Intermediate Filaments as Effectors of Cancer Development and Metastasis: A Focus on Keratins, Vimentin, and Nestin

Abstract

Intermediate filament (IF) proteins make up the largest family of cytoskeletal proteins in metazoans, and are traditionally known for their roles in fostering structural integrity in cells and tissues. Remarkably, individual IF genes are tightly regulated in a fashion that reflects the type of tissue, its developmental and differentiation stages, and biological context. In cancer, IF proteins serve as diagnostic markers, as tumor cells partially retain their original signature expression of IF proteins. However, there are also characteristic alterations in IF gene expression and protein regulation. The use of high throughput analytics suggests that tumor-associated alterations in IF gene expression have prognostic value. Parallel research is also showing that IF proteins directly and significantly impact several key cellular properties, including proliferation, death, migration, and invasiveness, with a demonstrated impact on the development, progression, and characteristics of various tumors. In this review, we draw from recent studies focused on three IF proteins most associated with cancer (keratins, vimentin, and nestin) to highlight how several "hallmarks of cancer" described by Hanahan and Weinberg are impacted by IF proteins. The evidence already in hand establishes that IF proteins function beyond their classical roles as markers and serve as effectors of tumorigenesis.

Keywords: cancer; hallmarks of cancer; intermediate filament; keratin; metastasis; nestin; vimentin.

Figure 1

Intermediate Filament (IF) Family of Proteins. (A) List of IF proteins, along with their class types, gene names, molecular weights, and expression patterns. Proteins discussed in this review are highlighted in dark green. (B) Schematic representation of the domain structure and polymerization of IF proteins. IF proteins become either homo- or heterodimerized through coiled-coil interactions between rod domains of monomers. Then, two dimers assemble in an antiparallel manner to form a nonpolar tetramer. Further polymerization of tetramers result in unit-length filaments and ultimately a filament of about 10 nm in diameter. For keratins, heterodimerization occurs between one type I and one type II keratin. While vimentin can form filaments on its own, nestin requires other IF proteins to form filaments. An arrow on the tail domain indicates the C-terminal end of the protein.

Figure 2

Signaling Pathways and Cellular Processes Regulated by Keratins, Vimentin, and Nestin. Proteins and cellular processes activated (arrows) or inhibited (bar-headed lines) by (A,C) keratins, (B) nestin, and (D) vimentin. (A) Keratins in blue are involved in either activation or inhibition of proteins in black, and upregulate pro-tumorigenic processes in red. For example, K19 enables activation of multiple signaling molecules, including HER2, Src, and Notch for cell proliferation. Alternatively, multiple keratins may converge on a same cellular process as illustrated by regulation of cell migration by K8, K14, K17, K19, and K80 through various signaling molecules, including STAT3, hnRNP K, p38, Erk, and Akt. Processes, such as chemoresistance, that are directly linked to keratins indicate lack of known mediators. (B) Downstream factors and pro-tumorigenic processes in red regulated by nestin. Some of the better-known roles of nestin include maintaining cell stemness through CDK5 inhibition. (C) Keratins in red inhibit proteins in black and downregulate pro-tumorigenic processes in blue. For example, K6 inhibits cell migration by inactivating Src. Interestingly, K19 activates Notch signaling pathway to promote cell proliferation in hepatocellular carcinomas but inhibits Notch signaling to suppress proliferation of breast cancer cells. Such a difference exemplifies context-dependent functions of keratins. (D) Downstream factors and pro-tumorigenic processes in red regulated by vimentin. Vimentin is upregulated in cells that have gone through the epithelial-to-mesenchymal transition, and it promotes invasion and migration via activation of Erk and Rac1 signaling pathways.