COMMENTARY

Perspective on Kaposi's Sarcoma: Facts, Concepts, and Conjectures

Marvin S. Reitz, Jr., Lata S. Nerurkar, Robert C. Gallo

Affiliations of authors: M. S. Reitz, Jr., R. C. Gallo, Institute of Human Virology, University of Maryland at Baltimore; L. S. Nerurkar, International Cancer Information Center, National Cancer Institute, Bethesda, MD.

Correspondence to: Robert C. Gallo, M.D., Institute of Human Virology, University of Maryland at Baltimore, 725 W. Lombard St., Rm. S307, Baltimore, MD 21201-1192 (e-mail: coleman{at}umbi.umd.edu).


    INTRODUCTION
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 
Kaposi's sarcoma (KS) is the most common tumor associated with human immunodeficiency virus type 1 (HIV-1) infection, occurring in approximately 30% of HIV-1-infected homosexual men. The incidence of KS has increased in this risk group by more than 100 000-fold relative to the general population (1,2). However, KS is also increased in nonhomosexual HIV-infected males by about 10 000-fold (2,3). In the absence of HIV-1 infection, KS occurs very rarely in three distinct epidemiologic forms: 1) the classic form (disease seen in older men from certain ethnic groups) (4,5), 2) the endemic form (prevalent in some parts of equatorial Africa) (5,6), and 3) a form associated with renal transplant patients (7,8). It has not been clear whether all four forms of KS represent the same disease, or, like leukemias, lymphomas, and many other cancers (or immunodeficiencies), they have distinct causes and/or pathogenetic mechanisms and share only the end stage proliferation (or death) of the same cell types. A putative causative agent is human herpesvirus 8 (HHV-8), also called KS-associated herpesvirus (9). HHV-8 nucleotide sequences are regularly found in all types of KS lesions (10-15), which has helped to define these tumor types as the same disorder.

Aspects of KS that stimulate interest in this tumor are as follows: 1) the striking frequency of KS in HIV-1 infection, especially among homosexual men (1,16); 2) the mixed cellularity of the tumor that makes definition of the tumor cell ambiguous (17-19); 3) the question of whether the tumor is hyperplastic or neoplastic in nature (20-22); 4) the absence of KS in brain tissue; 5) the more frequent occurrence of KS in males than in females (1,2,16); 6) the relative resistance of KS to conventional therapies (which, of course, becomes worse when a patient is immunodeficient); 7) the different epidemiologic forms (noted above); 8) the absence of similar tumors in animals; and 9) the question of how HIV-1 infection dramatically increases the incidence of KS, despite the absence of HIV sequences in the KS tumor cells (18,23). (HIV-1 sequences are found only in cells infiltrating the tumor.) Until recently, there have been few reports that characterize these aspects of KS. This lack of research is due, at least in part, to the absence of a good animal model of spontaneous or induced KS and, in part, to difficulties in culturing KS tumor cells.

In 1988, Gallo and colleagues (24,25) began to develop reproducible KS cell culture techniques to characterize the cultured cells (26-30), to study the role of HIV-1 in KS (31-35), to study and, when possible, to relate the in vitro cell culture data to clinical results (especially for data from KS biopsy specimens) (18), and to find biologic approaches to control tumor cell proliferation (36,37). Interpretations of the findings and hypotheses generated from this work are summarized below.


    KS Cell Types
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 
Early KS tumors contain a mixture of different cell types. The dominant "culturable" cell types are fibroblasts and activated endothelial cells, both of which have a spindle shape (the putative hallmark of the KS tumor cell) (17-19).

The cells cultured from KS tumors almost always have normal diploid karyotype, grow for a limited number of passages in culture, and produce transient benign tumors in immunodeficient mice. These tumors regress after about 10 days (19,25) and contain cells of mouse origin, indicating that the cultured xenotransplanted cells cannot proliferate indefinitely but, instead, provide growth factors that allow the formation of transient tumors in mice.

Similar phenomena can be initiated with a combination of inflammatory cytokines (e.g., interleukin 6 [IL-6], tumor necrosis factor, oncostatin M, and interferon gamma [IFN {gamma}]) (26,29,30,38-40). Of these cytokines, IFN {gamma} may be the most important because it can activate normal vascular endothelial cells (29) and because immunohistochemical analysis of KS lesions shows that this cytokine is readily detectable (41).


    Production of Growth Factors by KS Cells
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 
In turn, KS cells in in vitro culture generally produce IL-6, granulocyte-macrophage colony-stimulating factor, vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor (28,39,42). Of these factors, basic fibroblast growth factor may be the most important because it can serve as a potent autocrine growth factor for KS cells (28,38). Basic fibroblast growth factor may act through stimulation of cyclin E expression and cyclin-dependent kinase-2 activity (43). Antisense oligonucleotides against basic fibroblast growth factor block the growth of KS cells in vitro and in nude mice (44).


