Macrophage–tumor crosstalk: role of TAMR tyrosine kinase receptors and of their ligands

Schmidt, Thomas; Ben-Batalla, Isabel; Schultze, Alexander; Loges, Sonja

doi:10.1007/s00018-011-0863-7

Cited by 43 publications

(39 citation statements)

References 210 publications

(315 reference statements)

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“…Interaction of the GAS6/TAM RTK signaling axis with the stromal microenvironment in solid tumors has been associated with poor progression-free survival, 58,59 A similar mechanism may be active in chemotherapy-resistant AML patients that express GAS6 . This suggests a potential for novel therapies targeting GAS6 + leukemic blasts that could also simultaneously inhibit negative effects of GAS6 in the microenvironment, ultimately improving patient survival.…”

Section: Discussionmentioning

confidence: 99%

GAS6 expression identifies high-risk adult AML patients: potential implications for therapy

et al. 2013

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Emerging data demonstrate important roles for the TYRO3/AXL/MERTK receptor tyrosine kinase (TAM RTK) family in diverse cancers. We investigated the prognostic relevance of GAS6 expression, encoding the common TAM RTK ligand, in 270 adults (n=71 aged <60 years; n=199 aged ≥60 years) with de novo cytogenetically normal acute myeloid leukemia (CN-AML). Patients expressing GAS6 (GAS6+), especially those aged ≥60 years, more often failed to achieve a complete remission (CR). In all patients, GAS6+ patients had shorter disease-free (DFS) and overall (OS) survival than patients without GAS6 expression (GAS6−). After adjusting for other prognostic markers, GAS6+ predicted CR failure (P=0.02), shorter DFS (P=0.004) and OS (P=0.04). To gain further biologic insights, we derived a GAS6-associated gene-expression signature (P<0.001) that in GAS6+ patients included overexpressed BAALC and MN1, known to confer adverse prognosis in CN-AML, and overexpressed CXCL12, encoding stromal cell-derived factor, and its receptor genes, CXCR4 and CXCR7. This study reports for the first time that GAS6 expression is an adverse prognostic marker in CN-AML. Although GAS6 decoy receptors are not yet available in the clinic for GAS6+ CN-AML therapy, potential alternative therapies targeting GAS6+-associated pathways, e.g., CXCR4 antagonists may be considered for GAS6+ patients to sensitize them to chemotherapy.

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Section: Discussionmentioning

confidence: 99%

GAS6 expression identifies high-risk adult AML patients: potential implications for therapy

et al. 2013

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“…1,78,79 Gas6-mediated stimulation of the TAM receptors has been shown to result in multiple effects including regulation of cell survival, immune cell response, migration, and phagocytosis of apoptotic cells. 1,[77][78][79][80][81] The TAM receptors have overlapping functions as demonstrated by the very mild phenotypes affecting mice with gene deletions of the individual receptors, whereas the triple knockout mice are severely compromised suffering from immune cell proliferation, sterility, and blindness due to defective phagocytosis of apoptotic cells or defective trimming of the photoreceptor membranes in the retina. 1,2,79 In contrast to Gas6, protein S does not bind Axl but can interact with both Tyro3 and Mer.…”

Section: Protein S and Gas6 Interacting With Tam Receptorsmentioning

confidence: 99%

Vitamin K–Dependent Protein S: Beyond the Protein C Pathway

Dahlbäck

2017

Semin Thromb Hemost

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Protein S is a vitamin K-dependent plasma glycoprotein circulating in plasma at a concentration of around 350 nM. Approximately 60% of protein S in human plasma is bound to the complement regulatory protein C4b-binding protein (C4BP) in a high-affinity, high-molecular-weight complex. Protein S in plasma has multiple anticoagulant properties and heterozygous protein S deficiency is associated with increased risk of venous thrombosis. Homozygous deficiency in man and mice is associated with severe thrombosis in fetal life, defects in the vascular system development, and not compatible with life. Protein S has additional functions beyond being an anticoagulant. It affects the complement regulatory properties of C4BP, and moreover, protein S interacts with tyrosine kinase receptors of the TAM family, which comprises Tyro3, Axl, and Mer. The TAM receptor interaction is important for the ability of protein S to stimulate phagocytosis of apoptotic cells. This review will discuss the multiple functions of protein S, describing its role as cofactor to activated protein C with a subsequent focus on the other functions of protein S.

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“…[1][2][3] The TAM receptor family consists of Tyro3, Axl, and Mer 4 which all have been found to have transforming properties. [5][6][7] Mer expression has been shown on macrophages, natural killer (NK) cells, dendritic cells, megakaryocytes, and platelets, 8 but it is not known to be present on normal T and B lymphocytes at any stage of differentiation. Aberrant Mer expression was detected in not only acute myeloid leukemia (AML), 9 but also lymphocytic malignancies as T-cell acute lymphoblastic leukemia (T-ALL).…”

Section: Introductionmentioning

confidence: 99%

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

Krause¹,

Pfeiffer²,

Strube³

et al. 2015

Blood

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Key Points• Mer mediates quiescence and chemotherapy resistance in a CNS coculture model and causes CNS infiltration in immunodeficient mice.• Mer expression correlates with CNS positivity upon initial diagnosis in t(1;19)-positive pediatric ALL patients.Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer high ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer high t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer low counterparts.Leukemic cells from Mer high xenografts showed enhanced survival in coculture.Treatment of Mer high patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target. (Blood. 2015;125(5):820-830) Introduction TAM (Tyro3, Axl, and Mer) receptors have been advocated as therapeutic targets in human cancers including leukemia. 1-3 The TAM receptor family consists of Tyro3, Axl, and Mer 4 which all have been found to have transforming properties. [5][6][7] Mer expression has been shown on macrophages, natural killer (NK) cells, dendritic cells, megakaryocytes, and platelets, 8 but it is not known to be present on normal T and B lymphocytes at any stage of differentiation. Aberrant Mer expression was detected in not only acute myeloid leukemia (AML), 9 but also lymphocytic malignancies as T-cell acute lymphoblastic leukemia (T-ALL).10 Studies overexpressing Mer in fibroblasts found that it can induce extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-kB (NF-kB) and enhance cell survival via phosphatidylinositol 3-kinase (PI3K)/AKT. 2,11 Linger et al 12 reported that Mer is overexpressed on pre-B-cell ALL (B-ALL) cells of pediatric patients with t(1;19)(q23;p13) translocation. Furthermore, inhibition of Mer by RNA interference (RNAi) reduced survival and chemoresistance of pre-B-ALL cell lines and prolonged survival of xenografts.12 Pediatric ALL with t(1;19)(q23;p13) translocation is found in about 3% to 5% of ALL patients and has ...

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Macrophage–tumor crosstalk: role of TAMR tyrosine kinase receptors and of their ligands

Cited by 43 publications

References 210 publications

GAS6 expression identifies high-risk adult AML patients: potential implications for therapy

GAS6 expression identifies high-risk adult AML patients: potential implications for therapy

Vitamin K–Dependent Protein S: Beyond the Protein C Pathway

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

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