Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients

Han, Ju; Tian, Rui; Yong, Bicheng; Luo, Canqiao; Tan, Pingxian; Shen, Jingnan; Peng, Tingsheng

doi:10.1016/j.bbrc.2013.05.019

Cited by 97 publications

(105 citation statements)

References 21 publications

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“…However, the rate has been stagnant for 30 years, and disease prognosis is particularly poor for patients with recurrent and metastatic disease, partially due to the emergence of chemotherapy resistance. The abnormal control of cell proliferation in osteosarcoma has been linked to the suppression of apoptosis [15] , increased MMP expression [12,16] and the genetic alteration of oncogenes that regulate the cell cycle [17,18] .…”

Section: Introductionmentioning

confidence: 99%

Icaritin suppresses the proliferation of human osteosarcoma cells in vitro by increasing apoptosis and decreasing MMP expression

Wang

2014

Acta Pharmacol Sin

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Aim: To explore whether icaritin, a prenylflavonoid derivative of the Chinese tonic herb Epimedium, could suppress the proliferation of human osteosarcoma cells in vitro, and to elucidate the mechanisms of the action. Methods: Human osteosarcoma SaOS 2 cell line was used in the present study. The proliferation of the cells was examined using MTT assay and immunofluorescence DAPI staining. Cell motility was studied with the scratch assay. Cell apoptosis was determined by Annexin V-FITC and PI double staining using flow cytometry. Western blotting and RT-PCR were used to measure the expression of mRNAs and proteins in the cells. Results: Icaritin (5-15 μmol/L) suppressed the proliferation of SaOS 2 cells in vitro in a dose-dependent manner. Furthermore, the cell motility was significantly decreased after exposure to icaritin. Moreover, icaritin (5 μmol/L) time-dependently induced the apoptosis of SaOS 2 cells, markedly suppressed MMP-2 and MMP-9 expression, upregulated caspase-3 and caspase-9 expression, and increased the level of cleaved caspase-3 in the cells. Co-exposure to the caspase-3 inhibitor zVAD-fmk (10 μmol/L) compromised the icaritininduced caspase-3 expression and apoptosis in SaOS 2 cells. Conclusion: Icaritin suppresses the proliferation of SaOS 2 human osteosarcoma cells by increasing apoptosis and downregulating MMP expression.

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Section: Introductionmentioning

confidence: 99%

Icaritin suppresses the proliferation of human osteosarcoma cells in vitro by increasing apoptosis and decreasing MMP expression

Wang

2014

Acta Pharmacol Sin

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“…It is known that protein growth arrest specific 6 (Gas6) and protein S are two homologous proteins which depend on vitamin K for their biological functions. Gas6 can interact with receptor tyrosine kinases of the TAM family (Tyro-3, Axl, Mer), and alternated activity/expression of Gas6-Axl system is associated with the development of cancer [32,33].…”

Section: Discussionmentioning

confidence: 99%

Risk of breast cancer among patients with bioprosthetic or mechanical valve replacement: a population-based study in Sweden

Zöller

Giaccia

et al. 2015

Breast Cancer Res Treat

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The association between breast cancer and warfarin is inconclusive as most previous studies examined their association using patients with thromboembolism, whereas thromboembolism itself is a risk factor for cancer. We explored this issue using patients received mechanical heart valves replacement as a proxy for warfarin exposure as these patients need a lifelong warfarin treatment, and compared them with patients received bioprosthesis valves replacement (short-term warfarin treatment) in Sweden between 1987 and 2010. Patients who were operated on for valve replacement were identified from the Swedish Hospital Discharge Registry and linked to the Swedish Cancer Registry to examine the hazard ratios of subsequent breast cancer. A total of 12,242 women were operated on for valve replacement (5481 with mechanical valve and 6401 with bioprosthetic valve). For the entire cohort, the HR of breast cancer was 1.49 (95 % CI 1.09-2.02) among patients with mechanical valve replacement compared to those with bioprosthetic valve replacement. After controlling for a number of confounding factors using propensity score weighting, the HR was 1.69 (95 % CI 1.15-2.47). Our study found that patients with mechanical valve replacement have an increased risk of breast cancer compared to those with bioprosthetic valve replacement. If confirmed, this increased risk should be considered when recommending breast cancer screening for women with mechanical valve replacement. Long-term use of warfarin may explain the observed increase. If so, patients who have used warfarin long-term for other reasons should be studied for a possible increased risk of breast cancer.

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“…AXL-mediated downstream signaling events resulting in cell migration have been heavily studied [12,27,28], but the AXL activation mechanism responsible for this phenotype has been largely unknown. Localized Gas6 that is bound to PS on extracellular vesicles was previously reported to mediate ligand-dependent AXL activation [17], and the present study demonstrates that this lipid-ligand-induced AXL signaling enhances cell motility.…”

Section: Discussionmentioning

confidence: 99%

Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells

Zweemer

French

Mesfin

et al. 2017

Molecular Cancer Research

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Metastases are a major cause of cancer mortality. AXL, a receptor tyrosine kinase (RTK) aberrantly expressed in many tumors, is a potent oncogenic driver of metastatic cell motility and has been identified as broadly relevant in cancer drug resistance. Despite its frequent association with changes in cancer phenotypes, the precise mechanism leading to AXL activation is incompletely understood. In addition to its ligand growth arrest specific-6 (Gas6), activation of AXL requires the lipid moiety phosphatidylserine (PS). PS is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs during certain physiologic processes such as apoptosis. Here it is reported that exposure of cancer cells to PS-containing vesicles, including synthetic liposomes and apoptotic bodies, contributes to enhanced migration of tumor cells via a PS-Gas6-AXL signaling axis. These findings suggest that anti-cancer treatments that induce fractional cell killing enhance the motility of surviving cells in AXL-expressing tumors, which may explain the widespread role of AXL in limiting therapeutic efficacy.

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Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients

Cited by 97 publications

References 21 publications

Icaritin suppresses the proliferation of human osteosarcoma cells in vitro by increasing apoptosis and decreasing MMP expression

Icaritin suppresses the proliferation of human osteosarcoma cells in vitro by increasing apoptosis and decreasing MMP expression

Risk of breast cancer among patients with bioprosthetic or mechanical valve replacement: a population-based study in Sweden

Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells

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