Browsing by Subject "osteosarcoma"

Now showing 1 - 6 of 6
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    Enhancing anti-tumor potential: low-intensity vibration suppresses osteosarcoma progression and augments MSCs' tumor-suppressive abilities
    (2024) Xiong, Xue; Huo, Qingji; Li, Kexin; Cui, Changpeng; Chang, Chunyi; Park, Charles; Ku, BonHeon; Hong, Chin-Suk; Lim, HeeChang; Pandya, Pankita H.; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Lin, Chien-Chi; Kacena, Melissa A.; Pollok, Karen E.; Chen, Andy; Liu, Jing; Thompson, William R.; Li, Xue-Lian; Li, Bai-Yan; Yokota, Hiroki; Health Sciences, School of Health and Human Sciences
    Rationale: Osteosarcoma (OS), a common malignant bone tumor, calls for the investigation of novel treatment strategies. Low-intensity vibration (LIV) presents itself as a promising option, given its potential to enhance bone health and decrease cancer susceptibility. This research delves into the effects of LIV on OS cells and mesenchymal stem cells (MSCs), with a primary focus on generating induced tumor-suppressing cells (iTSCs) and tumor-suppressive conditioned medium (CM). Methods: To ascertain the influence of vibration frequency, we employed numerical simulations and conducted experiments to determine the most effective LIV conditions. Subsequently, we generated iTSCs and CM through LIV exposure and assessed the impact of CM on OS cells. We also explored the underlying mechanisms of the tumor-suppressive effects of LIV-treated MSC CM, with a specific focus on vinculin (VCL). We employed cytokine array, RNA sequencing, and Western blot techniques to investigate alterations in cytokine profiles, transcriptomes, and tumor suppressor proteins. Results: Numerical simulations validated LIV frequencies within the 10-100 Hz range. LIV induced notable morphological changes in OS cells and MSCs, confirming its dual role in inhibiting OS cell progression and promoting MSC conversion into iTSCs. Upregulated VCL expression enhanced MSC responsiveness to LIV, significantly bolstering CM's efficacy. Notably, we identified tumor suppressor proteins in LIV-treated CM, including procollagen C endopeptidase enhancer (PCOLCE), histone H4 (H4), peptidylprolyl isomerase B (PPIB), and aldolase A (ALDOA). Consistently, cytokine levels decreased significantly in LIV-treated mouse femurs, and oncogenic transcript levels were downregulated in LIV-treated OS cells. Moreover, our study demonstrated that combining LIV-treated MSC CM with chemotherapy drugs yielded additive anti-tumor effects. Conclusions: LIV effectively impeded the progression of OS cells and facilitated the transformation of MSCs into iTSCs. Notably, iTSC-derived CM demonstrated robust anti-tumor properties and the augmentation of MSC responsiveness to LIV via VCL. Furthermore, the enrichment of tumor suppressor proteins within LIV-treated MSC CM and the reduction of cytokines within LIV-treated isolated bone underscore the pivotal tumor-suppressive role of LIV within the bone tumor microenvironment.
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    MiR-34a-5p promotes the multi-drug resistance of osteosarcoma by targeting the CD117 gene.
    (Impact Journals, 2016-05-10) Pu, Youguang; Zhao, Fangfang; Wang, Haiyan; Cai, Wenjing; Gao, Jin; Li, Yinpeng; Cai, Shanbao; Department of Pediatrics, IU School of Medicine
    An association has been reported between miR-34a-5p and several types of cancer. Specifically, in this study, using systematic observations of multi-drug sensitive (G-292 and MG63.2) and resistant (SJSA-1 and MNNG/HOS) osteosarcoma (OS) cell lines, we showed that miR-34a-5p promotes the multi-drug resistance of OS through the receptor tyrosine kinase CD117, a direct target of miR-34a-5p. Consistently, the siRNA-mediated repression of CD117 in G-292 and MG63.2 cells led to a similar phenotype that exhibited all of the miR-34a-5p mimic-triggered changes. In addition, the activity of the MEF2 signaling pathway was drastically altered by the forced changes in the miR-34a-5p or CD117 level in OS cells. Furthermore, si-CD117 suppressed the enhanced colony and sphere formation, which is in agreement with the characteristics of a cancer stem marker. Taken together, our data established CD117 as a direct target of miR-34-5p and demonstrated that this regulation interferes with several CD117-mediated effects on OS cells. In addition to providing new mechanistic insights, our results will provide an approach for diagnosing and chemotherapeutically treating OS.
