GAS6/AXL Sinyal Yolu ve Kanserle İlişkisi
Özet
Gas6/Axl sinyal yolağı, reseptör tirozin kinaz (RTK) ailesine ait olan Axl reseptörünün, K vitaminine bağımlı Gas6 ligandı tarafından aktive edilmesiyle tetiklenen ve kanser progresyonunda kritik roller üstlenen bir mekanizmadır. Normal fizyolojik koşullarda hücre sağkalımı ve homeostazı düzenleyen bu yolak; meme, akciğer, mide ve pankreas gibi pek çok kanser türünde aşırı eksprese edilerek maligniteyi destekler. Axl aktivasyonu; PI3K/AKT, MAPK/ERK ve JAK/STAT gibi önemli hücresel yolakları uyararak kontrolsüz hücre proliferasyonunu teşvik eder ve apoptozu baskılayarak tümör hücrelerine hayatta kalma avantajı sağlar. Ayrıca bu sinyal yolağı, epitelyal-mezenkimal geçişi (EMT) indükleyerek hücrelerin göç ve istila yeteneklerini artırır, böylece metastaz oluşumunu doğrudan kolaylaştırır. Tümör mikroler çevresinde anjiyogenezi desteklemesi ve kemoterapi ile radyoterapiye karşı ilaç direnci geliştirmesi, Gas6/Axl yolağını modern kanser araştırmalarında stratejik bir biyobelirteç ve terapötik hedef haline getirmiştir. Bu kapsamda geliştirilen küçük molekül inhibitörleri ve monoklonal antikorlar, yolağın onkojenik etkilerini durdurarak hasta sağkalımını artırmayı amaçlayan gelecek vaat eden tedavi stratejileridir.
The Gas6/Axl signaling pathway is a mechanism triggered by the activation of the Axl receptor, a member of the receptor tyrosine kinase (RTK) family, by its vitamin K-dependent ligand Gas6, playing critical roles in cancer progression. While it regulates cell survival and homeostasis under normal physiological conditions, this pathway is overexpressed in various cancers such as breast, lung, gastric, and pancreatic, thereby supporting malignancy. Axl activation stimulates key cellular pathways, including PI3K/AKT, MAPK/ERK, and JAK/STAT, to promote uncontrolled cell proliferation and provides a survival advantage to tumor cells by suppressing apoptosis. Furthermore, this signaling pathway induces the epithelial-mesenchymal transition (EMT), enhancing the migration and invasion capabilities of cells, thus directly facilitating metastasis. Its role in promoting angiogenesis within the tumor microenvironment and developing resistance to chemotherapy and radiotherapy has made the Gas6/Axl pathway a strategic biomarker and therapeutic target in modern cancer research. In this context, therapeutic agents such as small molecule inhibitors and monoclonal antibodies are promising strategies aimed at halting the oncogenic effects of the pathway and improving patient survival.
Referanslar
Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell. 1988 9;54(6):787-793.
Wasilewski GB, Vervloet MG, Schurgers LJ. The Bone-Vasculature Axis: Calcium Supplementation and the Role of Vitamin K. Front. Cardiovasc. Med. 2019; 5:(6) 6.
Villoutreix BO, García de Frutos P, Lövenklev M, et al. SHBG region of the anticoagulant cofactor protein S: secondary structure prediction, circular dichroism spectroscopy, and analysis of naturally occurring mutations. Proteins. 1997; 29(4):478-491.
Kim KH, Kim EY, Kim Y, et al. Gas6 downregulation impaired cytoplasmic maturation and pronuclear formation independent to the MPF activity. PLoS One. 2011; 6(8): e23304.
Dahlbäck B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler. Thromb. Vasc. Biol. 2005; 25(7):1311-1320.
Wen L, Chen J, Duan L, Li S. Vitamin K‑dependent proteins involved in bone and cardiovascular health (Review). Mol. Med. Rep. 2018;18(1):3-15.
