Tumor vasculature
Tumor vasculature is another important component of the tumor microenvironment. Tumor vasculature arises from two different biological processes: angiogenesis consisting of the formation of new blood vessels from pre-existing vessels and vasculogenesis consisting of the formation of new blood vessels by recruitment of circulating endothelial progenitor cells[53]. Hypoxia inducible factors (HIFs) are one of the main signals regulating the process of angiogenesis which induce transcription of genes responsible for activation of angiogenesis[54]. Another important regulator is the vascular endothelial growth factor (VEGF) and its receptor (VEGFR), which can stimulate angiogenesis[55]. Tumor vasculature in EGFR mutant lung cancer is different from that in EGFR wild type lung cancer (Figure 1C). It was found that the vascular-poor area in lung adenocarcinoma with EGFR mutation is less than the tumor without EGFR mutation[56]. Another study found that tumors with mutations in exon 20 and 21 of EGFR exhibited a high level expression of VEGFR, while those with mutations in exon 19 of EGFR exhibited a low level expression of VEGFR[57]. For EGFR-TKIs resistant non-small cell lung cancer, heat shock protein 90 (Hsp90) inhibitors can overcome HGF-triggered resistance to EGFR-TKIs by reducing EGFR protein expression and tumor angiogenesis[58]. Another study found that Met activation by HGF stimulated the production of vascular endothelial growth factor (VEGF) and facilitated angiogenesis, which indicated that HGF induced EGFR-TKIs resistance and angiogenesis. Triple inhibition of EGFR, Met, and angiogenesis was useful for controlling the progression of EGFR-mutant lung cancer with HGF-triggered EGFR-TKIs resistance[59]. An in vivo and in vitro experiment on EGFR-TKIs combined with chemotherapy in the treatment of EGFR mutant lung cancer found that EGFR-TKIs combined with chemotherapy can inhibit tumor progression and angiogenesis by down regulating c-MYC and HIF-α pathways[60].