Differential Expression of Axl and Correlation with Invasion and Multidrug Resistance in Cancer Cells

Zhao, Yongfu; Sun, Xiance; Jiang, Lili; Yang, Fengjuan; Zhang, Zhaohai; Li, Jia

doi:10.3109/07357907.2012.657816

Cited by 19 publications

(9 citation statements)

References 21 publications

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“…We previously showed that Axl has a crucial role in promoting invasion, lymphatic metastasis, and multidrug resistance . In this study, we identified down‐regulating of Axl not only could effectively regulate the invasiveness, drug resistance of breast tumor cells in vitro , and animal models in vivo , but also related with clinicopathologic characteristics of human breast cancer.…”

Section: Discussionmentioning

confidence: 78%

“…In the previous studies, we concluded that Axl had a critical role in the PI3K/Akt‐PAK1 signal pathway and knockdown of it inhibits the metastasis properties of hepatocellular carcinoma . We also found that differential expressions of Axl are correlated with invasion and multidrug resistance in cancer cells . Given that Axl may have an important role in tumor metastasis and drug resistance, we have prompted in this study to explore its detailed mechanism in the regulation of tumor invasion and chemosensitivity via PI3K/Akt pathway.…”

Section: Introductionmentioning

confidence: 92%

“…The primary ligand for Axl, Growth arrest‐specific 6 (Gas6), is a vitamin K‐dependent protein that binds Axl with high affinity . In our previous study , we found 3.05‐fold increase of Axl in MCF‐7/ADR (adriamycin resistance) cells as compared with MCF‐7 cells and suggested Axl represents a promising gene for overcoming MDR (multiple drug resistance) in breast cancer therapy. What is more, Axl was also reported to be associated with invasion or chemosensitivity in some types of human cancers including human non‐small cell, T‐cell acute lymphoblastic leukemia, gastric, uterine endometrial, certain types of breast cancer, and ovarian cancers .…”

Section: Introductionmentioning

confidence: 99%

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Axl mediates tumor invasion and chemosensitivity through PI3K/Akt signaling pathway and is transcriptionally regulated by slug in breast carcinoma

Ren

et al. 2014

IUBMB Life

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The invasion and chemoresistance are crucial causes of morbidity and relapse for cancer patients. Axl is implicated in the modulation of cell invasion, cancer metastasis, and chemosensitivity in human breast carcinoma cell lines. Both breast cancer cell lines and tissues displayed increased expression of Axl, and it over expressed in highly metastatic breast cancer. The altered expression level of Axl was corresponding to the changed invasive phenotype and chemosensitivity of MDA-MB-231 cells both in vitro and in vivo. Further data indicated that experimental inhibition of Axl by RNAi assay inhibited phosphatidylinositol 3-kinase (PI3K)/Akt/GSK3b signaling pathway, resulted in the decrease of Slug expression, and further suppressed cell invasion properties and chemosensitivity. What is more, after the detection and statistics in human breast cancer specimens, we found the Axl expression was closely correlated with histological grade, lymph node metastasis, and clinical stage (P < 0.01). Taken together, these findings indicate that Axl exerts the role of tumor metastasis and chemosensitivity through activation of the PI3K/Akt/GSK3b signaling pathway, which is transcriptionally regulated by Slug. Our findings support the possibility that Axl is a novel regulator. It means by targeting Axl or its related signaling pathways, we can reduce the invasion and chemosensitivity of breast tumor. V C 2014 IUBMB Life, 66(7): [507][508][509][510][511][512][513][514][515][516][517][518] 2014

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Axl mediates tumor invasion and chemosensitivity through PI3K/Akt signaling pathway and is transcriptionally regulated by slug in breast carcinoma

Ren

et al. 2014

IUBMB Life

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“…Increased MER expression is associated with leukemias, lymphomas, melanoma, rhabdomyosarcomas, and gastric and prostate cancers (4)(5)(6). AXL and MER expression also has been directly correlated with poor prognosis in cancer (6)(7)(8)(9). Moreover, ectopic expression of AXL has been shown to confer resistance to EGF receptor therapy in lung cancer (10,11).…”

