Tenascin C in metastasis: A view from the invasive front

Abstract

The extracellular matrix protein tenascin C (TNC) is a large glycoprotein expressed in connective tissues and stem cell niches. TNC over-expression is repeatedly observed in cancer, often at the invasive tumor front, and is associated with poor clinical outcome in several malignancies. The link between TNC expression and poor survival in cancer patients suggests a role for TNC in metastatic progression, which is responsible for the majority of cancer related deaths. Indeed, functional studies using mouse models are revealing new roles of TNC in cancer progression and underscore its important contribution to the development of metastasis. TNC has a pleiotropic role in advancing metastasis by promoting migratory and invasive cell behavior, angiogenesis and cancer cell viability under stress. TNC is an essential component of the metastatic niche and modulates stem cell signaling within the niche. This may be crucial for the fitness of disseminated cancer cells confronted with a foreign environment in secondary organs, that can exert a strong selective pressure on invading cells. TNC is a compelling example of how an extracellular matrix protein can provide a molecular context that is imperative to cancer cell fitness in metastasis.

Keywords: extracellular matrix; invasion; metastasis; niche; stem cell; tenascin C.

Figure 1.

TNC structure and cancer associated domains. TNC is a multifunctional glycoprotein composed of several distinct domains. (A) Domain structure of full length human TNC protein (based on ref. 11). At the N-terminus, the assembly domain (AD) mediates the oligomerization of the protein where 2 trimers form a hexameric structure. Between the EGF-like repeats and the carboxy terminal fibrinogen globe (FG) are Fibronectin type III repeats (FNIII). In human TNC, 9 of the total 17 FNIII repeats are alternatively spliced providing the possibility of multiple different TNC isoforms. (B) Several alternatively spliced FNIII repeats have been identified in cancer. FNIII domains A1 and C are expressed in lung cancer and A1 domain in renal cell carcinoma. Colorectal carcinoma (CRC) expresses domains A1, A2 and A4 which are specifically enriched in CRC when compared to total TNC expression. Head and neck cancer exhibits A1 and AD2 domains while melanoma expresses A1 and AD1. In urothelial carcinoma, domains A1, B, C and D are present and associate with invasive cancer. FNIII domain B is expressed in ovarian cancer and is enriched compared to the short TNC isoform (lacking all alternatively spliced FNIII domains). Breast cancer expresses B and D domains that are associated with invasive behavior and the AD1 domain. It is important to note that these lists are not exhaustive and only include the domains that have been positively linked to a particular cancer. Information of complete isoforms is generally lacking. However, while the knowledge of different TNC isoforms expressed in cancer is still rudimentary and incomplete, the appearance of different domains in cancers may indicate a requirement for distinct aspects of TNC functions.

Figure 2.

TNC function in metastatic progression. At the primary tumor site, anti-adhesive TNC properties lead to alteration of intracellular pathways in cancer cells inducing the formation of actin-rich filopodia, favoring cell motility and invasive behavior. TNC is also associated with increased cancer cell proliferation and promotes angiogenesis within the tumor. At the secondary organ site, autocrine TNC supports cancer cell viability in a microenvironment that can exert a strong selective pressure. In breast cancer, TNC engages stem/progenitor signaling i.e. the Notch and Wnt pathways thereby promoting growth of micrometastasis. The development of macrometastasis is associated with reactive stroma which becomes a significant source of TNC protein.