Ch. 15 Cancer

The Warburg effect in tumor cells reflects a dramatic change in glucose uptake and sugar metabolism.

(A) Cells that are not proliferating will normally oxidize nearly all of the glucose that they import from the blood to produce ATP through the oxidative phosphorylation that takes place in their mitochondria. Only when deprived of oxygen will these cells generate most of their ATP from glycolysis, converting the pyruvate produced to lactate in order to regenerate the NAD+ that they need to keep glycolysis going (see Figure 2-47). (B) Tumor cells, by contrast, will generally produce abundant lactate even in the presence of oxygen. This results from a greatly increased rate of glycolysis that is fed by a very large increase in the rate of glucose import. In this way, tumor cells resemble the rapidly proliferating cells in embryos (and during tissue repair), which likewise require for biosynthesis a large supply of the small-molecule building blocks that can be produced from imported glucose

Properties of cancer cells: daggett

1) reduced dependence on signals; 2) less prone to apoptosis; 3) cancer cells maintain telomerase activity; 4) have a higher mutation rate; 5) invasive; 6) survive outside normal cell niche They grow (biosynthesize) when they should not, aided by a metabolism shifted from oxidative phosphorylation toward aerobic glycolysis. They go through the cell-division cycle when they should not. They escape from their home tissues (that is, they are invasive) and survive and proliferate in foreign sites (that is, they metastasize). They have abnormal stress responses, enabling them to survive and con- tinue dividing in conditions of stress that would arrest or kill normal cells, and they are less prone than normal cells to commit suicide by apoptosis. They are genetically and epigenetically unstable. They escape replicative cell senescence, either by producing telomerase or by acquiring another way of stabilizing their telomeres. In the next section of the chapter, we examine the mutations and molecular mechanisms that underlie these and other properties of cancer cells.

Properties of cancer cells:

1. A tumor grows from a single cancer cell. 2. Cancer cells invade neighboring tissue. 3. Cancer cells spread to other parts of the body. 4. Cancer cells may survive and establish a new tumor in another part of the body. All neoplasms have: 1.) *Parenchyma* - proliferating neoplastic cells 2.) *Supportive stroma* - connective tissue & blood vessels (desmoplasia, scirrhous) - Benign neoplasms: 1) Small 2) Well-demarcated 3) Slow-growing 4) Noninvasive 5) Non-metastatic 6) Well-differentiated - Malignant neoplams 1) Large 2) Poorly demarcated 3) Fast-growing 4) Invasive 5) Metastatic 6) Poorly differentiated

cancer

A disease in which some body cells grow and divide uncontrollably, damaging the parts of the body around them. Disease caused by abnormal and uncontrolled cell division resulting in localized growths (tumors), which may spread throughout the body. any malignant growth or tumor caused by abnormal and uncontrolled cell division

chromosomal translocation

A segment of one chromosome breaks off and attaches to a homologous chromosome generally result from swapping of chromosomal arms between heterologous chromosomes and hence are reciprocal in nature (Figure 1) (8,9). DNA double-strand breaks (DSBs) are prerequisites for such translocations, although little is known about their generation.

A Single Mutation Is Not Enough to Change a Normal Cell into a Cancer Cell what causes cancer?

An estimated 10^16 cell divisions occur in a normal human body in the course of a typical lifetime; in a mouse, with its smaller number of cells and its shorter life- span, the number is about 10^12. Even in an environment that is free of mutagens, mutations would occur spontaneously at an estimated rate of about 10^-6 mutations per gene per cell division—a value set by fundamental limitations on the accuracy of DNA replication and repair (see pp. 237-238). Thus, in a typical lifetime, every single gene is likely to have undergone mutation on about 10^10 separate occasions in a human, or on about 10^6 occasions in a mouse. Among the resulting mutant cells, we might expect a large number that have sustained deleterious mutations in genes that regulate cell growth and division, causing the cells to disobey the normal restrictions on cell proliferation. From this point of view, the problem of cancer seems to be not why it occurs, but why it occurs so infrequently. Clearly, if a mutation in a single gene were enough to convert a typical healthy cell into a cancer cell, we would not be viable organisms. Many lines of evidence indicate that the development of a cancer typically requires that a substantial number of independent, rare genetic and epigenetic accidents occur in the lin- eage that emanates from a single cell. One such indication comes from epidemi- ological studies of the incidence of cancer as a function of age (Figure 20-6). If a single mutation were responsible for cancer, occurring with a fixed probability per year, the chance of developing cancer in any given year of life should be independent of age. In fact, for most types of cancer, the incidence rises steeply with age— as would be expected if cancer is caused by a progressive, random accumulation of a set of mutations in a single lineage of cells. THerefore, Cancers Develop Gradually from Increasingly Aberrant Cells

sarcomas

Cancers that arise in the connective tissue cells, including bones, ligaments, and muscles.

