The prognostic role of Gas6/Axl axis in solid malignancies: a meta-analysis and literature review

Sheng Zhang, Xiang Shang Xu, Jie Xi Yang, Jian Hui Guo, Teng Fei Chao, YiXin Tong, Sheng Zhang, Xiang Shang Xu, Jie Xi Yang, Jian Hui Guo, Teng Fei Chao, YiXin Tong

Abstract

Background: Axl is a receptor tyrosine kinase that is involved in many pathological conditions and carcinogenesis. Gas6 is the major ligand of Axl. Activation of Gas6/Axl pathway is essential for cancer development. However, its prognostic significance in solid tumors remains unclear. Therefore, we performed this meta-analysis to elucidate the prognostic impact of Axl.

Methods: Published studies on Axl or Gas6 expression and overall survival (OS) and/or disease-free survival (DFS) were searched from databases. The outcome measurement is hazard ratio (HR) for OS or DFS related to Axl/Gas6 expression. Meta-analysis was performed using RevMan. The pooled HR was calculated by fixed-/random-effect models.

Results: A total of 3,344 patients from 25 studies were included. The results of meta-analysis showed that Axl overexpression was correlated with shorter OS (HR: 2.03, p<0.0001) and DFS (HR: 1.85, p<0.0001). In subgroup analysis, Axl expression was significantly correlated with poor prognosis in hepatocellular, esophageal and lung cancer. Axl expression was associated with differentiation grade, TNM stage, lymph node and distant metastasis.

Conclusion: These results suggest that Axl overexpression is correlated with poor prognosis in solid tumors. This correlation varies among different types of cancers. More studies are needed to further investigate the prognostic value of Axl.

Keywords: Gas6/Axl; biomarker; disease-free survival; meta-analysis; overall survival; prognosis; solid tumor.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flow chart of the selection process. Abbreviations: DFS, disease-free survival; OS, overall survival.
Figure 2
Figure 2
Forest plot of the hazard ratio for overall survival associated with Axl expression in all solid tumor patients. Abbreviations: CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 3
Figure 3
Forest plots of the hazard ratio for overall survival associated with Axl expression in breast cancer (A), liver cancer (B), esophageal cancer (C) and lung cancer (D). Abbreviations: CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 4
Figure 4
Forest plot of the hazard ratio for disease-free survival associated with Axl expression in all solid tumor patients. Abbreviations: CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 5
Figure 5
Forest plot of the hazard ratio for overall survival associated with Gas6 expression in all solid tumor patients. Abbreviations: CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 6
Figure 6
Relationship between Axl expression and poor differentiation grade (A), late (III/IV stage) TNM stage (B), lymph node metastasis (C) and distant metastasis (D) in all solid tumor patients. Abbreviations: CI, confidence interval; LN, lymph node; M–H, Mantel–Haenszel.
Figure 7
Figure 7
Funnel plots of HR of Axl expression for OS (A) and DFS (B) in all solid tumor patients. Abbreviations: DFS, disease-free survival; HR, hazard ratio; Ln, natural logarithm; OS, overall survival; SE, standard error.
Figure 8
Figure 8
Funnel plot of HR of Gas6 expression for OS in all solid tumor patients. Abbreviations: HR, hazard ratio; OS, overall survival; SE, standard error.

