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Supplementary Figure 5 from Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer

Supplementary Figure 7 from Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer

Supplementary Figure 6 from Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer

Supplementary Figure 3 from Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer

Supplementary Methods, Figure Legends 1-7, Table Legend 1 from Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer

Supplementary Figure 1 from Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer

Supplementary Figure 2 from Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer

There is compelling evidence that the tumor microenvironment plays a major role in mediating aggressive features of cancer cells, including invasive capacity and resistance to conventional and novel therapies. Among the different cell populations that infiltrate cancer stroma, mast cells (MCs) can influence several aspects of tumor biology, including tumor development and progression, angiogenesis, lymphangiogenesis, and tissue remodelling. Thyroid cancer (TC), the most frequent neoplasia of the endocrine system, is characterized by a MC infiltrate, whose density correlates with extrathyroidal extension and invasiveness. Recent evidence suggests the occurrence of epithelial-to-mesenchymal transition (EMT) and stemness in human TC. The precise role of immune cells and their mediators responsible for these features in TC remains unknown. Here, we review the relevance of MC-derived mediators (e.g., the chemokines CXCL1/GRO-α, CXCL10/IP-10, and CXCL8/IL-8) in the context of TC. CXCL1/GRO-αand CXCL10/IP-10 appear to be involved in the stimulation of cell proliferation, while CXCL8/IL-8 participates in the acquisition of TC malignant traits through its ability to induce/enhance the EMT and stem-like features of TC cells. The inhibition of chemokine signaling may offer novel therapeutic approaches for the treatment of refractory forms of TC.

Pulmonary arterial hypertension (PAH) is a rare disease characterized by a dramatic, progressive rise of pulmonary vascular resistance (PVR), leading to elevated pulmonary artery pressures, right ventricular (RV) overload, and, eventually, failure. Current evaluation of PAH is based on invasive hemodynamics (RHC), exercise capacity, echocardiography, and N-terminal pro brain natriuretic peptide (NT-proBNP) levels [1]; although published survival data support a strong clinical role for cardiac magnetic resonance imaging (CMR) of the RV, this technique is still underused [2]. Much research is currently focusing on the exploration of candidate soluble biomarkers of RV dysfunction and prognosis. Soluble ST2 (sST2) is a member of the interleukin 1-receptor family, which increases in response to acute and chronic cardiomyocyte strain [3]; its circulating levels rise in chronic and acutely decompensated heart failure, and the extent of their elevation seems to be especially related to the presence and severity of RV compromise [4,5]. The circulating ligand of sST2, interleukin 33 (IL-33), probably plays a role in several inflammatory states. The aimof the present studywas to assess peripheral serumlevels of sST2 and IL-33 in a group of patients with PAH of different etiology and severity compared with healthy controls, and to explore their possible relation with clinical features and with parameters of RV remodeling and failure as measured by CMR.

Thyroid cancer is the most common endocrine cancer, but its key oncogenic drivers remain undefined. In this study we identified the TYRO3 and AXL receptor tyrosine kinases as transcriptional targets of the chemokine CXCL12/SDF-1 in CXCR4-expressing thyroid cancer cells. Both receptors were constitutively expressed in thyroid cancer cell lines but not normal thyroid cells. AXL displayed high levels of tyrosine phosphorylation in most cancer cell lines due to constitutive expression of its ligand GAS6. In human thyroid carcinoma specimens, but not in normal thyroid tissues, AXL and GAS6 were often coexpressed. In cell lines expressing both receptors and ligand, blocking each receptor or ligand dramatically affected cell viability and decreased resistance to apoptotic stimuli. Stimulation of GAS6-negative cancer cells with GAS6 increased their proliferation and survival. Similarly, siRNA-mediated silencing of AXL inhibited cancer cell viability, invasiveness, and growth of tumor xenografts in nude mice. Our findings suggest that a TYRO3/AXL-GAS6 autocrine circuit sustains the malignant features of thyroid cancer cells and that targeting the circuit could offer a novel therapeutic approach in this cancer. Cancer Res; 71(5); 1792–804. ©2011 AACR.