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Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.

Ephrin receptors are the most common tyrosine kinase effectors operating during development. Ephrin receptor genes are reported to be up-regulated in the regenerating tail of the Podarcis muralis lizard. Thus, in the current study, we investigated immunolocalization of ephrin receptors in the Podarcis muralis tail during regeneration. Weak immunolabelled bands for ephrin receptors were detected at 15–17 kDa, with a stronger band also detected at 60–65 kDa. Labelled cells and nuclei were seen in the basal layer of the apical wound epidermis and ependyma, two key tissues stimulating tail regeneration. Strong nuclear and cytoplasmic labelling were present in the segmental muscles of the regenerating tail, sparse blood vessels, and perichondrium of regenerating cartilage. The immunolocalization of ephrin receptors in muscle that gives rise to large portions of new tail tissue was correlated with their segmentation. This study suggests that the high localization of ephrin receptors in differentiating epidermis, ependyma, muscle, and cartilaginous cells is connected to the regulation of cell proliferation through the activation of programs for cell differentiation in the proximal regions of the regenerating tail. The lower immunolabelling of ephrin receptors in the apical blastema, where signaling proteins stimulating cell proliferation are instead present, helps maintain the continuous growth of this region.

Hendra virus (HeV) and Nipah virus (NiV) are closely related paramyxoviruses that infect and cause disease in a wide range of mammalian hosts. To determine whether host receptor molecules play a role in species-specific and/or virus-specific infection we have cloned and characterized ephrin-B2 and ephrin-B3 ligands from a range of species, including human, horse, pig, cat, dog, bats (Pteropus alecto and Pteropus vampyrus) and mouse. HeV and NiV were both able to infect cells expressing any of the ephrin-B2 and ephrin-B3 molecules. There did not appear to be significant differences in receptor function from different species or receptor usage by HeV and NiV. Soluble ephrin ligands, their receptors and G-specific human monoclonal antibodies differentially blocked henipavirus infections suggesting different receptor affinities, overlapping receptor binding domains of the henipavirus attachment glycoprotein (G) and that the functional domains of the ephrin ligands may be important for henipavirus binding.

Background Ephrin (Eph) receptors are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate the clinical significance of EphA1, A4, A5 and A7 protein expression in non-small cell lung carcinoma (NSCLC). Methods EphA1, A4, A5 and A7 protein expression was assessed immunohistochemically in tissue microarrays of 88 surgically resected NSCLC and was analyzed in relation with clinicopathological characteristics and patients’ survival. Results Elevated EphA4 expression was significantly associated with low histopathological stage and presence of inflammation (p = 0.047 and p = 0.026, respectively). Elevated EphA7 expression was significantly associated with older patients’ age, presence of fibrosis and smaller tumor size (p = 0.036, p = 0.029 and p = 0.018, respectively). EphA1, A5 and A7 expression were positively associated with tumor proliferative capacity (p = 0.047, p = 0.002 and p = 0.046, respectively). Elevated EphA4, A5 and A7 expression were identified as predictors of favourable patients’ survival at both univariate (Log-rank test, 0 = 0.019, p = 0.006 and p = 0.012, respectively) and multivariate levels (Cox-regression analysis, p = 0.029, p = 0.068 and p = 0.044, respectively). Conclusions The present study supported evidence that Ephs may be involved in lung cancer progression, reinforcing their utility as clinical biomarkers for patients’ management and prognosis, as also as potential targets for future therapeutic interventions.

Summary Background Ephrin receptors (Ephs) are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, metastasis and angiogenesis. The aim of the present study was to evaluate the clinical significance of Eph-A2 and Eph-A4 expression in human benign and malignant thyroid lesions. Material/Methods Eph-A2 and Eph-A4 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 131 patients with benign and malignant lesions. Results Eph-A2 was significantly overexpressed in malignant compared to benign thyroid lesions (p