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    Patient Preferences Matter: A Qualitative Inquiry With Patients About the Surgical Decision for Osteosarcoma in the Lower Extremity
    (2020-06) Panoch, Janet Elizabeth; Goering, Elizabeth; Parrish-Sprowl, John; Hoffman-Longtin, Krista; Beckman, Emily
    Purpose The experience of surgical patient decision-making for amputation, rotationplasty, or limb salvage surgery for the lower extremity was explored with osteosarcoma survivors and parents. Issues and patient concerns were examined prospectively in Facebook posts and retrospectively in personal interviews. Recommendations were sought for the development of a decision aid. Methods A qualitative inquiry was conducted in two studies: 1) a content analysis of 15 Facebook posts on the Osteosarcoma and Ewing’s Sarcoma Support Group about the surgical decision, and 2) a narrative analysis of 20 interviews with survivors and parents about their lived experience. The interview guide was informed by a knowledge translation theoretical model. In-person or video interviews included 29 parents or adolescent-young adults between the ages of 14-71 across 15 states. Results Participants were concerned about making the best decision for themselves or their child. Having little time to make the decision contributes to feeling overwhelmed and uninformed. The lack of information about options, potential limitations, prosthetic needs, and long-term functional outcomes impacts the decision-making process. Resources for finding information are limited. Shared decision-making approaches were preferred though many decisions were made by the surgeon. Patients felt unprepared for complications encountered after limb salvage. Conclusions Limb salvage surgery remains the gold standard for most providers; participants felt there was a bias on the surgeon’s part for salvage. Potential complications and uncertainties of each option were largely omitted in consultations; information about living with a prosthesis is an unmet need for decision-making. The decision affected their quality of life in ways they did not anticipate, resulting in additional decisions. Implications The findings of this study can be used in medical education for orthopedic surgeons to understand the long-term outcomes of limb salvage surgery. Patient preferences matter in the decision and patients who are involved in the decision are more satisfied if they are prepared for the unknown and potential complications. Recommendations for a decision aid include an online format, content that includes a discussion of uncertainties as well as complications of each option, patient stories for long-term outcomes, and resources for psychosocial support.
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    Receptor Tyrosine Kinases in Osteosarcoma: 2019 Update
    (Springer, 2020) Greenfield, Edward M.; Collier, Christopher D.; Getty, Patrick J.; Orthopaedic Surgery, School of Medicine
    The primary conclusions of our 2014 contribution to this series were as follows: Multiple receptor tyrosine kinases (RTKs) likely contribute to aggressive phenotypes in osteosarcoma and, therefore, inhibition of multiple RTKs is likely necessary for successful clinical outcomes. Inhibition of multiple RTKs may also be useful to overcome resistance to inhibitors of individual RTKs as well as resistance to conventional chemotherapies. Different combinations of RTKs are likely important in individual patients. AXL, EPHB2, FGFR2, IGF1R, and RET were identified as promising therapeutic targets by our in vitro phosphoproteomic/siRNA screen of 42 RTKs in the highly metastatic LM7 and 143B human osteosarcoma cell lines. This chapter is intended to provide an update on these topics as well as the large number of osteosarcoma clinical studies of inhibitors of multiple tyrosine kinases (multi-TKIs) that were recently published.
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    Recurrent Metastatic High‑Grade Osteosarcoma: Disease Stabilization and Successful Pregnancy Outcome following Aggressive Multimodality Treatment
    (Wolters Kluwer, 2018) Khurana, Monica; Gruner, Barbara; Sathi, Bindu Kanathezhath; Medicine, School of Medicine
    Prognosis for refractory/recurrent metastatic osteosarcoma (OS) remains dismal with 3-year survival rates <20%. Achievement of more than 5 years of stable, refractory/recurrent metastatic OS disease in our patient is itself unique and attributable to multimodality therapy. Her high-dose chemotherapy regimen with alkylating agents did not lead to infertility, making her case even more unique. Successful disease stabilization and pregnancy outcome in our patient with metastatic multiple relapsed OS is one of the first cases published. We need further understanding and exploration of pathogenesis, chemoresistant mechanisms, and multimodality therapies including immunotherapy for OS.
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    Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma
    (MDPI, 2020-08-26) Pandya, Pankita H.; Cheng, Lijun; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Tang, Shan; Sinn, Anthony L.; Trowbridge, Melissa A.; Coy, Kathryn L.; Bailey, Barbara J.; Young, Courtney N.; Ding, Jixin; Dobrota, Erika A.; Dyer, Savannah; Elmi, Adily; Thompson, Quinton; Barghi, Farinaz; Shultz, Jeremiah; Albright, Eric A.; Shannon, Harlan E.; Murray, Mary E.; Marshall, Mark S.; Ferguson, Michael J.; Bertrand, Todd E.; Wurtz, L. Daniel; Batra, Sandeep; Li, Lang; Renbarger, Jamie L.; Pollok, Karen E.; Pediatrics, School of Medicine
    Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.