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

Zhang, Sheng; Xu, Xiangjie; Yang, Jie; Guo, Jian; Chao, Teng Fei; Tong, Yuru

doi:10.2147/ott.s150952

Cited by 29 publications

(22 citation statements)

References 49 publications

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“…Our investigation of the prognostic value of AXL and c-ABL indicated that high expression levels of these proteins in EAC patients were significantly associated with low patient survival and poor prognosis. Our results support the reports from other studies showing a strong association of AXL expression with poor prognosis in solid malignancies [24]. In addition, activation and overexpression of c-ABL have been associated with poor clinical outcome in solid tumors [13,25].…”

Section: Discussionsupporting

confidence: 92%

Co-overexpression of AXL and c-ABL predicts a poor prognosis in esophageal adenocarcinoma and promotes cancer cell survival

Hong¹,

Abid²,

Phillips³

et al. 2020

J. Cancer

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Background: Esophageal adenocarcinoma (EAC) is highly aggressive and characterized by poor prognosis. AXL expression has been linked to Barrett's tumorigenesis and resistance to chemotherapy, which is associated with c-ABL intracellular localization. However, the molecular and functional relationship between AXL and c-ABL and the clinical significance of the co-expression of these proteins in EAC remain unclear. Methods: We used immunohistochemical analysis (IHC) on tissue microarrays containing human EAC samples (n=53) and normal esophageal tissues (n=11) in combination with corresponding deidentified clinicopathological information to evaluate the expression and the prognostic significance of AXL and c-ABL in EAC. The data were statistically analyzed using Kruskal-Wallis, the chi-square, the Fisher's exact, and Pearson tests. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate cancer patient survival. We used a serum deprivation EAC cell model to investigate the pro-survival function of AXL and c-ABL using cell viability, apoptosis, and lactate dehydrogenase activity assays. We performed in vitro assays, including Western blotting, quantitative real-time PCR, and translational chromatin immunoprecipitation (TrIP-Chip) to study the molecular relationship between AXL and c-ABL in EAC cells. Results: IHC analysis revealed that AXL and c-ABL were overexpressed in 55% and 66% of EAC samples, respectively, as compared to normal tissues. Co-overexpression of the two proteins was observed in 49% of EAC samples. The chi-square test indicated a significant association between AXL and c-ABL expression in the EAC samples (χ 2 = 6.873, p = 0.032), and the expression of these proteins was significantly associated with EAC patient age (p < 0.001), tumor stage (p < 0.01), and lymph node status (p < 0.001). AXL and c-ABL protein expression data analysis exhibited an identical clinicopathological association profile. Additionally, we found a significant association between expression of AXL (χ 2 = 16.7, p = 0.002) or c-ABL (χ 2 = 13.4, p = 0.001) and survival of EAC patients. The Cox proportional hazards model and log rank test predicted a significant increase in mortality of patients with high expression of AXL [hazard ratio (HR): 2.86, 95% confidence interval (CI): 1.53-5.34, p = 0.003] or c-ABL [HR: 3.29, 95% CI: 1.35-8.03, p = 0.001] as compared to those patients with low expression of AXL or c-ABL proteins. Molecular investigations indicated that AXL positively regulates c-ABL protein expression through increased cap-dependent protein translation involving phosphorylation of EIF4E in EAC cells. Next, we investigated the functional relationship between AXL and c-ABL in EAC cells. We demonstrated that the pro-survival activity of AXL requires c-ABL expression in response to serum deprivation. Conclusion: This study highlights the importance of the co-overexpression of AXL and c-ABL proteins as a valuable prognostic biomarker and targeting these proteins could be an effective therapeutic...

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Section: Discussionsupporting

confidence: 92%

Co-overexpression of AXL and c-ABL predicts a poor prognosis in esophageal adenocarcinoma and promotes cancer cell survival

Hong¹,

Abid²,

Phillips³

et al. 2020

J. Cancer

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“…AXL expression was found to be a poor prognostic marker for OS and disease‐free survival after complete resection of early‐stage NSCLC . In advanced NSCLC, PFS for EGFR‐TKI treatment tended to be shorter in patients with AXL expression scores of 3+ than in those with scores of 0 to 2+, although the difference was not statistically significant.…”

Section: Discussionmentioning

confidence: 94%

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR‐mutated non–small cell lung cancer

et al. 2019

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Background Non‐small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR‐tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one‐fifth of NSCLC patients with acquired resistance to EGFR‐TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown. Methods Tumor tissue and plasma specimens were collected from 25 EGFR‐mutated NSCLC patients before EGFR‐TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme‐linked immunosorbent assays. Results AXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR‐TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue. Conclusion Plasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR‐mutated NSCLC.

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“…Moreover, AXL has emerged as a therapeutic drug target for TNBC treatment (65,66). In fact, AXL-CAR-T cell therapy in TNBC led to significant in vitro cytotoxicity and cytokine secretion as well as a reduction in tumor growth in an MDA-MB-231 xenograft mouse model (67).…”

Section: Receptor Tyrosine Kinase Axlmentioning

confidence: 99%

Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer

Dees

Ganesan

Singh

et al. 2020

Molecular Cancer Therapeutics

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

Cited by 29 publications

References 49 publications

Co-overexpression of AXL and c-ABL predicts a poor prognosis in esophageal adenocarcinoma and promotes cancer cell survival

Co-overexpression of AXL and c-ABL predicts a poor prognosis in esophageal adenocarcinoma and promotes cancer cell survival

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR‐mutated non–small cell lung cancer

Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer

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