What is Cancer?
Cancer Progress Report 2013: Contents
In this section you will learn:
Cancer is not one disease, but likely more than 200 different types of the disease.
Changes in the genetic material in a cell underpin cancer initiation and development in most cases.
A cancer cell's surroundings influence the development and progression of disease.
The development of cancer is a process that occurs over a period of many years.
The most advanced stage of cancer, metastatic disease, accounts for more than 90 percent of cancer deaths.
At its simplest, cancer can be considered a disease in which normal cells start “behaving badly”, multiplying uncontrollably, ignoring signals to stop, and accumulating to form a mass that is generally termed a tumor (see
Unfortunately, research has taught us that cancer is anything but simple.
First and foremost, there are perhaps as many as 200 different types or subtypes of cancer, each named for the organ or type of cell from which it originates. Moreover, cancer is complex at every level, from populations, to individuals, to specific cancers, to the molecular and genetic defects that drive these cancers.
Despite cancer’s complexity, we are beginning to exploit our growing knowledge of the molecular changes that generally drive cancer initiation and development for the benefit of patients, providing new ways to reduce the burden of cancer (see sidebar on
The Virtuous Cycle of Biomedical Research).
The Origins of Cancer
An in-depth understanding of what happens when normal cells become cancerous is essential if we are to answer the question: What is cancer?
We know that to keep our bodies healthy, most cells multiply or divide in a tightly controlled process to replace old and damaged cells. Sometimes, this well-regulated process goes awry, and cells do not die when they should or new cells form when they should not. These extra cells can accumulate, forming a tumor. What upsets this delicately balanced system and causes cancer?
The Genetic Basis of Cancer
Changes, or mutations, in the genetic material of normal cells can disrupt the balance of factors governing cell survival and division, and lead to cancer. This discovery, which was primarily enabled through NIH funding, was one of the greatest research advances in the modern era.
The genetic material of a cell is made of deoxyribonucleic acid (DNA) strands, which are composed of four units called bases. These bases are organized into genes, and the order, or sequence, of these bases provides the code for producing the various proteins a cell uses to function. The organization of DNA is similar to the way in which letters of the alphabet are carefully ordered to form words and sentences (see
The entirety of a person’s DNA is called a genome. Almost every cell in the body contains a copy of the genome, which is packaged together with proteins called histones into thread-like structures called chromosomes. In the analogy of the written word, the genome and chromosomes are similar to a story and the chapters that make up that story, respectively (see
Since a cell deciphers the DNA code to produce the proteins it needs to function, mutations in the code can result in altered protein amounts or functions, ultimately leading to cancer (see
There are many different types of mutations that can cause cancer. These range in size from a single base change (a letter is out of order or missing) to extra copies of a gene (a paragraph is repeated many times) to the deletion of a large segment of a chromosome (part of a chapter is missing) (see
Figure 6). Further, chromosomes can break and recombine, resulting in the production of entirely new proteins, like the one that causes most cases of chronic myelogenous leukemia (CML) and the one that leads to about 5 percent of non-small cell lung carcinomas.
Over the years, researchers have determined that cancer-associated genetic mutations are most often found in one of two classes of genes: proto-oncogenes and tumor suppressor genes. These genes normally regulate the natural processes of cell growth and death to keep our tissues and organs healthy.
Mutations in proto-oncogenes change them into oncogenes that result in altered proteins that can drive the initiation and progression of cancer. These altered proteins usually work by over activating the normal networks that drive cell division and survival; some can be directly targeted by precision medicines.
Tumor suppressor genes code for proteins that normally stop the emergence of cancer by repairing damaged DNA or by restraining signals that promote cell survival and division. Mutations in these genes typically inactivate them and can result in the production of dysfunctional proteins that do not stop the accumulation of harmful mutations or that allow overactive cells to survive, causing cancer to develop.