Sasaki T, Knyazev PG, Clout NJ, et al. Structural basis for Gas6-Axl signalling. The EMBO J. 2006;25(1):80–87.
O'Bryan JP, Frye RA, Cogswell PC, et al. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol. Cell. Biol. 1991;11(10):5016–5031.
Graham DK, DeRyckere D, Davies KD, et al. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat. Rev. Cancer. 2014;14(12):769–785.
Linger RM, Keating AK, Earp HS, et al. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv. Cancer Res. 2008; 100:35–83.
Budagian V, Bulanova E, Orinska Z, et al. Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum. Mol. Cell. Biol. 2005; 25(21):9324-9339.
Ekman C, Linder A, Akesson P, et al. Plasma concentrations of Gas6 (growth arrest specific protein 6) and its soluble tyrosine kinase receptor sAxl in sepsis and systemic inflammatory response syndromes. Crit Care. 2010;14(4): R158.
Rothlin CV, Ghosh S, Zuniga EI, et al. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell. 2007;131(6):1124–1136.
Zagorska A, Traves PG, Lew ED, et al. Diversification of TAM receptor tyrosine kinase function. Nat. Immunol. 2014;15(10):920–8.
Brand TM, Iida M, Stein AP, et al. AXL mediates resistance to cetuximab therapy. Cancer Res. 2014;74(18):5152–5164.
Mudduluru G, Ceppi P, Kumarswamy R, et al. Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. Oncogene. 2011;30(25):2888–2899.
Li R, Shi X, Ling F, et al. MiR-34a suppresses ovarian cancer proliferation and motility by targeting AXL. Tumour Biol. 2015;36(9):7277–7283.
Ott M, Litzenburger UM, Sahm F, et al. Promotion of glioblastoma cell motility by enhancer of zeste homolog 2 (EZH2) is mediated by AXL receptor kinase. PLoS One. 2012;7(10): e47663.
Mudduluru G, Allgayer H. The human receptor tyrosine kinase Axl gen promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008;28(3):161–176.
Sather S, Kenyon KD, Lefkowitz JB, et al. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Blood. 2007;109(3):1026–1033.
Valverde P. Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and downregulation. Biochem Biophys Res Commun. 2005;333(1):180–185.
Kanlikilicer P, Ozpolat B, Aslan B, et al. Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models. Mol Ther Nucleic Acids. 2017; 9:251–262.
Onken J, Torka R, Korsing S, et al. Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo. Oncotarget. 2016;7(9):9876–9889.
Hsieh MS, Yang PW, Wong LF, et al. The AXL receptor tyrosine kinase is associated with adverse prognosis and distant metastasis in esophageal squamous cell carcinoma. Oncotarget. 2016;7(24):36956–36970.
Hong CC, Lay JD, Huang JS, et al. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008;268(2):314–324.
Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010;70(4):1544–1554.
Gjerdrum C, Tiron C, Hoiby T, et al. Axl is an essential epithelial-tomesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci USA. 2010;107(3):1124–1129.
Elkabets M, Pazarentzos E, Juric D, et al. AXL mediates resistance to PI3K alpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell. 2015;27(4):533–546.
Dufies M, Jacquel A, Belhacene N, et al. Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells. Oncotarget. 2011;2(11):874–885.
Debruyne DN, Bhatnagar N, Sharma B, et al. ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT. Oncogene. 2016;35(28):3681–3691.
Corno C, Gatti L, Lanzi C, et al. Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells. Curr Med Chem. 2016;23(15):1496–512.
Burchert A, Attar EC, McCloskey P, et al. Determinants for transformation induced by the Axl receptor tyrosine kinase. Oncogene. 1998;16(24):3177–3187.
Balaji K, Vijayaraghavan S, Diao L, et al. AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers. Mol Cancer Res. 2017;15(1):45–58.
Maacha S, Hong J, von Lersner A, et al. AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking. Neoplasia. 2018; 20(10):1008–1022.
Fujimori T, Grabiec AM, Kaur M, et al. The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung. Mucosal Immunol. 2015;8(5):1021–1030.
Burstyn-Cohen T, Heeb MJ, Lemke G. Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J. Clin. Investig. 2009; 119, 2942–2953.
Angelillo-Scherrer A, Burnier L, Flores N, et al. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J. Clin. Investig. 2005; 115(2): 237-246.
Van Der Meer JHM, Van Der Poll T, Van’t Veer C. TAM receptors, Gas6, and protein S: Roles in inflammation and hemostasis. Blood. 2014, 123, 2460–2469.
Caberoy NB, Alvarado G, Bigcas JL, et al. Galectin-3 is a new MerTK-specific eat-me signal. J Cell Physiol. 2012;227(2):401–7.
Caberoy NB, Zhou Y, Li W. Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis. The EMBO J. 2010;29(23):3898–910.
Wu X, Liu X, Koul S, et al. AXL kinase as a novel target for cancer therapy. Oncotarget. 2014;5(20):9546–63.
Braunger J, Schleithoff L, Schulz AS, et al. Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site. Oncogene. 1997;14(22):2619–31.
Fridell YW, Jin Y, Quilliam LA, et al. Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase. Mol Cell Biol. 1996;16(1):135–45.
Bellosta P, Costa M, Lin DA, et al. The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding. Mol Cell Biol. 1995;15(2):614–25.
Meyer AS, Miller MA, Gertler FB, et al. The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells. Sci Signal. 2013;6(287):ra66.
Vouri M, Croucher DR, Kennedy SP, et al. Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells. Oncogenesis. 2016;5(10):e266.
Mudduluru, G. Axl and its mediated Signaling Axis in cancer. Johannes Haybaeck (Ed.), Mechanisms of molecular carcinogenesis. Switzerland: Springer International Publishing. 2017; 39-60.
Wimmel A, Glitz D, Kraus A, et al. Axl receptor tyrosine kinase expression in human lung cancer cell lines correlates with cellular adhesion. Eur J Cancer. 2001; 37(17):2264-2274.
Zhang YX, Knyazev PG, Cheburkin YV, et al. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res. 2008;68(6):1905-1915.
Rankin EB, Fuh KC, Taylor TE, et al. AXL is an essential factor and therapeutic target for metastatic ovarian cancer. Cancer Res. 2010; 70(19):7570-7579.
Wu CW, Li AF, Chi CW, et al. Clinical significance of AXL kinase family in gastric cancer. Anticancer Res. 2002;22(2B):1071-1078.
Shikawa M, Sonobe M, Nakayama E, et al. Higher expression of receptor tyrosine kinase Axl, and differential expression of its ligand, Gas6, predict poor survival in lung adenocarcinoma patients. Ann. Surg. Oncol. 2013; 20 (3), 467–476.
Tanaka K, Tokunaga E, Inoue Y, et al. Impact of Expression of Vimentin and Axl in Breast Cancer. Clin. Breast Cancer 2016;16: 520–526.
Lozneanu L, Pinciroli P, Ciobanu DA, et al. Computational and Immunohistochemical Analyses Highlight AXL as a Potential Prognostic Marker for Ovarian Cancer Patients. Anticancer Res. 2016; 36, 4155–4163.
Cardone C, Blauensteiner B, Moreno-ViedmaV, et al. AXL is a predictor of poor survival and of resistance to anti-EGFR therapy in RAS wild-type metastatic colorectal cancer. Eur. J. Cancer 2020; 138: 1–10.
Liu J, Wang K, Yan Z, et al. Axl Expression Stratifies Patients with Poor Prognosis after Hepatectomy for Hepatocellular Carcinoma. PLoS ONE. 2016; 11: e0154767.
Bottai G, Raschioni C, Szekely B, et al. AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients. NPJ Breast Cancer 2016; 2: 16033.
Mudduluru G, Vajkoczy P, Allgayer H. Myeloid zinc finger 1 induces migration, invasion, and in vivo metastasis through Axl gene expression in solid cancer. Mol Cancer Res. 2010;8(2):159–69.
Martinelli E, Martini G, Cardone C, et al. AXL is an oncotarget in human colorectal cancer. Oncotarget. 2015; 15;6(27):23281-96.
Huang M, Liu M, Huang D, et al. Tumor perivascular cell-derived extracellular vesicles promote angiogenesis via the Gas6/Axl pathway. Cancer Lett. 2022; 524:131-143.
Sawabu T, Seno H, Kawashima T, et al. Growth arrest-specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathway. Mol Carcinog. 2007;46(2):155-64.
He L, Lei Y, Hou J, et al. Implications of the Receptor Tyrosine Kinase Axl in Gastric Cancer Progression. Onco Targets Ther. 2020;22 (13): 5901-5911.
Bae CA, Ham IH, Oh HJ, et al. Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma. Gastric Cancer. 2020; 23(5):824-836.
D'Alfonso TM, Hannah J, Chen Z, et al. Axl receptor tyrosine kinase expression in breast cancer. J Clin Pathol. 2014;67(8):690-696.
Wang C, Jin H, Wang N, et al. Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling. Theranostics. 2016 ;6(8):1205-1219.
Leconet W, Chentouf M, du Manoir S, et al. Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis. Clin Cancer Res. 2017; 23(11):2806-2816.
Ishikawa M, Sonobe M, Nakayama E, et al. Higher expression of receptor tyrosine kinase Axl, and differential expression of its ligand, Gas6, predict poor survival in lung adenocarcinoma patients. Ann Surg Oncol. 2013;20 (3):S467-76.
Wang D, Bi L, Ran J, et al. Gas6/Axl signaling pathway promotes proliferation, migration and invasion and inhibits apoptosis in A549 cells. Exp Ther Med. 2021;22(5):1321.
Kanzaki R, Naito H, Kise K, et al. Gas6 derived from cancer-associated fibroblasts promotes migration of Axl-expressing lung cancer cells during chemotherapy. Sci Rep. 2017;7(1):10613.
Choi YJ, Kim JH, Rho JK, et al. AXL and MET receptor tyrosine kinases are essential for lung cancer metastasis. Oncol Rep. 2017;37(4):2201-2208.
Song X, Wang H, Logsdon CD, et al. Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer. 2011 15;117(4):734-743.
Koorstra JB, Karikari CA, Feldmann G, et al. The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther. 2009;8(7):618-626.
Ludwig KF, Du W, Sorrelle NB, et al. Small-Molecule Inhibition of Axl Targets Tumor Immune Suppression and Enhances Chemotherapy in Pancreatic Cancer. Cancer Res. 2018 78(1):246-255. doi: 10.1158/0008-5472.
Rea K, Pinciroli P, Sensi M, et al. Novel Axl-driven signaling pathway and molecular signature characterize high-grade ovarian cancer patients with poor clinical outcome. Oncotarget. 2015; 6(31):30859-75. doi: 10.18632/oncotarget.5087.
Hutterer M, Knyazev P, Abate A, et al. Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res. 2008; 14(1):130-138. doi: 10.1158/1078-0432.CCR-07-0862.
Avilla E, Guarino V, Visciano C, et al. Activation of TYRO3/AXL tyrosine kinase receptors in thyroid cancer. Cancer Res. 2011;71(5):1792-804. doi: 10.1158/0008-5472.
Ben-Batalla I, Schultze A, Wroblewski M, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 2013 Oct 3;122(14):2443-52. doi: 10.1182/blood-2013-03-491431.
Xu J, Jia L, Ma H, et al. Axl gene knockdown inhibits the metastasis properties of hepatocellular carcinoma via PI3K/Akt-PAK1 signal pathway. Tumour Biol. 2014; 35(4):3809-17. doi: 10.1007/s13277-013-1521-5.
