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An understanding of cancer cell biology opens the way to new treatments

The better we understand the tricks that cancer cells use to survive, proliferate, and spread, the better are our chances of finding ways to defeat them. The task is made more challenging because cancer cells are highly mutable and, like weeds or parasites, rapidly evolve resistance to treatments used to exterminate them.

Moreover, because mutations arise randomly, every case of cancer is likely to have its own unique combination of genes mutated. Even within an individual patient, tumor cells do not all contain the same genetic lesions. Thus, no single treatment is likely to work in every patient, or even for every cancer cell within the same patient. And the fact that cancers generally are not detected until the primary tumor has reached a diameter of 1 cm or more – by which time it consists of hundreds of millions of cells that are already genetically diverse and often have already begun to metastasize – makes treatment ever harder still.

Yet, in spite of these difficulties, an increasing number of cancers can be treated effectively. Surgery remains a highly effective tactic, and surgical techniques are continually improving: in many cases, if a cancer has not spread far, it can often be cured simply cutting it out. Where surgery fails, therapies based on the intrinsic peculiarities of cancer cells can be used.

Lack of normal cell-cycle control mechanisms, for example, may help make cancer cells particularly vulnerable to DNA damage: whereas a normal cell will halt its proliferation until such damage is repaired, a cancer cell may charge ahead regardless, producing daughter cells that may die because they inherit too many unrepaired breakages in their chromosomes. Presumably for this reason, cancer cells can often be killed by does of radiotherapy or DNA-damaging chemotherapy that leave normal cells relatively unharmed.

Surgery, radiation, and chemotherapy are long-established treatments, but many novel approaches are also being enthusiastically pursued. In some cases, as with loss of a normal response to DNA damage, the very feature that helps to make the cancer cell dangerous also makes it vulnerable, enabling doctors to kill it with a properly targeted treatment.

Some cancers of the breast and ovary, for example, owe their genetic instability to the lack of a protein (Brca1 or Brca2) needed for accurate repair of double-strand breaks in DNA; the cancer cells survive by relying on alternative types of DNA repair mechanisms. Drugs that inhibit one of these alternative DNA repair mechanisms kill the cancer cells by raising their genetic instability to such a level that the cells die from chromosome fragmentation when they attempt to divide. Normal cells, which have an intact double-strand break repair mechanisms, are relatively unaffected, and the drugs seem to have few side effects.

Another set of strategy aims to use the immune systems to kill the tumor cells, taking advantage of tumor-specific cell-surface molecules to target the attack. Antibodies that recognize these tumor molecules can be produced in vitro and injected into the patient to mark the tumor cells for destruction. Other antibodies, aimed to the immune cells, can promote the elimination of cancer cells by neutralizing the inhibitory cell-surface molecules that keep immune system’s killer cells in check. The latter antibodies have been remarkably effective in clinical trials and, in principle, should be useful for treating a variety of different cancers.

Retype from Essential Cell Biology 4th Ed. Page 720-721


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Colorectal cancer illustrates how loss of a tumor suppressor gene can lead to cancer

Colorectal cancer provides one well-studied example of how a tumor suppressor can be identified and its role in tumor growth determined. Colorectal cancer arises from the epithelium lining the colon and rectum; most cases are seen in old people and do not have any discernible hereditary cause.

A small proportion of cases, however, occur in families that are exceptionally prone to the disease and show an unusually early onset. In one set of such “predisposed” families, the affected individuals develop colorectal cancer in early adult life, and the onset their disease is foreshadowed by the development of hundreds or thousands of little tumors, called polyps, in the epithelial lining of the colon and rectum.

