https://www.endo.theclinics.com/article/S0889-8529(12)00036-9/pdf

The insulin-like growth factor system in cancer.

The insulin-like growth factor (IGF) family and the IGF-1 receptor (IGF-1R) play an important role in cancer. This intricate and complex signaling pathway provides many opportunities for therapeutic intervention, and several novel therapeutics aimed at the IGF-1R, particularly monoclonal antibodies and small molecule tyrosine kinase inhibitors, are under clinical investigation. This article provides a patent overview of the IGF signaling pathway and its complexity, addresses the justification for the use of IGF-1R-targeted therapy, and reviews the results of in vivo and in vitro novel therapeutics. Over the past year, the completion of several phase I, II, and III trials have provided interesting new information about the clinical activity of these novel compounds, particularly CP-751,871, IMC-A12, R1507, AMG-479, AVE-1642, MK-0646, XL-228, OSI-906, and BMS-754807. We review the important preliminary results from clinical trials with these compounds and conclude with a discussion about future therapeutic efforts.

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Insulin-like Growth Factor: Current Concepts and New Developments in Cancer Therapy

Glioblastoma (GBM), a uniformly lethal brain cancer, is characterized by diffuse invasion and abnormal activation of multiple receptor tyrosine kinase (RTK) signaling pathways, presenting a major challenge to effective therapy. The activation of many RTK pathways is regulated by extracellular heparan sulfate proteoglycans (HSPG), suggesting these molecules may be effective targets in the tumor microenvironment. In this study, we demonstrated that the extracellular sulfatase, SULF2, an enzyme that regulates multiple HSPG-dependent RTK signaling pathways, was expressed in primary human GBM tumors and cell lines. Knockdown of SULF2 in human GBM cell lines and generation of gliomas from Sulf2(-/-) tumorigenic neurospheres resulted in decreased growth in vivo in mice. We found a striking SULF2 dependence in activity of PDGFRα, a major signaling pathway in GBM. Ablation of SULF2 resulted in decreased PDGFRα phosphorylation and decreased downstream MAPK signaling activity. Interestingly, in a survey of SULF2 levels in different subtypes of GBM, the proneural subtype, characterized by aberrations in PDGFRα, demonstrated the strongest SULF2 expression. Therefore, in addition to its potential as an upstream target for therapy of GBM, SULF2 may help identify a subset of GBMs that are more dependent on exogenous growth factor-mediated signaling. Our results suggest the bioavailability of growth factors from the microenvironment is a significant contributor to tumor growth in a major subset of human GBM.

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Heparan sulfate sulfatase SULF2 regulates PDGFRα signaling and growth in human and mouse malignant glioma

Ionizing irradiation is a widely applied therapeutic method for the majority of solid malignant neoplasms, including brain tumors where, depending on localization, this might often be the only feasible primary intervention.Without doubt, it has been proved to be a fundamental tool available in the battlefield against cancer, offering a clear survival benefit in most cases. However, numerous studies have associated tumor irradiation with enhanced aggressive phenotype of the remaining cancer cells. A cell population manages to survive after the exposure, either because it receives sublethal doses and/or because it successfully utilizes the repair mechanisms. The biology of irradiated cells is altered leading to up-regulation of genes that favor cell survival, invasion and angiogenesis. In addition, hypoxia within the tumor mass limits the cytotoxicity of irradiation, whereas irradiation itself may worsen hypoxic conditions, which also contribute to the generation of resistant cells. Activation of cell surface receptors, such as the epidermal growth factor receptor, utilization of signaling pathways, and over-expression of cytokines, proteases and growth factors, for example the matrix metalloproteinases and vascular endothelial growth factor, protect tumor and non-tumor cells from apoptosis, increase their ability to invade to adjacent or distant areas, and trigger angiogenesis. This review will try to unfold the various molecular events and interactions that control tumor cell survival, invasion and angiogenesis and which are elicited or influenced by irradiation of the tumor mass, and to emphasize the importance of combining irradiation therapy with molecular targeting.

