107
KSHV infection induces spindle cell morphology in endothelial cells, as evi-denced by extensive in vitro data and in vivo observations in the past two decades
[ 152 , 155 , 157 – 159 ]. These spindle cells harbor an incompletely transformed phe-
notype characterized by excessive proliferation [ 160 – 162 ] and loss of contact inhi-
bition [ 158 , 163 , 164 ], although they do not necessarily induce malignancy. This
differs dramatically from real cancers. Instead, KSHV-infected spindle cells may
promote the onset of KS, PEL, and MCD in the context of an appropriate environ-
ment. Over 95% of healthy people who are infected with KSHV have no symptoms
during their lifetime, whereas those who become immunosuppressed display severe
symptoms or even death, suggesting that the suppressed immune system is one of
the most important factors synergizing with KSHV to induce tumorigenesis.
Another essential element is inflammation, as KS lesions occur at sites of injury, to
which many inflammatory cells and cytokines are recruited [ 165 ]. As discussed
above, angiogenesis starts early during KS pathogenesis and persist throughout KS
progression, indicating the presence of a third key element. Therefore, immune
escape, inflammation, and angiogenesis act together to establish a permissive condi-
tion that allows KSHV to function as an oncogenic virus.
7.5.2 KSHV-Induced Angiogenesis and Lymphangiogenesis
The transportation system in the human body is supported by two tubular networks,
blood vessels and lymphatic vessels, which are interconnected but relatively inde-
pendent [ 166 ]. The vessels are formed by endothelial cells. KS is highly vascular-
ized. KSHV directly infects endothelial cells, which may facilitate the
neovascularization process. On the other hand, proangiogenic cytokines secreted by
KSHV-infected cells induce vessel formation in a paracrine manner.
The first key factor shown to induce angiogenesis in KS is basic fibroblast growthfactor (bFGF) [ 167 – 170 ], which is highly expressed in KS tissues. Since then,
increasing evidence supports that KSHV plays an essential role in altering the phe-
notype of infected cells. The tight junctions between endothelial cells are also dis-
rupted by KSHV through the degradation of VE-cadherin, which initiates
angiogenesis [ 171 , 172 ]. KSHV-infected endothelial cells form vascular tubes on
Matrigel, induce capillary morphogenesis in 3D cultures, and display an enhanced
invasive capability [ 148 , 173 – 176 ]. The vascular endothelial growth factor (VEGF)
family and related signaling pathways are required for angiogenesis, which can also
be usurped by KSHV for its own benefit.
Many KSHV-encoded proteins participate in these processes. KSHV LANA,which is encoded by ORF73, increases the proliferation and life span of primary
human umbilical vein endothelial cells (HUVEC) and maintains its ability to form
vessel-like structures in vitro [ 177 ]. LANA also interacts with Daxx and interferes
with the Daxx/Ets-1 complex, which antagonizes the inhibitory activity of Daxx on
VEGF receptor expression, thereby contributing to its high expression in infected
cells [ 178 ]. Another protein complex that is targeted by LANA is EZH2 via the
7 KSHV Epidemiology and Molecular Biology