The prognosis of patients with metastatic and recurrent osteosarcoma has not improved over the last 30 years because no effective treatment strategy has been established for lung metastases. Although ...molecular‐targeted drugs that modify the extracellular environment, such as antifibrotic agents, have been developed for cancer treatment, the suppressive effects of antifibrotic agents on osteosarcoma lung metastasis are unclear. Osteosarcomas need to adapt to considerable changes with respect to the stiffness of the environment and fibrosis during lung metastasis and may thus be vulnerable to fibrotic suppression as they originate at the site of a stiff bone with considerable fibrosis. In our study, we investigated whether fibrosis was a therapeutic target for suppressing osteosarcoma metastasis. Lung tissue samples from patients and a mouse model (LM8‐Dunn model) showed that lung metastatic colonization of osteosarcoma cells proceeded with massive lung fibrosis. Metastatic osteosarcoma LM8 cells proliferated in a scaffold‐dependent manner; the proliferation was less dependent on YAP‐mediated mechanotransduction on soft polyacrylamide gels. The antifibrotic agents pirfenidone and nintedanib suppressed lung metastasis in the LM8‐Dunn model. The osteosarcoma cells did not show increased proliferation, as reported in breast cancer, after continuous culture in a soft environment. We speculated that the antifibrotic agents were effective because the osteosarcoma cells remained scaffold‐dependent in the soft tissue environment. Thus, antifibrotic strategies may be useful in suppressing lung metastasis of bone and soft tissue tumors with stiff primary sites such as those in osteosarcoma.
What's new?
Osteosarcomas originate at the site of a stiff bone with considerable fibrosis and need to adapt to considerable changes during lung metastasis. However, the potential of an anti‐fibrosis strategy for suppressing lung metastasis remains unclear. Here, the authors show that osteosarcoma cells remain scaffold‐dependent in a soft tissue environment and provide evidence of lung metastasis suppression by anti‐fibrotic agents. The effectiveness of anti‐fibrotic agents was dependent on the adaptability of osteosarcoma cells to a soft environment and the efficiency of mechanotransduction. The unveiled proliferation mechanism in soft environments offers a novel perspective in tumour biophysical research.
Background and Objectives
The aim of this study is to assess the survival, function, radiographic appearance, and modes of failure of extracorporeal irradiated (ECI) autografts in a long‐term ...setting.
Methods
We retrospectively reviewed 87 patients who were treated for bone and soft tissue tumors using ECI autografts between 1988 and 2009.
Results
The 56 patients had a minimum follow‐up of 10 years, and the median follow‐up period was 16.5 years. The reimplantation procedures included 24 osteoarticular grafts, 16 intercalary grafts, 10 autograft‐prosthetic composite grafts, and 6 hemicortical grafts. The 15‐year graft and event‐free survival rates were 76.8% and 47.9%, respectively. Infection and structural failure were the most common reasons for additional surgery. The time for additional surgery was significantly longer in patients with composite grafts (P < .01). The median Musculoskeletal Tumor Society score and the International Society of Limb Salvage score were 80% and 84%, respectively.
Conclusions
ECI autografts are a durable option for reconstruction after resection of musculoskeletal tumors and provide good function over more than 15 years. Most graft failures occurred within 5 years of the index surgery. However, composite grafts showed a tendency to fail more than 10 years after the surgery.
Structural phase transitions of calcium strontium sulfoaluminate series, (Ca1–x Sr x )8AlO212(SO4)2 ((CS)AS-x) with x = 0.80–1.00, are systematically investigated by powder X-ray diffraction, ...dielectric measurements, and pyroelectric measurements, to clarify a phase diagram of (CS)AS-x (x = 0.80–1.00). A pure strontium sulfoaluminate, (CS)AS-1.00, is found to undergo three phase transitions, which take place successively on cooling from a prototypical cubic phase with the symmetry of Im3̅m. Though the room-temperature phase of (CS)AS-1.00 was previously reported to be of polar Pcc2, the pyroelectric measurements clarified a nonpolar character of the crystal symmetry. The dielectric measurements suggest a possibility of an antiferroelectric ground state of (CS)AS-x in the Sr-rich compositions. As x decreases, the ground state changes to a short-range-ordered state, implying a unique phase transition from the antiferroelectric state to the antiferroelectric-relaxor state. The present study provides an intriguing playground for designing new ferro/antiferroelectric materials.