Lee HJ, Jeng YM, Chen YL, et al. Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma. Carcinogenesis. 2014; 35(4):769-75. doi: 10.1093/carcin/bgt372.
Batur T, Argundogan A, Keles U, et al. AXL Knock-Out in SNU475 Hepatocellular Carcinoma Cells Provides Evidence for Lethal Effect Associated with G2 Arrest and Polyploidization. Int J Mol Sci. 2021; 22(24):13247. doi: 10.3390/ijms222413247.
Paccez JD, Vasques GJ, Correa RG, et al. The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target. Oncogene. 2013;32(6):689-98. doi: 10.1038/onc.2012.89.
Axelrod HD, Valkenburg KC, Amend SR, et al. AXL Is a Putative Tumor Suppressor and Dormancy Regulator in Prostate Cancer. Mol Cancer Res. Molecular Cancer Research. 2019;17(2):356-369. doi: 10.1158/1541-7786.MCR-18-0718.
Han J, Tian R, Yong B, et al. Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients. Biochem Biophys Res Commun. 2013;435(3):493-500. doi: 10.1016/j.bbrc.2013.05.019.
Li Q, Wang X, Jiang N, et al. Exosome-transmitted linc00852 associated with receptor tyrosine kinase AXL dysregulates the proliferation and invasion of osteosarcoma. Cancer Med. 2020; (17):6354-6366. doi: 10.1002/cam4.3303.
Janssen JW, Schulz AS, Steenvoorden AC, et al. A novel putative tyrosine kinase receptor with oncogenic potential. Oncogene. 1991;6(11):2113-20.
Varnum BC, Young C, Elliott G, et al. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature. 1995;373(6515):623-6. doi: 10.1038/373623a0.
Bellosta P, Zhang Q, Goff SP, et al. Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation. Oncogene. 1997 Nov 13;15(20):2387-97. doi: 10.1038/sj.onc.1201419.
Goruppi S, Ruaro E, Schneider C. Gas6, the ligand of Axl tyrosine kinase receptor, has mitogenic and survival activities for serum starved NIH3T3 fibroblasts. Oncogene. 1996;12(3):471–80.
Allen MP, Zeng C, Schneider K, et al. Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt. J. Mol. Endocrinol. 1999 Feb;13(2):191-201. doi: 10.1210/mend.13.2.0230.
May CD, Garnett J, Ma X, et al. AXL is a potential therapeutic target in dedifferentiated and pleomorphic liposarcomas. BMC Cancer. 2015; 15:901.
Katagiri M, Hakeda Y, Chikazu D, et al. Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, a receptor tyrosine kinase signaling, in mouse osteoclasts. Int. J. Biol. Chem. 2001;276(10):7376–82.
Sinha S, Boysen J, Nelson M, et al. Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B Cells to Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK Inhibitors. Clin. Cancer Res. 2015;21(9):2115–26.
Bell JB, Eckerdt FD, Alley K, et al. MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma. Mol. Cancer Res. 2016;14(10):984–93.
Sainaghi PP, Castello L, Bergamasco L, et al. Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. J. Cell. Physiol. 2005;204(1):36–44.
Yuen HF, McCrudden CM, Huang YH, et al. TAZ expression as a prognostic indicator in colorectal cancer. PLoS One. 2013;8(1):e54211.
Lay JD, Hong CC, Huang JS, et al. Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL. Cancer Res. 2007;67(8):3878–87.
Tai KY, Shieh YS, Lee CS, et al. Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1. Oncogene. 2008;27(29):4044– 55.
Wang X, Saso H, Iwamoto T, et al. TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase. Cancer Res. 2013;73(21):6516–25.
Li Y, Ye X, Tan C, et al. Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene. 2009;28(39):3442–55.
Shieh YS, Lai CY, Kao YR, et al. Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia. 2005;7(12):1058–64.
Zdżalik-Bielecka D, Poświata A, Kozik K, et al. The GAS6-AXL signaling pathway triggers actin remodeling that drives membrane ruffling, macropinocytosis, and cancer-cell invasion. PNAS USA. 2021;118(28):e2024596118. doi: 10.1073/pnas.2024596118.
