STRUCTURE AND FUNCTION OF NORMAL CELLS
All normal cells of the human body have some common features and consist of the same basic components. These include the nucleus, the cytoplasm, and the cell (plasma) membrane (Figure 1-1).
Figure 1-1 Normal cells have a nucleus and a cytoplasm. On the outside, the cell is delimited by a plasma membrane. In the cytoplasm, there are organelles, such as mitochondria, smooth and rough endoplasmic reticulum (SER and RER, respectively), Golgi apparatus, and lysosomes. Nucleus
The nucleus is the essential part of most living cells. It consists of nucleic acids, such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and nuclear proteins. In resting cells, these components are arranged into aggregates known as chromatin and a specialized organelle composed primarily of RNA known as the nucleolus. In the dividing of cells—that is, during mitosis—the chromatin is restructured and the strands of DNA condense into chromosomes. The resting cells have a nuclear membrane, which delimits the nucleus from the cytoplasm. This membrane disappears in mitosis and reappears after cell division is completed. The DNA of the nucleus contains essential genetic material that is identical for all cells of an individual body. This genetic material consists of genes that are differentially expressed in various tissues and organs. Differential expression of genes allows the cells to assume unique features in various tissues and organs and to perform specialized functions. Such cells are called differentiated, in contrast to embryonic cells, which have not undergone specialization and which are therefore termed undifferentiated. The genetic information encoded in the DNA is transcribed into the nuclear RNA. From the nuclear RNA, the message is transmitted by transfer RNA (tRNA) and messenger RNA (mRNA) into the cytoplasm (Figure 1-2). The ribosomal RNA (rRNA) serves as a template for translating the genetic messages into proteins. Protein synthesis is essential for the maintenance of life. Proteins are needed for cellular growth, replication, metabolism, respiration, and other essential functions. Proteins also act as structural elements, maintaining the cell's shape and the internal organization of the cytoplasm. None of these elementary functions (and many others that we mention later) would be possible without the nucleus, which acts as the main overseer of all critical cytoplasmic events. All human cells, except the red blood cells and platelets, need a nucleus for survival.
Figure 1-2 Transcription and translation by RNA of the genetic code stored in the DNA leads to protein synthesis on ribosomes. mRNA, messenger RNA; RER, rough endoplasmic reticulum; tRNA, transfer RNA. Cytoplasm
All cells have cytoplasm. However, the amount of cytoplasm and its structure vary from one cell to another. In embryonic cells, the cytoplasm is scant and contains few organelles. In specialized, highly differentiated cells, such as liver or kidney cells, the cytoplasm is more abundant and is replete with organelles. The ratio of the nucleus to the cytoplasm, the so-called nucleocytoplasmic (N : C) ratio, is high in undifferentiated embryonic cells and much lower in differentiated cells of adult tissues. As we shall see later, many tumor cells are also undifferentiated and have a high N : C ratio. The principal cytoplasmic organelles are the mitochondria, ribosomes, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to these, some cells have organelles for specialized functions. For example, muscle cells have myofilaments composed of actin and myosin, which are essential for contraction; glandular cells have secretory granules, which contain enzymes or mucus destined for excretion. Furthermore, it is important to note that the cytoplasmic ground substance of all cells consists of an amorphous matrix called hyaloplasm and a fibrillar meshwork called cytoskeleton. Each cell is also enclosed by an outer plasma membrane, which forms the border between one cell and other cells or the extracellular spaces. This membrane, which is semipermeable, must remain intact to preserve the viability of the cell. Mitochondria.
Mitochondria are double-membrane–bound cytoplasmic organelles, involved primarily in the generation of energy (see Figure 1-1). Hence, mitochondria are rich in oxidative enzymes. These enzymes (e.g., cytochrome oxidase) are attached to the double membrane that encloses each mitochondrion and to the cristae that are seen by electron microscopy on the inside of cross-sectioned mitochondria. Energy generated by the mitochondria is essential for all other cellular functions. Cells with complex functions, such as liver cells and nerve cells, require a considerable amount of energy and therefore contain numerous mitochondria. By comparison, undifferentiated cells, including many malignant tumor cells, have few mitochondria. Ribosomes.
