-
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 -
Advances in Experimental Medicine and... 2020Sarcomas comprise a heterogeneous group of rare malignancies of mesenchymal origin including more than 70 subtypes. They may arise in muscle, bone, cartilage and other... (Review)
Review
Sarcomas comprise a heterogeneous group of rare malignancies of mesenchymal origin including more than 70 subtypes. They may arise in muscle, bone, cartilage and other connective tissues. Their high histological and genetic heterogeneity makes diagnosis and treatment very challenging. Deregulation of heparanase has been found in several sarcoma subtypes and high expression levels have been correlated with poor prognosis in Ewing's sarcoma and osteosarcoma. Altered expression of specific heparan sulfate proteoglycans and heparan sulfate biosynthetic enzymes has also been observed. Advances in molecular pathogenesis of sarcomas have evidenced the critical role of several heparan sulfate binding growth factors and receptor tyrosine kinases, highly interconnected with the microenvironment, in sustaining tumor growth and progression. Interference with heparanase/heparan sulfate functions represents a potential therapeutic approach in sarcoma. In this chapter, we summarize the current knowledge about the biological significance of heparanase expression and its potential as a therapeutic target in subtypes of both soft tissue and bone sarcomas. Particular emphasis is given to the involvement of heparan sulfate proteoglycans and their synthesizing and modifying enzymes in bone physiology and disorders leading up to the pathobiology of bone sarcomas. The chapter also describes the cooperation between exostin loss-of-function and heparanase upregulation in hereditary Multiple Osteochondroma syndrome as a paradigmatic example of constitutive alteration of the heparanase/heparan sulfate proteoglycan system which may contribute to progression to malignant secondary chondrosarcoma. Preclinical evidence of the role of heparanase as a promising therapeutic target in various sarcoma subtypes is finally resumed.
Topics: Glucuronidase; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Sarcoma
PubMed: 32274719
DOI: 10.1007/978-3-030-34521-1_15 -
Frontiers in Cell and Developmental... 2022Post-translational modifications comprise series of enzymatically-driven chemical modifications, virtually involving the entire cell proteome, that affect the fate of a... (Review)
Review
Post-translational modifications comprise series of enzymatically-driven chemical modifications, virtually involving the entire cell proteome, that affect the fate of a target protein and, in turn, cell activity. Different classes of modifications can be established ranging from phosphorylation, glycosylation, ubiquitination, acetylation, methylation, lipidation and their inverse reactions. Among these, SUMOylation and NEDDylation are ubiquitin-like multi-enzymatic processes that determine the bound of SUMOs and NEDD8 labels, respectively, on defined amino acidic residues of a specific protein and regulate protein function. As fate-determinants of several effectors and mediators, SUMOylation and NEDDylation play relevant roles in many aspects of tumor cell biology. Bone represents a preferential site of metastasis for solid tumors (e.g., breast and prostate cancers) and the primary site of primitive tumors (e.g., osteosarcoma, chondrosarcoma). Deregulation of SUMOylation and NEDDylation affects different aspects of neoplastic transformation and evolution such as epithelial-mesenchymal transition, adaptation to hypoxia, expression and action of tumor suppressors and oncogenic mediators, and drug resistance. Thereby, they represent potential therapeutic targets. This narrative review aims at describing the involvement and regulation of SUMOylation and NEDDylation in tumor biology, with a specific focus on primary and secondary bone tumors, and to summarize and highlight their potentiality in diagnostics and therapeutic strategies.
PubMed: 35465332
DOI: 10.3389/fcell.2022.889002 -
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 -
EFORT Open Reviews Feb 2020Chondrosarcomas in children and adolescents are uncommon and constitute < 5% of all chondrosarcomas. There are very few studies discussing extremity chondrosarcomas in...
Chondrosarcomas in children and adolescents are uncommon and constitute < 5% of all chondrosarcomas. There are very few studies discussing extremity chondrosarcomas in young patients.The pelvis is the most common site, followed by the proximal femur.As cartilaginous tumours can be quite challenging to diagnose, it is best for these lesions to be discussed in a multidisciplinary meeting which includes a radiologist and a pathologist specializing in bone tumours.Treatment principles are similar to those in adults, with adequate surgical excision respecting oncologic principles being the mainstay of treatment. Select extremity Grade I chondrosarcomas may be managed with extended intralesional curettage without increasing the risk for local recurrence or metastatic disease, but case selection is critical and should be based on clinical, imaging and histological characteristics.Chondrosarcomas are resistant to chemotherapy and relatively radioresistant. For mesenchymal chondrosarcomas, there may be a role for chemotherapy, though data on this is limited.Prognosis and rate of recurrence correlate directly to the adequacy of the surgical resection.Chondrosarcomas in younger patients behave in a similar fashion to those in adults, and outcomes in the young are no different from those in adults. Cite this article: 2020;5:90-95. DOI: 10.1302/2058-5241.5.190052.
PubMed: 32175095
DOI: 10.1302/2058-5241.5.190052 -
Annals of Palliative Medicine Nov 2021Intracranial mesenchymal chondrosarcoma (IMC) is a rare primary malignant tumor in the skull, but mostly originates from the abnormal residual chondrocytes in the... (Review)
Review
Intracranial mesenchymal chondrosarcoma (IMC) is a rare primary malignant tumor in the skull, but mostly originates from the abnormal residual chondrocytes in the embryonic period, which grow slowly, and primarily occurs at the junction of the cartilage of the skull base. IMC is difficult to diagnose by preoperative imaging and is easily misdiagnosed. It needs to be differentiated from meningiomas, gliomas, hemangioma, fibroids, etc.; this article introduces a case of primary IMC in a 38-year-old female teacher, and reviews the literature on the diagnosis and treatment of symptoms. The patient suffered from persistent severe headaches without nausea and vomiting. There was no obvious abnormality in the physical examination. Magnetic resonance imaging (MRI) of the head showed a circular space-occupying lesion on the right frontal bone and forehead; the mass was approximately 5.9 cm × 5.2 cm × 5.5 cm, and there was a large edema band surrounding it. The space-occupying effect was obvious; bilateral ventricles were compressed, and on the right side, the midline structure was shifted to the left. The patient was initially diagnosed with simple meningioma. After admission, the right frontal lobe meningioma was resected under general anesthesia, and the tumor tissue was completely removed in blocks. The postoperative pathology report stated: malignant tumor of the right frontal lobe; consider mesenchymal chondrosarcoma. Following a difficult pathological consultation at the Provincial Medical Association, the tumor was found to be consistent with mesenchymal chondrosarcoma. Intracranial chondrosarcoma is a very rare malignant tumor. Other intracranial masses, such as meningioma and glioma, should be distinguished through differential diagnosis. At present, more attention is paid to surgical intervention and combined radiotherapy and chemotherapy for the treatment of IMC, which should also be the future treatment option.
Topics: Adult; Bone Neoplasms; Chondrosarcoma; Chondrosarcoma, Mesenchymal; Female; Humans; Magnetic Resonance Imaging; Skull
PubMed: 34872324
DOI: 10.21037/apm-21-2290 -
Acta Cytologica 2022Small round cell sarcomas (SRCSs) account for most solid malignancies in the pediatric age group and are a part of group of malignant tumors characterized by... (Review)
Review
BACKGROUND
Small round cell sarcomas (SRCSs) account for most solid malignancies in the pediatric age group and are a part of group of malignant tumors characterized by heterogenous clinical presentation and overlapping microscopic features of small, round, primitive cells. In addition to the recently established certain genetically defined subset of undifferentiated round cell sarcomas of soft tissue and bone, this group of sarcomas include desmoplastic small round cell tumor, poorly differentiated synovial sarcoma, alveolar rhabdomyosarcoma, mesenchymal chondrosarcoma, and small cell osteosarcoma. Although, those entities share clinical and cytomorphologic features and cannot be unequivocally classified based on clinical presentation and morphology alone. Most of SRCSs characterizes of particular patterns of protein expression or genetic changes and ancillary tests remain necessary to confirm or rule out a specific diagnosis. Subtle but occasionally distinctive cytologic features narrows the number of differential diagnoses and helps to select appropriate ancillary tests necessary for the final diagnosis. Thus, when adequate fine needle aspiration (FNA) biopsy specimen is combined with ancillary tests, a specific histologic diagnosis can be made in almost all cases. However, due to complex cytologic features of SRCS as well as various quality and diversity of FNA smears, there are cases in that cytologic features which do not entirely match the known diagnostic criteria.
SUMMARY
The aim of this review was to summarize cytomorphologic criteria and to present rare and divergent cytological features of SRCSs. Careful assessment of clinical presentation, cytological features, immunohistochemical patterns, and molecular alternations is necessary for an accurate diagnosis. Knowing of rare and divergent microscopic findings that does not fit with the known cytological criteria will help to avoid misdiagnosis.
KEY MESSAGES
The role of FNA biopsies diagnosing soft tissue and bone tumors has been increasing because of the ability of ancillary tests to assist in the diagnosis of specific tumors. SRCSs may be diagnosed accurately in cytology specimens. Access to clinical and radiographic presentation, utility of ancillary tests, understanding complexity of cytological features, and awareness of the rare cytologic findings that differ from that of the established diagnostic criteria are essential to make correct diagnosis.
