Vascular endothelial growth factor (VEGF) also known as vascular permeability factor (VPG) exists in a number of isoforms in human and rodent tissues including VEGF206h/205r, VEGF189h/188r, VEGF165h/164r, VEGF145h/144r and VEGF121 that differ in their molecular masses and biological activities. The VEGF isoforms bind with two tyrosine-kinase receptors, KDR/flk-1 and flt-1. In addition, VEGF165 binds with co-receptor, neuropilin-1, which is expressed in human endothelial cells and several types of non-endothelial cells including solid tumors. Recent studies on the role of estrogen in the regulation of tumor angiogenesis demonstrated that this steroid induces neovascularization in parallel with early induction of VEGF and the VEGFR2- (flk-1/KDR) protein expression in both blood vessels and non-endothelial cells (30). Moreover, estrogen-induced rat pituitary tumors in Fisher 344 rats express higher VEGF164 and neuropilin-1 levels compared to control untreated rats (31). These findings suggest that over-expression of VEGF and its receptor (VEGFR-2) may play an important role in the early phases of estrogen induced tumor angiogenesis in some endocrine tissues.
FIBROBLAST GROWTH FACTORS & RECEPTORS Fibroblast growth factors (FGFs)
Basic Fibroblast Growth Factor (now known as FGF-2) is one of an ever-expanding family of FGFs several of which possess mitogenic, angiogenic, and hormone regulatory functions (32). FGF-2 immunoreactivity was described originally in the non-hormone producing folliculo-stellate cells of the pituitary (33). In one mouse model, estrogen-induced tumorigenesis was associated with parallel increases in the expression of a pituitary tumor transforming gene (PTTG) as well as FGF-2 (33). In turn, both PTTG and FGF-2 have been shown to be increased in mRNA expression in papillary thyroid cancer that was also associated with lymph nodal invasion and distant metastasis. These findings were upheld even after consideration of other known prognostic factors such as age and gender ofthe patient and size and type ofthe tumor (34). Similarly, increased concentrations of FGF-2 in the serum of patients with differentiated papillary thyroid carcinoma has also been reported (35).
Fibroblast growth factor receptors (FGFRs)
There are 4 mammalian FGFR genes encoding a complex family of transmembrane receptor tyrosine kinases (RTKs) (36). Each prototypic receptor is composed of 3 immunoglobulin (Ig)-like extracellular domains, 2 of which are involved in ligand binding, a single transmembrane domain, a split tyrosine kinase, and a COOH-terminal tail with multiple autophosphorylation sites. Multiple forms of cell-bound or secreted receptors are produced by the same gene. Tissue-specific alternative splicing, variable polyadenylation sites and alternative initiation of translation result in truncated receptor forms (37;38). The first two extracellular loops of FGFR1 can be secreted as soluble circulating FGF binding proteins (39) but their physiological importance remains to be established. Different FGFRs can dimerize, so that truncated forms of FGFR1 block signalling through FGFR1, 2, and 3 (40).
Structural alterations of FGFRs may play a role in human tumorigenesis. FGFR1 is highly expressed in the brain (41) but the shorter (2 Ig-domain) form of FGFR1 is more abundant in some CNS glioblastomas (42). Anti-sense targeted interruption of FGFR1 reduces malignant melanoma cell proliferation and differentiation (43). FGFR2 exon switching has been observed to accompany prostate cell transformation (44).
The expression of FGF-2 and one of its receptors FGFR1 was recently compared in differentiated thyroid cancers, normal thyroids, multinodular goiters, and Graves' disease specimens. The investigators noted that FGF-2 was significantly over-expressed in thyroid carcinomas compared with normal thyroid tissue. More interestingly, increased FGF-2 mRNA expression was independently associated with lymph nodal invasion and distant metastasis at tumor presentation (34).
The biological relevance of the FGF signaling system in thyroid cell growth has been further hinted at from genetically altered mice. Mice deficient for FGFRR2-IIIb were generated by placing translational stop codons and an IRES-LacZ cassette into exon IIIb of FgfR2. Expression of the alternatively spliced receptor isoform, FgfR2-IIIc, is not affected in these mice. The FGFR2-IIIb deficient mice, however, show dysgenesis of several non-endocrine as well as endocrine tissues including the thyroid, adrenals, pancreas, and pituitary. These findings are particularly interesting in view of the fact that FGF ligand expression is not altered with normal FGF8, FGF10, Bmp4, and Msx1 in this animal model (45).
In contrast, gain-of-function mutations in the FGFR-3 gene have been described to result in inhibition of cartilaginous cell growth in the growth plate suggesting an important growth inhibitory signal for this receptor. RT-PCR examination confirmed the expression of this growth factor in papillary thyroid carcinomas. Over-expression of FGFR-3 was successful in specific binding of 125I-FGF-2. Growth rates of cells over-expressing FGFR-3, however, were similar to those of control cells (46). Cells over-expressing FGFR3 continued to grow beyond the density of control cells. These interesting findings suggest a role for FGFR3 in thyroid cancer cell adhesion and/or invasiveness.
NGF is a growth factor that generally results in anti-proliferative and anti-invasive effects in neuroendocrine tumors. NGF inhibits thyrocyte invasion and reverts the effect of retinoic acid in these cells. This effect is likely mediated by an increase in adhesion to the extracellular matrix proteins laminin and collagen IV and the inhibition of cell migration. NGF also induces expression of its receptor p75 NGF receptor. This receptor can be the subject of rearrangements. Indeed, the thyroid TRK onco-genes are generated by chromosomal rearrangements juxtaposing the neurotrophic tyrosine receptor kinase type 1 (NTRK1) tyrosine kinase domain to foreign activating sequences. TRK oncoproteins display a constitutive tyrosine kinase activity in NIH3T3 cells (47). The TRK oncoproteins' signal transduction involves several signal transducers activated by the NGF-stimulated NTRK1 receptor including fibroblast growth factor receptor substrate (FRS) FRS2 and FRS3, two related adapter proteins activated by fibroblast growth factor and NTRK1 receptors, in the signaling of the thyroid TRK-T1 and TRK-T3 oncogenes. FRS2 and FRS3 are recruited and activated by TRK-T1 and TRK-T3. Expression studies show different expression patterns of the FRS adapters in normal and tumor thyroid samples. FRS3 is expressed in both normal and thyroid tumor samples, whereas FRS2 is not expressed in normal thyroid but is differentially expressed in some tumors. These data are consistent with the notion that the FRS2 and FRS3 adapter proteins may have a role in thyroid carcino-genesis triggered by TRK oncogenes and provide the basis for a new dimension of pharmaco-therapeutic possibilities.
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