Cancer Cells have an Altered Sugar Metabolism Warburg Effect

Given sufficient oxygen, normal adult tissue cells will generally fully oxidize almost all the carbon in the glucose they take up to CO2, which is lost from the body as a waste product. A growing tumor needs nutrients in abundance to provide the building blocks to make new macromolecules. Correspondingly, most tumors have a metabolism more similar to that of a growing embryo than to that of normal adult tissue. Tumor cells consume glucose avidly, importing it from the blood at a rate that can be as much as 100 times higher than neighboring normal cells. Moreover, only a small fraction of this imported glucose is used for production of ATP by oxidative phosphorylation. Instead, a great deal of lactate is produced, and many of the remaining carbon atoms derived from glucose are diverted for use as raw materials for synthesis of the proteins, nucleic acids, and lipids required for tumor growth (Figure 20-12). This tendency of tumor cells to de-emphasize oxidative phosphorylation even when oxygen is plentiful, while at the same time taking up large quantities of glucose, can be shown to promote cancer cell growth and is called the Warburg effect—so named because Otto Warburg first noticed the phenomenon in the early twentieth century. It is this abnormally high glucose uptake that allows tumors to be selectively imaged in whole-body scans (see Figure 20-1), thereby providing a way to monitor cancer progression and responses to treatment.

Clonal evolution. Tumor Progression Involves Successive Rounds of Random Inherited Change Followed by Natural Selection: process in which an initial population of slightly abnormal —descendants of a single abnormal ancestor—evolve from bad to worse through successive cycles of random inherited change followed by natural selection. At each stage of progression, some individual cell acquires an additional muta- tion or epigenetic change that gives it a selective advantage over its neighbors, making it better able to thrive in its environment—an environment that, inside a tumor, may be harsh, with low levels of oxygen, scarce nutrients, and the nat- ural barriers to growth presented by the surrounding normal tissues. The larger the number of tumor cells, the higher the chance that at least one of them will undergo a change that favors it over its neighbors. The offspring of the best-adapted cells continue to divide, eventually producing the dominant clones in the developing lesion a kind of speciation often occurs: the original cancer cell lineage can diversify to give many genetically different vig- orous subclones of cells. These may coexist in the same mass of tumor tissue; or they may migrate and colonize separate environments suited to their individual quirks, where they settle, thrive, and progress as independently evolving metas- tases. As new mutations arise within each tumor mass, different subclones may gain an advantage and come to predominate, only to be overtaken by others or outgrown by their own sub-subclones. The increasing genetic diversity as a cancer progresses is one of the chief factors that make cures difficult.

In this schematic diagram, a tumor develops through repeated rounds of mutation and proliferation, giving rise eventually to a clone of fully malignant cancer cells. At each step, a single cell undergoes a mutation that either enhances cell proliferation or decreases cell death, so that its progeny become the dominant clone in the tumor. Proliferation of each clone hastens the occurrence of the next step of tumor progression by increasing the size of the cell population that is at risk of undergoing an additional mutation. The final step depicted here is invasion through the basement membrane, an initial step in metastasis. In reality, there are more than the three steps shown here, and a combination of genetic and epigenetic changes are involved. Not shown here is the fact that, over time, a variety of competing subclones will often arise in a tumor

Metastasis

Malignant tumors typically give rise to metastases, making the cancer hard to eradicate. Shown inthis fusion image is a whole-body scan of a patient with metastatic non-hodgkin's lymphoma (NhL). The background image of the body's tissues was obtained by CT (computed x-ray tomography) scanning. PET scan reveals tumor cells in yellow, detected by its unusually high uptake of radioactively labeled fluorodeoxyglucose (FDG). high FDG uptake occurs in cells with unusually active glucose uptake and metabolism, which is a characteristic of cancer cells (see Figure 20-12). The yellow spots in the abdominal region reveal multiple metastases.

