AUTOCRINE ROLE OF
FGF2 IN VASCULAR TUMORS
Blood vessels may represent
the site of origin for neoplasms, hamartomas, and vessel malformations.
Neoplasms include benign tumors and tumor-like lesions (hemangioma), tumors
of intermediate malignancy (hemangioendothelioma), and malignant tumors
(angiosarcoma) (Enzinger, 1995). The pathogenesis of vascular tumors is
at present unknown, even though the local, uncontrolled release of growth
factors and/or lytic enzymes has been hypothesized to facilitate endothelial
cell proliferation and the formation of vascular lacunae (Enzinger, 1995).
Benign vascular tumor
A close relationship exists
between the formation of vascular tumors and angiogenesis. This relationship
is also apparent in Kaposi's sarcoma (KS). Classic KS is a relatively benign,
highly vascularized neoplasm. A clinically aggressive form of KS develops
in a significant percentage of acquired immune deficiency syndrome (AIDS)
patients (Levine, 1993). Histologically, KS is characterized by the presence
of spindle-shaped cells, inflammatory cells and newly formed blood vessels
(Enzinger, 1995). KS lesions express various markers for vascular endothelial
cells, suggesting that KS spindle cells are of endothelial cell lineage
(Sturzl et al.,
1992).
Kaposi
sarcoma
Several experimental evidences
implicate FGF2 in the pathogenesis of vascular lesions, including KS and
hemangiomas. In vitro, AIDS-KS cells derived from different patients
express high levels of FGF2 which is released in the extracellular media
(Albini et al., 1994). Antisense oligonucleotides directed against
FGF2 mRNA inhibit both the growth of AIDS-KS cells and the angiogenic activity
associated with these cells, including the induction of KS-like lesions
in nude mice (Ensoli et al.,
1994b). FGF2 immunoreactivity is detected
both in classic and AIDS-associated KS lesions in humans (Ensoli et
al., 1994a) and recombinant FGF2 synergizes with HIV-1-Tat protein
in inducing the formation of vascular lesions closely resembling early
KS into nude mice (Ensoli et al., 1994).
Interestingly, cytokines
from activated T cells induce FGF2 upregulation and the acquisition of
a AIDS-KS spindle cell-like phenotype in normal endothelial cells (Barillari
et
al., 1992; Fiorelli et al., 1995). Finally, coexpression of
FGF2 and endothelial phenotypic markers CD31 and von Willebrand factor
has been found in the proliferating phase of human hemangioma but not in
vascular malformations (Takahashi et al., 1994). Taken together,
the data suggest that FGF2 produced by cells of the endothelial lineage
may play important autocrine and paracrine roles in the pathogenesis of
vascular tumors.