Biology Cancer

Cancer is the proliferation (growth) of malignant cells—cells that grow inappropriately, disrupt normal tissue structure and function, and, frequently, can survive in the blood stream and proliferate at distal sites. Cancer, if unchecked, can kill the organism in which it exists.

Loss of growth control per se does not define a cell as malignant. Malignant cells have additional properties, specifically an ability to migrate and infiltrate the surrounding normal tissue (invasiveness) and induce a blood supply to feed the growing tumor (angiogenesis). Cancer cells invariably lose their differentiated properties (anaplasia), and they eventually acquire the ability to colonize and invade distal tissues (metastasis).

Loss of growth control. All cancers are characterized by abnormal cell growth (hyperproliferation, or neoplasia). Neoplasias may be benign (not invasive or metastatic) or malignant (invasive and frequently metastatic). Benign tumors are rarely fatal, because their growth, however abundant, is rarely unlimited (and, additionally, they are rarely invasive or metastatic). Malignant tumors, by contrast, tend to grow progressively, even if slowly.

Normal cell proliferation is controlled by an exquisite balance between processes that stimulate growth and those that inhibit growth. When this balance is upset, abnormal growth occurs. Abnormal growth is generally caused by an increase in growth-stimulatory processes, as well as a decrease in growth-inhibitory processes.

External signals. Many growth stimulatory and inhibitory processes are triggered by signals that originate outside the cell (the cellular microenvironment). These external signals can be delivered by small diffusible molecules, such as growth factors, cytokines or circulating hormones, or by large molecules, such as components of the extracellular matrix or basement membrane. They can also be delivered by adjacent or nearby cells. For example, fibroblasts, which produce the collagen-rich matrix (stroma) that underlies most epithelial layers, signal and instruct the epithelial cells. External growth-regulatory molecules generally act by binding and altering transmembrane cell-surface receptors. The altered receptors then associate with or modify intracellular proteins at the underside of the cell-surface. These molecules, in turn, produce small diffusible chemical signals inside cells that, by interacting with or modifying yet other intracellular proteins, eventually send a signal to the cell nucleus. In the nucleus, specific genes that stimulate or inhibit progression through the cell cycle are then switched on or off.

Cellular senescence. Cell proliferation can also be governed by signals that originate within cells. A prime example is cellular senescence, an intrinsic program that causes mitotic cells to irreversibly withdraw from the cell cycle.

Most cells from adult organisms cannot divide indefinitely, owing to a process termed replicative senescence. In humans (and certain other species), replicative senescence occurs because cells lose a small amount of DNA from the chromosome ends (the telomeres) after each round of DNA replication, and cells irreversibly arrest growth when they acquire one (or more) critically short telomere. Such cells are said to be replicatively senescent. Mitotic cells enter a state that closely resembles replicative senescence when Figure 1 Human fetal fibroblasts, prior to replicative senescence (Presenescent panel, left), grow in culture until they form a single, ordered, continuous layer on the culture dish. After about fifty doublings, the cultures become senescent (Senescent panel, middle). The senescent cells are flattened and enlarged, and form a layer with many gaps. The right panel shows cells from a human fibrosarcoma, a tumor formed from fibroblasts. The tumor cells form a disorganized layer, and will eventually grow atop one another. All the cells in the panels were stained for the presence of the senescence-associated betagalactosidase, an enzyme that is expressed by senescent cells. Cells that express this enzyme appear as darker areas in the panels. SOURCE: Author they experience sublethal DNA damage, supraphysiological growth signals, or expression of certain oncogenes (genes that promote neoplastic growth). Replicative senescence, then, is a special example of a more general process termed cellular senescence. Short telomeres, DNA damage, over-exuberant growth signals, and oncogenes all have the potential to change a normal cell into a precancerous or cancer cell. Thus, cellular senescence, or the senescence response, suppresses tumorigenesis by preventing the growth of cells at risk for malignant transformation.