Sarcoma is a rare type of cancer for which new therapeutic agents are required. Ferroptosis is a nonapoptotic cell death triggered by iron-mediated lipid peroxidation. We found that TFRC, an iron ...uptake protein, was expressed at higher levels in sarcoma cell lines than in noncancer and carcinoma cell lines. Glutathione peroxidase 4 (GPX4) protects cells against ferroptosis, and its inhibition using RAS-selective lethal 3 (RSL3) had an antitumor effect that was more pronounced in sarcoma cell lines, particularly synovial sarcoma cells, compared to non-sarcoma cells. Because NF-κB can provoke ferroptosis, we examined the role of SHARPIN, an activator of NF-κB, in sarcoma. We found that SHARPIN expression was significantly associated with reduced survival in cohorts of patients with cancer, including sarcoma. In addition, SHARPIN promoted the sensitivity of sarcoma cells to ferroptosis. Further analyses revealed that the PGC1α/NRF2/SLC7A11 axis and BNIP3L/NIX-mediated mitophagy are regulated through NF-κB and PRMT5 downstream of SHARPIN. Our findings suggest that ferroptosis could have a therapeutic effect in sarcoma, particularly in subpopulations with high TFRC and SHARPIN expression.
An improper ferroelectric is a certain type of ferroelectrics whose primary order parameter is not polarization but another physical quantity such as magnetization. In contrast to a conventional ...proper ferroelectrics as represented by Pb(Zr,Ti)O3 and BaTiO3, the improper ferroelectrics has been inconceivable for practical applications thus far. Herein, we illustrate the great potential of improper ferroelectrics for efficient conversion of temperature fluctuation to electric energy, as demonstrated with (Ca0.84Sr0.16)8AlO212(MoO4)2 (CSAM‐16). The present study has experimentally proven that CSAM‐16 achieves an excellent electrothermal coupling factor and high electric field sensitivity for pyroelectric energy conversion that approach a practical level for application to self‐powered autonomous electronic devices for rapidly spreading wireless sensor networks. The present results provide a novel approach to developing innovative pyroelectric energy harvesting devices using improper ferroelectrics.
Excellent pyroelectric energy harvesting performance is demonstrated with an aluminate sodalite‐type oxide (Ca0.84Sr0.16)8AlO212(MoO4)2 (CSAM‐16) that exhibits improper ferroelectricity, in which spontaneous polarization occurs without an associated divergent increase of dielectric permittivity. The present results provide a novel approach to the development of innovative pyroelectric energy harvesting devices involving improper ferroelectrics.
Clear cell sarcoma (CCS) is a rare but chemotherapy-resistant and often fatal high-grade soft-tissue sarcoma (STS) characterized by melanocytic differentiation under control of ...microphthalmia-associated transcription factor (MITF). Eribulin mesilate (eribulin) is a mechanistically unique microtubule inhibitor commonly used for STS treatment, particularly liposarcoma and leiomyosarcoma. In this study, we examined the antitumor efficacy of eribulin on four human CCS cell lines and two mouse xenograft models. Eribulin inhibited CCS cell proliferation by inducing cell-cycle arrest and apoptosis, shrunk CCS xenograft tumors, and increased tumor vessel density. Eribulin induced MITF protein upregulation and stimulated tumor cell melanocytic differentiation through ERK1/2 inactivation (a MITF negative regulator)
and
Moreover, tumor reoxygenation, probably caused by eribulin-induced vascular remodeling, attenuated cell growth and inhibited ERK1/2 activity, thereby upregulating MITF expression and promoting melanocytic differentiation. Finally, downregulation of MITF protein levels modestly debilitated the antiproliferative effect of eribulin on CCS cells. Taken together, eribulin suppresses CCS through inhibition of cell proliferation and promotion of tumor differentiation by acting both directly on tumor cells and indirectly through tumor reoxygenation.
Abstract
Approximately 60–70% of
EWSR1
-negative small blue round cell sarcomas harbour a rearrangement of
CIC
, most commonly
CIC-DUX4
.