Abu-Thuraia A, Goyette MA, Boulais J, et al. AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network. Nat. Commun. 2020;11(1):3586. doi: 10.1038/s41467-020-17415-x.
Özkara G, Öztürk O and Aydoğan HY. Kanser ve Metastaz: Hücre Adezyon Molekülleri ve Hücreler Arası Bağlantıların Önemi. Experimed. 2020; 10(1): 38-48.
Chen T, You Y, Jiang H, et al. Epithelial-mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis. J. Cell. Physiol. 2017;232(12):3261–72.
Nieto MA. Epithelial-Mesenchymal Transitions in development and disease: old views and new perspectives. Int. J. Dev. Biol.2009;53(8–10):1541–7.
Sokeland G, Schumacher U. The functional role of integrins during intra- and extravasation within the metastatic cascade. Mol. Cancer. 2019; 18:12.
Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–890.
Gjerdrum C, Tiron C, Hoiby T, et al. Axl is an essential epithelial-tomesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proceedings of the National Academy of Sciences of The United States Of America (PNAS). 2010;107(3):1124–1129.
Goyette MA, Duhamel S, Aubert L, et al. The Receptor Tyrosine Kinase AXL Is Required at Multiple Steps of the Metastatic Cascade during HER2-Positive Breast Cancer Progression. Cell Rep. 2018;23(5):1476–1490.
Cichon MA, Szentpetery Z, Caley MP, et al. The receptor tyrosine kinase Axl regulates cell-cell adhesion and stemness in cutaneous squamous cell carcinoma. Oncogene. 2014;33(32):4185–4192.
Asiedu MK, Beauchamp-Perez FD, Ingle JN, et al. AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells. Oncogene. 2014;33(10):1316–1324.
Singh M, Yelle N, Venugopal C, et al. EMT: Mechanisms and therapeutic implications. J. Pharmacol. Exp. Ther. 2018;182:80–94.
Lin JZ, Wang ZJ, De W, Zheng M, Xu WZ, Wu HF, Armstrong A, Zhu JG. Targeting AXL overcomes resistance to docetaxel therapy in advanced prostate cancer. Oncotarget. 2017;8(25):41064–41077.
Vural P. Fizyolojik ve Patolojik Anjiogenezde Vasküler Endotelyal Büyüme Faktörünün Rolü. Turk J Bıochem. 2018; 16(1): 53-62.
Fridell YW, Villa J Jr, Attar EC, et al. GAS6 induces Axl-mediated chemotaxis of vascular smooth muscle cells. J. Biol. Chem. 1998;273(12):7123–6.
Ramjiawan RR, Griffioen AW and Duda DG. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis. 2017;20(2):185–204.
Ruan GX, Kazlauskas A. Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis. J. Biol. Chem. 2013;288(29):21161–21172.
Holland SJ, Powell MJ, Franci C, et al. Multiple roles for the receptor tyrosine kinase axl in tumor formation. Cancer Res. 2005;65(20):9294–92303.
Gallicchio M, Mitola S, Valdembri D, et al. Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood. 2005;105(5):1970–1976.
Xiao Y, Zhao H, Tian L, et al. S100A10 is a critical mediator of GAS6/AXL-induced angiogenesis in renal cell carcinoma. Cancer Res. 2019. https://doi.org/10.1158/0008-5472.
Ben-Batalla I, Erdmann R, Jorgensen H, et al. Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia. Clin. Cancer Res. 2017;23(9):2289–2300.
Schoumacher M, Burbridge M. Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies. Curr. Oncol. Rep. 2017;19(3):19.
Huang M, Liu M, Huang D, et al. Tumor perivascular cell-derived extracellular vesicles promote angiogenesis via the Gas6/Axl pathway. Cancer Lett. 2022; 524:131-143. doi: 10.1016/j.canlet.2021.10.023.
