Kaposi's sarcoma (KS) is of special interest not only because
of its association with the epidemic of human immunodeficiency
virus (HIV) infection (AIDS-KS), but also because studies of its
pathogenesis appear likely to contribute to a deeper understanding
of tumor biology, particularly angiogenesis. This is true despite
a major paradox: researchers are still uncertain as to whether
or not the four types of KS actually represent a single disease
and even whether or not KS, which can certainly produce tumors,
is a true neoplasm.
KS tumors are characterized by a significant complexity of cell
types. Many normal cells infiltrate into the mass generally referred
to as the KS lesion [1-3]. Furthermore, in most patients with
this disorder, it remains difficult to prove that there are truly
clonal, proliferating, malignant cells at any time.
Our group and another group from Israel have established KS cell
lines that are truly neoplastic; our tumor cell line (KS Y-1,
derived from AIDS-KS)  produces metastatic disease in mice,
whereas the other cell line (derived from a patient with classic
KS) is tumorigenic but not metastatic . However, these lines
are derived from cells that appear to be quite rare in KS lesions,
because many attempts have been made to establish cell lines from
other cell types, with no success. Another possibility, which
most likely accounts for the majority of KS lesions, is that the
significant event may be hyperplasia-induced and maintained by
the spindle cell, which secretes or releases cytokines that permit
infiltration and proliferation of other cell types [6-10]. Our
work has focused on characterizing cells from KS lesions in terms
of the phenotype and cytokines they secrete and their ability
to create model KS lesions when inoculated into nude mice. We
have demonstrated that most of the KS spindle cells that clearly
were not neoplastic [11,12] have the same phenotype as that of
most of the in situ spindle cells [2,13] and can produce a lesion
in mice that is histopathologically indistinguishable from early
The multifocal nature of this tumor raises the question of whether
this could be hyperplasia, rather than neoplasia, at least in
its early stage. If so, the abnormal milieu of HIV-infected individuals
may be permitting an increased local proliferation of a variety
of cell types, depending upon the local environment. If this is
the case, the spindle cell may have become seeded in the blood
and disseminated to sites where it can reside and induce local
inflammation-like changes. Neoplastic conversion may be a chance
Culture of cells from primary biopsy specimens of patients with
KS is achieved by using conditioned media from activated T-cells
[11,14,15]. These cells have a spindle-shaped morphology and an
activated endothelial-cell phenotype that is identical to that
of most in situ spindle cells [2,13].
Conversely, normal endothelial cells grown in a medium that contains
inflammatory cytokines from activated T-cells give rise to a similar
or identical type of spindle-shaped cell [13,16]. In both cases,
these cells have receptors for a great number and variety of cytokines.
The predominant cytokines involved in producing this activated
cell are interleukin-1 (IL-1), tumor necrosis factor, and gamma
interferon. Of importance, these cytokines are the same inflammatory
cytokines increased in KS lesions (B.E., unpublished data, 1995).
Once activated in this way, the spindle cell then proliferates
and produces its own cytokines in very large amounts. This is
particularly true of basic fibroblast growth factor (bFGF), which
is not released in significant amounts by normal cells . The
KS spindle cells have receptors for bFGF and produce and release
more bFGF than any other known cell both in vitro and in vivo
[6,17,18]. Basic fibroblast growth factor is also highly expressed
by in situ spindle cells of both classic KS and AIDS-KS lesions,
inducing autocrinic KS cell growth. Upon release, bFGF promotes
angiogenesis and KS-like lesions that are indistinguishable from
those induced by KS spindle cells or lesions induced by cytokine-activated
endothelial cells [6,17-19].
The spindle cell also produces vascular endothelial cell growth
factor, platelet-derived growth factor, IL-6, granulocyte-macrophage
colony stimulating factor (GM-CSF), and IL-8 [6,8,9,20]. Some
of these cytokines also serve an autocrinic function in keeping
the spindle cell functioning. The most important factor, however,
appears to be bFGF, because most spindle cell growth can be blocked
by polyclonal antibodies to bFGF or antisense oligodeoxynucleotides
directed against bFGF [6,17].The derivation of the KS spindle
cell has been recently elucidated. Most of the current findings
indicate a microvascular endothelial origin in an activated state
[2,3,13]. Cultured spindle cells do lack the vascular endothelial
cell marker FVIII-RA; however, this molecule is released in the
presence of inflammatory cytokines. In fact, when KS cells are
cultured in their absence, the expression of this molecule is
regained . In addition, these cells present other specific
endothelial cell markers, such as CD34, Chaderin-5, and ELAM-1
. Other spindle-shaped cells present in patients with KS are
macrophages/dendritic cells [2,19].