The understanding that cancer can be caused by genetic changes that lead to altered proteins and disruption of normal cell behaviors has spurred the development of cancer drugs that target these proteins. This approach, treating cancer patients based on the genetic and molecular profile of their cancer, is referred to as personalized cancer medicine, molecularly based medicine, precision medicine, or tailored therapy. Although it is a relatively new concept, it is already transforming the prevention, detection, diagnosis, and treatment of cancer.
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Beyond Genetics: The Role of Epigenetics
It is clear that mutations in the genome of a normal cell can lead to cancer. However, recent research has shown that changes in the regions of the genome available for use by a cell also influence the development of cancer. To return to the analogy of a book, these changes in genome accessibility alter how the book is read; for example, creasing a page to hide one or more sentences. Understanding how these changes arise and how they affect cellular functions is part of the field of research called epigenetics.
Each cell in an individual contains the same 25,000 genes. Natural differences in genome accessibility, which generate different patterns of gene usage, lead to the diverse array of cell types in our bodies. Special chemical marks on DNA and histones together determine genome accessibility, and thus gene usage, in a given cell type. The sum of these chemical marks, called epigenetic marks, is referred to as the epigenome.
Most cancer cells have profound abnormalities in their epigenomes when compared with normal cells of the same tissue. In many cases, these epigenetic defects work in conjunction with permanent changes in the genetic material of the cell to promote cancerous behaviors.
One of the most exciting discoveries is that some epigenetic abnormalities are reversible. As a result, researchers are exploring whether therapies that work by reversing specific epigenetic defects can be used to treat cancer. The potential of this concept is highlighted by the fact that there are already four FDA-approved epigenetic drugs, which are used to successfully treat some patients with lymphoma or preleukemia who are nonresponsive to traditional chemotherapy. With efforts underway to map the epigenetic changes in all major types of cancer, it seems likely that more epigenetic drugs are destined to benefit many more patients in the near future and for years to come.
It is clear that cancer develops as a result of alterations to the genetic material of a cell that cause malfunctions in its behavior. Research has revealed, however, that cancer cannot be understood simply by characterizing the abnormalities within cancer cells. Interactions between cancer cells and their environment, known as the tumor microenvironment, as well as interactions with the person as a whole, profoundly affect and can actively promote cancer development (see
Figure 7). This means that cancer is much more complex than an isolated mass of proliferating cancer cells, which adds immense complexity to the answer to the question: What is cancer?
Key components of the tumor microenvironment include the matrix of proteins that surrounds the cancer cells, blood and lymphatic vessels, nutrients, hormones, and the immune system. Some of these cancer-influencing factors are normal parts of the tissue in which the cancer is growing, for example, the protein matrix surrounding the cancer cells. Others, such as hormones and nutrients, percolate and act throughout the body, including the tumor microenvironment. Yet others are actively recruited or formed as a result of signals emanating from the cancer cells; for example, many cancer cells release molecules that trigger the growth of new blood and lymphatic vessels. Whether passive participants or active recruits, the various components of the microenvironment are often used by cancers to advance their growth and survival.
The immune system and the blood and lymphatic vasculature are not only important elements of the tumor microenvironment that shape the course of cancer, but are also global factors that affect the whole body. Therefore, if we are to advance our mission to prevent and cure all cancers, we must develop a more comprehensive, whole-patient picture of cancer.
The Immune System
The immune system can be considered an integrated network of organs, tissues, cells, and cell products that protects our bodies from disease-causing pathogens. For example, it is responsible for clearing the viruses that cause the common cold and the bacteria that lead to some forms of meningitis.
Only about 2 percent of immune cells are circulating in the blood at any given time; the rest are percolating through our tissues, including any tumors that are present, constantly on patrol. As it does with pathogens, the immune system can identify and eliminate cancer cells. Clearly, this function of the immune system sometimes fails, and some cancer cells evade the immune system, forming tumors. As researchers have learned more about the components of the immune system and how they interact with cancer cells, they have been able to design therapies that modify a patient’s immune system to make it capable of destroying the patient’s cancer cells. Progress in this critical area of cancer treatment is highlighted in this report in the
Special Feature on Immunotherapy.
