Dataset Information

Autotaxin-β interaction with the cell surface via syndecan-4 impacts on cancer cell proliferation and metastasis.

ABSTRACT: Autotaxin (ATX) promotes cancer cell metastasis through the production of lysophosphatidic acid (LPA). ATX binds to αvβ3 integrins controlling metastasis of breast cancer cells. We screened a series of cancer cell lines derived from diverse human and mouse solid tumors for the capacity of binding to ATX and found only a modest correlation with their level of αvβ3 integrin expression. These results strongly suggested the existence of another cell surface ATX-interacting factor. Indeed, ATXα has been shown to bind heparan-sulfate chains because of its unique polybasic insertion sequence, although the biological significance is unknown. We demonstrated here, that among all cell surface heparan-sulfate proteoglycans, syndecan-4 (SDC4) was essential for cancer cell interaction with ATXβ but was restrained by heparan-sulfate chains. In addition, exogenous ATXβ-induced MG63 osteosarcoma cell proliferation required physical interaction of ATXβ with the cell surface via an SDC4-dependent mechanism. In a preclininal mouse model, targeting SDC4 on 4T1 mouse breast cancer cells inhibited early bone metastasis formation. Furthermore, SDC4-prometastatic activity was totally abolished in absence of ATX expression. In conclusion our results determined that ATX and SDC4 are engaged in a reciprocal collaboration for cancer cell metastasis providing the rational for the development of novel anti-metastasis therapies.

SUBMITTER: Leblanc R

PROVIDER: S-EPMC6145688 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Autotaxin-β interaction with the cell surface via syndecan-4 impacts on cancer cell proliferation and metastasis.

Leblanc Raphael R Sahay Debashish D Houssin Audrey A Machuca-Gayet Irma I Peyruchaud Olivier O

Oncotarget 20180904 69

Autotaxin (ATX) promotes cancer cell metastasis through the production of lysophosphatidic acid (LPA). ATX binds to αvβ3 integrins controlling metastasis of breast cancer cells. We screened a series of cancer cell lines derived from diverse human and mouse solid tumors for the capacity of binding to ATX and found only a modest correlation with their level of αvβ3 integrin expression. These results strongly suggested the existence of another cell surface ATX-interacting factor. Indeed, ATXα has b ...[more]

PMID: 30237860

Similar Datasets

Project description:Syndecans are transmembrane heparan sulphate proteoglycans. Their role in the development of the malignant phenotype is ambiguous and depends upon the particular type of cancer. Nevertheless, syndecans are promising targets in cancer therapy, and it is important to elucidate the mechanisms controlling their various cellular effects. According to earlier studies, both syndecan-1 and syndecan-2 promote malignancy of HT-1080 human fibrosarcoma cells, by increasing the proliferation rate and the metastatic potential and migratory ability, respectively. To better understand their tumour promoter role in this cell line, syndecan expression levels were modulated in HT-1080 cells and the growth rate, chemotaxis and invasion capacity were studied. For in vivo testing, syndecan-1 overexpressing cells were also inoculated into mice. Overexpression of full length or truncated syndecan-1 lacking the entire ectodomain but containing the four juxtamembrane amino acids promoted proliferation and chemotaxis. These effects were accompanied by a marked increase in syndecan-2 protein expression. The pro-migratory and pro-proliferative effects of truncated syndecan-1 were not observable when syndecan-2 was silenced. Antisense silencing of syndecan-2, but not that of syndecan-1, inhibited cell migration. In vivo, both full length and truncated syndecan-1 increased tumour growth and metastatic rate. Based on our in vitro results, we conclude that the tumour promoter role of syndecan-1 observed in HT-1080 cells is independent of its ectodomain; however, in vivo the presence of the ectodomain further increases tumour proliferation. The enhanced migratory ability induced by syndecan-1 overexpression is mediated by syndecan-2. Overexpression of syndecan-1 also leads to activation of IGF1R and increased expression of Ets-1. These changes were not evident when syndecan-2 was overexpressed. These findings suggest the involvement of IGF1R and Ets-1 in the induction of syndecan-2 synthesis and stimulation of proliferation by syndecan-1. This is the first report demonstrating that syndecan-1 enhances malignancy of a mesenchymal tumour cell line, via induction of syndecan-2 expression.

Project description:BackgroundOral squamous cell carcinoma (OSCC) is the most lethal oral malignant tumor, however, clinical outcomes remain unsatisfactory. The Hedgehog/Gli2 pathway plays a pivotal role in tumor progression, yet the regulatory mechanism governing its involvement in the malignant evolution process of OSCC remains elusive.MethodsOSCC animal tissue samples were used to detect the activation of the Hedgehog/Gli2 pathway in OSCC. Based on the clinical information of oral cancer patients in TCGA database, the role of this pathway in patients was analyzed, and the activation status of this pathway was verified in human OSCC cells. After activating or inhibiting the Hedgehog pathway, the effects of this pathway on the biological function of OSCC cells and its regulatory mechanism were examined. Interfering the expression of Gli2, a key transcription factor in this pathway, revealed the role of Hedgehog/Gli2 pathway in the malignant evolution of OSCC cells.ResultsThe Hedgehog pathway exhibits abnormal activation in animal models of OSCC. Clinical data from TCGA demonstrate a significant enrichment of the Hedgehog pathway in patients with OSCC, and Gli2, a key downstream factor of this pathway, is closely associated with the occurrence and progression of OSCC. Cellular studies have revealed aberrant activation of this pathway in human OSCC cells, which exerts its function by modulating the activation of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathways. Subsequent investigations further confirm the pivotal involvement of Gli2 in the Hedgehog pathway activation, underscoring its potential as a therapeutic target for inhibiting malignant proliferation and metastasis of OSCC cells through modulation of EMT and Wnt/β-catenin pathways.ConclusionThe Hedgehog/Gli2 pathway induces EMT and activates Wnt/β-catenin pathway to trigger the malignant proliferation and metastasis of OSCC cells, and Gli2 plays a key role in this process, which suggests that targeting Gli2 may be a promising therapeutic strategy for inhibiting the proliferation and metastasis of OSCC.

Dataset Information

Autotaxin-β interaction with the cell surface via syndecan-4 impacts on cancer cell proliferation and metastasis.

Publications

Autotaxin-β interaction with the cell surface via syndecan-4 impacts on cancer cell proliferation and metastasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets