The product of growth arrest-specific gene 6 (Gas6) is a unique vitamin K-dependent autocrine growth factor for mesangial cells, and warfarin inhibits mesangial cell proliferation by interfering with the activation process of Gas6
/span>. A recent series of studies has revealed the in vivo roles of Gas6 and its receptor Axl in the progression of acute and chronic glomerulonephritis, diabetic nephropathy, chronic allograft rejection, and human kidney diseases. This review summarizes these studies and discusses the possible interventions targeting the Gas6/Axl pathway to prevent the progression of kidney diseases.
Sasaki T, etal., EMBO J. 2006 Jan 11;25(1):80-7. Epub 2005 Dec 15.
Receptor tyrosine kinases of the Axl family are activated by the vitamin K-dependent protein Gas6. Axl signalling plays important roles in cancer, spermatogenesis, immunity, and platelet function. The crystal structure at 3.3 A resolution of a minimal human ... (more)
n style='font-weight:700;'>Gas6/Axl complex reveals an assembly of 2:2 stoichiometry, in which the two immunoglobulin-like domains of the Axl ectodomain are crosslinked by the first laminin G-like domain of Gas6, with no direct Axl/Axl or Gas6/Gas6 contacts. There are two distinct Gas6/Axl contacts of very different size, both featuring interactions between edge beta-strands. Structure-based mutagenesis, protein binding assays and receptor activation experiments demonstrate that both the major and minor Gas6 binding sites are required for productive transmembrane signalling. Gas6-mediated Axl dimerisation is likely to occur in two steps, with a high-affinity 1:1 Gas6/Axl complex forming first. Only the minor Gas6 binding site is highly conserved in the other Axl family receptors, Sky/Tyro3 and Mer. Specificity at the major contact is suggested to result from the segregation of charged and apolar residues to opposite faces of the newly formed beta-sheet.
BACKGROUND - AIM: In animal experiments, growth arrest-specific 6 (Gas6) protein plays a key role in the development of mesangial cell and glomerular hypertrophy in the early phase of diabetic nephropathy, and diabetic nephropathy is prevented by warfarin-indu
ced inhibition of GAS6 protein. It was shown that GAS6 intron 8 c.834 + 7G > A polymorphism is protective against type 2 diabetes mellitus, and AA genotype is associated with higher blood levels of GAS6 protein. Our aim is to investigate whether this polymorphism is a risk factor for diabetic nephropathy in type 2 diabetes mellitus. METHOD: Eighty-seven patients with diabetic nephropathy were compared with 66 non-diabetic controls in terms of GAS6 intron 8 c.834 + 7G > A polymorphism. Patients with history of stroke, ischemic heart disease were excluded. Each patient was examined by the ophthalmologist to determine diabetic retinopathy. RESULTS: Frequency of GG, GA and AA genotypes are similar in diabetic nephropathy and control groups according to GAS6 intron 8 c.834 + 7G > A polymorphism (p = .837). Rate of diabetic retinopathy was 54.02%. In the subgroup analysis, GA genotype was significantly more frequent than GG genotype in patients with diabetic retinopathy when compared to without diabetic retinopathy (p = .010). CONCLUSION: In our study, GAS6 intron 8 c.834 + 7G > A polymorphism was not associated with diabetic nephropathy in type 2 diabetes mellitus. However, heterozygous state of this polymorphism may be a risk factor for diabetic retinopathy in patients with diabetic nephropathy.
Gas6, a product of the growth-arrest-specific gene 6, protects neurons from serum deprivation-induced apoptosis. Neuronal apoptosis is also caused by amyloid beta protein (Abeta), whose accumulation in the brain is a characteristic feature of Alzheimer's disease
. Abeta induces Ca(2+) influx via L-type voltage-dependent calcium channels (L-VSCCs), leading to its neurotoxicity. In the present study, we investigated effects of Gas6 on Abeta-induced cell death in primary cultures of rat cortical neurons. Abeta caused neuronal cell death in a concentration- and time-dependent manner. Gas6 significantly prevented neurons from Abeta-induced cell death. Gas6 ameliorated Abeta-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Prior to cell death, Abeta increased influx of Ca(2+) into neurons through L-VSCCs. Gas6 significantly inhibited the Abeta-induced Ca(2+) influx. The inhibitor of L-VSCCs also suppressed Abeta-induced neuronal cell death. The present cortical cultures contained few non-neuronal cells, indicating that Gas6 affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that Gas6 rescues cortical neurons from Abeta-induced apoptosis. Furthermore, the present study indicates that inhibition of L-VSCC contributes to the neuroprotective effect of Gas6.
Axl is a receptor tyrosine kinase originally identified as a transforming gene product in human myeloid leukemia cells. Previously, we showed that Axl expression correlated with neointima formation in balloon-injured rat carotid, and that Axl expression was highly regulated by angiotensin II. In the
present study we tested the mechanisms by which Axl regulates vascular smooth muscle cell (VSMC) growth focusing on its ability to inhibit apoptosis. Treatment of cultured rat aortic VSMC for 24 h with 0% serum resulted in 19.8 +/- 1.4% apoptotic cells. Treatment of VSMC with 100 ng/ml Gas6 (the putative ligand for Axl) decreased apoptosis to 8.9 +/- 0.7% (P = 0.002, N = 17) as compared to a decrease with 10% serum to 3.0 +/- 0.2% (P = 0.001, N = 17). The ability of Gas6 to prevent apoptosis required both Gas6 binding to Axl and Axl kinase activity since treatment with a soluble, competitive Axl extracellular domain protein or transfection of a kinase inactive mutant (Axl-K567R) completely prevented the anti-apoptotic effect. Prevention of apoptosis by Gas6-Axl required activation of phosphatidyl inositol 3-kinase (PI3K) as shown by treatment with LY294002 or transfection of an Axl deletion mutant that does not bind PI3K (Axl- triangle up PI3K). There was no significant role for ERK1/2 in the anti-apoptotic effects of Gas6-Axl since ERK1/2 activity was maintained in cells transfected with Axl- triangle up PI3K and Axl-K567R. These findings establish the Gas6-Axl-PI3K-Akt pathway as an anti-apoptotic mechanism for VSMC that may be important in the response to vascular injury.
OBJECTIVE: The receptor tyrosine kinase Axl and its ligand Gas6 are involved in the development of renal diabetic disease. In vascular smooth muscle cells (VSMCs) Axl is activated by reactive oxygen species and stimulates migration and cell survival, suggesting
a role for Axl in the vascular complications of diabetes. METHODS AND RESULTS: We investigated the effect of varying glucose concentration on Axl signaling in VSMCs. Glucose exerted powerful effects on Gas6-Axl signaling with greater activation of Akt and mTOR in low glucose, and greater activation of ERK1/2 in high glucose. Plasma membrane distribution and tyrosine phosphorylation of Axl were not affected by glucose. However, coimmunoprecipitation studies demonstrated that glucose changed the interaction of Axl with its binding partners. Specifically, binding of Axl to the p85 subunit of PI3-kinase was increased in low glucose, whereas binding to SHP-2 was increased in high glucose. Furthermore, Gas6-Axl induced migration was increased in high glucose, whereas Gas6-Axl mediated inhibition of apoptosis was greater in low glucose. CONCLUSIONS: This study demonstrates a role for glucose in altering Axl signaling through coupling to binding partners and suggests a mechanism by which Axl contributes to VSMC dysfunction in diabetes.
Aghourian MN, etal., Blood. 2016 Feb 11;127(6):769-77. doi: 10.1182/blood-2015-02-628867. Epub 2015 Nov 19.
Venous thromboembolism is a common complication of cancer. Based on recent evidence that (1) growth arrest-specific 6 (Gas6) regulates the expression of tissue factor during venous thrombosis, and (2) cancer promotes a procoagulant milieu, we hypothesize that ... (more)
pan style='font-weight:700;'>Gas6 may be involved in cancer-induced coagulopathy. Venous thrombi were induced in both wild-type (WT) and Gas6-deficient ((-/-)) mice with cancer. WT mice with cancer developed larger thrombi than their healthy counterparts; these larger thrombi induced by cancer were not seen in Gas6(-/-) mice. Whole genome microarray analysis of differential gene expression in WT and Gas6(-/-) endothelial cells exposed to M27 murine lung carcinoma cells reveal that Gas6 increases prostaglandin E synthase (Ptges) expression in endothelial cells. This was confirmed using real-time polymerase chain reaction and immunofluorescence staining. Culture of WT endothelial cells with M27 increases the secretion of prostaglandin E2 (PGE2), the enzymatic product of Ptges, in WT but not in Gas6(-/-) endothelial cells. In WT endothelial cells, Ptges expression was regulated through extracellular signal-regulated kinase 1/2 phosphorylation (ERK1/2). In vitro, PGE2 activates platelets after binding to its receptor, EP3. In vivo, EP3 receptor antagonism reversed the effect of cancer-induced thrombosis in WT mice. These results show that Gas6, through upregulation of PGE2, contributes to cancer-induced venous thrombosis.
Happonen KE, etal., J Biol Chem. 2016 May 13;291(20):10586-601. doi: 10.1074/jbc.M115.699058. Epub 2016 Mar 22.
Upon activation, platelets release plasma membrane-derived microparticles (PMPs) exposing phosphatidylserine on their surface. The functions and clearance mechanism of these microparticles are incompletely understood. As they are pro-coagulant and potentially pro-inflammatory, rapid clearance from
the circulation is essential for prevention of thrombotic diseases. The tyrosine kinase receptors Tyro3, Axl, and Mer (TAMs) and their ligands protein S and Gas6 are involved in the uptake of phosphatidylserine-exposing apoptotic cells in macrophages and dendritic cells. Both TAMs and their ligands are expressed in the vasculature, the functional significance of which is poorly understood. In this study, we investigated how vascular TAMs and their ligands may mediate endothelial uptake of PMPs. PMPs, generated from purified human platelets, were isolated by ultracentrifugation and labeled with biotin or PKH67. The uptake of labeled microparticles in the presence of protein S and Gas6 in human aortic endothelial cells and human umbilical vein endothelial cells was monitored by flow cytometry, Western blotting, and confocal/electron microscopy. We found that both endothelial cell types can phagocytose PMPs, and by using TAM-blocking antibodies or siRNA knockdown of individual TAMs, we show that the uptake is mediated by endothelial Axl and Gas6. As circulating PMP levels were not altered in Gas6(-/-) mice compared with Gas6(+/+) mice, we hypothesize that the Gas6-mediated uptake is not a means to clear the bulk of circulating PMPs but may serve to locally phagocytose PMPs generated at sites of platelet activation and as a way to effect endothelial responses.
Yanagita M, etal., Am J Pathol. 2001 Apr;158(4):1423-32.
Proliferation of mesangial cells is a hallmark of glomerular disease, and understanding its regulatory mechanism is clinically important. Previously, we demonstrated that the product of growth arrest-specific gene 6 (Gas6) stimulates mesangial cell proliferation
through binding to its cell-surface receptor Axl in vitro. We also showed that warfarin and the extracellular domain of Axl conjugated with Fc portion of human IgG1 (Axl-Fc) inhibit mesangial cell proliferation by interfering the Gas6/Axl pathway in vitro. In the present study, therefore, we examined in vivo roles of Gas6 and Axl in an experimental model of mesangial proliferative glomerulonephritis induced by the injection of anti-Thy1.1 antibody (Thy1 GN). In Thy1 GN, expression of Gas6 and Axl was markedly increased in glomeruli, and paralleled the progression of mesangial cell proliferation. Administration of warfarin or daily injection of Axl-Fc inhibited mesangial cell proliferation, and abolished the induction of platelet-derived growth factor-B mRNA and protein in Thy1 GN. Moreover, the anti-proliferative effect of warfarin was achieved at lower concentrations than those in routine clinical use. These findings indicate that the Gas6/Axl pathway plays a key role in mesangial cell proliferation in vivo, and could be a potentially important therapeutic target for the treatment of renal disease.
In vascular smooth muscle cells, Axl is a key receptor tyrosine kinase, because it is upregulated in injury, increases migration and neointima formation, and is activated by reactive oxygen species. Reaction of glutathione with cysteine residues (termed "glutathiolation") is an important posttransla
tional redox modification that may alter protein activity and protein-protein interactions. To investigate the mechanisms by which reactive oxygen species increase Axl-dependent vascular smooth muscle cell function we assayed for glutathiolated proteins that associated with Axl in a redox-dependent manner. We identified glutathiolated nonmuscle myosin heavy chain (MHC)-IIB as a novel Axl interacting protein. This interaction was specific in that other myosins did not interact with Axl. The endogenous ligand for Axl, Gas6, increased production of reactive oxygen species in vascular smooth muscle cells and also increased the association of Axl with MHC-IIB. Antioxidants ebselen and N-acetylcysteine decreased the association of Axl with MHC-IIB in response to both Gas6 and reactive oxygen species. Blocking the Axl-MHC-IIB interaction with the specific myosin II inhibitor blebbistatin decreased phosphorylation of Axl and activation of extracellular signal-regulated kinase 1/2 and Akt. Association of MHC-IIB with Axl was increased in balloon-injured rat carotid vessels. Finally, expression of MHC-IIB was upregulated in the neointima of the carotid artery after balloon injury similar to upregulation of Axl protein expression, as shown in our previous studies. These results demonstrate a novel interaction between Axl and MHC-IIB in response to reactive oxygen species. This interaction provides a direct link between Axl and molecular motors crucial for directed cell migration, which may mediate increased migration in vascular dysfunction.
Gas6 (encoded by growth arrest-specific gene 6) is a vitamin-K dependent protein highly homologous to coagulation protein S that is secreted from platelet alpha-granules and has recently been demonstrated to participate in platelet thrombus formation. The curren
t study evaluated the contribution of each of the three known Gas6 receptors (Axl, Sky and Mer) in human and mouse platelet function. Flow cytometry analyses confirmed that all three receptors are present on both human and mouse platelets. Pre-incubation of human platelets with either an anti-Gas6 antibody or blocking antibodies to Sky or Mer inhibited platelet aggregation and degranulation responses to both ADP and the PAR-1 activating peptide, SFLLRN, by more than 80%. In contrast, a stimulatory anti-Axl antibody increased activation responses to these agonists, suggesting a potentiating role for Gas6 in platelet activation. Moreover, in a mouse model of thrombosis, administration of Gas6 or Sky blocking antibodies resulted in a decrease in thrombus weight similar to clopidogrel but, unlike clopidogrel, produced no increase in template bleeding. Thus, Gas6 enhances platelet degranulation and aggregation responses through its known receptors, promoting platelet activation and mediating thrombus formation such that its inhibition prevents thrombosis without increasing bleeding.
The product of the growth arrest-specific gene 6 (GAS6), a ligand for the Axl, Sky, and Mer tyrosine kinase receptors, is a vitamin K-dependent protein, structurally related to anticoagulant protein S. Gas6-deficient mice ar
e protected against thrombosis, demonstrating the importance of this protein in the cardiovascular system. The present study was aimed at determining the human GAS6 intron-exon structure and analyzing the gene for the presence of allelic variants that could be associated with atherothrombotic disease. Online analyses allowed us to localize 15 GAS6 exons and to determine the sequence of their intron-flanking regions, in a chromosome 13 region spanning 43.8 kb of DNA. SSCP analysis of PCR-amplified GAS6 exons with their intron-flanking regions from a minimum of 12 control DNA samples, revealed the presence of eight different variants, which were confirmed to be single nucleotide polymorphisms (SNPs). Three of them (c.1263G>C, c.1332C>T, and c.1869T>C) are localized in exons 11, 12, and 14, and appear to be neutral since they do not modify the encoded amino acid. The other SNPs (c.280+170C>G, c.712+26G>A, c.713-155C>T, c.834+7G>A, and c.1478-94C>G) are in introns 3, 7, 8, and 12. A preliminary analysis of five of these SNPs in a group of 110 healthy controls and 188 patients with atherothrombotic disease has revealed statistically significant differences between controls and stroke patients in the allelic distributions of one of these variants (c.834+7G>A in intron 8). The SNP identification in GAS6 reported here would be very useful in future association studies aimed at determining the physiologic role of GAS6 in stroke and other human diseases.
Shuvy M, etal., Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1829-40. doi: 10.1152/ajpheart.00240.2010. Epub 2011 Feb 18.
Renal failure is associated with aortic valve calcification. Using our rat model of uremia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular c
alcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n = 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n = 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosis-related genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.
OBJECTIVE: This study explored the level and clinical significance of serum Gas6 in patients with oral squamous cell carcinoma (OSCC). METHODS: A total of 128 OSCC patients and 145 normal controls were selected. Enzyme-linked immunosorbent assay was used to de
tect Gas6 concentration in sera from the OSCC patients and controls. The correlations of serum Gas6 concentration and clinicopathological characteristics of OSCC patients were assessed, and the prognostic significance of serum Gas6 was evaluated with a Kaplan-Meier curve and log-rank test. RESULTS: The results showed that serum Gas6 concentration was significantly higher in OSCC patients than in controls (P < 0.05). OSCC patients with late TNM stage (III, IV) had a relatively high serum Gas6 concentration compared with those with early stage (I, II) (P < 0.01) and patients with poorly differentiated tumors had a higher level of serum Gas6 than those with well-differentiated tumors (P < 0.01). Multivariate logistic regression analysis demonstrated that high serum Gas6 was an independent risk factor for lymph nodal metastases in OSCC patients (OR = 2.79, 95% CI: 1.72-4.48). For predicting OSCC development, ROC curve analysis showed a sensitivity of 0.63 with a specificity of 0.92 (AUC = 0.79, 95% CI: 0.74-0.85). Cox analysis revealed that high serum Gas6 was an independent biomarker for predicting poor overall survival in OSCC patients (HR = 2.07, 95% CI: 1.79-3.62). In addition, we found that Gas6 expression was increased in OSCC tissues and it may significantly decrease E-cadherin expression, and increase P-cadherin and N-cadherin expression, in OSCC cells. Further, Gas6 could promote the migratory and invasive ability of OSCC cells in vitro. CONCLUSION: Taken together, these results suggest that Gas6 increases the metastatic capacity of OSCC cells and serum Gas6 could be a candidate biomarker for diagnostic and prognostic use in OSCC patients.
OBJECTIVE: Preeclampsia (PE) is a hypertensive disease of pregnancy complicating 2-8% of all pregnancies. The exact pathophysiology still remains unknown. Growth arrest-specific 6 (Gas6) is a member of the vitamin K-dependent protein family and it has
been suggested as a novel atherothrombotic risk factor with anti-angiogenic and pro-atherogenic properties. The goal of the our study was to investigate the relationships between the c.834 + 7G > A polymorphism of GAS6, plasma Gas6 levels and PE. METHODS: A total of 150 women, including 82 preeclamptic pregnant women and 68 normotensive pregnant (NP) women, were recruited in the current study. Blood samples were taken from all participants. Plasma Gas6 levels measured by an enzyme-linked immunosorbent assay. GAS6 polymorphism was determined using a PCR-RFLP method. RESULTS: The plasma Gas6 levels of preeclamptic patients were significantly lower than those of NP women (8.65 ± 3.70 ng/ml and 10.89 ± 4.23 ng/ml respectively, p < 0.001). The GG genotype was the most prevalent, and the risk of PE was 3.5-fold higher in pregnant women with GG genotype compared to woman with AA genotype (p < 0.01). The A allele was less frequent in preeclamptic patients than in control subjects (OR = 2.118, 95% CI = 1.330-3.371, p < 0.001). CONCLUSIONS: Our results suggest that GAS6 c.834 + 7G > A polymorphism may have a pivotal role in the pathogenesis of PE suggesting that the A allele has a protective role for PE.
Hall MO, etal., Exp Eye Res. 2005 Nov;81(5):581-91. Epub 2005 Jun 9.