Topics: Biopsy, Fine-Needle; Bone Neoplasms; Child; Diagnosis, Differential; Humans; Sarcoma; Soft Tissue Neoplasms
PubMed: 35417916
DOI: 10.1159/000524260 -
Journal of Cancer Research and... Apr 2024Bone sarcomas encompass a group of spontaneous mesenchymal malignancies, among which osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma are the most common... (Review)
Review
Bone sarcomas encompass a group of spontaneous mesenchymal malignancies, among which osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma are the most common subtypes. Chondrosarcoma, a relatively prevalent malignant bone tumor that originates from chondrocytes, is characterized by endogenous cartilage ossification within the tumor tissue. Despite the use of aggressive treatment approaches involving extensive surgical resection, chemotherapy, and radiotherapy for patients with osteosarcoma, chondrosarcoma, and chordoma, limited improvements in patient outcomes have been observed. Furthermore, resistance to chemotherapy and radiation therapy has been observed in chondrosarcoma and chordoma cases. Consequently, novel therapeutic approaches for bone sarcomas, including chondrosarcoma, need to be uncovered. Recently, the emergence of immunotherapy and immune checkpoint inhibitors has garnered attention given their clinical success in various diverse types of cancer, thereby prompting investigations into their potential for managing chondrosarcoma. Considering that circumvention of immune surveillance is considered a key factor in the malignant progression of tumors and that immune checkpoints play an important role in modulating antitumor immune effects, blockers or inhibitors targeting these immune checkpoints have become effective therapeutic tools for patients with tumors. One such checkpoint receptor implicated in this process is programmed cell death protein-1 (PD-1). The association between PD-1 and programmed cell death ligand-1 (PD-L1) and cancer progression in humans has been extensively studied, highlighting their remarkable potential as biomarkers for cancer treatment. This review comprehensively examines available studies on current chondrosarcoma treatments and advancements in anti-PD-1/PD-L1 blockade therapy for chondrosarcoma.
Topics: Humans; Chondrosarcoma; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Bone Neoplasms; Immune Checkpoint Inhibitors; Immunotherapy
PubMed: 38687921
DOI: 10.4103/jcrt.jcrt_2269_23 -
European Journal of Radiology Apr 2021Chondrosarcoma is a malignant cartilage matrix-producing tumour. Those arising de novo are called primary chondrosarcomas and are the second commonest primary malignant... (Review)
Review
Chondrosarcoma is a malignant cartilage matrix-producing tumour. Those arising de novo are called primary chondrosarcomas and are the second commonest primary malignant bone tumours. Numerous types of primary chondrosarcoma exist, namely conventional central (intramedullary), periosteal (juxta-cortical), clear cell, mesenchymal, and dedifferentiated. The biologic aggressiveness, prognosis and thus management of chondrosarcoma are dependent on the histological sub-type and grade. Accurate pre-operative diagnosis is therefore essential in determining management and outcome which requires a multidisciplinary approach taking into account clinical features, imaging findings and histopathology. In this review, we present the pertinent multimodality imaging features which aid in the differentiation of low-grade and high-grade conventional central chondrosarcoma.
Topics: Bone Neoplasms; Bone and Bones; Chondrosarcoma; Diagnostic Imaging; Humans; Prognosis
PubMed: 33578088
DOI: 10.1016/j.ejrad.2021.109579 -
Journal of Surgical Case Reports Jun 2022Chondrosarcoma is a highly aggressive malignant tumor originating from cartilaginous and mesenchymal tissues. The aim of this report is to describe a rare case of...
Chondrosarcoma is a highly aggressive malignant tumor originating from cartilaginous and mesenchymal tissues. The aim of this report is to describe a rare case of nasosinusal chondrosarcoma with orbito-cerebral extension. Our patient was a 55-year-old with a right cheek swelling evolving over a year, with unilateral right nasal obstruction gradually becoming bilateral associated with hyposmia, bilateral exophthalmos, reduced bilateral deep visual acuity and permanent headaches. The clinical examination found a tumor obstructing the two nasal cavities. Imaging showed a lobulated heterogeneous tissue process occupying the paranasal sinuses, with calcifications and enhancement at its periphery, extending to the orbito-cerebral area. The histopathological analysis was in favor of chondrosarcoma. The patient was first treated with an incomplete surgical resection by an endonasal route due to the extension to the orbit and the brain and received adjuvant radiotherapy. Surgical excision is a prognostic factor in this type of sarcomas and reduces recurrence rates.
PubMed: 35755017
DOI: 10.1093/jscr/rjac286