Emmanoulides, Miles, and Mitsuyasu have written an excellent review summarizing our current understanding of the pathogenesis of AIDS-related Kaposi's sarcoma (AIDS/KS). The authors cover what is currently well established and also provide their viewpoint on future developments in AIDS/KS. My commentary will highlight some of the major questions related to this complex disease.
It is well known that AIDS/KS develops most frequently in homosexual or bisexual men. This feature is difficult to reconcile with the present understanding of the disease. For example, it is unlikely that human herpesvirus type 8 (HHV-8), also called KS-related herpesvirus (KSHV), spreads only in this population, as numerous studies indicate that HHV-8 is widespread. Human herpesvirus type 8 has been detected in HIV-negative patients with classic KS, individuals with the African form of KS, and those who develop KS after a renal transplant. This virus also is present in patients with other malignant and premalignant skin disorders who do not have KS or HIV infection . The cause of the differences in the risk for KS in patients with HHV-8 is thus unclear.
Role of Sex Hormones
Kaposi's sarcoma develops predominantly in men with or without HIV infection and is exceedingly rare in women. It is natural to propose that sex hormones may be responsible for these differences in the development of KS. It is well established that sex hormones are ligands, which, upon binding to their cognate receptors, activate their respective receptors and regulate various genes directly by binding to response elements or by protein/protein interaction . The lack of androgen and estrogen receptors in KS tissue, however, argues against a direct effect of these hormones in the tumor . It is possible that hormone metabolites that do not require specific receptors may have direct effects. Alternatively, these hormones may act indirectly by regulating paracrine growth factors at distant sites.
I believe that sex hormones have an important role in AIDS/KS based on the epidemiology of the disease and the findings from HIV tat transgenic mice that develop KS-like vascular tumors in the skin of male mice only. The role of sex hormones could potentially be studied by treating male HIV tat transgenic mice with female or male sex hormones and then measuring the decrease or increase in the rate of tumor development. Similarly, female mice could be treated with androgens, with the expectation that KS-like tumors would develop only in hormone-treated animals. These experiments could also be done by cross-breeding HIV tat transgenic animals with transgenics overexpressing androgen or estrogen receptors. Understanding how sex hormones influence KS is likely to have a broader application in vascular biology.
A Variable Course
AIDS/KS has an extremely variable course, which can be dormant in some individuals and rapidly progressive in others. The course of AIDS/KS is often independent of the host's immune competence. An understanding of this phenomenon is likely to provide insight into the biology of this tumor. For example, indolent disease may represent a premalignant state or lower grade of malignancy that can evolve to a high-grade malignancy--a situation analogous to chronic lymphocytic leukemia undergoing Richter's transformation.
Definition of genetic events in AIDS/KS and the order of such events, similar to that defined for colon cancer, not only would provide a better understanding of the disease but also could result in diagnostic tools to predict outcome. For example, KS has long been considered to be a benign proliferative process, at least in some cases. It is possible that the recently described herpesvirus (HHV-8) or another putative agent can directly or indirectly induce a benign or premalignant lesion prior to the activation of oncogene(s) or loss of tumor-suppressor gene(s). These benign lesions may respond to antiviral therapy. However, a neoplastic tumor with genetic alterations would be highly unlikely to respond to antiviral therapy.
The isolation and long-term propagation of KS spindle cells and, more recently, the isolation of transformed tumor cells lines [4,5] have provided a better understanding of autocrine and paracrine growth factors, as outlined by Emmanoulides and colleagues. The hierarchial role of these factors remains to be established. It is likely that multiple factors are induced in response to one or more genetic events.
In addition, the isolation of transformed cell lines documents that KS is a clonal disease, at least in some cases. Rabkin et al have also documented clonality in KS by testing primary tumor tissues from women with KS by studying heterozygosity of the androgen receptor loci using the x-linked methylation assay . Studies of a large number of women with KS and examination of early and late disease would help determine whether KS is clonal from the onset or whether it begins as a polyclonal disease with evolution to a clonal disease over time.
A Remarkable Discovery
My final comment relates to the role of HHV-8 in the development of KS. Chang and Moore have made a remarkable discovery using the representational difference assay (RDA) pioneered by Widler's group. Chang and Moore have shown the presence of unique DNA sequences in the KS tumor tissue that are not present in normal skin from the same patient. The DNA sequences represent a new herpesvirus, currently known as human herpesvirus (HHV).
It is tempting to speculate that HHV-8 is the etiologic agent for KS. However, at present, no conclusive data exist to support or refute its role. Additional work is required to address this issue. Such research will need to isolate and propagate the virus, determine the permissive cell types (in addition to B lymphocytes), determine its tranforming ability, possibly by taking leads from the work performed on similar herpesviruses, including Epstein-Barr virus and herpesvirus saimiri.