Elsevier

Seminars in Cancer Biology

Volume 26, June 2014, Pages 69-77
Seminars in Cancer Biology

Review
Manipulation of endothelial cells by KSHV: Implications for angiogenesis and aberrant vascular differentiation

https://doi.org/10.1016/j.semcancer.2014.01.008Get rights and content

Abstract

Kaposi sarcoma (KS), a viral cancer associated to Kaposi sarcoma herpesvirus (KSHV) infection, is currently the most common tumor in men in sub-Saharan Africa. KS is an angiogenic tumor and characterized by the presence of aberrant vascular structures in the lesion. Although our understanding of how KSHV causes the aberrant differentiation of endothelial cells and the typical vascular abnormalities in KS tumors is far from complete, the experimental evidence reviewed here provides a comprehensive description of the role of KSHV in the pathogenesis of this unusual tumor. In contrast to other tumor viruses, whose interference with cellular processes relating to cell cycle, apoptosis and DNA damage may be at the heart of their oncogenic properties, KSHV may cause KS primarily by its ability to engage with the differentiation and function of endothelial cells.

Although the intracellular pathways engaged by KSHV in the endothelial cells are being explored as drug targets, a better understanding of the impact of KSHV on endothelial cell differentiation and vasculogenesis is needed before the encouraging findings can form the basis for new targeted therapeutic approaches to KS.

Section snippets

Kaposi's sarcoma – an endothelial cancer?

Moritz Kaposi described the first cases of Kaposi's sarcoma (KS) as an idiopathic multiple pigmented sarcoma of the skin already in 1872 [1]. The following decades of epidemiological studies of KS revealed uneven geographic distribution, which evoked the suggestion that exogenous factors could contribute to the disease. The search for a causative agent of KS created a long list of candidates including numerous microbes and finally culminated to the discovery of Kaposi's sarcoma associated

KSHV infection of ECs recapitulates the endothelial phenotypes found in KS lesions

KSHV infects various types of ECs in culture, and numerous studies describing consequences of KSHV infection of primary or immortalized vascular and lymphatic ECs support their use as a valuable model to understand KSHV biology and pathogenesis [18]. Upon infection by KSHV in tissue culture several ECs adopt a spindle-like morphology and become arranged to form ‘swarms’ of parallel elongated spindle cells resembling the appearance of KS tumor cells in the lesions [19]. This is often accompanied

KSHV-induced reprogramming beyond EC fate

The extraordinarily plastic, reprogrammable phenotype of LECs was thought to be limited to different EC types. Two recent reports revealed the capacity of LECs to transdifferentiate into non-EC types by demonstrating KSHV-induced, Notch activation dependent reprogramming of LECs into mesenchymal cells via endothelial-to-mesenchymal transition [38], [54]. In line with these findings, induction of proteins typically found in mural or smooth muscle cell has also been reported in recombinant

Mechanisms of KSHV-induced aberrant angiogenesis and endothelial function typical of KS tumors

How does KSHV achieve these features of aberrant angiogenesis and EC differentiation typical of KS tumors and do they tell us anything about what the virus needs to change in the infected EC in order to achieve its ‘aims’, such as long-term persistence or reactivation to produce new viral progeny? KSHV genome is equipped with a number of gene products capable of inducing a variety of signaling pathways involved in angiogenesis and vascular differentiation. The following paragraphs will

Mouse models of KS with angiogenic phenotypes

There is still a paucity of in vivo models to study the angiogenic and tumorigenic effects of KSHV. Although it is possible to infect mice with KSHV and to identify virus-infected cells in different cell types by PCR or immunofluorescence, the murine cells do not support a complete viral replication program leading to very limited viral replication and absence of vascular abnormalities or KS-like lesions [96], [97] (own unpublished observations). As already described above, engraftment of nude

Translating our understanding of the role of KSHV in angiogenesis into new therapeutic approaches

The experimental evidence reviewed in the preceding sections indicates that the impact of KSHV on angiogenesis and endothelial function, including the development of KS, requires the continued presence of the virus, i.e. that no ‘hit and run’ mechanisms such as virus-induced permanent alterations to the genetic integrity – and, as far as we know, the epigenetic landscape – of the infected cell appear to be involved. This suggests that it should be possible to target either the virus, or

Conflict of interest

None declared.

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