Tenascin-C and carcinoma cell invasion in oral and urinary bladder cancer

Abstract

Carcinoma invasion is a complex process regulated by genetic and epigenetic factors as well. A relevant supportive condition for cancer cell migration is the reorganization of the extracellular matrix (ECM), which is realized in an orchestrated multicellular manner including carcinoma cells and stromal fibroblasts. An important key player in the process of ECM reorganization is Tenascin-C (Tn-C). The molecule occurs as different isoforms generated by alternative splicing and de novo glycosylation. Large variants of Tn-C are abundantly re-expressed in the invasive front of many carcinoma types. A special role for initiating migration and accompanied epithelial to mesenchymal transition has been suggested. Here, we review the current knowledge concerning the tumor biological importance of Tn-C, the synthesis and alternative splicing during the invasive process in general, and give an overview on the impact of Tn-C in urothelial carcinoma of the urinary bladder (UBC) and oral squamous cell carcinoma (OSCC).

Keywords: 3D, 3 dimensional; BM, basement membane; CAF, cancer associated fibroblast; ECM reorganization; ECM, extracellular matrix; EMT, epithelial – mesenchymal transition; FGF2, fibroblast growth factor 2; FNIII, fibronectin type III like repeats; Fn, fibronectin; Ln, laminin; Lnγ2, laminin gamma 2 chain; MMP, matrix metalloproteinase; OSCC, oral squamous cell carcinoma; PDGF, platelet derived growth factor; RNA, ribonucleic acid; TGFβ1, transforming growth factor beta 1; TPA, tetradecanoylphorbol acetate; Tn-C, tenascin-C; UBC, urothelial carcinoma of the urinary bladder; alternative splicing; carcinoma invasion; hnRNPs, heterogeneous nuclear ribonucleoproteins; mRNA, messenger RNA; oncFn, oncofetal fibronectin; oncTn-C, oncofetal tenascin-C; oral squamous cell carcinoma; tenascin-C; urothelial carcinoma of the urinary bladder.

Figure 1.

Schematic representation of the structure of a single chain of human tenascin-C (TA = Tenascin-C assembly domian, FBG = terminal fibrinogen like globular domain).

Figure 2.

Tn-C and its proposed role during invasion and epithelial to mesenchymal transition of carcinoma cells in oral cancer. The process of the development of an invasive carcinoma cell phenotype starts with the mutual activation of stromal and cancer cells, followed by an increased synthesis and secretion of oncofetal Tn-C variants (oncTn-C) by carcinoma cells and stromal fibroblasts (1) This process is accompanied by growth factor mediated fibro-/myofibroblast phenotype transition co-activated by an autocrine ED-A⁺ fibronectin signaling via α_vβ₇ integrin (2). Activated myofibroblasts / cancer associated fibroblasts (CAF´s) produce oncofetal fibronectin variants (oncFn) and reorganize the oncTn-C / oncFn matrix together with other adhesion proteins like Laminins in a provisional manner (3). This provisional matrix mediates invasive phenotype conversion of cancer cells via β6 integrin signaling associated with up regulation of for instance MMP9, Tn-C itself and the migration promoting laminin γ2 chain (Lnγ2) (4). Finally, the carcinoma cells develop an epithelial to mesenchymal transition (EMT) phenotype (5).