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Cancers Sep 2023Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the... (Review)
Review
Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the standard treatment for localized MCS is only surgical resection, and there are no established treatment guidelines for patients with advanced and metastatic MCS. Due to the low incidence of MCS, the pathology of these tumors is still unknown, and other therapeutic options are lacking. Some studies show the potential role of the PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression in the pathogenesis of MCS. These findings provide an opportunity to use protein kinases and BCL2 inhibitors as potential therapy in MCS. In this review, we summarize the current knowledge about MCS diagnosis and treatment options. We show the immunological and molecular biomarkers used in the diagnosis of MCS. In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies.
PubMed: 37760551
DOI: 10.3390/cancers15184581 -
Cancers Nov 2023Sarcomas are a heterogeneous group of malignant mesenchymal tumors, including soft tissue and bone sarcomas. Macrophages in the tumor microenvironment, involved in... (Review)
Review
Sarcomas are a heterogeneous group of malignant mesenchymal tumors, including soft tissue and bone sarcomas. Macrophages in the tumor microenvironment, involved in immunosuppression and leading to tumor development, are called tumor-associated macrophages (TAMs). TAMs are very important in modulating the microenvironment of sarcomas by expressing specific markers and secreting factors that influence immune and tumor cells. They are involved in many signaling pathways, such as p-STAT3/p-Erk1/2, PI3K/Akt, JAK/MAPK, and JAK/STAT3. TAMs also significantly impact the clinical outcomes of patients suffering from sarcomas and are mainly related to poor overall survival rates among bone and soft tissue sarcomas, for example, chondrosarcoma, osteosarcoma, liposarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma. This review summarizes the current knowledge on TAMs in sarcomas, focusing on specific markers on sarcoma cells, cell-cell interactions, and the possibly involved molecular pathways. Furthermore, we discuss the clinical significance of macrophages in sarcomas as a potential target for new therapies, presenting clinical relevance, possible new treatment options, and ongoing clinical trials using TAMs in sarcoma treatment.
PubMed: 37958467
DOI: 10.3390/cancers15215294 -
Scandinavian Journal of Surgery : SJS :... Sep 2023Primary sarcomas of bone are rare malignant mesenchymal tumors. The most common bone sarcomas are osteosarcoma, Ewing's sarcoma, and chondrosarcoma. The prognosis has... (Review)
Review
Primary sarcomas of bone are rare malignant mesenchymal tumors. The most common bone sarcomas are osteosarcoma, Ewing's sarcoma, and chondrosarcoma. The prognosis has improved over the years, but bone sarcomas are still life-threatening tumors that need a multidisciplinary approach for diagnosis and treatment. Bone sarcomas arising in the pelvis present a unique challenge to orthopedic oncologists due to the absence of natural anatomical barriers, the close proximity of vital neurovascular structures, and the high mechanical demands placed on any pelvic reconstruction following the excision of the tumor. While radiotherapy has an important role especially in Ewing's sarcoma and chemotherapy for both Ewing's sarcoma and osteosarcoma, surgery remains the main choice of treatment for all three entities. While external hemipelvectomy has remained one option, the main aim of surgery is limb salvage. After complete tumor resection, the bone defect needs to be reconstructed. Possibilities to reconstruct the defect include prosthetic or biological reconstruction. The method of reconstruction is dependent on the location of tumor and the surgery required for its removal. The aim of this article is to give an insight into pelvic bone sarcomas, their oncological and surgical outcomes, and the options for treatment based on the authors' experiences.
Topics: Humans; Sarcoma, Ewing; Bone Neoplasms; Prognosis; Sarcoma; Osteosarcoma; Pelvic Bones; Pelvis; Soft Tissue Neoplasms
PubMed: 37438963
DOI: 10.1177/14574969231181504 -
Journal of Cancer Research and Clinical... Dec 2023Sarcomas are a diverse group of malignant neoplasms of mesenchymal origin. They develop rarely, but due to poor prognosis, they are a challenging and significant... (Review)
Review
Sarcomas are a diverse group of malignant neoplasms of mesenchymal origin. They develop rarely, but due to poor prognosis, they are a challenging and significant clinical problem. Currently, available therapeutic options have very limited activity. A better understating of sarcomas' pathogenesis may help develop more effective therapies in the future. The Sonic hedgehog (Shh) signaling pathway is involved in both embryonic development and mature tissue repair and carcinogenesis. Shh pathway inhibitors are presently used in the treatment of basal cell carcinoma. Its increased activity has been demonstrated in many sarcomas, including osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, and malignant rhabdoid tumor. In vitro studies have demonstrated the effectiveness of inhibitors of the Hedgehog pathway in inhibiting proliferation in those sarcomas in which the components of the pathway are overexpressed. These results were confirmed by in vivo studies, which additionally proved the influence of Shh pathway inhibitors on limiting the metastatic potential of sarcoma cells. However, until now, the efficacy of sarcomas treatment with Shh pathway inhibitors has not been established in clinical trials. The reason for that may be the non-canonical activation of the pathway or interactions with other signaling pathways, such as Wnt or Notch. In this review, we present the Shh signaling pathway's role in the pathogenesis of sarcomas, including both canonical and non-canonical signaling. We also propose how this knowledge could be potentially translated into clinics.
Topics: Humans; Hedgehog Proteins; Sarcoma; Sarcoma, Ewing; Osteosarcoma; Bone Neoplasms
PubMed: 37815662
DOI: 10.1007/s00432-023-05441-3 -
JCI Insight Sep 2023Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is...
Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat - a class I selective histone deacetylase (HDAC) inhibitor - had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.
Topics: Humans; Animals; Mice; Kruppel-Like Factor 4; Osteoarthritis; Inflammation; Histone Deacetylase Inhibitors; Bone Neoplasms
PubMed: 37681413
DOI: 10.1172/jci.insight.170513 -
Pathology Aug 2023Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript...
Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges. We applied NKX3.1 immunohistochemistry which was recently reported as a highly specific marker as well as methylome and copy number profiling to a set of 45 well characterised MCS cases to evaluate their potential diagnostic value. Methylome profiling revealed a highly distinct cluster for MCS. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. NKX3.1 immunohistochemistry showed positivity in 36% of tumours, the majority of which was rather focal and weak. Taken together, NKX3.1 expression showed a low sensitivity but a high specificity in our analysis. Methylome profiling on the other hand represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. Furthermore, it can aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.
Topics: Humans; Chondrosarcoma, Mesenchymal; Immunohistochemistry; Epigenome; Bone and Bones; Cell Differentiation; Bone Neoplasms
PubMed: 37225644
DOI: 10.1016/j.pathol.2023.03.003