While some immune responses have anticancer effects that can be exploited for cancer treatment, research has established that other immune responses can, instead, promote cancer development and progression in some situations (14). For example, persistent inflammation, which occurs as a result of constant stimulation of the immune system, creates an environment that enables cancer formation, growth, and survival. Infection with pathogens such as hepatitis B or C viruses, as well as continual exposure to toxins like alcohol or asbestos, can cause this destructive persistent inflammation.
Since the immune system has both tumor-promoting and antitumor functions, we need to learn more about its intricacies if we are to fully exploit it for patient benefit. This will only be achieved through more research into this promising area of science.
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Blood and Lymphatic Vessel Networks
Like normal cells, cancer cells require nutrients and oxygen to rapidly grow and survive. They must also get rid of the toxic substances they generate through their use of these fuels. To achieve these goals, many cancer cells promote the growth of new blood and lymphatic vessels, processes called angiogenesis and lymphangiogenesis, respectively.
Among the many molecules cancer cells use to induce angiogenesis and lymphangiogenesis is a family of growth factors called VEGFs. These molecules attach to proteins on the surface of the cells that form blood and lymphatic vessel walls, stimulating vessel growth.
Some cancers are more dependent than others on the growth of new blood and lymphatic vessels to thrive. These cancers, such as the most common type of kidney cancer in adults (renal cell carcinoma), are particularly susceptible to a group of drugs that target the VEGFs or the proteins to which VEGFs bind, the VEGF receptors, impeding blood and lymphatic vessel growth.
In addition to nourishing tumors, the new network of blood and lymphatic vessels provides a route by which cancer cells can escape their primary location. Once cancer cells enter the vessels, they have the potential to move to and grow in other areas of the body where they can establish new tumors; this is called metastasis. Metastasis is responsible for more than 90 percent of the morbidity and mortality associated with cancer.
Many cancers, particularly those that arise in tissues other than the blood, are progressive in nature (see
Figure 8). They begin with one or more changes to the genetic material of normal cells. These mutations continue to accumulate over time, first turning normal cells into precancerous cells, which multiply to form precancerous lesions. As more mutations arise within a precancerous lesion, some cells evolve into cancer cells, further dividing to form a tumor. Further mutations can cause some cancer cells to become capable of metastasizing, leading to the emergence of metastatic cancer.
Metastatic disease is a dire occurrence that almost inevitably leads to death. A fundamental understanding of this process is essential to conquering cancer. Research over the past few decades has just begun to teach us why metastatic disease is so difficult to treat. To begin, metastasis is a complex, multistep process, and virtually every step can be achieved through multiple different pathways. Thus, obstructing only one pathway therapeutically is generally insufficient to stop the entire process. Compounding this problem is the fact that cancer cells can travel to other parts of the body before the initial tumor is found, and then lie dormant in this location, becoming active years later to form a metastatic tumor. Currently, we do not know enough about cancer cell dormancy to either efficiently locate and eliminate these cells or design therapies that could prevent them from reawakening, facts that underscore the critical need for further research in these areas.
Improvements in our understanding of the development of cancer have allowed us to detect some precancerous lesions and intercept them before they become life-threatening. For example, in the cervix, precancerous lesions are called cervical intraepithelial neoplasia. These can be detected using the Papanicolaou (Pap) test and can be removed or destroyed by several procedures including cryocautery, electrocautery, and laser cautery.
It is clearly advantageous to detect and stop cancer as early as possible in the course of its development, particularly prior to metastasis. Currently, we successfully do this for some cancers. Only through more research will we be able to apply this approach more generally to cancers that kill. We obviously must support the research needed to fully understand the metastatic process if we are to ultimately cure and control all cancers.
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Progress Report 2013 Contents