Su Weiping, Gutmann David H, Perry Arie, Abounader Roger, Laterra John, Sherman Larry S
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA.
Glia. 2004 Feb;45(3):297-306. doi: 10.1002/glia.10340.
Malignant peripheral nerve sheath tumors (MPNSTs) are invasive peripheral nerve neoplasms that express both the receptor tyrosine kinase c-Met and its ligand hepatocyte growth factor (HGF). The combined expression of these proteins has been implicated in tumor cell growth and metastasis. However, HGF/c-Met autocrine activity requires the presence of a serine protease, the HGF activator (HGFA), and, in some cells, the CD44 transmembrane glycoprotein. Here, we found that HGFA, HGF, c-Met, and CD44 are coexpressed in MPNSTs but their localization did not correlate with increased cell proliferation. The ST8814 MPNST cell line also expresses all of these proteins, can convert pro-HGF to active HGF, and exhibits constitutive c-Met phosphorylation. Blocking c-Met activity or expression inhibits the invasive behavior of these cells but not their proliferation. Interestingly, although a CD44 splice variant contributes to MPNST cell invasion and interacts with c-Met and HGF in ST8814 cells, it is not required for c-Met activation. These data indicate that an HGF/c-Met autocrine loop can promote MPNST invasion through a CD44-independent mechanism and suggest that c-Met, HGFA, and HGF are potential molecular targets to inhibit MPNST metastasis.
恶性外周神经鞘瘤（MPNSTs）是侵袭性外周神经肿瘤，表达受体酪氨酸激酶c-Met及其配体肝细胞生长因子（HGF）。这些蛋白的联合表达与肿瘤细胞的生长和转移有关。然而，HGF/c-Met自分泌活性需要丝氨酸蛋白酶HGF激活剂（HGFA）的存在，并且在某些细胞中还需要CD44跨膜糖蛋白。在这里，我们发现HGFA、HGF、c-Met和CD44在MPNSTs中共表达，但它们的定位与细胞增殖增加无关。ST8814 MPNST细胞系也表达所有这些蛋白，能将前HGF转化为活性HGF，并表现出组成性c-Met磷酸化。阻断c-Met活性或表达可抑制这些细胞的侵袭行为，但不影响其增殖。有趣的是，虽然一种CD44剪接变体有助于MPNST细胞侵袭，并在ST8814细胞中与c-Met和HGF相互作用，但它不是c-Met激活所必需的。这些数据表明，HGF/c-Met自分泌环可通过不依赖CD44的机制促进MPNST侵袭，并提示c-Met、HGFA和HGF是抑制MPNST转移的潜在分子靶点。
