Tenascin-C and Fibronectin during tumor angiogenesis and ex vivo angiogenesis in engineered biomaterials – ANGIOMATRIX
The coordinate role of tenascin-C and fibronectin in angogenesis during tumorigenesis will be addressed at the mechanistic and molecular level by combining in vivo and ex vivo approaches by using mouse tumor models and artificial and cell-derived extracellular matrix (ECM) with defined tenascin-C and fibronectin expression levels.
1.- A major cell type of blood vessels are endothelial cells. The effect of tenascin-C (TNC) on endothelial cells appears to be non-cell autonomous as in presence of TNC, the assembly of a FN matrix network by endothelial cells is modified, resulting in altered cell-matrix and cell-cell adhesion. We observed that TNC modulates endothelial cell migration depending on the assay system used. We also observed an effect of TNC on matrigel tubulogenesis, endothelial cell sprouting in a fibrin gel and retinal angiogenesis.
2.- RNA profiling of vascularized versus non-vascularized tumor tissue has revealed a gene signature where TNC and FN are amongst the most highly induced genes. By using tumor tissue with no or high TNC several candidates have been identified that are regulated in a TNC-dependent manner. A huge collection of genes is now available for a comprehensive understanding of the role of TNC in the fomation of tumor blood vessels in context with FN and other matrix molecules. A genetic model for one of the candidates is in progress.
3.- An important mechanism by which TNC promotes tumor angiogenesis has been identified. This involves Wnt activation in endothelial and tumor cells (Saupe et al., manuscript in preparation).
We have established multiple complementing in vivo, ex vivo and in vitro angiogenesis models with defined expression of TNC. We have used them to address the role of TNC in the many steps leading to blood vessel formation. These models will now be extended to investigate a combined action of TNC and FN on tumor blood vessel formation. In the newly established multiple angiogenesis models a potential impact of our newly identified gene candidates on blood vessel formation will be investigated in detail. This will be done in dependence of TNC alone and in combination with FN.
Van Obberghen-Schilling E*, Tucker RP, Saupe F, Gasser I, Cseh B, & Orend G*. 2011. Fibronectin and tenascin-C: accomplices in vascular morphogenesis during development and tumor growth. Special issue “Angiogenesis in Development and Cancer” (Djonov V and Ribatti D; eds). Int J Develop Biol, 55:511-525. * corresponding authors.
The extracellular matrix (matrix) provides instructive signals to cells during development, homeostasis and in disease states such as cancer. The matrix can regulate cell and tissue behavior by initiating biochemical and mechanical signaling cascades through interactions with specialized transmembrane matrix receptors and by regulating the action of soluble factors. Although much emphasis has been placed on the role of angiogenic cytokines in endothelial cell behavior, today it is well established that the matrix is equally important in vessel homeostasis and remodeling. Angiogenesis is potentially the key step from tumor dormancy towards cancer. Several drugs targeting the tumor vasculature in cancer are already applied in the clinics with unsatisfying and even adverse results. Therefore, we need to understand more about the biology of tumor angiogenesis. Fibronectin and Tenascin-C are two matrix components with angiogenic activities. They are frequently co-expressed at high levels (around blood vessels and in the stroma of tumors) during tumor angiogenesis, which suggests a causal role of these molecules in cancer. Both molecules regulate endothelial cell behavior with Fibronectin potentially promoting vessel stability and Tenascin-C counteracting the functions of Fibronectin. We propose that Tenascin-C and Fibronectin act in concert to control endothelial plasticity during tumor angiogenesis. The major aim of this project is to decipher the function of Tenascin-C and Fibronectin, alone and in combination, in tumor angiogenesis. Therefore, we will (i) analyze the molecular mechanisms that underlie their assembly and angiogenic activities (e.g. involvement of cell surface receptors and downstream signaling effectors), (ii) gather pertinent information for development of novel drugs (e.g. peptides) targeting these matrix molecules as well as their receptors to regulate their angiogenic activities in diseased tissues, and (iii) develop novel matrix-supplemented 3D culture systems (e.g. self-gelling alginate-based hydrogel) that mimic the tissue microenvironment, thus potentially facilitate vessel regeneration and normalization in diseased tissues in the future.
Project coordination
Gertraud OREND (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - ADR DE STRASBOURG - ADR 16) – gertraud.orend@inserm.u-strasbg.fr
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
INSERM INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - ADR DE STRASBOURG - ADR 16
CNRS - IBDC CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE COTE D'AZUR
INSERM INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - ADR DE STRASBOURG - ADR 16
Help of the ANR 550,000 euros
Beginning and duration of the scientific project:
- 36 Months
