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Figure 3. Angiogenesis and osteosarcoma microenvironment. (A) Mesenchymal stem cells (MSCs) produce IL-6 and STAT3 pathway activation promoting cisplatin and DOX resistance. (B) Macrophages promotes angiogenesis by VEGFA production in osteosarcoma. (C) VEGFA ligand binds to VEGFR activating angiogenesis pathway, throw PI3K/AKT/mTOR or Ras. Some anti-angiogenesis tyrosine kinase inhibitors alone or in combination with mTOR inhibitors are approved in second line in osteosarcoma. (D) Integrin pathway actives SRC and FAK promoting angiogenesis and apoptosis inhibition. (E) Chemokine (C-C motif) ligand 3 (CCL3) binding to G-protein coupled C-C chemokine receptor 5(CCR5) promoting VEGFA expression by downregulation of miR-374b, activation of JNK/ERK/p38 and hypoxia-inducible factor (HIF) in human osteosarcoma cells. (F) The canonical Wnt/β- catenin pathway contributes to chemotherapy resistance and osteosarcoma progression. WNT actives the Frizzled (FZD) and low-density lipoprotein receptor 5/6 (LRP5/6) binding disheveled (DVL) and Axin protein complex release of β-catenin and lead the translocation of β-catenin to the nucleus to activates genes active in chemoresistance. (G) Endostatin inhibit the activity of integrin, VEGFR and WNT pathways. AKT: Protein kinase B; CCD1: CyclinD1; DOX: doxorubicin; DNA-PK: DNA-dependent protein kinase, ERK: extracellular signal-regulated kinase; FAK: focal adhesion kinase; gp130: glycoprotein 130; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; IL-: interleukine-6; IL-6R: IL-6 receptor; JAK: Janus Kinase; JNK: JUN N-terminal kinase; MARK2: microtubule affinity-regulating kinase 2; MYC: myc proto-oncogene; NF-κB: nuclear factor-κB; SRC: SRC protein kinase; STAT3: signal transducer and activator of transcription 3; VEGF: vascular epidermal growth factor; VEGFR: vascular epidermal growth factor receptor.