By studying these families, investigators traced the development of the polyps to a deletion or inactivation of a tumor suppressor gene called APC – for Adenomatouus Polyposiss Coli. (Note that the protein encoded by this gene is different from the anaphase-promoting complex, also abbreviated APC). Affected individuals inherit one mutant copy is enough for normal behavior, all the cells of these individuals are only one mutational step away from total loss of the gene’s function (as compared to two steps away for a person who inherits two normal copies of the gene). The individual tumors arise from cells that have undergone a somatic mutation that inactivates the remaining good copy. Because the number of new mutations required is smaller, the disease strikes these individuals at an earlier age.

But what about the great majority of colorectal cancer patients, who have inherited two good copies pf APC and do not have the hereditary condition or any significant family history of cancer? When their tumors are analyzed, it turns out that in more than 60% of cases, although both copies of APC are present in the adjacent normal tissues, the tumor cells themselves have lost or inactivated both copies of this gene, presumably through two independent somatic mutations.

All these findings clearly identify APC as a tumor suppressor gene, and knowing its sequence and mutant phenotype, one can begin to decipher how its loss helps to initiate the development of cancer. As explained in “How we know”, the APC gene was found to encode an inhibitory protein that normally restricts the activation of the Wnt signaling pathway, which is involved in stimulating cell proliferation in the crypts og the gut lining, as described earlier. When APC is lost, the pathways is hyperactive and epithelial cells proliferate to excess, generating a polyp. Within this growing mass of tissue, further mutations occur, sometimes resulting in invasive cancer.

Figure. Colorectal cancer often begins with loss of the tumor suppressor gene APC, leading to growth of a polyp.

(A) Thousands of small polyps, and a few much larger ones, are seen in the lining of the colon of a patient with an inherited APC mutation (whereas individuals without an APC mutation might have one or two polyps). Through further mutations, some of these polyps will progress to become invasive cancers, unless the tissue is removed surgically.

(B) Cross section of one such polyp; note the excessive quantities of deeply infolded epithelium, corresponding to crypts full of abnormal, proliferating cells.

A, courtesy of John Northover and Cancer Research UK; B, courtesy of Anne Campbell.

Figure. A polyp in the epithelial lining of the colon or rectum, caused by loss of the APC gene, progress to cancer by accumulation of further mutations.

The diagram shows a sequence of mutations that might underlie a typical case of colorectal cancer. After the initial mutation, all subsequent mutations occur randomly in a single cell that had already acquired the previous mutations. A sequence of events such as that shown here would usually be spread over 10 to 20 years or more. Though most colorectal cancers are thought to begin with loss of the APC tumor suppressor gene, the subsequent sequence of mutations is quite variable; indeed, many polyps never progress to cancer.

Retype from Essential Cell biology chapter 20, p 719-720

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Cells organize the collagen that they secrete

To do their job, collagen fibrils must be correctly aligned. In skin, for example, they are woven in a wickerwork pattern (pola anyaman), or in alternating layers (lapisan bolak-balik) with different orientations so as to resist tensile stress in multiple directions. In tendons, which attach muscles to bone, they are aligned in parallel bundles along the major axis of tension.

The connective-tissue cells that produce collagen control this orientation, first by depositing the collagen in an oriented fashion and then by rearrange it. During development of the tissue, fibroblast work on the collagen they have secreted, crawling over it and pulling on it – helping to compact it into sheets and draw it out into cables.

This mechanical role of fibroblasts n shaping collagen matrices has been demonstrated dramatically in cell culture. When fibroblasts are mixed with a meshwork of randomly oriented collagen fibrils that form a gel in a culture dish, the fibroblasts tug on the meshwork, drawing in collagen from their surroundings and compacting it.

If two small pieces of embryonic tissue containing fibroblasts are placed far apart on a collagen gel, the intervening collagen becomes organized into a dense band of aligned fibers that connect the two explants. The fibroblasts migrate out from the explants along the aligned collagen fibers. Thus, the fibroblasts influence the alignment of the collagen fibers, and the collagen fibers in turn affect the distribution of the fibroblasts.