    Role of HIV-1 Tat
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 
HIV-1 Tat protein promotes growth of KS cells (33-35) mainly by elevating levels of free basic fibroblast growth factor. Because Tat binds to heparan sulfate in the extracellular matrix (45), it is likely to act by displacement of basic fibroblast growth factor from the matrix. Tat also appears to affect cell growth and adherence through its RGD (Arg-Gly-Asp) integrin-binding motif (33).


    Presence of Tat in KS Cells
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 
HIV-1 Tat protein is found in KS spindle cells (primary tissue biopsy results) (32). KS cells do not contain HIV-1 sequences (23). However, Tat is released from acutely infected T cells (34) and can be taken up by nearby cells (34,46). Thus, it is reasonable to conclude that KS spindle cells acquire Tat from the extracellular fluid.


    Role of HIV-1
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 
We propose that the role of HIV-1 in KS is not the usual mechanism ascribed—namely, a simple induction of immunodeficiency—because the classic form of KS occurs without substantial apparent immunodeficiency; even HIV-1-associated KS can occur without detectable immunodeficiency (47,48); and HIV-2, simian immunodeficiency virus, and other agents that induce immunodeficiency are not generally associated with KS, even when accompanied by infection with HHV-8 (49) or a related virus (50,51). Instead, we hypothesize that the role of HIV-1 in KS is more active and also indirect—namely, increasing inflammatory cytokines and providing HIV-1 Tat. This hypothesis predicts that there are important differences in Tat from HIV-1 and from HIV-2 or simian immunodeficiency virus. The hypothesis also suggests that KS begins as a hyperplasia and not as a single neoplastic clone.


    KS and Malignancy
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 
There is evidence, however, that at least some late-stage KS tumors evolve to malignant tumors. This is based on two recent observations. First, Rabkin et al. (20,21) have shown in a few cases that late stage KS tumors are clonal. This finding may not be so clear-cut, however; more extensive studies by Gill et al. (22) have shown polyclonality, oligoclonality, and apparent monoclonality in KS from different patients. Nonetheless, we may infer from all of the results that some late stage KS tumors are clonal and may represent a step in the neoplastic evolution of the tumor. Second, only three KS cell lines with neoplastic properties have been established worldwide, one in Israel, one in Italy, and one in the United States. These cells show immortalized growth, have marker chromosomes, and induce malignant tumors in immunodeficient mice. Siegal et al. (52) obtained a permanent cell line (KS SKL) from a biopsy of a KS lesion; the lesion was located in the buccal mucosa of a renal transplant patient who also had KS. This cell line induces malignant but nonmetastatic tumors. Lunardi-Iskandar et al. (36) developed a cell line (KS Y-1) from a pleural effusion obtained from a patient who had HIV-1-associated, advanced pulmonary KS. These cells were proven to be derived from the patient because human histocompatibility leukocyte antigen haplotypes, as determined by polymerase chain reaction, were the same as those seen in the patient's tissues, and after many passages the cells retained the morphology and cell surface markers characteristic of the first-passage cells (53). More recently, Albini et al. (54) established the third cell line, called KS AMM. These three lines (KS SKL, KS Y-1, and KS AMM) have similar chromosomal hyperploidy and the same deletions in the short arm of chromosome 3 (55), and their characteristics suggest that they are primitive or poorly differentiated endothelial cells. These characteristics may be involved in the neoplastic phenotype.

Thus, these findings suggest that, after protracted hyperplastic proliferation, some spindle cells (the more aggressive and uniform cell type in a KS tumor) are seen in some cases of late stage KS. Alternatively, it is possible that all cases of KS begin as a neoplasm, that the neoplastic cell is rare or at least not dominant, and that it is morphologically indistinguishable from other spindle cells. The accompanying leukocytes, fibroblasts, and endothelial cells represent a reactive hyperplasia (with the probable recruitment of these cell types by the neoplastic cells). KS may be somewhat analogous to Hodgkin's disease except that in Hodgkin's disease, the neoplastic cells are easily seen as the "mirror image" giant cells known as Reed-Sternberg cells. It will be important to determine whether molecular probes specific for the neoplastic KS cell can be prepared from the KS cell lines. If so, these probes might be used to identify the neoplastic cell in early KS (if present) and in KS progression.