Cellular senescence appears to be a major barrier that cells must overcome in order to become malignant. Several lines of evidence support this idea. First, most, if not all, malignant tumors contain cells that have overcome cellular senescence. (Many tumor cells accomplish this by expressing telomerase, the enzyme that replenishes the telomeric DNA that is lost during DNA replication. Telomerase is expressed by the germ line and early embryonic cells, but is repressed in most adult cells.) Second, some oncogenes act by allowing cells to ignore senescence-inducing signals. Cells that express such oncogenes continue to proliferate despite short telomeres, DNA damage, or other potentially oncogenic conditions. Third, cellular senescence is controlled by the p53 and pRB tumor-suppressor proteins, the two most commonly mutated tumor suppressors in human cancers. Finally, mutant mice have been generated in which cells fail to respond to senescence signals. Such animals invariably die from cancer at an early age.

Cellular senescence is also thought to contribute to aging. At first glance, this idea may seem at odds with its tumor-suppressive function. It is consistent, however, with the theory of evolutionary antagonistic pleiotropy. This theory predicts that, because the force of natural selection declines with increasing age, some traits that were selected to optimize fitness during development or young adulthood can have unselected deleterious effects in aged organisms. In the case of cellular senescence, the irreversible growth arrest may be the selected trait that prevents the proliferation of cells at risk for malignant transformation. Other features of the senescent phenotype, such as resistance to programmed cell death and changes in cell function, may be unselected and deleterious.

Some senescent cells are resistant to programmed cell death (apoptosis), and all senescent cells display changes in cell function. The functional changes can be striking. For example, senescent fibroblasts secrete degradative enzymes, inflammatory cytokines (small molecules that attract macrophages or neutrophils), and growth factors. Thus, senescent fibroblasts can create a microenvironment that resembles chronic wounding, which can disrupt tissue structure and/or function as senescent cells accumulate. Senescent cells appear to be relatively rare in young tissues, but more common in old tissues. As discussed below, their ability to disrupt tissue structure may contribute to aging, as well as the rise in late-life cancers.

Apoptosis. Most tissues achieve and maintain proper size by a balance between cell proliferation and death. All cells are capable of an orderly suicide process, termed programmed cell death or apoptosis. Apoptosis is important during embryogenesis, where it can rid the fetus of excess or damaged cells, or cells that fail to receive signals needed for proper function. Apoptosis is also important in adults, where it helps maintain the size of cell populations or tissues. Equally important, apoptosis removes damaged cells from adult tissues, and thus is another tumorsuppressive mechanism.

Many tumor cells develop defects in the control of apoptosis. Consequently, many tumor cells survive under circumstances that would cause their normal counterparts to die. There is limited but compelling evidence that, in at least some tissues, apoptosis declines with increasing age. This decline may also contribute to the increase in age-related cancer.

Loss of differentiation. Another feature of cancer is abnormal differentiation, or anaplasia. All cells contain the same DNA, and hence the same genome (30,000 to 50,000 genes, in humans). However, each cell expresses (transcribes into RNA and translates into protein) only 10 to 20 percent of its genome. The selective expression of genes is termed differentiation, and it is responsible for the characteristics that distinguish different cell types from each other.

Differentiation begins early in embryogenesis. By adulthood, most tissues have matured and function much as they will throughout life. Nonetheless, differentiation is an ongoing process in tissues that rely on stem cells for renewal or repair. Stem cells are mitotic cells that, upon division, either produce another stem cell or produce a differentiated cell. In the skin, for example, stem cells renew themselves, but more frequently they give rise to basal keratinocytes. Basal keratinocytes, in turn, divide and differentiate into cells that form the upper layers of the epidermis. Throughout life, basal cells divide and progressively differentiate into upper keratinocytes, including the outermost postmitotic cells, which are eventually sloughed off. The stem cells divide relatively infrequently, but often enough to maintain the pool of basal cells. Differentiation not only determines which specialized proteins are made by a cell, but also whether cells are mitotic or postmitotic, whether a cell proliferates or dies, and whether and how a cell migrates or communicates with other cells.