Circulating vascular endothelial cells can be found in normal
persons, but circulating spindle cells are very uncommon. In fact,
the numbers in normal persons are so low that we have been unable
to characterize fully these cells in that population . In
patients with HIV-related KS, spindle cells are 85-fold more common
in peripheral blood. In most HIV-infected patients who do not
have KS, spindle cell numbers are nearly the same as those in
control patients . In HIV-infected homosexual men, however,
spindle cell numbers are nearly 20-fold higher than in controls
. These differences in cell numbers may have some clinical
importance, if they can be used to monitor response to therapy
or progression of KS.
KS-like lesions can be produced in nude mice by inoculating them
with spindle cells [11,12,17]. The tumor produced is of mouse
origin, which is grown in response to cytokines secreted by the
human cells. A medium that is conditioned by spindle cells has
the same effect. This suggests that the spindle cell, regardless
of whether it is neoplastic or not, may be driving the KS lesion
from early stages. In particular, bFGF appears to be the major
mediator of these lesions [17,19], although recent data suggest
that vascular endothelial cell growth factor can amplify the angiogenic
response to bFGF (F. Samaniego, md, unpublished data, 1995).
The HIV transactivator (Tat) protein, which is released from acutely
infected T-cells, probably by a process of exocytosis, also plays
an important role in the development of KS . It not only increases
KS spindle-cell growth, but also induces the migration, invasion,
and adhesion of KS cells and cytokine-activated endothelial cells
[13,16,22-24]. Most important, the Tat protein is synergistic
with bFGF in inducing angiogenesis and KS lesion development .
We also know that normal endothelial cells are not responsive
to the Tat protein unless first exposed to inflammatory cytokines
[13,16,22-24]. The Tat protein is detected in AIDS-KS lesions,
and it co-stains with the integrin receptors alpha 5/beta 1 and
alpha V/beta 3, which function as the receptors for this protein
[19,24]. In fact, the Tat protein appears to mimic the effect
of the extracellular matrix protein, the natural ligands of these
receptors . By these effects, the Tat protein may be the factor
increasing the frequency and aggressiveness of KS in HIV-1-infected
Many infectious agents have been associated with KS; however,
only recently has a definitive link with an infectious agent other
than HIV-1 been found. Specifically, recent data indicate that
a novel herpesvirus is detected in all forms of KS [25,26]. This
virus, called KS-HV or HHV-8, has also been found in a subtype
of AIDS-associated B-cell lymphomas  and in peripheral blood
mononuclear cells from KS  but not in KS spindle cells representative
of both the hyperplastic and tumor phases of KS (S. Colombini,
md, unpublished data, 1995). Although there is no evidence that
this virus causes KS, it is possible that it may initiate inflammatory
cytokine production in infected cells within the lesions and may
trigger the mechanisms of KS development.
The recent evidence of this virus, however, does not explain the
elevated rates and aggressiveness of KS in HIV-infected homosexual
men, compared with the rates in other HIV-infected groups, as
in the normal population, which continues to puzzle epidemiologists
and clinicians alike. In fact, HHV-8 is present in all forms of
KS with about the same prevalence. The production of spindle cells
in response to exposure to inflammatory cytokines suggests that
these cell messengers are implicated. We know from our own laboratory
studies that inflammatory cytokines can cause endothelial cells
to become activated and detach, which would enable them to enter
the circulation, and that in HIV-1-infected individuals, the Tat
protein may increase KS development and progression. An increase
in inflammatory cytokine levels [28-31] and the presence of the
extracellular Tat protein in AIDS-KS, coupled with the results
of our in vitro studies, clearly show that inflammatory cyto-kines
from activated T-cells induce activated spindle cells, which begin
to proliferate and assume many of the characteristics associated
with KS lesions.
The evidence strongly suggests that inflammatory cytokines, perhaps
produced after infection with HHV-8, plus the HIV Tat protein
trigger development of early KS. Development of activated spindle
cells, apparently derived from microvascular endothelium, provides
a self-perpetuating, autocrine supported mechanism for further
development of the hyperplastic lesion. In more advanced stages,
a true neoplastic process may develop.
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