Fibronectin and tenascin-C: accomplices in vascular morphogenesis during development and tumor growth

Abstract

In addition to soluble factors, the extracellular matrix (ECM) also plays a vital role in normal vasculogenesis and in the pathological angiogenesis of many disease states. Here we will review what is known about the role of the ECM molecules fibronectin and tenascin-C in the vasculature and highlight a potential collaborative interplay between these molecules in developmental and tumorigenic angiogenesis. We will address the evolution of these modular proteins, their cellular interactions and how they become assembled into an insoluble matrix that impacts the assembly of other ECM proteins and the bioavailability of pro-angiogenic factors. The role of fibronectin and tenascin-C networks in tumor angiogenesis and metastasis will be described. We will elaborate on lessons learned about their role in vessel function from the functional ablation or the ectopic expression of both molecules. We will also elaborate on potential mechanisms of how fibronectin and tenascin-C affect cell adhesion and signaling that are relevant to angiogenesis.

Tenascin-C: Exploitation and collateral damage in cancer management

“…106 Upon destruction of blood vessels with 2 anti-angiogenic drugs in a well-established insulinoma model and in a murine xenograft tumor model with Lewis lung carcinoma cells it was observed that revascularization occurred along so called matrix sleeves positive for collagen IV, interpreted as remnants of vascular basement membranes. 107 Whether these matrix sleeves contained tenascin-C had not been addressed but is likely since tenascin-C is found to be highly expressed around newly formed tumor blood vessels (reviewed in 19 , 2 ). Given its instrumental role in promoting tumor angiogenesis 4,13 it is an intriguing possibility that tenascin-C may also promote revascularization upon anti angiogenic treatment.…”

“…Both ECM molecules bind to each other and are frequently coexpressed in cancer tissue in particular around newly formed blood vessels. 19 Tenascin-C was shown to counteract cell adhesion to fibronectin through competition with syndecan-4 binding to fibronectin. 108 Thus both molecules might play a role as accomplices in tumor progression.…”

“…108 Thus both molecules might play a role as accomplices in tumor progression. 19 Recently it was shown that adhesion to fibronectin promotes DNA damage recognition and chemosensitization to cisplatin via the potentiation of the DNA damage signaling response (DDR) in human colon cancer cells and tumor derived myofibroblasts. 109 Cisplatin induced phosphorylation of gH2AX, a molecule that is implicated in safeguarding the mitotic process even in the absence of DNA damage.…”

Tenascin-C: Form versus function

“…This collection of functions is reflected in the wide ranging consequences of genetic deletion of tenascin-C in mice. Reported abnormalities include reduced FN during dermal wound healing, 4 hyperactivity, 5 reduced kidney regeneration, 6 reduced haematopoiesis, 7 increased tumor monocyte population, 8 abnormal tumor organization and angiogenesis, 9,10 and aberrant immune responses, [11][12][13] among many others (reviewed in 14,15 ). Genetic variation at the human tenascin-C gene locus is associated with 6-fold increase in risk of Achilles tendon injury, 16 non-syndromic hearing loss, 17 and increased risk of developing adult asthma.…”

Microenvironment and tumor progression of melanoma: New therapeutic prospectives

“…Tenascin C (TNC) is an ECM glycoprotein frequently upregulated in several inflammatory diseases as well as in neoplastic pathologies; this protein is highly involved in the regulation of cellular migration, proliferation, invasion, and angiogenesis (van Obberghen-Schilling et al, 2011). TNC exists in numerous isoforms that are the result of alternative splicings, and are heterogeneously expressed in both normal and neoplastic tissues (Leprini et al, 1994).…”