Because differentiation integrates cell growth and death with function, it is not surprising that tumors invariably show signs of abnormal differentiation. Tumor cells are generally less differentiated than surrounding normal cells, and the most aggressive tumors tend to be the least differentiated. Some cancers may arise directly from the least differentiated cells in a tissue, or from the stem cells. In other cases, a cancer cell may acquire an abnormal pattern of gene expression, leading to a less differentiated state.

Childhood and young-adult cancers tend to be poorly differentiated, generally arising from precursor or stem cells. Cancers of old adults, by contrast, include both poorly differentiated and relatively well-differentiated tumors.

Angiogenesis, invasion, and metastasis. Malignant tumors acquire the ability to migrate and invade the surrounding normal tissue (invasiveness). They also stimulate the formation of blood vessels (angiogenesis), which provide the growing tumor with nutrients. The most malignant tumors acquire the ability to survive in the blood stream and colonize distal tissues (metastasis). These abilities are also characteristic of fetal cells. Hence, the anaplasia of tumor cells is often responsible for their invasive, metastatic, and angiogenic properties.

Cancer cells become invasive when they secrete enzymes that degrade the extracellular matrix and stroma, and they become angiogenic when they secrete cytokines that attract endothelial and other cells needed for blood vessel formation. Many tumor cells also secrete factors that cause stromal fibroblasts to secrete degradative enzymes and endothelial attractants. Although cancer incidence increases exponentially with age, tumors in very old individuals tend to be less aggressive than tumors in middle-aged adults. This age-dependent difference may reflect the response of the surrounding host cells. Indeed, some tumors are less vascularized in older hosts because their endothelial cells respond much less well to tumor-derived angiogenic factors.

Metastasis requires that solid tumor cells acquire the ability to survive in the hostile environments of the bloodstream and a foreign (ectopic) tissue. Most normal cells (and even most preneoplastic or benign tumor cells) undergo apoptosis when placed in a foreign environment. Metastatic tumor cells either fail to sense environmental cues that normally cause cell death, or they fail to execute the apoptotic program. In addition, metastatic tumor cells frequently express cell-surface proteins that allow them to adhere to and infiltrate an ectopic site.

Genomic instability. Another hallmark of malignant tumors is genomic instability. A prime cause of cancer is the accumulation of mutations. Most cancers develop from preneoplastic cells—cells that have acquired mutations (one, or a few) that confer a growth or survival advantage. Preneoplastic cells are not malignant, but are predisposed to malignant transformation upon acquiring additional mutations. During the 1980s and 1990s, cancers were thought to develop because cells successively acquired a discrete number of mutations, generally half a dozen or so, depending on the tissue. However, recent findings show that most tumors harbor many mutations, often exceeding several dozen.

Spontaneous mutation at any locus tends to occur once every hundred thousand or so cell divisions. How, then, do tumors acquire dozens of mutations during progression to malignancy? Most cancer cells eventually acquire a mutation in one or more genes that ensure genomic stability—the remarkable fidelity with which nuclear DNA and chromosome organization are maintained. These proteins, often referred to as guardians of the genome, include the p53 tumor suppressor, which halts the cell cycle when DNA is damaged. They also include proteins that regulate chromosome segregation during mitosis and participate in DNA repair. As discussed below, some of these genes can be considered longevity assurance genes—genes that, when lost or mutated, shorten life span and accelerate certain age-related pathologies.

Once a cell loses the activity of one or more guardians of the genome, the genome becomes unstable and mutations occur much more frequently. A high mutation rate allows cancer cells to evolve rapidly. Thus, the genomic instability of cancer cells allows rapid selection for cells that have ever more aggressive and malignant properties.