biology Review Cytoskeletal Remodeling in Cancer Jaya Aseervatham Department of Ophthalmology, University of Texas Health Science Center at Houston, Houston, TX 77054, USA; [email protected]; Tel.: +146-9767-0166 Received: 15 October 2020; Accepted: 4 November 2020; Published: 7 November 2020 Simple Summary: Cell migration is an essential process from embryogenesis to cell death. This is tightly regulated by numerous proteins that help in proper functioning of the cell. In diseases like cancer, this process is deregulated and helps in the dissemination of tumor cells from the primary site to secondary sites initiating the process of metastasis. For metastasis to be efficient, cytoskeletal components like actin, myosin, and intermediate filaments and their associated proteins should co-ordinate in an orderly fashion leading to the formation of many cellular protrusions-like lamellipodia and filopodia and invadopodia. Knowledge of this process is the key to control metastasis of cancer cells that leads to death in 90% of the patients. The focus of this review is giving an overall understanding of these process, concentrating on the changes in protein association and regulation and how the tumor cells use it to their advantage. Since the expression of cytoskeletal proteins can be directly related to the degree of malignancy, knowledge about these proteins will provide powerful tools to improve both cancer prognosis and treatment. Abstract: Successful metastasis depends on cell invasion, migration, host immune escape, extravasation, and angiogenesis. The process of cell invasion and migration relies on the dynamic changes taking place in the cytoskeletal components; actin, tubulin and intermediate filaments. This is possible due to the plasticity of the cytoskeleton and coordinated action of all the three, is crucial for the process of metastasis from the primary site. Changes in cellular architecture by internal clues will affect the cell functions leading to the formation of different protrusions like lamellipodia, filopodia, and invadopodia that help in cell migration eventually leading to metastasis, which is life threatening than the formation of neoplasms. Understanding the signaling mechanisms involved, will give a better insight of the changes during metastasis, which will eventually help targeting proteins for treatment resulting in reduced mortality and longer survival. Keywords: cytoskeleton; cancer; actin; actin binding proteins; myosin; tubulin; intermediate filaments; RhoGTPase; PP2a; PKA 1. Introduction Metastasis, the major cause of death in cancer is a highly coordinated multistep process that involves the stroma, blood vessels, and the cytoskeleton. Successful metastasis depends on invasion, migration, extravasation, and angiogenesis. Invasion is a localized process that occurs in the tumor–host interface, where the tumor and stromal cells exchange enzymes and cytokines that modulate local extra cellular membrane (ECM) and stimulate cell migration [1]. The central event this process is the cytoskeletal reorganization that lead to the formation of membrane ruffles, lamellipodia, filopodia, and invadopodia [2] (Figure1). Membrane ru ffles are actin-rich membrane protrusions which occur in cellular zones undergoing rapid reorganization of the plasma membrane that precedes the formation of lamellipodia [3]. Lamellipodia are transient, actin-rich membrane protrusions, formed at the leading edge of the cell. They protrude and retract providing the driving force for cell locomotion. If it is stable Biology 2020, 9, 385; doi:10.3390/biology9110385 www.mdpi.com/journal/biology Biology 2020, 9, 385 2 of 40 enough,Biology 2020 it, 9 establishes, x integrin-mediated adhesion with the substratum, contract and then detach2 of the 39 rear end of the cells, which repeats itself over and again to aid in cell migration [4]. Filopodia are substratum, contract and then detach the rear end of the cells, which repeats itself over and again to finger-like protrusions of actin filaments that support slow migration in the absence of lamellipodia. aid in cell migration [4]. Filopodia are finger-like protrusions of actin filaments that support slow They act as sensory and guidance organelle, probing the environment for clues [5]. Invadopodium are migration in the absence of lamellipodia. They act as sensory and guidance organelle, probing the specialized actin-based protrusions that enable cells to invade the basement membrane and blebs are environment for clues [5]. Invadopodium are specialized actin-based protrusions that enable cells to outward bulges in the plasma membrane that are created by the actin–myosin networks. In the absence invade the basement membrane and blebs are outward bulges in the plasma membrane that are of actin