A theme emerging during the past few years is that members of the small leucine-rich proteoglycan gene family affect cell growth by interacting with multiple receptor tyrosine kinases (RTKs), mostly by a physical down-regulation of the receptors, thereby depriving tumor cells of pro-survival signals. Decorin binds and down-regulates several RTKs, including Met, the receptor for hepatocyte growth factor. Here we demonstrate that decorin blocks several biological activities mediated by the Met signaling axis, including cell scatter, evasion, and migration. These effects were mediated by a profound down-regulation of noncanonical ␤-catenin levels. In addition, Myc, a downstream target of ␤-catenin, was markedly down-regulated by decorin, whereas phosphorylation of Myc at threonine 58 was markedly induced. The latter is known to destabilize Myc and target it for proteasomal degradation. We also discovered that systemic delivery of decorin using three distinct tumor xenograft models caused down-regulation of Met and a concurrent suppression of ␤-catenin and Myc levels. We found that decorin protein core labeled with the near infrared dye IR800 specifically targeted the tumor cells expressing Met. Even 68-h post-injection, decorin was found to reside within the tumor xenografts with little or no binding to other tissues. Collectively, our results indicate a role for a secreted proteoglycan in suppressing the expression of key oncogenic factors required for tumor progression.Biological activities are triggered, modulated, and maintained mostly by the complex interplay among extracellular matrix molecules, multifunctional growth factors, and their surface receptors (1). Genetic and biochemical studies have revealed that many of the matrix components are indeed signaling molecules that can affect the behavior of cells during development and disease progression (2). Decorin, a prototype member of the small leucine-rich proteoglycans (SLRPs) 3 (3-8), is involved in a multitude of biological processes including collagen fibrillogenesis (9 -12), modulation of various growth factors and receptors (13-22), renal diseases (23-25), angiogenesis (26, 27), wound healing (28), myocardial infarction (29), lung and tendon mechanics (30 -32), infectious diseases (33, 34), bone and tooth development (35, 36), connective tissue development (37-41), and bone marrow stromal cell biology (42).The involvement of decorin in cancer progression has been demonstrated in mutant mice. Although the decorin-null mice do not spontaneously develop malignant neoplasms, mice carrying a targeted deletion of both decorin and the tumor suppressor p53 succumb within 3-4 months to aggressive lymphomas at a rate faster than p53-null mice alone (43), suggesting that decorin is permissive for tumorigenesis. In accordance with this study, ϳ30% of decorin-null animals, which were backcrossed into a different genetic background, displayed spontaneous occurrence of intestinal tumors, and both the tumor burden and frequency were enhanced by subjecting the mutant mi...

Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the ␣2␤1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the ␣2␤1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the ␣2␤1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express ␣2␤1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.

Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000–20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a “needle in a haystack”. This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway.