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.

Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface

“…Despite that, we could not demonstrate direct interaction between SDC4 and ATX. Our results strongly support the hypothesis that the physical interaction of ATXβ with adhesive molecules induces the functional changes in ATX required for LPA biological functions [67]. In addition to binding to the cell surface, Jethwa and colleagues have suggested that ATX can bind to the surface of cell-secreted exosomes [68].…”

Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

“…TPX2, DLGAP4, DSN1, RBL1, FAM83D, MYBL2, PABPC1L, UBE2C, CTSA, MMP9, SULF2, CSE1L, SALL4, ZNF217, PFDN4, AURKA, RAE1, and PMEPA1) associated with poor prognosis in many human cancer types 51 . Moreover, this region harboured genes encoding proteins with a whey-acidic-protein (WAP) motif including putative human cancer biomarkers SLPI, PI3, and WFDC2 51,53 , and several Cell Adhesion Molecules (CAMs), for instance, metastasis promoters CDH4 and SDC4 49,54,55 , Table 4. Several genes in A3 1-31 Mb significantly enriched pathways in cancer (Table 4) including the transcription factor E2F1 recently identified as a key regulator of a set of metastasis promoter genes in HBCs 56 .…”

Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis

“…At this time, ATX accumulated in the vicinity of blood vessels, which coincided with the major site of fibrosis. This is significant in ATX signaling because it is thought that the bulk levels of ATX are much less important than the specific binding of ATX to the cell surface through integrins and syndecan-4, which channels LPA signaling to its receptors [62][63][64]. DEX attenuated this perivascular accumulation of ATX, which is probably part of the mechanism for the observed decrease in fibrosis.…”