Triggering Kaposis Sarcomagenesis

Thus, although alone not transforming, latent genes may still enhance tumor cell proliferation and survival, likely contributing to the more aggressive nature of late-stage or "nodular" KS tumors in which most tumor cells express KSHV latent genes. Similarly, lytic genes may also contribute to KS tumor progression by activating mitogenic signaling cascades by their paracrine secretions. Nonetheless, the question as to what initially triggers this unusual cancer remains unclear, as expression of KSHV latent and lytic genes does not normally result in the development of KS. In this regard, recent work suggests that dysregulated expression of a single KSHV lytic gene, vGPCR, may be responsible for initiating KS.

Initiation of Kaposi's Sarcomagenesis by vGPCR

Compelling evidence implicates vGPCR in the initiation of Kaposi's sarcomagenesis. In particular, when a KS model in which endothelial-specific retroviral transduction was utilized to target candidate KSHV oncogenes to the vascular endothelium of mice, it was observed that only vGPCR produced vascular tumors in mice that were strikingly similar to human KS lesions [9]. vGPCR experimental tumors expressed key histopathological and molecular hallmarks for KS, suggestive of an important role for the vGPCR in the initiation of this enigmatic disease.

Dysregulated Expression of vGPCR Triggers KS

However, as vGPCR is a lytic gene, normally expressed only in cells destined for lysis, it was unclear how it could be the gene responsible for initiating KS. One explanation could be that dysregulation of the normal viral gene program, leading to expression of vGPCR in nonlytic cells, may trigger KS. Under these circumstances, unregulated vGPCR signaling to mitogenic and survival pathways may promote direct cell transformation while the continuous secretion of cytokines and growth factors may induce the recruitment and subsequent indirect (paracrine) cell transformation of neighboring endothelial cells (Figure 2). vGPCR oncogenesis may thereby provide a "double-hit" that requires susceptibility to both direct and paracrine cell transformation [10], consistent with the profound vulnerability of endothelial cells to vGPCR oncogenesis. Of note, the paracrine nature of vGPCR experimental tumors is remarkably similar to paracrine transformation of KSHV-infected endothelial cells in vitro [6]. However, the circumstances leading to vGPCR dysregulation have yet to be defined. Similarly, the contribution of other KSHV latent and lytic genes to the initiation and progression of KS remains poorly understood.

Dysregulated expression of vGPCR

Figure 2 Dysregulated (nonlytic) expression of vGPCR. Unregulated vGPCR signaling to survival pathways may promote direct cell transformation while continuous secretion of chemokines and growth factors may induce the recruitment and subsequent indirect (paracrine) cell transformation of neighboring "bystander" endothelial cells. (see color insert)

Kaposi's sarcomagenesis

Figure 2 Dysregulated (nonlytic) expression of vGPCR. Unregulated vGPCR signaling to survival pathways may promote direct cell transformation while continuous secretion of chemokines and growth factors may induce the recruitment and subsequent indirect (paracrine) cell transformation of neighboring "bystander" endothelial cells. (see color insert)

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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