Cytoskeleton Structure and Function

In many ways, the cytoskeleton is analogous to the skeleton of the human body in that it provides form and shape to the cell, but its function is much more complex. It is important in cell movement, cell division, adhesion, and communication with other cells and extracellular matrix as well as the regulation of many intracellular processes. The cytoskeleton is composed of filamentous structures generally classified according to size, including microtubules (22 nm), intermediate filaments (8 to 10 nm), and microfilaments (7 nm).


Microtubules are composed primarily of tubulin, a 55-kd protein. In its polymerized form, tubulin forms a microtubu-lar network radiating from the perinuclear region of the cell. This network is important in regulating and maintaining the location of endoplasmic reticulum and Golgi apparatus within the cell. During cell division, microtubules are rapidly organized as part of the mitotic spindle. During the transition from metaphase to anaphase, duplicated chromosomes are pulled apart by contracting spindle microtubules toward the centrosomes of each daughter cell. Anticancer drugs such as vincristine and vinblastine inhibit the formation of microtubules and are hence thought to be antimitotic. One additional function of the microtubules is that they are important in cellular distribution of intermediate filaments and cortical actin filaments. Disruption of the microtubules of cultured cells by colchicine, however, does not necessarily prevent cell locomotion, which seems more dependent on the actin microfilaments.


FIGURE 32-1. Schematic depicting the multistep process of cancer cell invasion through the basement membrane. Cells must separate from their primary tumor mass and then degrade a basement membrane barrier to allow infiltration.


FIGURE 32-1. Schematic depicting the multistep process of cancer cell invasion through the basement membrane. Cells must separate from their primary tumor mass and then degrade a basement membrane barrier to allow infiltration.

Intermediate Filaments

Intermediate filaments are composed of different types of proteins, depending on the type of cell, that form relatively stable polymers.13 Cytokeratins are specific to epithelial cells, whereas vimentin is found in mesenchymal cells, desmin in muscle cells, and glial fibrillary acidic protein in neural cells. Because specificity is maintained after transition to malignancy, anaplastic-appearing tumor cells may often be characterized by immunohistochemistry using antibodies recognizing specific intermediate filament proteins. Closely related to the microtubule system, intermediate filaments form a delicate network surrounding the nucleus that extend into the cytoplasm toward the cell periphery. In epithelial cells, keratin intermediate filaments join with the cell membrane at desmosomes, which are specialized junctions between adjoining cells. As such, intermediate filaments are thought to provide structural integrity and tensile strength to epithelial membranes. Experiments with mouse and rat tumor cell lines suggest that enhanced expression of intermediate filaments may be related to the ability of tumor cells to invade and metastasize.14"16

Actin Microfilaments

The actin cytoskeleton is important in determining and maintaining cell shape and polarity but is also known to be involved in a diverse array of other cellular functions, including the transmission of intracellular signals and protein synthesis by the sorting of messenger RNA (mRNA).17 The actin cytoskeleton interacts with the cell surface membrane at multiple levels, including junctional complexes, apical microvilli, cellular adhesion molecules, and integrins. Microfilaments are composed primarily of actin. In a fully polymerized state, actin forms stress fibers anchoring a cell to its matrix through adhesion plaques. Cells interact with their matrix through heterodimeric receptors, consisting of an a and a P subunit, known as integrins. The prototypic adhesion plaque is composed of an O^ integrin (fibronectin receptor)

interacting with talin, vinculin, a-actinin, and capping proteins. This assembly forms the attachment point for one end of an actin stress fiber. These focal contacts are sites of communication of the cell with its external environment.

The loss of actin stress fibers has been associated with oncogenic transformation and increased metastatic potential. Abnormally low cellular levels of F-actin have been suggested as a marker of transformation in human bladder tumors.18 A disordered actin microfilament architecture has been associated with increased metastatic potential in several tumor models, including murine melanoma and fibrosarcoma models.1920 A loss of order in the actin microfilament architecture has also been observed as a late phenomenon in the progression of human colonic polyps to cancer.21 Mutated forms of actin have been shown to either increase or decrease metastatic potential. Transfection of a mutated form of P-actin with the substitution of a leucine for an arginine at position 28 reduces the metastatic potential of highly aggressive murine B16 melanoma cells.22 These cells developed organized actin stress fibers, were less motile in vitro, were less invasive in collagen gels, and produced fewer lung metastases in mice after tail vein inoculation. On the other hand, transformed HUT-14 human fibroblasts, which express a mutant actin with a single amino acid substitution at position 244, resulted in fewer actin filaments and enhanced invasiveness.23

The actin system is dynamic in locomotion and in transmitting cellular signals. Cells migrate by advancing a leading edge. Motile cells have polarity, with a leading edge exhibiting microspikes and lamellipodia, both of which are dependent on actin filaments. Cell movement is associated with rearrangement of actin architecture at the advancing cell border by actin polymerization and depolymerization.24 When two migrating cells come in contact, advancement of the leading edge immediately stops. This inhibition of locomotion is thought to be mediated by a rapid alteration in the actin-based cortical cytoskeleton. The acdn cytoskeleton has been linked to chemotactic receptors associated with G proteins and cyclic adenosine monophosphate (cAMP),25 and in response to a chemotactic stimulus, increased cellular cAMP promotes F-actin assembly.26

Thyrotropin has been shown to induce stress fibers in cultured thyroid cancer cells.27 Just how perturbations in actin structure and function affect thyroid cancer growth and behavior is not known but is an exciting area for investigation. Most work on thyroid-stimulating hormone (TSH) effects has centered on its ability to induce thyrocyte growth. Perturbation of cell growth control results in tumors, but tumorigenicity is independent of metastatic phenotype.28 Because not all tumors have the ability to invade and metastasize, it follows that the cellular characteristics related to invasion such as matrix attachment, protease production, and locomotion are under separate control from the cell properties regulating growth.

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