The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma

Alvarez, Hector A.; Montgomery, Elizabeth A.; Karikari, Collins; Canto, Marcia Irene; Dunbar, Kerry B.; Wang, Jean S.; Feldmann, Georg; Hong, Seung‐Mo; Haffner, Michael C.; Meeker, Alan K.; Holland, Sacha J.; Yu, Jiaxin; Heckrodt, Thilo J.; Zhang, Jing; Ding, Pingyu; Goff, Dane A.; Singh, Rajinder; Roa, Juan Carlos; Marimuthu, Arivusudar; Riggins, Gregory J.; Eshleman, James R.; Nelkin, Barry D.; Pandey, Akhilesh; Maitra, Anirban

doi:10.4161/cbt.10.10.13248

Cited by 82 publications

(68 citation statements)

References 34 publications

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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).…”

mentioning

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.

130

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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mentioning

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.

130

129

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“…Interestingly, gene expression analysis in prostate cancer cells treated with Anxa2 shows increase in expression of Axl which is also a tyrosine kinase receptor for GAS-6. Axl expression is correlated with metastasis and poor prognosis in a wide range of cancers such as breast cancer, prostate cancer, pancreatic cancer, ovarian cancer, renal cell carcinoma and esophageal adenocarcinoma [96][97][98][99][100]. Signaling through GAS-6 and its receptor Axl promotes invasion of prostate cancer cells towards the bone and regulates prostate cancer proliferation and survival [101].…”

Section: Chemotaxis Towards Bonementioning

confidence: 99%

Homing of Cancer Cells to the Bone

Mishra

Shiozawa

Pienta

et al. 2011

Cancer Microenvironment

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A variety of tumor cells preferentially home to the bone. The homing of cancer cells to the bone represents a multi-step process that involves malignant progression of the tumor, invasion of the tumor through the extracellular matrix and the blood vessels and settling of the tumor cells in the bone. Gaining a greater understanding as to the mechanisms used by cancer cells in these processes will facilitate the design of drugs which could specifically target the homing process. In this review we will discuss the properties of tumor cells and the bone microenvironment which promote homing of a cancer cell to the bone. We will highlight the different steps and the molecular pathways involved when a cancer cell metastasize to the bone. Since bone is the major home for hematopoietic stem cells (HSCs), we will also highlight the similarities between the homing of cancer and HSC to the bone. Finally we will conclude with therapeutic and early detection strategies which can prevent homing of a cancer cell to the bone.

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“…We thus suggested a therapeutic approach for treating local advanced ESCC by considering serum levels of EGF and VEGF as biomarkers. AXL RTK has demonstrated potential to become a novel target for cancer targeted therapy, including in EAC (20). We recently demonstrated that patients positive for AXL in tumor tissue have increased risks of death and distant metastasis, and their median survival time dramatically decreased from about 47 to 14 months.…”

Section: Esophageal Cancermentioning

confidence: 99%

Translational research in thoracic surgery—the National Taiwan University Hospital experience

2016

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Thoracic surgeons should be more aware of the latest information about histopathological, genetic and epigenetic alterations that may influence treatment policy and patient outcome in the biomolecular era. Translational research studies often produce a promising diagnostic tool or new treatment that can be used clinically. The results of these translational studies may even change the practical guidelines and current staging system in thoracic malignancies. The following article summarizes the experiences of translational research in esophageal cancer and non-small cell lung cancer (NSCLC) at National Taiwan University Hospital in Taiwan.

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The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma

Cited by 82 publications

References 34 publications

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

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

Homing of Cancer Cells to the Bone

Translational research in thoracic surgery—the National Taiwan University Hospital experience

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