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2017;67(1):7–30.
    1. Janssen JW, Schulz AS, Steenvoorden AC, et al. A novel putative tyrosine kinase receptor with oncogenic potential. Oncogene. 1991;6(11):2113–2120.
    1. 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.
    1. Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol. 2008;8(5):327–336.
    1. Brown M, Black JR, Sharma R, Stebbing J, Pinato DJ. Gene of the month: Axl. J Clin Pathol. 2016;69(5):391–397.
    1. Feneyrolles C, Spenlinhauer A, Guiet L, et al. Axl kinase as a key target for oncology: focus on small molecule inhibitors. Mol Cancer Ther. 2014;13(9):2141–2148.
    1. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.
    1. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.
    1. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics REporting recommendations for tumour MARKer prognostic studies (REMARK) Eur J Cancer. 2005;41(12):1690–1696.
    1. Zhang S, Tong YX, Xu XS, Lin H, Chao TF. Prognostic significance of SATB1 in gastrointestinal cancer: a meta-analysis and literature review. Oncotarget. 2017;8(29):48410–48423.
    1. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634.
    1. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–1101.
    1. Mc Cormack O, Chung WY, Fitzpatrick P, et al. Growth arrest-specific gene 6 expression in human breast cancer. Br J Cancer. 2008;98(6):1141–1146.
    1. 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.
    1. Gustafsson A, Martuszewska D, Johansson M, et al. Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival. Clin Cancer Res. 2009;15(14):4742–4749.
    1. Gjerdrum C, Tiron C, Høiby T, et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010;107(3):1124–1129.
    1. Hector A, Montgomery EA, Karikari C, et al. The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma. Cancer Biol Ther. 2010;10(10):1009–1018.
    1. 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;117(4):734–743.
    1. Lee CH, Yen CY, Liu SY, et al. Axl is a prognostic marker in oral squamous cell carcinoma. Ann Surg Oncol. 2012;19(Suppl 3):S500–S508.
    1. Chen PX, Li QY, Yang Z. Axl and prostasin are biomarkers for prognosis of ovarian adenocarcinoma. Ann Diagn Pathol. 2013;17(5):425–429.
    1. 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.
    1. 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(Suppl 3):S467–S476.
    1. Akitake-Kawano R, Seno H, Nakatsuji M, et al. Inhibitory role of Gas6 in intestinal tumorigenesis. Carcinogenesis. 2013;34(7):1567–1574.
    1. Pinato DJ, Mauri FA, Lloyd T, et al. The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma. Br J Cancer. 2013;108(3):621–628.
    1. Dunne PD, McArt DG, Blayney JK, et al. AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early-stage colon cancer. Clin Cancer Res. 2014;20(1):164–175.
    1. Fleuren ED, Hillebrandt-Roeffen MH, Flucke UE, et al. The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma. Oncotarget. 2014;5(24):12753–12768.
    1. Brand TM, Iida M, Stein AP, et al. AXL is a logical molecular target in head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(11):2601–2612.
    1. Hsieh MS, Yang PW, Wong LF, Lee JM. The AXL receptor tyrosine kinase is associated with adverse prognosis and distant metastasis in esophageal squamous cell carcinoma. Oncotarget. 2016;7(24):36956–36970.
    1. Jiang C, Zhou L, Wang H, Zhang Q, Xu Y. Axl is a potential cancer prognostic marker for the migration and invasion of nasopharyngeal carcinoma. Adv Clin Exp Med. 2016;25(3):531–537.
    1. Qu XH, Liu JL, Zhong XW, Li XI, Zhang QG. Insights into the roles of hnRNP A2/B1 and AXL in non-small cell lung cancer. Oncol Lett. 2015;10(3):1677–1685.
    1. Reichl P, Dengler M, van Zijl F, et al. Axl activates autocrine transforming growth factor-β signaling in hepatocellular carcinoma. Hepatology. 2015;61(3):930–941.
    1. Hattori S, Kikuchi E, Kosaka T, et al. Relationship between increased expression of the Axl/Gas6 signal cascade and prognosis of patients with upper tract urothelial carcinoma. Ann Surg Oncol. 2016;23(2):663–670.
    1. Liu J, Wang K, Yan Z, et al. Axl expression stratifies patients with poor prognosis after hepatectomy for hepatocellular carcinoma. PLoS One. 2016;11(5):e0154767.
    1. Roland CL, May CD, Watson KL, et al. Analysis of clinical and molecular factors impacting oncologic outcomes in undifferentiated pleomorphic sarcoma. Ann Surg Oncol. 2016;23(7):2220–2228.
    1. Tanaka K, Tokunaga E, Inoue Y, et al. Impact of expression of vimentin and Axl in breast cancer. Clin Breast Cancer. 2016;16(6):520–526.
    1. Wang C, Jin H, Wang N, et al. Gas6/Axl axis contributes to chemore-sistance and metastasis in breast cancer through Akt/GSK-3β/β-catenin signaling. Theranostics. 2016;6(8):1205–1219.
    1. Jin G, Wang Z, Wang J, et al. Expression of Axl and its prognostic significance in human breast cancer. Oncol Lett. 2017;13(2):621–628.
    1. Lee HJ, Jeng YM, Chen YL, Chung L, Yuan RH. Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma. Carcinogenesis. 2014;35(4):769–775.
    1. Wimmel A, Glitz D, Kraus A, Roeder J, Schuermann M. Axl receptor tyrosine kinase expression in human lung cancer cell lines correlates with cellular adhesion. Eur J Cancer. 2001;37(17):2264–2274.
    1. Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012;44(8):852–860.
    1. Elkabets M, Pazarentzos E, Juric D, et al. AXL mediates resistance to PI3Ka inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell. 2015;27(4):533–546.
    1. D’Alfonso TM, Hannah J, Chen Z, Liu Y, Zhou P, Shin SJ. Axl receptor tyrosine kinase expression in breast cancer. J Clin Pathol. 2014;67(8):690–696.
    1. Liu L, Greger J, Shi H, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009;69(17):6871–6878.
    1. 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.
    1. Vuoriluoto K, Haugen H, Kiviluoto S, et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2011;30(12):1436–1448.
    1. Sun WS, Fujimoto J, Tamaya T. Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine endometrial cancers. Ann Oncol. 2003;14(6):898–906.
    1. 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):155–164.
    1. Jiang T, Liu G, Wang L, Liu H. Elevated serum Gas6 is a novel prognostic biomarker in patients with oral squamous cell carcinoma. PLoS One. 2015;10(7):e0133940.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit