THE ROLE OF VEGF FAMILY IN ANGIOGENESIS, TUMOR GROWTH AND METASTASIS
2014
Tumor growth is dependent on angiogenesis, and cells in tumor tissues produce various angiogenic factors to induce neovascularization. Among tumor-derived angiogenic factors,
members of the vascular endothelial growth factor (VEGF) family are most frequently and
highly expressed in various solid tumors. VEGF-A, the prototype of VEGF, is the most
powerful pro-angiogenic factor that binds to VEGF receptor-1 (VEGFR-1, also called FMSRelated
Tyrosine Kinase-1/Flt-1) and VEGFR-2 (also called Kinase Insert Domain
Receptor/KDR or Fetal Liver Kinase -1/Flk-1). While the VEGFR-2-transduced angiogenic
signals, pathways, and functions are well characterized, the VEGFR-1-mediated functions are
poorly understood. The angiogenic functions of placental growth factor (PlGF), which is a
specific VEGFR-1-binding ligand, remain controversial. The role of VEGF-B in tumor
angiogenesis is still unclear. In addition, the two other VEGF family members, VEGF-C and
VEGF-D are the major lymphangiogenic factors that contribute to lymphatic metastasis.
The work contained in this thesis aimed to study the role of VEGF family members in
angiogenesis, tumor growth and metastasis. Our work shows that PlGF exhibits a duality in
modulation of angiogenesis and tumor growth in a VEGF-A-dependent manner. This is noted
when the tumor cell-derived PlGF sensitizes the tumor to the anti-angiogenic and anti-tumor
effects of anti-VEGF drugs. We also noted that anti-VEGF treatment induces various
vascular alterations in mouse healthy tissues. Additionally, we revealed the collaborative
interaction between FGF-2 and VEGF-C in promotion of lymphangiogenesis and metastasis.
In paper I, using two independent tumor models, we show that PlGF modulated tumor growth,
angiogenesis, and vascular remodeling through a VEGF-dependent mechanism in either a
positive or a negative manner. In the VEGF-A positive model, PlGF inhibited tumor growth
and angiogenesis, leading to normalized tumor vasculature with dilated vessel lumens,
infrequent vascular branches and increased perivascular cell coverage. Surprisingly, in the
VEGF-A negative model, overexpression of PlGF resulted in the opposite phenotype to that
seen in the VEGF-A positive model, namely accelerated tumor growth rates and abundant
chaotic tumor vessels. Our data uncovered the molecular mechanisms underlying the
complex interplay between PlGF and VEGF-A. These findings have conceptual implications
for anti-angiogenic cancer therapy.
In paper II, we show that tumors from humans and mice with high levels of expression of
PlGF were hypersensitive to anti-VEGF-A and anti-VEGFR-2 therapies. We then validated
this finding with a loss-of-function experiment using PLGF shRNA in a human
choriocarcinoma cell line. Down-regulation of PlGF significantly accelerated tumor growth
rate and led to resistance to anti-VEGF drugs. We also show that VEGFR-2 and VEGFR-1
neutralizing antibodies displayed opposing effects on tumor growth and angiogenesis. These
findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and
sensitizes treatment effect of anti-VEGF drugs in VEGF-A positive tumors, PlGF level in
VEGF-A positive tumor may potentially be a predictive marker of anti-VEGF cancer therapy.
In paper III, we investigated vascular alteration in various organs after systemic treatment
with anti-VEGF-A, anti-VEGFR-1 and anti-VEGFR-2 neutralizing antibodies. This study
provides functional and structural mechanisms for anti-VEGF drug-induced adverse effects in
patients.
In paper IV, we looked into the role of fibroblast growth factor-2 (FGF-2) and VEGF-C on
angiogenesis, lymphangiogenesis and tumor metastasis. The results showed that FGF-2 and
VEGF-C could both separately and collaboratively promote angiogenesis and
lymphangiogenesis in the cornea of the mouse and in the mouse tumor tissue, resulting in
pulmonary and lymph node metastases in animal models. By blocking VEGFR-3 and FGF
receptor-1 (FGFR-1), we also revealed the fact that VEGFR-3-induced lymphatic endothelial
cell (LEC) tip formation is a necessity for FGF-2-FGFR-1 signaling stimulated
lymphangiogenesis. This study suggests that combined targeting of FGF-2 and VEGF-C
might be an effective approach for cancer therapy and prevention of metastasis.
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