In turn, VEGFR-3, also known as Flt-4, is located on lymphendothelial cells,
inducing proliferation and survival [98–100].
3.1 VEGF and Angiogenesis
Tumor growth and metastatic dissemination demand previous formation of new
blood vessels from an existing vascular network, in a process known as angiogenesis. As a consequence of neovascularization, solid tumor cells receive the oxygen
and nutrients necessary for their survival and growth and also become able to
migrate through blood circulation, establishing distant metastases [101, 102].
Under physiologic conditions, especially during the female reproductive cycle
and wound healing, a fine balance between pro-angiogenic and antiangiogenic
factors takes place. On the other hand, pathological angiogenesis can be found in
several diseases, such as rheumatoid arthritis, age-related macular degeneration,
proliferative diabetic retinopathy, atherosclerosis, and postischemic vascularization
of the myocardium. Mainly in solid tumors, the dynamic balance between pro- and
antiangiogenic factors is disrupted, with a clear overexpression of pro-angiogenic
mediators, providing an ideal condition for neovascularization and tumor metastasis.
Therefore, the inhibition of angiogenesis is well-established as a promising strategy
in the development of novel antitumor drugs [103–105].
Fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs),
tumor necrosis factor alpha (TNF-α), angiogenin, cyclooxygenase-2 (COX-2),
interleukin-8 (IL-8), neptine, and vascular endothelial growth factors (VEGFs) are
known positive modulators of angiogenesis. Among them, VEGFs are highlighted
as the most important, being implicated in physiologic and pathological angiogenesis [104, 106]. VEGF expression and release are regulated by environmental
factors, such as hypoxia and pH; by other growth factors, such as PDGF, TNF-α,
transforming growth factor-β, and insulin-like growth factor-1, among others; by
cytokines, such as IL-6 and IL-1; and by hormones, such as estrogen. VEGF
overexpression has been associated with poor prognosis and progression of several
tumor types, e.g., renal cell carcinoma; colorectal, gastric, and pancreatic carcinomas; breast, prostate, and lung cancers; and melanoma [104, 107].
The VEGFs family comprises six structurally related proteins: VEGF-A, VEGFB, VEGF-C, VEGF-D, VEGF-E, and the placental growth factor (PlGF). VEGF-A,
usually mentioned only as VEGF, is the most important growth factor among this
family and represents the most potent pro-angiogenic endothelial chemoattractant
released by cancer cells [108], mediating this effect mainly by VEGFR-2
activation [97].
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inducing proliferation and survival [98–100].
3.1 VEGF and Angiogenesis
Tumor growth and metastatic dissemination demand previous formation of new
blood vessels from an existing vascular network, in a process known as angiogenesis. As a consequence of neovascularization, solid tumor cells receive the oxygen
and nutrients necessary for their survival and growth and also become able to
migrate through blood circulation, establishing distant metastases [101, 102].
Under physiologic conditions, especially during the female reproductive cycle
and wound healing, a fine balance between pro-angiogenic and antiangiogenic
factors takes place. On the other hand, pathological angiogenesis can be found in
several diseases, such as rheumatoid arthritis, age-related macular degeneration,
proliferative diabetic retinopathy, atherosclerosis, and postischemic vascularization
of the myocardium. Mainly in solid tumors, the dynamic balance between pro- and
antiangiogenic factors is disrupted, with a clear overexpression of pro-angiogenic
mediators, providing an ideal condition for neovascularization and tumor metastasis.
Therefore, the inhibition of angiogenesis is well-established as a promising strategy
in the development of novel antitumor drugs [103–105].
Fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs),
tumor necrosis factor alpha (TNF-α), angiogenin, cyclooxygenase-2 (COX-2),
interleukin-8 (IL-8), neptine, and vascular endothelial growth factors (VEGFs) are
known positive modulators of angiogenesis. Among them, VEGFs are highlighted
as the most important, being implicated in physiologic and pathological angiogenesis [104, 106]. VEGF expression and release are regulated by environmental
factors, such as hypoxia and pH; by other growth factors, such as PDGF, TNF-α,
transforming growth factor-β, and insulin-like growth factor-1, among others; by
cytokines, such as IL-6 and IL-1; and by hormones, such as estrogen. VEGF
overexpression has been associated with poor prognosis and progression of several
tumor types, e.g., renal cell carcinoma; colorectal, gastric, and pancreatic carcinomas; breast, prostate, and lung cancers; and melanoma [104, 107].
The VEGFs family comprises six structurally related proteins: VEGF-A, VEGFB, VEGF-C, VEGF-D, VEGF-E, and the placental growth factor (PlGF). VEGF-A,
usually mentioned only as VEGF, is the most important growth factor among this
family and represents the most potent pro-angiogenic endothelial chemoattractant
released by cancer cells [108], mediating this effect mainly by VEGFR-2
activation [97].
172
L. M. Lima et al.