Ribosomes are small granules composed of RNA. They may be arranged into aggregates that float freely in the cytoplasm, called polysomes or free ribosomes, or they may be attached to the membranes of the rough endoplasmic reticulum (RER). The ribosomes are involved in protein synthesis. Structural proteins and enzymes needed for the maintenance of basic cell functions (“proteins for internal purposes”) are synthesized on the free ribosomes. Those intended for excretion (“export or luxury proteins”) are synthesized on the RER and discharged from the cells through the cisternae lined by the membranes of the RER. Endoplasmic Reticulum.
The endoplasmic reticulum is a meshwork of membranes that are in continuity with the outer plasma membranes on one side and the nuclear membrane on the other (Figure 1-3). With use of electron microscopy, one can distinguish two forms of endoplasmic reticulum: the RER and the smooth endoplasmic reticulum (SER). As stated earlier, the RER is the site of protein synthesis. SER has complex functions, the most important of which are the catabolism (i.e., metabolic degradation) of drugs, hormones, and various nutrients and the synthesis of steroid hormones. SER is therefore most prominent in liver cells, known for their complex catabolic functions. The hormone-secreting gonadal cells of the testis and ovary and the adrenocortical cells that synthesize steroid hormones (e.g., estrogens, androgens, and corticosteroids) also have prominent SER.
Figure 1-3 Endoplasmic reticulum. It consists of rough endoplasmic reticulum (RER) arranged into ribosome-studded cisternae and vesicles of smooth endoplasmic reticulum (SER). Golgi Apparatus.
The Golgi apparatus is a synthetic organelle adjacent to the nucleus (see Figure 1-3). Its tubules and flattened cisternae, which are its main components, give rise laterally to vesicles. The vesicles arising from the concave side of the Golgi apparatus—the maturing surface—become secretory granules, lysosomes, and specialized structures, such as melanosomes. Melanosomes are the melanin-containing organelles of pigmented cells (melanocytes) in the skin and eye. The convex face is in continuity with the endoplasmic reticulum. Many proteins synthesized in the endoplasmic reticulum pass through the Golgi apparatus, where they are biochemically modified before being packaged into secretory granules or lysosomes. Glycoproteins and lipoproteins (i.e., proteins linked to a carbohydrate or lipid) are formed in the Golgi apparatus. These complex proteins are then incorporated into the internal cell membranes (e.g., endoplasmic reticulum) or the outer plasma membrane or are secreted from the cell. Lysosomes.
Lysosomes are membrane-bound digestive cytoplasmic organelles that are rich in lytic enzymes. The lysosomes originate as small vesicles budding from enzymes on the maturing face of the Golgi apparatus (Figure 1-4). These primary lysosomes contain acid hydrolases, which are digestive enzymes that are maximally active in an acidic milieu (i.e., at low pH levels). Under normal circumstances, the lytic enzymes are tightly enclosed by a lysosomal outer membrane and do not harm the cell. Even if some lysosomal content is spilled into the cytoplasm, the acid hydrolases would cause little damage in normal cytoplasm, which has a neutral pH. However, if the cell is injured and the pH of the cytoplasm becomes acidic, enzymes released from the lysosomes could cause damage.