Fibroblasts presumably play a similar role in generating long-range order in the ECM inside the body – in helping to create tendons, for example, and the tough, dense layers of connective tissue that ensheathe and bind together most organs. Fibroblast migration is also important for healing wounds.

retype from Essential Cell biology 4th edition chapter 20, p.690


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Collagen provides tensile strength in animal connective tissues

Collagen is a protein found in all animals, and it comes in many varieties. Mammals have about 20 different collagen genes, coding for the variant forms of collagen required in different tissues. Collagens are the chief proteins in bone, tendon, and skin (leather is pickled collagen), and they constitute 25% of the total protein mass in a mammal – more than any other type of protein.

The characteristic feature of a typical collagen molecule is its long, stiff, triple-stranded helical structure, in which three collagen polypeptide chains are wound around one another in a ropelike superhelix. Some types of collagen molecules in turn assemble into ordered polymers collagen fibrils, which are thin cables 10-300 nm in diameter and many micrometers long: these can pack together into still thicker collagen fibers. Other types of collagen molecules decorate the surface of collagen fibrils and link the fibrils to one another and to other components in the ECM.

The connective-tissue cells that manufacture and inhabit the ECM go by various names according ti the tissue: in skin, tendon, and many other connective tissues, they are called fibroblasts; in bone, they are called osteoclasts. They make both the collagen and the other macromolecules of the matrix.

Almost all of these molecules are synthesized intracellularly and then secreted in the standard way, by exocytosis. Outside of the cell, they assemble into huge, cohesive aggregates. If assembly were to occur prematurely, before secretion, the cell would become choked with its own products.

In the case of collagen, the cells avoid this catastrophe by secreting collagen molecules in a precursor form, called procollagen, with additional peptide extensions at each end that obstruct premature assembly into collagen fibrils. Extracellular enzymes – called procollagen proteinases – cut off these terminal extensions to allow assembly only after the molecules have emerged into the extracellular space.

Some people have a genetic defect in one of these proteinases, or in procollagen itself, so that their collagen fibrils do not assembly correctly. As a result, their connective tissues have a lower tensile strength and are extraordinarily stretchable.

Cells in tissues have to be able to degrade matrix as well as make it. This ability is essential for tissue growth, repair, and renewal; it also important where migratory cells, such as macrophages, need to burrow (menggali) through the thicket (semak-semak) of collagen and other ECM polymers. Matrix proteases that cleave extracellular proteins play a part in many disease processes, ranging from arthritis, where they contribute to the breakdown of cartilage in affected joints, to cancer, where they help cancer cells invade normal tissue.

retype from Essential Cell biology 4th edition chapter 20, p.688

image: James morris

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Animal connective tissues consist largely of ECM

It is traditional to distinguish four major types of tissues in animals:

  • connective
  • epithelial
  • nervous
  • muscular.

But the basic architectural distinction is between connective tissues and the rest. In connective tissues, ECM is plentiful and carries the mechanical load. In other tissues, such as epithelia, ECM is scanty (sangat sedikit), and the cells are directly joined to one another and carry the mechanical load themselves. We discuss the connective tissues first.

Animal connective tissues are enormously varied. They can be tough and flexible like tendons or the dermis of the skin; hard and dense like bone; resilient (elastis) and shock-absorbing like cartilage; or soft and transparent like the jelly that fills the interior of the eye. In all these examples, the bulk of the tissue is occupied by ECM, and the cells that produce the matrix are scattered within it like raisins (kismis) in a pudding.

In all of these tissues, the tensile strength – whether great or small – is chiefly provided not by a polysaccharide, as in plants, but by a fibrous protein: collagen. The various types of connective tissues owe their specific characters to the type of collagen that they contain, to its quantity, and, most importantly, to the other molecules that are interwoven with it in varying proportions. These include the rubbery protein elastin, which gives the walls of arteries their resilience as blood pulses through them, as well as a host of specialized polysaccharide molecules, which we discuss shortly.

retype from Essential Cell biology 4th edition chapter 20, p.688


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ECM and connective tissues

Plants and animals have evolved their multicellular organization independently, and their tissues are constructed on different principles. Animals prey on other living things – and often are preyed on by other animals – and for this they must be strong and agile: they must possess tissues capable of rapid movement, and the cells that form those tissues must be able to generate and transmit forces and to change shape quickly.

