106
7.5 KSHV-Related Pathogenesis
7.5.1 An Overview of KSHV-Related Pathogenesis
In established KS lesions, spindle cells account for most of the cell mass and are
considered as the driving force of KS; however, KS also contains heterogeneous cell
types including B cells, plasma cells, T cells, and monocytes, which orchestrate an
inflammatory microenvironment. Interestingly, KS is not formed by a monotonous
clonal outgrowth of mesenchymal cells as traditional cancers. In fact, KS lesions
progress in a stepwise manner with unique features. Considerable angiogenesis and
inflammatory cell infiltration are present at the initial stages. The patched lesions
are reddish but flat. Despite lack of in vivo data of de novo KSHV infection, it is
speculated that KSHV infects endothelial cells from unknown sources, either the
blood vascular system or lymphatic vascular system. Initial infection of endothelial
cells promotes endothelial cell proliferation and differentiation, which leads to neo-
vascularization [ 147 ]. Whether KSHV infects lymphocytes and endothelial cells
simultaneously remains unclear. It is also possible that newly formed vessels recruit
lymphocytes to the infection sites and KSHV subsequently infects the recruited
cells. The subsequent stage is the plaque stage, as the infected cells constantly
undergo excessive proliferation as well as endothelial-to-mesenchymal transition
[ 148 ] and are transformed into spindle cells. The lesions become more edematous
and continue to progress toward the next stage, the nodular stage, which is featured
by visible tumor masses. In this stage, the tumor consists of mainly spindle cells.
The spindle cells express multiple endothelial markers such as CD31, CD34, and
CD36, indicative of their endothelial origin [ 149 , 150 ]. Although a lymphatic endo-
thelial origin of KS spindle cells has been suggested [ 151 – 154 ], it remains contro-
versial which endothelial cell type, the lymphatic endothelial cell (LEC) or blood
vascular endothelial cell (BEC), is primarily infected by KSHV. However, we may
not be able to tease apart one from the other, as HSHV infection tends to alter the
transcription patterns of the terminally differentiated cells to a mixed expression of
both LEC and BEC markers [ 152 , 155 , 156 ].
Fig. 7.2 Model for the switch of the latent phase and lytic phase. The model for the switch of the
latent phase and lytic phase: LANA and RTA control the switch between latency and lytic reactiva-
tion through targeting of the RBP-Jκ effector protein
S. Li et al.