic Institute [28]. Variants resistant to DX (U-2OS/DX580 and Saos-2/DX580), MTX (U-2OS/MTX300; Saos-2/MTX300), and CDDP (U-2OS/CDDP4μg and Saos-2/CDDP6μg) were established by exposing the drug-sensitive U-2OS and Saos-2 parental cell lines to stepwise increasing concentrations of each drug, as previously described [29–31].…”

Section: Methodsmentioning

confidence: 99%

Targeting CDKs with Roscovitine Increases Sensitivity to DNA Damaging Drugs of Human Osteosarcoma Cells

et al. 2016

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Cyclin-dependent kinase 2 (CDK2) has been reported to be essential for cell proliferation in several human tumours and it has been suggested as an appropriate target to be considered in order to enhance the efficacy of treatment regimens based on the use of DNA damaging drugs. We evaluated the clinical impact of CDK2 overexpression on a series of 21 high-grade osteosarcoma (OS) samples profiled by using cDNA microarrays. We also assessed the in vitro efficacy of the CDKs inhibitor roscovitine in a panel of drug-sensitive and drug-resistant human OS cell lines. OS tumour samples showed an inherent overexpression of CDK2, and high expression levels at diagnosis of this kinase appeared to negatively impact on clinical outcome. CDK2 expression also proved to be relevant for in vitro OS cells growth. These findings indicated CDK2 as a promising candidate therapeutic marker for OS and therefore we assessed the efficacy of the CDKs-inhibitor roscovitine in both drug-sensitive and -resistant OS cell lines. All cell lines resulted to be responsive to roscovitine, which was also able to increase the activity of cisplatin and doxorubicin, the two most active DNA damaging drugs used in OS chemotherapy. Our results indicated that combined treatment with conventional OS chemotherapeutic drugs and roscovitine may represent a new candidate intervention approach, which may be considered to enhance tumour cell sensitivity to DNA damaging drugs.

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“…Saos-2, U-2OS, MG-63, SK-ES-1, SK-N-MC, and RD-ES were provided by American Type Culture Collection, ATCC; the alveolar rhabdomyosarcoma cell line SJ-RH30 was kindly provided by Dr. A. Rosolen (University of Padua, Padua, Italy)[22]; Ewing sarcoma cell lines TC-71 and 6647 were kindly provided by T.J. Triche (Children's Hospital, Los Angeles, CA); the ASP14 cell line, a stable cell line generated from A673 ES cell line transfected with doxycycline(DOX)-inducible shRNA targeting EWS-FLI1 was kindly provided by H. Kovar (St. Anna Kinderkrebsforshung, Vienna). The osteosarcoma IOR/OS10 and the Ewing cell line LAP-35 were obtained in the Experimental Oncology Lab, Rizzoli Institute (Bologna) and were previously described [8], [23]. The RD/18, a clone of the commercially available cell line RD (Flow Laboratories), and the CC-A cell lines were kindly gifted by Prof. P.L.…”

Section: Methodsmentioning

confidence: 99%

“…Over-expression of IR-A is in fact emerging as a feature of cancer cells where it mediates cell survival, proliferation, and migration under insulin and IGF-2 stimulus [1], [4], [5]. An autocrine loop involving IGF-2 and IR-A is active in different sarcomas, such as rhabdomyosarcoma and osteosarcoma cells [6], [7], [8]. Recently, we have demonstrated exclusive presence of IR-A in Ewing sarcoma [9].…”

Section: Introductionmentioning

confidence: 92%

Metformin as an Adjuvant Drug against Pediatric Sarcomas: Hypoxia Limits Therapeutic Effects of the Drug

et al. 2013

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Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas.

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Redundancy of autocrine loops in human osteosarcoma cells

Cited by 79 publications

References 15 publications

In vitro biosafety profile evaluation of multipotent mesenchymal stem cells derived from the bone marrow of sarcoma patients

In vitro biosafety profile evaluation of multipotent mesenchymal stem cells derived from the bone marrow of sarcoma patients

Targeting CDKs with Roscovitine Increases Sensitivity to DNA Damaging Drugs of Human Osteosarcoma Cells

Metformin as an Adjuvant Drug against Pediatric Sarcomas: Hypoxia Limits Therapeutic Effects of the Drug

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