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].