    Human Herpesvirus 8
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 
HHV-8 is clearly associated with KS. From its detection, it has been put forth as the cause of KS and is viewed by some as a directly transforming tumor virus. Several arguments lead to this conclusion; however, important counter arguments or findings encourage us to ponder the issue further.

Herpesvirus-related DNA sequences from KS-associated herpesvirus or HHV-8 were discovered in the DNA of KS lesions by use of subtractive hybridization (9). The presence of HHV-8 has been shown to be associated closely with all forms of KS (10-15), including acquired immunodeficiency syndrome (AIDS)-associated KS, classic (Mediterranean) KS, endemic (African) KS, and transplant-associated KS, indicating a common etiology in spite of epidemiologic differences. HHV-8 incidence also is closely associated with pleural effusion lymphomas (56) and multicentric Castleman's disease (57), a lymphoproliferative disease; the incidence of both diseases is elevated in patients with AIDS. HHV-8 can be detected before the onset of KS, strengthening the conclusion that HHV-8 plays a necessary etiologic role (13,58,59). The virus is present in the majority of the abnormal spindle cells in mid- to late-stage KS lesions (60), although it is present in only a minority of the cells of the earliest lesions (61). As with most herpesviruses, HHV-8 is in a latent stage of expression in the majority of the infected cells in KS lesions, and only a few gene products, perhaps restricted to only products required to maintain the viral genome, are expressed (60,62).

The close association of HHV-8 infection with KS is certainly consistent with an important etiologic role for the virus, but it obviously is not highly efficient at causing KS. The incidence of HHV-8 in normal populations remains somewhat controversial, but most recent results suggest the incidence in the United States may be 2%-7% (63,64). This is clearly a much higher percentage than the lifetime risk of KS occurrence. As mentioned above, the incidence of KS increases dramatically with HIV-1 infection, suggesting that HIV-1 is an extremely efficient cofactor in augmenting the necessary but very inefficient role of HHV-8 in KS. The incidence of infection is higher in Italy, where the classic form of KS is prevalent, and the incidence of infection in different parts of Italy is generally proportional to the incidence of KS (65,66), further suggesting a causative role. Again, however, the incidence of HHV-8 is far higher than the prevalence of KS, indicating a very low efficiency of the virus.

Before the HIV epidemic, an HIV-negative KS was endemic in parts of Africa, although with a far lower incidence than is currently observed with AIDS-associated KS. The incidence of HHV-8 infection in several parts of Africa has been reported to be around 60% (49,65,67). However, some of these areas have a very high incidence of AIDS-associated KS (although far less than 60%, obviously), whereas other areas have a relatively low incidence. Of interest, the areas with high incidences of HHV-8 and KS also have high levels of HIV-1 infection, whereas the areas with high incidences of HHV-8 and low incidences of KS have low levels of HIV-1 but high levels of HIV-2 infection. This finding suggests that there are important differences between HIV-1 and HIV-2 in their ability to serve as a cofactor for HHV-8 in KS. It is noteworthy that HIV-1 Tat generally contains an RGD motif, which is important for ligand binding to integrins, whereas HIV-2 Tat does not. Thus, the epidemiologic data indicate that HHV-8 infection is a necessary, but not very efficient, factor for KS (similar to viruses, such as human T-cell lymphotropic virus type I, human papillomavirus, Epstein-Barr virus, and hepatitis virus involved in human cancers) and that KS requires other cofactors. HIV-1 appears to be the cofactor in AIDS-associated KS; the cofactors involved in the other forms of KS are not clear.

What is the role of HHV-8 in the induction of KS? The HHV-8 genome has been completely sequenced (68), and a number of viral genes appear to be potentially important for KS or lymphoma. These genes include functional homologues for ß chemokines (viral macrophage inflammatory protein-I [or IA], -II [or IB], and -III [or IC]) (69,70), a chemokine receptor (open-reading frame 74) (71,72), a cytokine (viral IL-6) (69,70), cell cycle regulatory proteins (viral cyclin D) (71,73-75), and antiapoptotic factors [viral Bcl-2 (76,77) and viral FLICE (caspase-8)-inhibitory proteins (FLIP) (78)]. Of these genes, during latent-phase expression in KS lesions, only viral cyclin D and viral FLIP are expressed (75,79,80). Both are encoded on single RNA transcripts; one contains coding sequences for both proteins, and the other also contains the coding region for latent nuclear antigen (79,81-83), a protein of unknown function. This observation suggests that viral FLIP and viral cyclin D are expressed in KS lesions, although this has not been demonstrated directly by immunohistochemistry.