filaments protrusions can be formed by microtubules (MT) [6]. Cytoskeletal organization created by the actin–myosin networks. In the absence of actin filaments protrusions can be formed is regulated by Rho GTPases. Rac controls the formation of lamellipodia and membrane ruffles by microtubules (MT) [6]. Cytoskeletal organization is regulated by Rho GTPases. Rac controls the while Cdc42 and Rho control the formation of filopodia and actin myosin contractility respectively. formation of lamellipodia and membrane ruffles while Cdc42 and Rho control the formation of The migratory property and the plasticity of cell migration presents a major challenge in controlling filopodia and actin myosin contractility respectively. The migratory property and the plasticity of cell tumor cell proliferation [7]. migration presents a major challenge in controlling tumor cell proliferation [7]. Lamellipodia Stress fibers Filopodia Figure 1. Immunofluorescent image of HeLa cells showing different actin structures. PFA fixed HeLa Figure 1. Immunofluorescent image of HeLa cells showing different actin structures. PFA fixed HeLa cells were stained for actin (red) (Phalloidin 647) and image was taken using airy scan mode in Zeiss cells were stained for actin (red) (Phalloidin 647) and image was taken using airy scan mode in Zeiss 800 confocal microscope using 63× objective. Nucleus is shown in blue (blue). Scale bar = 5 µm. 800 confocal microscope using 63 objective. Nucleus is shown in blue (blue). Scale bar = 5 µm. × The focusfocus ofof this this review review is tois provideto provide an overallan overall understanding understanding of how of the how cells the adapt cells and adapt achieve and immortalityachieve immortality by modifying by modifying the cytoskeleton. the cytoskeleton. The unique The feature unique is feature that, the is reviewthat, the gives review an updated,gives an birdsupdated, eye birds view ofeye the view global of the changes global inchanges the cytoskeleton in the cytoskeleton not limiting not itselflimiting to actin itself and to actin actin and binding actin proteinsbinding proteins but including but including the changes the changes in tubulin in andtubulin intermediate and intermediate filaments filaments as well. Althoughas well. Although is it not possibleis it not topossible review to all review the work all onthe the work changes on the involved changes in involved cytoskeleton in cytoskeleton during cancer, during an attempt cancer, has an beenattempt made has to been provide made the to readersprovide about the readers the global about changes the global taking changes place taking during place cancer during progression. cancer Theprogression. review starts The byreview giving starts a brief by introductiongiving a brie aboutf introduction the protein about structure the protein and its regulation,structure and which its areregulation, hijacked which and modified are hijacked when and the modified cells achieve when tumorigenic the cells achieve properties. tumorigenic properties. 2. Cytoskeleton of the Cell The cytoskeleton of eukaryotes is a dynamic co complexmplex three-dimensional network of filamentous filamentous proteins present within thethe cytoplasm.cytoplasm. It It consists consists of of microfilaments microfilaments mainly composed of of G actin, intermediate filaments filaments made made up up of of keratins keratins and and vimentins vimentins and and microtubules microtubules composed composed of ofα andα and β- βtubulin-tubulin [8] [ 8(Figure] (Figure 2a2 a,b).and b). Cytoskeleton Cytoskeleton plays plays an an essential essential role role in in controlling controlling the the cell cell shape shape byby providing mechanical support, enabling cell motilitymotility andand facilitatingfacilitating intraintra cellularcellular transport.transport. It also serves asas a a sca scaffoldffold for for signaling signaling cascades cascades by providing by providing sites for sites localization for localization and anchoring and anchoring of signaling of molecules.signaling molecules. Dysregulation Dysregulation of cytoskeleton of cytoskeleton leads to numerous leads to numerous diseases including diseases including cancer [9]. cancer [9]. Biology 2020, 9, 385 3 of 40 Biology 2020, 9, x 3 of 39 (a) (b) Figure 2. ((aa)) Immunofluorescent Immunofluorescent image image of of HeLa HeLa cells sh showingowing actin (green) tubulin (red tubulin antibody labelled with Cy3 secondary) and nucleus (blue). PFA fixedfixed HeLa cells were stained for actin (Phalloidin 488) and alpha tubulin (Alexa 647) andand image was taken using airy scan mode in Zeiss 800 confocal microscope usingusing 6363× objective. Scale bar = 55 µm.µm. ( b)) Graphical representation of the × cytoskeletal components of a cell likelike actin,actin,