Survival of the retina requires the daily phagocytosis of photoreceptor outer segments (OS) by the overlying retinal pigment epithelium (RPE). OS phagocytosis by cultured RPE requires serum and we have recently shown that the vitamin K-dependent serum protein, Gas6
an>, can completely replace serum in this process. Surprisingly, however, we show here that 4-month-old Gas6 knockout mice have normal appearing retinas, except for a reduced ratio of outer segment to inner segment length. We also show that removal of Gas6 from serum does not abrogate the ability of serum to support OS phagocytosis by rat RPE. Both of these findings suggest the presence of an additional serum ligand that is able to support OS phagocytosis by RPE cells. Protein S (PS) is a vitamin K-dependent serum protein with a high degree of structural similarity to Gas6, and a well characterized role in blood coagulation. We report here that recombinant rat PS is able to stimulate OS phagocytosis, and similar to Gas6, it does so through a Mer-dependent mechanism. This is the first demonstration of a common role for Gas6 and PS in any biological process. The existence of redundant ligands for Mer-dependent OS phagocytosis underscores the critical role of this process in the maintenance of retinal function.
BACKGROUND & AIMS: The growth arrest-specific gene 6 (Gas6) protein is a vitamin K-dependent protein that binds to the Axl subfamily of tyrosine kinase receptors and exerts antiapoptotic and proliferative effects. Because Gas6
n> plays a role in development and tissue remodelling, we studied its expression as well as that of its high-affinity receptor Axl in a well-characterized model of hepatic regeneration from precursor oval cells. METHODS: Hepatic regeneration was induced by treating rats with acetylaminofluorene followed by partial hepatectomy. RESULTS: Oval cell accumulation, which predominated in periportal regions, reached a maximum at days 9 and 14 after hepatectomy and declined thereafter. Oval cells expressed Gas6 protein and messenger RNA (mRNA). Axl mRNA hepatic levels paralleled the number of oval cells, and immunohistochemistry showed Axl expression in these cells. WB-F344 cells, a hepatocytic precursor cell line, also expressed Gas6 and Axl. Addition of Gas6 significantly increased the number of WB-F344 cells cultured with or without serum. Gas6 did not increase cell entry in the S phase of the cell cycle but inhibited 15-d-prostaglandin J2-induced WB-F344 cell apoptosis. CONCLUSIONS: Our data demonstrate an expression of Gas6 and of its receptor Axl by oval cells during hepatic regeneration. Because the Gas6/Axl couple protects from apoptosis a hepatocytic precursor cell line, these results strongly suggest that the Gas6/Axl couple favors oval cell accumulation in regenerating liver by an autocrine/paracrine mechanism.
BACKGROUND & AIMS: Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a re
ceptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response and carcinogenesis. METHODS: HSCs were obtained from WT and Axl(-/-) mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated WT and Axl(-/-) mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. RESULTS: In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl(-/-) mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. CONCLUSIONS: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.
PURPOSE: Axl, which is in the TAM family of receptor tyrosine kinases, and its ligand, growth arrest-specific gene 6 (Gas6), have been associated with worse prognoses after the surgical treatment of some types of cancers. We herein investigated the biological si
gnificance of the protein expression of Axl and Gas6 on the outcomes of patients with upper tract urothelial carcinoma (UTUC). METHODS: The protein expression of Axl and Gas6 was evaluated by immunohistochemistry, and their relationships with clinicopathological features were investigated in surgical specimens obtained from 161 patients who had been surgically treated for UTUC. RESULTS: Axl labeling was strong in 67 of 161 (42 %) cases, while Gas6 labeling was strong in 72 of 161 (45 %) cases. The strong expression of Axl correlated with that of Gas6. A high pathological stage (p = 0.009), strong expression of Gas6 (p = 0.038), and strong expression of Axl (p = 0.016) were independent factors for predicting worse cancer-specific survival (CSS). In a subgroup analysis of patients with pT < 2 (N = 53), no significant difference in CSS was observed between patients weakly and strongly expressing Axl/Gas6. In contrast, a subgroup analysis of patients with pT >/= 2 (N = 108) revealed that the expression levels of Axl and Gas6 correlated with CSS. CONCLUSION: The protein expression of Axl and its ligand Gas6 may be a useful indicator for a worse clinical outcome in UTUC patients, especially patients with pT >/= 2, who underwent radical nephroureterectomy.