human Cancer Cells Are Genetically Unstable

Most human cancer cells accumulate genetic changes at an abnormally rapid rate and are said to be genetically unstable. breaks and rearrangements can occur which can elucidate instability the cells of many cancers show grossly abnormal sets of chromosomes, with duplications, deletions, and translocations that are visible at mitosis cancer cells can contain an unusually large amount of heterochromatin—a condensed form of interphase chromatin that silences genes----> epigenetic changes of chromatin structure can also contribute to the cancer cell phenotype genetic instability observed in cancer cells can arise from defects in the ability to repair DNA damage or to correct replication errors --->DNA translocations and duplications, defects in chromosome segregation during mitosis, which provide another possible source of chromosome instability and changes in karyotype.

Stages of progression in the development of cancer of the epithelium of the uterine cervix.

Pathologists use standardized terminology to classify the types of disorders they see, so as to guide the choice of treatment. (A) In a stratified squamous epithelium, dividing cells are confined to the basal layer. (B) In this low-grade intraepithelial neoplasia (righthalf of image), dividing cells can be found throughout the lower third of the epithelium; the superficial cells are still flattened and show signs of differentiation, but this is incomplete. (C) In high-grade intraepithelial neoplasia, cells in all the epithelial layers are proliferating and exhibit defective differentiation. (D) True malignancy begins when the cells move through or destroy the basal lamina that underlies the basal layer of epithelium and invade the underlying connective tissue. TRUE MALIGNANCY-- basal lamina has been breached, cells have enlarged nuclei, small cytoplasm, clear zone,

replicative cell senescence Human cancer cells avoid replicative cell senescence in one of two ways.

Phenomenon observed in primary cell cultures as they age, in which cell proliferation slows down and finally halts. generally progressive shortening of the telomeres at the ends of chromosomes, a process that eventually changes their structure They can maintain the activity of telomerase as they proliferate, so that their telomeres do not shorten or become uncapped, or they can evolve an alternate mechanism based on homologous recombination (called ALT) for elongating their chromosome ends. Regardless of the strategy used, the result is that the cancer cells continue to proliferate under conditions when normal cells would stop.

Proto-oncogene -> oncogene

Somatically acquired mutations "Dominant gene" mutation Proto-oncogene when highly expressed, can also become an oncogene via transcriptional amplification. Three ways 1. Translocation to new locus: Excess protein 2. Gene amplification : Excess protein 3. Point mutation: Hyperactive protein

What causes cancer? what causes the cells to go rogue? HPV changes genes for ovarian cancer

defects in genes that regulate cell growth and division somatic mutations; spontaneous; can be influenced by environment and mutagens

Chromosomal translocations are very common in human cancer. Explained kinda

The molecular mechanisms of chromosomal translocations are complex and are not fully understood. Recent studies showed organization of genomes is higher-order in the nucleus and every chromosome or chromatin has its preferential position and territory. These findings suggest the spatial arrangements of chromosomes and gene loci in the interphase nucleus are responsible for non-random chromosomal translocations in human cancer. Chromosomal translocations are favored in neighboring chromosomes or genes in spatial proximity within the nucleus. Chromosomal translocations leading to cancer are generally via two ways, formation of oncogenic fusion protein or oncogene activation by a new promoter or enhancer.

Melanoma

The most serious form of skin cancer; black appearance; very aggressive/ invasive

tumor progression

The process by which an initial mildly disordered cell behavior gradually evolves into a full-blown cancer. Normal Hyperplastic Dysplastic Neoplastic Metastatic an initial mild disorder of cell behavior evolves gradually into a full-blown cancer. Chronic myelogenous leukemia again provides a clear example. It begins as a disorder characterized by a nonlethal overproduction of white blood cells and continues in this form for several years before changing into a much more rapidly progressing illness that usually ends in death within a few months. In the early chronic phase, the leukemic cells are distinguished mainly by the chromosomal translocation (the Philadelphia chro- mosome) mentioned previously, although there may well be other, less visible genetic or epigenetic changes. In the subsequent acute phase, cells that show not only the translocation but also several other chromosomal abnormalities over- run the hemopoietic (blood-forming) system. It appears that cells from the initial mutant clone have undergone further mutations that make them proliferate even more vigorously, so that they come to outnumber both the normal blood cells and their ancestors with the primary chromosomal translocation.

metastasis

The spread of cancer cells to locations distant from their original site; invasive cancer

Steps in the process of metastasis.

This example illustrates the spread of a tumor from an organ such as the bladder to the liver. Tumor cells may enter the bloodstream directly by crossing the wall of a blood vessel, as diagrammed here, or, more commonly perhaps, by crossing the wall of a lymphatic vessel that ultimately discharges its contents (lymph) into the bloodstream. Tumor cells that have entered a lymphatic vessel often become trapped in lymph nodes along the way, giving rise to lymph-node metastases. Studies in animals show that typically far fewer than one in every thousand malignant tumor cells that enter the bloodstream will colonize a new tissue so as to produce a detectable tumor at a new site.

Cross-section of a colon adenocarcinoma that has metastasized to the lung.

This tissue slice shows well-differentiated colorectal cancer cells forming cohesive glands in the lung. The metastasis has central pink areas of necrosis where dying cancer cells have outgrown their blood supply. Such anoxic regions are common in the interior of large tumors.

carcinoma

a cancer arising in the epithelial tissue of the skin or of the lining of the internal organs. epithelial tumors comprise 80% of cancer

epithelial tumor (carcinoma)

as it begins to grow/spread/invade/metastasize it breaks through basal lamina enters into surrounding CT making way into vessels where it can disseminate into blood/lymphatics and spread

Warburg effect

cancer cells preferentially use glycolysis while decreasing oxidative phosphorylation -use of glycolysis under normal oxygen conditions (aerobic glycolysis) -allows products of glycolysis to be used for rapid cell growth -activated by oncogenes and mutant tumor suppressors tendency of tumor cells to de-emphasize oxidative phosphorylation even when oxygen is plentiful, while at the same time taking up large quantities of glucose, can be shown to promote cancer cell growth

Cancer Cells have an Abnormal Ability to Survive Stress and DNA Damage

cancer cells require additional mutations to elude or break through these defenses against cellular misbehavior. are found to contain mutations that drive the cell into an abnormal state, where metabolic processes may be unbalanced and essential cell compo- nents may be produced in ill-matched proportions. chromosome breakage and other forms of DNA damage are commonly observed during the development of cancer, reflecting the genetic instability that cancer cells display. Thus, to survive and divide without limit, a prospective cancer cell must accumulate mutations that disable the normal safety mechanisms that would otherwise induce a cell that is stressed, to die. -properties of many types of cancer cells is that they fail to undergo apoptosis when a normal cell would do so (Figure 20-13). While cancer cells tend to avoid apoptosis, this does not mean that they rarely die. On the contrary, in the interior of a large solid tumor, cell death often occurs on a massive scale: living conditions are difficult, with severe competition among the cancer cells for oxygen and nutrients. Many die, but typically much more by necrosis than by apoptosis (Figure 20-14). The tumor grows because the cell birth rate outpaces the cell death rate, but often by only a small margin. For this reason, the time that a tumor takes to double in size can be far longer than the cell-cycle time of the tumor cells. Both increased cell division and decreased apoptosis can contribute to tumorigenesis

malignant

cancerous

myelomas

cancerous plasma cells

leukemias, lymphomas, and myelomas

cancers of lymphatic tissue, bone marrow, and blood cells

Cancer Cells Display an Altered Control of Growth

driving force for development of a cancer has to come from some sort of selective advantage possessed by the mutant cells. Most obviously, a mutation or epigenetic change can confer such an advantage by increasing the rate at which a clone of cells proliferates or by enabling it to continue proliferating when normal cells would stop. Cancer cells that can be grown in culture, or cultured cells artificially engineered to contain the types of mutations encountered in cancers, typically show a transformed phenotype. They are abnormal in their shape, their motility, their responses to growth factors in the culture medium, and, most characteristically, in the way they react to contact with the substratum and with one another. Normal cells will not divide unless they are attached to the substratum; transformed cells will often divide even if held in suspension. Normal cells become inhibited from moving and dividing when the culture reaches confluence (where the cells are touching one another); transformed cells continue moving and dividing even after confluence, and so pile up in layer upon layer in the culture dish (Figure 20-11). In addition, transformed cells no longer require all of the positive signals from their surroundings that normal cells require. Their behavior in culture gives a hint of the ways in which cancer cells may misbehave in their natural environment, embedded in a tissue. But cancer cells in the body show other peculiarities that mark them out from normal cells, beyond those just described.

benign

harmless; not cancerous

basal cell carcinoma

malignant tumor of the basal cell layer of the epidermis; originates in epidermal skin cells

neoplasm

new growth (tumor)

Most Cancers Derive from a Single Abnormal Cell Primary tumor

original tumor; the source of metastasis; metastatic cancer can be traced to primary tumor A benign glandular tumor (pink cells; an adenoma) remains inside the basal lamina (yellow) that marks the boundary of the normal structure (a duct, in this example). In contrast, a malignant glandular tumor (red cells; an adenocarcinoma) can develop from a benign tumor cell, and it destroys the integrity of the tissue, as shown. There are many different forms that such tumors may take.

How do protooncogenes become oncogenes?

point or deletion mutation, translocation, and gene amplification mutation, regulatory mutation, chromosome rearrangements

cancer cells contain what kind of mutations?' Somatic mutations that alter DNA sequence appear to be a fundamental and universal feature, and cancer is in this sense a genetic disease.

somatic mutation; a single abnormal cell is to give rise to a tumor, it must pass on its abnormality to its progeny: the aberration has to be heritable. -Thus, the development of a clone of cancer cells depends on genetic changes. The tumor cells contain somatic mutations: they have one or more shared detectable abnormalities in their DNA sequence that distinguish them from the normal cells surrounding the tumor, as in the example of CML just described. (The mutations are called somatic because they occur in the soma, or body cells, not in the germ line). Cancers are also driven by epigenetic changes—persistent, heritable changes in gene expression that result from modifications of chromatin structure without alteration of the cell's DNA sequence. Thus, carcinogenesis (the generation of cancer) can be linked to mutagenesis (the production of a change in the DNA sequence). This correlation is particularly clear for two classes of external agents: (1) chemical carcinogens (which typically cause simple local changes in the nucleotide sequence), and (2) radiation such as x-rays (which typically cause chromosome breaks and translocations) or ultravio- let (UV) light (which causes specific DNA base alterations). As would be expected, people who have inherited a genetic defect in one of several DNA repair mechanisms, causing their cells to accumulate mutations at an elevated rate, run a heightened risk of cancer. Those with the disease xeroderma pigmentosum, for example, have defects in the system that repairs DNA damage induced by UV light, and they have a greatly increased incidence of skin cancers.

cancer stem cells

stem cells that divide and yield cancer cells and abnormal specialized cells

The Tumor Microenvironment Influences Cancer Development

stroma are highly active development of a tumor relies on a two-way communication between the tumor cells and the tumor stroma, just as the normal development of epithelial organs relies on communication between epithelial cells and mesenchymal cells provides a framework for the tumor. It is composed of normal connective tissue containing fibroblasts and inflammatory white blood cells, as well as the endothelial cells that form blood and lymphatic vessels with their attendant pericytes and smooth muscle cells (Figure 20-15). As a carcinoma progresses, the cancer cells induce changes in the stroma by secreting signal proteins that alter the behavior of the stromal cells, as well as proteolytic enzymes that modify the extracellular matrix. The stromal cells in turn act back on the tumor cells, secreting signal proteins that stimulate cancer cell growth and division as well as proteases that further remodel the extracellular matrix. In these ways, the tumor and its stroma evolve together, like weeds and the ecosystem that they invade, and the tumor becomes dependent on its particular stromal cells. Experiments using mice indicate that the growth of some transplanted carcinomas depends on the tumor-associated fibroblasts and normal fibroblasts will not do. Such environmental requirements help to protect us from cancer, as we discuss next in considering the critical phenomenon called metastasis.

Cancers Develop Gradually from Increasingly Aberrant Cells

the development of a cancer requires a gradual accumulation of mutations in a number of different genes helps to explain tumor progression, whereby Carcinomas and other solid tumors evolve in a similar way (Figure 20-8). Although many such cancers in humans are not diagnosed until a relatively late stage, in some cases it is possible to observe the earlier steps and, as we shall see later, to relate them to specific genetic changes cervical cancer example, caused by a virus, leads to change in transformation of epithelial cells

basal cell

type of stem cell found in the stratum basale and in the hair matrix that continually undergoes cell division, producing the keratinocytes of the epidermis

Substratum

underlying layer, a foundation