Fibroblast Growth Factor-2 Free from Extracellular Matrix Is Increased in Papillary Thyroid Carcinomas and Graves' Thyroids

Abstract

Fibroblast growth factor (FGF)-2 is stored in the extracellular matrix (ECM). We hypothesized that FGF-2 is mobilized from the ECM and binds to receptors on the surface of FGF-2 responsive cells during thyroid enlargement. To test this hypothesis, we estimated levels of FGF-2 free from ECM in thyroids by comparing the efficiency of two methods for FGF-2 extraction (low salt and high salt). Because the high salt concentration (more than 1.5 M NaCl) is necessary to release FGF-2 from the normal ECM, FGF-2 extracted by low salt is indicative of ECM-free FGF-2. Human papillary thyroid carcinomas, normal part thyroid, and Graves' thyroid tissues were homogenized separately in an extraction buffer containing either 0 M NaCl (low salt) or 2.0 M NaCl (high salt), and the concentration of FGF-2 in the extracts was measured by enzyme-linked immunosorbent assay (ELISA). The yields of low and high salt extracts of immunoreactive (ir)FGF-2 from papillary carcinomas (low salt: 40.0 +/- 7.5, high salt: 233 +/- 53 ng/g tissue, mean +/- SE) were significantly higher than those of normal thyroid tissues extracted by the corresponding salt concentration (low salt: 14.6 +/- 1.8, high salt: 123 +/- 12 ng/g tissue). On the other hand, the extractable irFGF-2 from Graves' thyroid tissues (low salt: 25.2 +/- 2.5, high salt: 135 +/- 24 ng/g tissue) were not significantly different from that of normal thyroid tissues. However, the ratio of the extractable irFGF from carcinomas and Graves' thyroids by low salt to that by high salt (0 M/2 M ratio = 0.206 +/- 0.051, 0.209 +/- 0.025) were significantly higher than that of normal thyroids (0.120 +/- 0.014) (p < 0.05). These results suggest that intratissue ECM-free FGF-2 is increased in papillary thyroid carcinomas and Graves' thyroid tissues, and therefore a greater amount of FGF-2 may be available for stimulation of FGF-2 responsive cells.

Making the cut: Protease-mediated regulation of angiogenesis

“…In addition to their role in facilitating the migration of tumor and EC, MMPs have been shown to promote angiogenesis through their release of angiogenic factors stored in the ECM such as VEGF [46,109] and bFGF [110,111]. It is widely appreciated that these matrix-bound growth factors represent a potential pool of stored growth factors whose release results in an increase in the bioavailability of angiogenic stimulators without a concomitant increase in the expression of these stimulators.…”

Angiogenesis in Atherogenesis

“…72 One of the major functions of the MMPs has been described to promote angiogenesis by releasing angiogenic factors stored in the extracellular membrane such as VEGF and FGF-2. [73][74][75][76][77] Similarly, the cleaving of angiogenesis inhibitors by MMPs such plasminogen and collagen XVIII into the cryptic, endogenous angiogenesis inhibitors, angiostatin and endostatin, respectively, suggests that MMPs can produce the negative regulators of angiogenesis as well. 78,79 Interestingly, intact ADAMTS1 and ADAMTS8 inhibit angiogenesis in vitro, as shown in 2 functional angiogenesis assays.…”

A Subpopulation of Fibroblast Growth Factor-2-Binding Heparan Sulfate is Lost in Human Papillary Thyroid Carcinomas

“…However, the mechanism of activation of FGF-2 in carcinoma tissues is unclear, because the FGF-2 in neoplasms is indis¬ tinguishable quantitatively and qualitatively from that in normal tissues (9,10). It has been demonstrated that FGF-2 is stored in the ex¬ tracellular matrix (ECM) presumably by binding to heparan sulfate proteoglycans (11,12).…”