Figure 1-4 Lysosomes. Primary (1°) lysosomes, which originate from the Golgi apparatus, give rise to heterophagosomes and autophagosomes. Undigested material in phagosomes is extruded from the cell or remains in the cytoplasm as lipofuscin-rich residual bodies. RER, rough endoplasmic reticulum. The primary lysosomes fuse with other cytoplasmic vesicles to form secondary lysosomes. Typically, they fuse with the absorptive vesicles originating from the invaginated plasma membrane to form secondary lysosomes, which are also called heterophagosomes. Secondary lysosomes that are involved in the autodigestion of a cell's own organelles are called autophagosomes. The digestive enzymes in secondary lysosomes degrade the material enclosed within its membrane. The metabolites obtained through this intracellular digestion are reutilized within the cell's cytoplasm. The undigested residues are extruded from the cytoplasm into the extracellular spaces by reverse endocytosis or exocytosis, a process that is colloquially known as cellular defecation. Some of the undigested material, mostly complex lipids derived from cell membranes, may remain within the cytoplasm as “residual bodies.” These residual bodies typically contain lipid-rich brown pigment known as lipofuscin, a term derived from the Greek word lipos (meaning “fat”) and the Latin word fuscus (meaning “brown”). Lipofuscin is also known as the brown pigment of aging because it is commonly found in cells of elderly persons. With aging, all cellular processes become less efficient. Energy-dependent processes, such as lysosomal digestion and exocytosis, are especially affected. Therefore, cells in an old organism contain more lipofuscin than those in a metabolically active, more vigorous young body. The hyaloplasm, which is the ground substance of the cytoplasm, has no distinct structure and appears as an “empty” space on electron microscopic studies. Biochemically, hyaloplasm consists predominantly of water, but it also contains minerals, proteins, carbohydrates, and lipids. The hyaloplasm is the fluid phase of the cell that contains the organelles. In between the organelles, the hyaloplasm is traversed by a network of filaments that form the cytoskeleton. Three types of filaments are recognized: microfilaments, composed of actin and myosin and measuring 5 nm in diameter; microtubules, which are 22-nm thick and composed of tubulin; and intermediate filaments, named so because their diameter (10 nm) is intermediate between that of microfilaments and microtubules. In contrast to microfilaments and microtubules, which have the same biochemical composition in all cells, the intermediate filament proteins are cell-type–specific proteins (Table 1-1). The intermediate filaments of epithelial cells contain keratins, mesenchymal cells contain vimentin, muscle cells contain desmin, glial cells contain glial acidic fibrillary protein (GAFP), and the neural cells contain neurofilament proteins. Intermediate filament proteins are useful markers for those cell types. Pathologists use antibodies to intermediate filaments for typing of tumors because tumor cells retain the same intermediate filament proteins as the normal cells from which they arise. For example, carcinomas, which are tumors involving epithelial cells, express keratin, whereas sarcomas, which are tumors of mesenchymal cells, express vimentin. Table 1-1 -- Proteins of Cytoskeletal Filaments | Type of Filament | Diameter (nm) | Protein |
|---|
| Microfilaments | 5 | Actin, myosin | | Intermediate filaments | 10 | Epithelial—keratins | | Mesenchymal—vimentin | | Muscle—desmin | | Glia—GFAP | | Nerve—neurofilaments | | Microtubules | 22 | Tubulin |
GFAP, glial fibrillary acidic protein. |
The function of the cytoskeleton is to maintain cell shape and to enable the cell to adapt to external mechanical pressure. Cytoskeletal filaments are also important for cell movement and the traffic of organelles in the cytoplasm. Microtubules also form the mitotic spindle during cell division. Plasma Membrane
The plasma membrane forms the outer surface of the cell (Figure 1-5). The plasma membrane is composed of proteins, lipids, and carbohydrates that are arranged in a polarized complex bilayer that has an internal and external surface. On the internal side, the plasma membrane is in continuity with the membrane of the endoplasmic reticulum. Invaginations of the plasma membrane give rise to endocytotic vesicles, which fuse with primary lysosomes to form heterophagosomes. The cytoplasmic surface of the cell membrane also serves as an anchorage site for cytoskeletal filaments. For example, intermediate filaments composed of keratin aggregate at the site of desmosomes, the typical intercellular bridges that interconnect epithelial cells of the skin (e.g., oral and vaginal mucosa). Microtubules are integral parts of cilia, which are specialized parts of the cell surface that have the ability to move and propel the cell (e.g., sperm) or to move the external secretions of the cell. For example, mucus is moved by the cilia of the bronchial ciliated cells; dysfunction of these cilia may predispose an individual to bronchial infection (bronchitis).
Figure 1-5 Plasma membrane. The bilipid layer also contains proteins and carbohydrates, which perform complex functions and serve as receptors, adhesion molecules, and transducers of signals. The external surface of the plasma membrane serves as the site of contact between the cell and the environment. This interaction between the cell and the environment is maintained through the action of specialized portions of the cell membrane that serve as receptors, adhesion molecules, transducers of signals, or metabolic channels. The complexity of the plasma membrane varies from one cell type to another. The plasma membrane of cells is a living structure that is maintained by active expenditure of energy. The structural integrity of the plasma membrane is a prerequisite for the maintenance of all essential cellular functions. Rupture or major damage of the cell membrane that cannot be repaired invariably leads to cell death. |