A calpain-6/YAP axis in sarcoma stem cells that drives the outgrowth of tumors and metastases.

Sarcomas include cancer stem cells, but how these cells contribute to local and metastatic relapse is largely unknown. We previously showed the pro-tumor functions of calpain-6 in sarcoma stem cells. Here, we use an osteosarcoma cell model, osteosarcoma tissues and transcriptomic data from human tumors to study gene patterns associated with calpain-6 expression or suppression.

Metastatic Progression of Osteosarcomas: A Review of Current Knowledge of Environmental versus Oncogenic Drivers.

Metastases of osteosarcomas are heterogeneous. They may grow simultaneously with the primary tumor, during treatment or shortly after, or a long time after the end of the treatment. They occur mainly in lungs but also in bone and various soft tissues.

Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence.

Sarcomas are still unsolved therapeutic challenges. Cancer stem cells are believed to contribute to sarcoma development, but lack of specific markers prevents their characterization and targeting. Here, we show that calpain-6 expression is associated with cancer stem cell features.

Correction: Osteoblastic heparan sulfate glycosaminoglycans control bone remodeling by regulating Wnt signaling and the crosstalk between bone surface and marrow cells.

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Osteoblastic heparan sulfate glycosaminoglycans control bone remodeling by regulating Wnt signaling and the crosstalk between bone surface and marrow cells.

Stimulating bone formation is an important challenge for bone anabolism in osteoporotic patients or to repair bone defects. The osteogenic properties of matrix glycosaminoglycans (GAGs) have been explored; however, the functions of GAGs at the surface of bone-forming cells are less documented. Syndecan-2 is a membrane heparan sulfate proteoglycan that is associated with osteoblastic differentiation.

Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice.

Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1α (HIF1α) is a crucial hypoxic factor for chondrocyte growth and survival during development. The major metalloproteinase matrix metalloproteinase 13 (MMP13) is also associated with chondrocyte hypertrophy in adult articular cartilage, the lack of which protects from cartilage degradation and osteoarthritis (OA) in mice.

Increased NF-κB Activity and Decreased Wnt/β-Catenin Signaling Mediate Reduced Osteoblast Differentiation and Function in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mice.

The prevalent human ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with reduced bone formation and bone loss in mice. The molecular mechanisms by which the ΔF508-CFTR mutation causes alterations in bone formation are poorly known. In this study, we analyzed the osteoblast phenotype in ΔF508-CFTR mice and characterized the signaling mechanisms underlying this phenotype.

Role of syndecan-2 in osteoblast biology and pathology.

Syndecans 1-4 are a family of transmembrane proteins composed of a core protein and glycosaminoglycan chains. Although the four syndecans have common functions, they appear to be connected to different signaling pathways, and their expression occurs in a cell- and development-specific pattern. In contrast to other syndecans, syndecan-2 expression increases during osteoblast differentiation.

Cadherin-mediated cell-cell adhesion and signaling in the skeleton.

Direct cell-to-cell interactions via cell adhesion molecules, in particular cadherins, are critical for morphogenesis, tissue architecture, and cell sorting and differentiation. Partially overlapping, yet distinct roles of N-cadherin (cadherin-2) and cadherin-11 in the skeletal system have emerged from mouse genetics and in vitro studies. Both cadherins are important for precursor commitment to the osteogenic lineage, and genetic ablation of Cdh2 and Cdh11 results in skeletal growth defects and impaired bone formation.

Targeting the E3 ubiquitin casitas B-lineage lymphoma decreases osteosarcoma cell growth and survival and reduces tumorigenesis.

Targeting receptor tyrosine kinase (RTK) degradation may be an interesting approach to reduce RTK cell signaling in cancer cells. Here we show that increasing E3 ubiquitin ligase casitas B-lineage lymphoma (c-Cbl) expression using lentiviral infection decreased osteosarcoma cell replication and survival and reduced cell migration and invasion in murine and human osteosarcoma cells. Conversely, c-Cbl inhibition using short hairpin RNA (shRNA) increased osteosarcoma cell growth and survival, as well as invasion and migration, indicating that c-Cbl plays a critical role as a bone tumor suppressor.

Targeted inhibition of T-cell factor activity promotes syndecan-2 expression and sensitization to doxorubicin in osteosarcoma cells and bone tumors in mice.

Alterations of Wnt signaling appear to be involved in the pathogenesis of osteosarcoma, presenting mutations of adenomatous polyposis coli (APC) and epigenetic downregulation of Wnt inhibitory factor 1. However, the precise role of Wnt effectors in the bone cancer progression remains unclear. We previously showed that Wnt/β-catenin/T-cell factor (TCF) activation are responsible for the repression of syndecan-2, a key modulator of apoptosis and chemosensitivity in osteosarcoma cells, suggesting a role of Wnt signaling in chemoresistance.

Calpain-6 is an endothelin-1 signaling dependent protective factor in chemoresistant osteosarcoma.

Bone tumors strongly influence normal tissues and stimulate bone cells for the production of cytokines supporting proliferation and abnormal survival in cancer cells. We previously reported that the proteoglycan syndecan-2 controls the activity of various cytokines and growth factors and also modulates apoptosis and response to cytotoxic agents in osteosarcoma cell lines. Here, we show that syndecan-2 has a stronger tumor suppressor activity in vivo.

High Wnt signaling represses the proapoptotic proteoglycan syndecan-2 in osteosarcoma cells.

Osteosarcoma is characterized by frequent relapse and metastatic disease associated with resistance to chemotherapy. We previously showed that syndecan-2 is a mediator of the antioncogenic effect of chemotherapeutic drugs. The purpose of this work was to elucidate molecular mechanisms responsible for the low expression of syndecan-2 in osteosarcoma.

Syndecan-2 affects the basal and chemotherapy-induced apoptosis in osteosarcoma.

Syndecans are transmembrane heparan sulfate proteoglycans controlling cell adhesion, migration, and proliferation. We previously showed that syndecan-2 is involved in the control of apoptosis in cultured osteosarcoma cells. These data led us to the hypothesis that syndecan-2 may play a role in the apoptotic signaling in bone tumors.

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation.

Osteosarcoma is the most common primary bone tumour in young adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of osteosarcoma treatment. The identification of signals that promote apoptosis may provide clues to develop new therapeutic strategies for chemoresistant osteosarcoma.

Dual involvement of protein kinase C delta in apoptosis induced by syndecan-2 in osteoblasts.

Syndecans are proteoglycans that act as signaling molecules. Previously, we showed that syndecan-2 (SYND2) is involved in the control of osteoblastic (OB) cell apoptosis. Here, we show a novel functional interaction between SYND2 and protein kinase C delta (PKCdelta).

Syndecan-2 overexpression induces osteosarcoma cell apoptosis: Implication of syndecan-2 cytoplasmic domain and JNK signaling.

Syndecans are cell surface heparan sulfate proteoglycans that serve as co-receptors and modulate the actions of a number of extracellular ligands. Syndecans thereby regulate cell adhesion, proliferation, and differentiation. Studies in cancer cells suggest that syndecans may also modulate cell viability.

Apoptosis in membranous bone formation: role of fibroblast growth factor and bone morphogenetic protein signaling.

Membranous ossification occurs by the condensation of mesenchymal cells followed by their progressive differentiation into osteoblasts that form a mineralized matrix in ossification centers. The balance between proliferating and differentiated osteogenic cells at the suture areas between calvarial bones is essential for the control of suture maintenance and membranous bone formation. The mechanisms of regulation of na apoptosis in suture areas begin to be understood.

Transforming growth factor-beta inhibits CCAAT/enhancer-binding protein expression and PPARgamma activity in unloaded bone marrow stromal cells.

The molecular mechanisms regulating the adipogenic differentiation of bone marrow stromal cells in vivo remain largely unknown. In this study, we investigated the regulatory effects of transforming growth factor beta-2 (TGF-beta2) on transcription factors involved in adipogenic differentiation induced by hind limb suspension in rat bone marrow stromal cells in vivo. Time course real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis of gene expression showed that skeletal unloading progressively increases the expression of CCAAT/enhancer-binding protein (C/EBP)alpha and C/EBPbeta alpha at 5 days in bone marrow stromal cells resulting in increased peroxisome proliferator-activated receptor gamma (PPARgamma2) transcripts at 7 days.

Growth factors and bone formation in osteoporosis: roles for fibroblast growth factor and transforming growth factor beta.

Osteoporosis is characterised by excess bone fragility resulting from bone loss and altered bone microarchitecture. Bone loss occurring during aging and after menopause in women is known to result from an imbalance between bone formation and resorption. Bone formation is dependent on the commitment of osteoprogenitor cells, the proliferation of pre-osteoblasts, their differentiation into mature osteoblasts synthesising bone matrix and the life-span of mature osteoblasts.

Protein kinase C-dependent upregulation of N-cadherin expression by phorbol ester in human calvaria osteoblasts.

Cell-cell adhesion mediated by cadherins is believed to play an essential role in the control of cell differentiation and tissue formation. Our recent studies indicate that N-cadherin is involved in human osteoblast differentiation. However, the signalling molecules that regulate cadherins in osteoblasts are not known.

Role of N-cadherin and protein kinase C in osteoblast gene activation induced by the S252W fibroblast growth factor receptor 2 mutation in Apert craniosynostosis.

Apert (Ap) syndrome is characterized by premature cranial suture ossification caused by fibroblast growth factor receptor 2 (FGFR-2) mutations. We studied the role of cadherins and signaling events in the phenotypic alterations induced by the Ap FGFR-2 S252W mutation in mutant immortalized fetal human calvaria osteoblasts. The FGFR-2 mutation caused increased expression of the osteoblast markers alkaline phosphatase (ALP), type 1 collagen (COLIA1), and osteocalcin (OC) in long-term culture.

Increased osteoblast apoptosis in apert craniosynostosis: role of protein kinase C and interleukin-1.

Apert syndrome is an autosomal dominant disorder characterized by premature cranial ossification resulting from fibroblast growth factor receptor-2 (FGFR-2)-activating mutations. We have studied the effects of the prominent S252W FGFR-2 Apert mutation on apoptosis and the underlying mechanisms in human mutant osteoblasts. In vivo analysis of terminal deoxynucleotidyl transferase-mediated nick-end labeling revealed premature apoptosis of mature osteoblasts and osteocytes in the Apert suture compared to normal coronal suture.

The Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation induces PKC-independent downregulation of FGFR-2 associated with premature calvaria osteoblast differentiation.

We recently showed that the Apert Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation causes premature osteoblast differentiation and increased subperiosteal calvaria bone matrix formation. To gain further insight into the cellular mechanisms involved in these effects, we examined the effects of the mutation on the expression of FGFRs in relation to cell proliferation and differentiation markers in vivo and in vitro, and we analyzed the underlying signaling pathways in mutant cells. Immunohistochemical analysis of the Apert calvaria suture showed that the Ser252Trp FGFR-2 mutation increased type 1 collagen, osteocalcin, and osteopontin expression in preosteoblasts compared to normal, whereas cell growth was not affected.