Revisiting the Tenascins: Exploitable as Cancer Targets?

Abstract

For their full manifestation, tumors require support from the surrounding tumor microenvironment (TME), which includes a specific extracellular matrix (ECM), vasculature, and a variety of non-malignant host cells. Together, these components form a tumor-permissive niche that significantly differs from physiological conditions. While the TME helps to promote tumor progression, its special composition also provides potential targets for anti-cancer therapy. Targeting tumor-specific ECM molecules and stromal cells or disrupting aberrant mesenchyme-cancer communications might normalize the TME and improve cancer treatment outcome. The tenascins are a family of large, multifunctional extracellular glycoproteins consisting of four members. Although each have been described to be expressed in the ECM surrounding cancer cells, tenascin-C and tenascin-W are currently the most promising candidates for exploitability and clinical use as they are highly expressed in various tumor stroma with relatively low abundance in healthy tissues. Here, we review what is known about expression of all four tenascin family members in tumors, followed by a more thorough discussion on tenascin-C and tenascin-W focusing on their oncogenic functions and their potential as diagnostic and/or targetable molecules for anti-cancer treatment purposes.

Proteomic profiling of canine fibrosarcoma and adjacent peritumoral tissue

“…Interestingly, it also overexpressed in chondrosarcoma, Ewing sarcoma and dermatofibrosarcoma protuberans and known to promote cancer cell survival and migration as well as metastasis and malignancy therein [40][41][42][43] . Furthermore, TNC has been advocated as a potential target in STS treatment, and TNC specific ligands are available for experimental use [44] . FSCN1, an actin-binding protein with important functions in cell motility and migration, has been found to play an important role in development of osteosarcoma and chondrosarcoma [45 , 46] .…”

A virological view of tenascin-C in infection

“…Notably, most studies looking at broad host responses after viral infection using omics approaches only serve to correlate levels of tenascin-C expression with disease phenotype. Therefore, loss and gain of function validation of the proposed roles for tenascin-C as well as mechanistic studies revealing the mode of action and signaling modulation by this protein during viral replication are imperative ( 95 ).…”

Advances on the roles of tenascin-C in cancer

“…Targeting the tumor matrix has recently got some attention ( Cox, 2021 ). Given its prominent expression in cancer and multiple pro-tumorigenic roles, TNC might represent a valid anti-cancer target (reviewed in Spenlé et al, 2015b ; Tucker and Degen, 2022 ). Briefly, antibodies, nanobodies and novel peptides are being used to improve radiotherapy or drug uptake into tumor tissues, as well as for tumor imaging (reviewed in Tucker and Degen, 2022 ).…”

“…Given its prominent expression in cancer and multiple pro-tumorigenic roles, TNC might represent a valid anti-cancer target (reviewed in Spenlé et al, 2015b ; Tucker and Degen, 2022 ). Briefly, antibodies, nanobodies and novel peptides are being used to improve radiotherapy or drug uptake into tumor tissues, as well as for tumor imaging (reviewed in Tucker and Degen, 2022 ). Similarly, repression of TNC expression by siRNA and aptamers has also been exploited (reviewed in Spenlé et al, 2015b ).…”

“…Some gene mutations are known to lead to tumor formation; however, the extracellular matrix (ECM) and the 3D context matters for these mutations to instigate a tumor (reviewed in Bissell and Hines, 2011 ). The glycoprotein tenascin-C (TNC) is an ECM molecule that plays multiple and context-dependent roles in cancer that have been comprehensively reviewed elsewhere ( Midwood and Orend, 2009 ; Midwood et al, 2016 ; Lowy and Oskarsson, 2015 ; Tucker and Degen, 2022 ). Here, we will summarize and critically review new information on how TNC impacts tumor progression and will put forward new concepts of how TNC regulates tumor immunity, which offers potential novel targeting opportunities.…”