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confidence: 99%

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

Bosurgi¹,

Bernink²,

Cuevas³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

127

129

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The receptor tyrosine kinases Axl and Mer, belonging to the Tyro3, Axl and Mer (TAM) receptor family, are expressed in a number of tumor cells and have well-characterized oncogenic roles. The therapeutic targeting of these kinases is considered an anticancer strategy, and various inhibitors are currently under development. At the same time, Axl and Mer are expressed in dendritic cells and macrophages and have an essential function in limiting inflammation. Inflammation is an enabling characteristic of multiple cancer hallmarks. These contrasting oncogenic and anti-inflammatory functions of Axl and Mer posit a potential paradox in terms of anticancer therapy. Here we demonstrate that azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced inflammationassociated cancer is exacerbated in mice lacking Axl and Mer. Ablation of Axl and Mer signaling is associated with increased production of proinflammatory cytokines and failure to clear apoptotic neutrophils in the intestinal lamina propria, thereby favoring a tumor-promoting environment. Interestingly, loss of these genes in the hematopoietic compartment is not associated with increased colitis. Axl and Mer are expressed in radioresistant intestinal macrophages, and the loss of these genes is associated with an increased inflammatory signature in this compartment. Our results raise the possibility of potential adverse effects of systemic anticancer therapies with Axl and Mer inhibitors, and underscore the importance of understanding their tissue and cell type-specific functions in cancer.T he proto-oncogenes AXL and MER were first cloned from chronic myelogenous and lymphoblastic leukemia cells (1-3). Increased expression of AXL has been reported in lung, breast, ovarian, gastric, pancreatic, and prostate cancers; leukemias and lymphomas; melanoma; and glioblastoma multiforme (4, 5). Increased MER expression is associated with leukemias, lymphomas, melanoma, rhabdomyosarcomas, and gastric and prostate cancers (4-6). AXL and MER expression also has been directly correlated with poor prognosis in cancer (6-9). Moreover, ectopic expression of AXL has been shown to confer resistance to EGF receptor therapy in lung cancer (10, 11). Multiple studies have demonstrated AXL and MER function in survival, invasion, and metastasis in a variety of tumors (12-15); thus, attention has focused on the pharmacologic targeting of AXL and MER in cancer. Axl and Mer share structural homology in the kinase domain with other tyrosine kinases, including conserved molecular interactions with ATP; however, several unique features of the active site allow for selective inhibition (16), and small-molecule inhibitors as well as biologics are in preclinical development (6,(16)(17)(18)(19).Axl and Mer are associated with another distinct feature of cancer-inflammation. Tumor-promoting inflammation has been described as an enabling characteristic that promotes the acquisition of cancer hallmarks and orchestrates tumor progression (20). Chronic inflammation increases the risk of colorectal canc...

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“…AXL-depleted murine breast cancer cells with breast cancer stem-cell-like properties were more sensitive to paclitaxel and etoposide compared to AXL-competent cells [17]. Similarly, inhibition of AXL signaling in MCF-7 cells with acquired resistance to conventional chemotherapies restored their sensitivity [91]. In TNBC and NSCLC cells that have undergone an EMT, inhibition of AXL can synergize with antimitotic agents such as docetaxel and paclitaxel but not with gemcitabine, doxorubicin, or cisplatin [92].…”

Section: Conventional Erapiesmentioning

confidence: 99%

AXL as a Target in Breast Cancer Therapy

Colavito

2020

Journal of Oncology

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AXL is a receptor tyrosine kinase (RTK) that has been implicated in diverse tumor-promoting processes such as proliferation, migration, invasion, survival, and apoptosis. AXL therefore plays a role in cancer progression, and AXL has been implicated in a wide variety of malignancies from solid tumors to hematopoietic cancers where it is often associated with poor prognosis. In cancer, AXL has been shown to promote epithelial to mesenchymal transition (EMT), metastasis formation, drug resistance, and a role for AXL in modulation of the tumor microenvironment and immune response has been identified. In light of these activities multiple AXL inhibitors have been developed, and several of these have entered clinical trials in the U.S. In breast cancer, high levels of AXL expression have been observed. The role of AXL in cancer with a focus on therapeutic implications for breast cancer is discussed.

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Differential Expression of Axl and Correlation with Invasion and Multidrug Resistance in Cancer Cells

Cited by 19 publications

References 21 publications

Axl mediates tumor invasion and chemosensitivity through PI3K/Akt signaling pathway and is transcriptionally regulated by slug in breast carcinoma

Axl mediates tumor invasion and chemosensitivity through PI3K/Akt signaling pathway and is transcriptionally regulated by slug in breast carcinoma

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

AXL as a Target in Breast Cancer Therapy

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