Effects of irradiation on tumor cell survival, invasion and angiogenesis.

https://hal.archives-ouvertes.fr/hal-00601186/document

The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells

Increased expression and activation of receptor tyrosine kinases frequently occur in human brain tumors, mediating a variety of growth-promoting pathways and leading to radioresistance; however, little is known about their motogenic potency relative to one another. In this study, we found co-expression of Insulin like growth factor-1 receptor (IGF-1R) and platelet derived growth factor receptor (PDGFR) in two high-grade gliomas (HGG) cell lines 18 and 38. Dual targeting of IGF-1R and PDGFR increased cell death in both 18 and 38 cell lines in comparison to inhibition of either receptor alone. In addition, co-inhibition of IGF-1R and PDGFR increased radiosensitivity in 18 cells but failed to intensify the effect of radiation in 38 cells. In HGG cells, radiation-induced cell death has been connected to the activation of c-Jun-NH2-terminal kinase-1 (JNK1). We found that JNK1 was weakly expressed in 38 cells while it had an elevated expression in 18 cells. Exposure to ionizing radiation induced JNK1 activation only in 18 cells without affecting the protein activity in 38 cells. These results suggest that in 18 cell line radiation-activated JNK1 may provide an anti-proliferative signaling, parallel to receptors co-targeting. To test this hypothesis, HGG cells were treated with dominant negative JNK1 (dnJNK1) and the response to radiation was assayed in presence or absence of receptors co-inhibition. Indeed dnJNK protected 18 cells against γ-irradiation-induced cell death. dnJNK treatment did not influence radiation response of the 38 cell line, which expressed low levels of JNK1. In conclusion we found that IGF-1R and PDGFR co-inhibition caused an increased cell death in two HGG cell line and induced the radiosensitization of the JNK1 expressing cell line.

Dual targeting of IGF-1R and PDGFR inhibits proliferation in high-grade gliomas cells and induces radiosensitivity in JNK-1 expressing cells.

Periodontal disease is one of the major dental pathologies that affect human populations worldwide at high prevalence rates (Petersen, 2003). Periodontal diseases represents a family of heterogeneous chronic inflammatory lesions that involve the periodontium, a connective tissue protected by the epithelium, important to attach the teeth to the bone in the jaws and to support the teeth during function (Taylor, 2003). It is well known that periodontal diseases are caused by the interaction between periodontopathogens, almost gram-negative bacteria that grows on the teeth, and the host immune response to the chronic infection which results in tissue destruction (Ratcliff & Johnson, 1999; Reynolds & Meikle, 1997).

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Growth Factors and Connective Tissue Homeostasis in Periodontal Disease

Brown and white adipocytes are found together at discrete anatomical locations; the multilocular UCP1-positive adipocytes that are interspersed among white adi- pocytes are also known as brite or beige adipocytes (1). Brown adipose tissue (BAT) undergoes a significant reduction in the course of human life. This study aims to characterize developmental patterns of BAT and white AT in specific anatomical locations by comparing fetal and adult human fat depots. Several depots of the subcutaneous and visceral compartments were evaluated in 12 subjects during fetal development (from 16 up to 39 weeks) using immunohistology, morphometry and TEM. Comparison with the corresponding fat depot found in adults was then performed. Fat tissue was first detected in the vasculo-adipocytic anlages in the upper portion of the subcutaneous area. In particular, the cervical depot had a layered structure where the vast majority of adipocytes in deep as well as superficial layers had a clear multilocular UCP1-positive aspects. Adrenergic fibers appear in the fat anlages only in the final stage of development and after UCP1 protein expression. Zic1 (brown) and Hoxc8 (white/brite) adipocytes markers have been tested in different depots and at different time points of development (2). Findings suggest that phenotypic conver- sion and/or other mechanisms may drive the “whitening” of some depots, leading to BAT disappearance in adult humans. Uncovering the mechanisms involved in brown/brite adipocyte recruitment and maintenance in adult humans would have the potential to inspire therapeutic strategies that increase energy expenditure and to curb obesity and metabolic diseases.

Monica Banita

Papers

Dual targeting of IGF-1R and PDGFR inhibits proliferation in high-grade gliomas cells and induces radiosensitivity in JNK-1 expressing cells.

Growth Factors and Connective Tissue Homeostasis in Periodontal Disease

Developmental aspects of the adipose tissue. From fetal to adult humans