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oxygen sensing and angiogenesis in the tumor microenvironment - Coggle…

- - - - targeting hypoxia and angiogenesis in cancer
        
        disrupting the positive feed-forward loop between pathological angiogenesis, hypoxia and HIFa
        
        strategy
        
        blockade of HIF-1a and/or HIF2a
        
        HIF1: digoxin, PX-478
        
        HIF2a: belzutifam
        
        chemotherapy
        
        low dose metronomic
        
        antiangiogenic agents have been shown to be effective and well-tolerated when administered as LDM therapies in pre-clinical cancer models
        
        LDM chemotherapy on based on splitting chemotherapeutic agents into small, frequent doses , thus limiting cell killing with a favorable safety profile
        
        LDM decreases hypoxia, angiogenesis and metastasis in pre-clinical models of breast cancer
        
        maximum tolerated dose
        
        MTD chemotherapy is based on applying max dose possible causing significant adverse effects and massive cancer cell killing, associated with necrosis, increased hypoxia and further emergence of therapy resistance leading to recurrence and metastasis
      - hypoxia in tumor cells
        
        a trigger to escape dormancy
        
        low O2 activates a molecular angiogenic switch repaired for metastasis
        
        oxygen sensing pathways promoting angiogenesis in cancer cells
        
        HIF activation
        
        hypoxia response
        
        angiogenic factor expression
        
        VEGF, PDGF, ANGPT2, EPO
        
        VEGF signaling
        
        2 more items...
        
        HIFa/b complex binds to HREs
      - cancer cells hijack angiogenesis in the absence of inflammation
        
        implanting cancer cells in an avascular site trigger vessel sprouting, essential for tumor growth
      - oncogenes are pro-angiogenic
        
        c-MYC
        
        Angiogenic properties in epidermis
        
        EGFR
        
        VEGF, bFGF, IL-8 upregulation
        
        SRC
        
        VEGF upregulation, TSP1 downregulation
        
        ODC
        
        Novel angiogenic factor
        
        KRAS, HRAS
        
        VEGF upregulation, TSP1 downregulation
      - angiogenesis leads to immature, structurally unsound vessels in cancer
      - tumor microenvironment composition is reinforced by angiogenesis
        
        excessive tumoral angiogenesis can promote, rather than alleviate hypoxia
        
        :arrow_down: oxygen, :arrow_up_down: nutrients and cytokines :arrow_down: pH :arrow_up: carbon dioxide
      - angiogenic vessels provide an exit route for cancer cells
    - - development of ovarian follicles
      - corpus luteum formation
      - endometrial proliferation
      - embryo implantation
      - embryogenesis
      - successful wound healing
    - - goal: stimulation
        
        limb ischemia
        
        wound healing
        
        cerebral ischemia
        
        reconstructive surgery
        
        myocardial ischemia
        
        ulcer healing
      - goal: inhibition
        
        Ocular neovascularisation
        
        endometriosis
        
        athlerosclerosis
        
        rheumatoid arthritis
        
        tumor growth and dissemination
        
        metastasis
        
        Kaposi's sarcoma
        
        psoriasis
        
        hemangiomas