CIC-DUX4
sarcoma (CDS) is an aggressive and often fatal ...high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The
CIC-DUX4
fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a
DUX4
pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both
in vitro
and
in vivo
. Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.
Background: Few studies have described the characteristics and prognostic factors of patients with metastatic extrauterine leiomyosarcoma (euLMS). Therefore, we retrospectively investigated the ...clinicopathological features, clinical outcomes, and prognostic factors of patients with euLMS. Methods: We recruited 61 patients with metastatic euLMS treated from 2006 to 2020 and collected and statistically analyzed information on patient-, tumor-, and treatment-related factors. The median follow-up period was 21.1 months. Results: Sixty-one patients with euLMS and a median age of 59 years were included. Furthermore, their five-year overall survival (OS) rate was 38.3%. Univariate analysis revealed that primary tumor size >10 cm, synchronous metastasis, initial metastatic sites >1, and no metastasectomy with curative intent were significantly associated with poor OS rate. Multivariate analysis identified primary tumor size >10 cm as an independent prognostic factor for poor OS. Among 24 patients who received metastasectomy with curative intent, the interval from the initial diagnosis to development of metastasis ≤6 months was significantly correlated with unfavorable OS. Among 37 patients who did not receive metastasectomy, chemotherapy after metastasis development was significantly related to better OS. Conclusions: Complete metastasectomy should be considered for metastatic euLMS treatment. Moreover, chemotherapy could prolong survival in patients with metastasis who are ineligible for metastasectomy.
Pelvic osteosarcoma has a poor prognosis compared to osteosarcomas in other locations, and the reasons for this remain unknown. Surgical resection of pelvic osteosarcoma is technically demanding and ...often results in dysfunction and complications. In this study, we investigated the reasons underlying the poor prognosis of pelvic osteosarcoma by comparing it to femoral osteosarcoma using data from the Bone Tumor Registry in Japan. We used propensity score analysis to determine whether surgical resection of pelvic osteosarcoma improved its prognosis. We demonstrated that pelvic osteosarcoma had a poor prognosis because it occurred more often in the elderly, often had larger tumor size, and had metastasis at presentation more often in comparison to femoral osteosarcoma. These three factors were also associated with the non-surgical treatment of pelvic osteosarcoma, which also led to a poor outcome. The overall survival rate was only comparable in pelvic osteosarcoma and femoral osteosarcoma in cases treated with surgical resection. Propensity score analysis revealed that surgical treatment improved the prognosis of pelvic osteosarcoma. As such, we propose that surgical resection should be considered based on tumor stage and patient age in order to improve the prognosis of pelvic osteosarcoma.
Although biological resources are essential for basic and preclinical research in the oncological field, those of sarcoma are not sufficient for rapid development of the treatment. So far, some ...sarcoma cell lines have been established, however, the success rate was low and the established sarcoma types were frequently biased. Therefore, an efficient culture method is needed to determine the various types of sarcomas. Organoid culture is a 3-dimentional culture method that enables the recapitulation of the tumor microenvironment and the success rate reported is higher than the 2-dimentional culture. The purpose of this study was to report our newly established organoids from human epithelioid sarcoma using the air-liquid interface organoid culture method.
We treated 2 patients with epithelioid sarcoma in our institute. The remaining sarcoma specimens after surgical resection were embedded in collagen type 1 gels according to the air-liquid interface organoid culture method. After serial passages, we xenografted the organoids to NOD-scid IL2Rgnull (NSG) mice. Using the developed tumors, we performed histological and genomic analyses to compare the similarities and differences with the original epithelioid sarcoma from the patient.
Organoids from the epithelioid sarcoma could be serially cultured and maintained in collagen type 1 gels for more than 3 passages. Developed orthotopic tumor xenografts were detected in the NSG mice. After the process was repeated severally, the patient derived organoid lines from the epithelioid sarcoma were established. The established organoids showed loss of integrase interactor 1 expression with polymerase chain reaction and immunohistochemical analyses. The xenografted organoids of the epithelioid sarcoma had histologically similar phenotypes with the original tumor and genetically resembled it to some degree.
The present study demonstrated 2 novel established organoid models of epithelioid sarcoma, and our organoid models could be used to investigate the molecular pathogenesis and develop a novel treatment.
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