Some of the viral genes, including K1, K9 (viral interferon regulatory factor, an interferon regulatory factor homologue), K12, and open-reading frame 74, have been shown to transform NIH 3T3 fibroblasts in transfection experiments (84-88). The NIH 3T3 transformation system, however, is highly artificial; genes from nontransforming viruses that are not related to neoplasia, such as adenovirus 5 and HHV-6, have been shown to transform rodent cells (89,90). K1 has been shown to enable T-cell transformation and lymphomagenesis in marmosets when it is substituted for the STP gene of Herpesvirus saimiri (87), suggesting that it has the potential to play a role in cell transformation under relatively natural circumstances. It should be noted, however, that, with the possible exception of a K12-encoded protein, these genes are lytic-phase genes that are not expressed in the majority of cells in KS lesions. HHV-8 infection of primary human endothelial cells results in cells with some of the properties of transformation, such as extended lifespan (91), but the virus is not present in all of the cells and it is necessary to invoke a paracrine mechanism to make the argument that cell replication is virus driven.

The strongest argument against the relevance of virus-transforming genes in the etiology of KS comes from studies indicating that not all KS lesions are clonal, as would generally be expected if the cells were transformed and as is the case in, for example, Epstein-Barr virus-associated Burkitt's lymphoma (92,93). This result and the results of Flore et al. (91), suggesting that HHV-8 contributes to the growth of the relevant KS cells by a paracrine mechanism, may mean that HHV-8 causes KS by stimulating the growth or survival of spindle cells through the release of soluble factors; the spindle cells may or may not be infected. These soluble factors could be virally encoded, such as viral IL-6 and the viral macrophage inflammatory proteins, or induced in infected cells by viral trans-activating factors. In this scenario, the absence of HHV-8 in a majority of the cells in early lesions (61) would not rule out a role for HHV-8 in the induction and maintenance of KS lesions because HHV-8 infection would then be required only in a minority of the cells. This hypothesis could explain another aspect of KS, which is that, when cells from lesions are put into culture, outgrowth of virus-negative spindle cells is quite rapid, and virus is lost within a few passages (19,94,95). The three known immortalized KS-derived cell lines (36,52,54) are also virus negative (96). Perhaps tissue culture conditions provide an environment that makes whatever factor HHV-8 provides to the KS lesion microenvironment unnecessary or even inhibitory. In any case, the cause-and-effect relationship between HHV-8 and KS is not simple.

Two of the more powerful arguments for a direct causative role of HHV-8 in KS are that the virus is present in peripheral blood mononuclear cells before the appearance of KS (13,58,59) and is present in the majority of cells in all but early lesions (60,61). There are, however, alternative interpretations. A few years ago, Browning et al. (97) showed that activated endothelial cells could be found in peripheral blood mononuclear cell populations, albeit rather infrequently. These cells were found more often and in greater numbers in patients with KS and also in HIV-1-infected homosexual men before the appearance of KS. We proposed that this is because of the known increase in the level of IFN {gamma} in HIV-infected patients (98,99). Such an increase can activate macrophages and endothelial cells and promote their entry into the circulation, presumably to migrate to sites of inflammation. It is possible that some of these cells carry HHV-8 and may home to microscopic KS lesions and other sites of inflammation. It is also possible that, once present, HHV-8 can undergo a markedly augmented replication because of the inflammatory microenvironment present in these lesions. Indeed, preliminary data suggest that HHV-8 replication is enhanced by inflammatory cytokines (100).

If either or both of these possibilities are the case, however, it certainly does not exclude the possibility that HHV-8 plays a necessary role in KS pathogenesis, particularly if HHV-8 acts through a paracrine mechanism, as suggested by the work of Flore et al. (91). It is even possible that inflammatory cellular cytokines could drive the replication or expression of HHV-8 and viral paracrine factors could drive the replication of the KS spindle cells, resulting in a vicious cycle of cytokine expression that might sometimes result in transformation and clonal outgrowth of one of the replicating cells.

A large body of information has been accumulated on KS, including the lesions themselves, the role of inflammatory cytokines, the role of HIV, and the role of HHV-8. What remains is to fully understand the details of these different aspects of the disease and to use this information to develop effective preventive and therapeutic approaches. Although this may make the job remaining seem straightforward, it must be remembered that the devil is in the details.


    NOTES
 
We thank Ms. Anna Mazzuca for her diligent editorial assistance.


    REFERENCES
 Top
 Introduction
 KS Cell Types
 Production of Growth Factors...
 Role of HIV-1 Tat
 Presence of Tat in...
 Role of HIV-1
 KS and Malignancy
 Human Herpesvirus 8
 Notes
 References
 

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Manuscript received February 14, 1999; revised June 24, 1999; accepted July 1, 1999.


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