Plants, by contrast, are sedentary: their tissues are more or less rigid, although their cells are weak and fragile if isolated from the supporting matrix that surrounds them. In plants, the supportive matrix is called the cell wall, a boxlike structure that encloses, protects, and constrains the shape of each of its cells. Plant cells themselves synthesize, secrete, and control the composition of this ECM: a cell wall can be thick and hard, as in wood, or thin and flexible, as in a leaf.

But the principle of tissue construction is the same in either case: many tiny boxes are cemented together, with a delicate cell living inside each one. Indeed, as we noted in Chapter 1, it was the close-packed mass of microscopic chambers that Robert Hooke saw in a slice of cork three centuries ago that inspired the term “cell.”

Animal tissues are more diverse. Like plant tissues, they consist of both cells and ECM, but these components are organized in many different ways. In some tissues, such as bone or tendon, ECM is plentiful and mechanically all-important; in others, such as muscle or epidermis, ECM is scanty, and the cytoskeletons of the cells themselves carry the mechanical load. We begin with a brief discussion of plant cell and tissues, before considering those animals.

retype from Essential Cell biology 4th edition chapter 20, p.684


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Cell communities: tissues, stem cells, and cancer

Cells are the building block of multicellular organisms. This seems a simple statement, but it raises deep problems. Cells are not like bricks: they are small and squishy (licin). How can they be used to construct a giraffe or a giant redwood tree? Each cell is enclosed in a flimsy membrane less than a hundred-thousandth of a millimeter thick, and it depends on the integrity of this membrane for its survival.

How, then, can cells be joined together robustly form muscles that can lift an elephant’s weight? Most mysterious of all, if cells are the building blocks, where is the builder and where are the architect’s plans? How are all the different cell types in a plant or an animal produced, with each in its proper place in an elaborate pattern?

Most of the cells in multicellular organisms are organized into cooperative assemblies called tissues, such as nervous, muscle, epithelial, and connective tissues found in vertebrates. In this chapter, we begin by discussing the architecture of tissues from a mechanical point of view. We will see that tissues are composed not only of cells, with their internal framework of cytoskeletal filaments, but also extracellular matrix, which cells secrete around themselves; it is this matrix that gives supportive tissues such as bone or wood their strength.

The matrix provides one way to bind cells together, but cells can also attach to one another directly. Thus, we also discuss the cell junctions that link cells together in the flexible, mobile tissues of animals. These junctions transmit forces either from the cytoskeleton of one cell to that of the next, or from the cytoskeleton of a cell to the ECM.

But there is more to the organization of tissues than mechanics. Just a building needs plumbing, telephone lines, and other fitting, so an animal tissues requires blood vessels, nerves, and other components formed from a variety of specialized cell type. All the tissue components have to be appropriately organized and coordinated, and many of them require continual maintenance and renewal.

Cells die and have to be replaced with new cells of the right type, in the right places, and in the right numbers. In this third section of this chapter, we discuss hoe these processes are organized, as well as the crucial role that stem cells, self-renewal undifferentiated cells, play in the renewal and repair on some tissues.

Disorders of tissue renewal are a major medical concern, and those due to the misbehavior of mutant cells underlie the development of cancer. We discuss cancer in the final section of this chapter and of the book as a whole. Its study requires a synthesis of knowledge of cells an tissues at natural selection and the social organization of cells in the tissues. Many fundamental advances in cell biology have been driven by cancer research, and basic cell biology in return continues to deepen our understanding of the disease and provide us with renewed optimism about its treatment.

retype from Essential Cell biology 4th edition chapter 20, p.683