Kenneth Crump
Growth for the sake of growth is the ideology of the cancer cell.
—Author and environmentalist, Edward Abbey
Key Points
· Not all tumors are cancer.
· A tumor can be benign, premalignant, or malignant.
· Cancer is, by definition, malignant.
· Cancer is characterized by three criteria: uncontrolled growth, invasion, and metastasis.
· The process by which normal cells become cancer cells is called multistep carcinogenesis.
· There are three basic steps to multistep carcinogenesis: initiation, promotion, and progression.
· When cancer spreads to other locations in the body, beyond just localized tissue invasion, it is called metastasis.
· A cancer must overcome the body’s defenses and complete multiple steps in order to metastasize.
· Common cancer categories in veterinary medicine are carcinomas, sarcomas, and hematopoietic tumors.
· The grade of a tumor and the stage of the disease both significantly impact the plan for treatment.
· The grade of a tumor indicates how closely it resembles the tissue from which it is derived.
· Stage refers to the extent of the cancer based on the size and location of the primary tumor, the number of tumors, and the degree of tumor spread into lymph nodes or beyond.
Introduction
In general, cancer is defined as an uncontrolled growth of cells. In order to better understand cancer, it is helpful to know how tumors form. Usually, cells grow and divide in a controlled and orderly manner. Under normal circumstances, the balance between cell reproduction and internally programmed cell death (called apoptosis) is maintained by the many natural mechanisms of the body. The body tightly regulates both processes to ensure healthy organs and tissues. Sometimes, however, cells continue to reproduce even when new cells are not needed. Alterations and mutations in cell DNA can disrupt the orderly balance of cell reproduction and cell death, causing changes in the normal regulatory process. As a result of unregulated growth, a mass of tissue, called a tumor, can then develop. Virtually any type of normal cell may undergo the changes that eventually create a tumor.
Although every cancer may be considered a tumor, not every tumor is cancer (also called malignant). In this chapter, we explore what makes a tumor malignant, the steps cells take to become a cancer, the different classifications of cancers, how they spread, and how a cancer’s grade and stage help predict its progress and its eventual destruction with treatment.
Tumor Versus Cancer
Although any type of cell can eventually create a tumor, not all tumors become malignant or cancerous. Countless mutations and alterations of cell DNA occur continuously in the body. The cell’s ability to recognize and repair these genetic errors prevents the majority of potential mutations from persisting. However, when a solid tissue mass is formed by the continued abnormal growth of cells, it is called a tumor. Tumor is not synonymous with cancer. A tumor can be benign, premalignant, or malignant. Cancer is, by definition, malignant.
A benign tumor grows in a limited, nonaggressive manner, and does not invade surrounding tissues, nor does it spread to other parts of the body. The term “benign” implies a mild and nonprogressive disease, and most benign tumors are harmless to a patient’s health. However, some benign tumors may still produce negative health effects by producing a “mass effect,” whereby the patient’s normal daily life is impacted by the size or position of the tumor. An example of mass effect is a large benign tumor that has grown at the base of a dog’s tail, obstructing normal defecation. The tumor itself poses no threat to the patient’s health, but its size and position impact normal daily function. The general criteria for removing seemingly benign tumors in animals are as follows: (1) if the tumor is growing rapidly, (2) if it bothers the patient, or (3) if it bothers the owner.
A premalignant tumor is a tissue that is not yet malignant but is poised to become malignant. If left untreated, premalignant tumors are generally associated with a significantly increased risk of cancer. Often, the multiple genetic changes that transform a premalignant tumor into cancer take years to accumulate. During this time, its biological behavior slowly changes from that of a normal tissue to more cancer-like properties. Clinical and laboratory tests are designed to identify premalignant tissue while it is still in early stages, thereby preventing the development of cancer. Appropriate treatment depends on the particular premalignant tumor detected.
Malignant tumors typically become progressively worse and could result in death. They are characterized by three criteria: uncontrolled growth, invasion, and metastasis:
· Malignant tumors fundamentally alter the regulation of their own growth. In order for normal cells to become malignant, the genetic makeup of the cells regulating cell growth must be altered. Natural tumor suppressor genes, which inhibit cell division and survival, are often disabled by these alterations. In this way, the malignant cells become immortal, resulting in uncontrolled growth.
· Invasion refers to the intrusion into and destruction of adjacent tissues. Whereas a benign tumor may produce a “mass effect,” impacting a patient’s normal daily life by its size or position, a malignant tumor actually infiltrates its surrounding tissues. The infiltration results in the destruction of surrounding normal tissues, which can lead to pain; fixation of the tumor, restricting mobility; or organ dysfunction. Tumor invasion can impact the function of any structure or organ in the body.
· Metastasis describes the spread of a tumor to another location in the body, beyond the primary site. The path it takes and its metastatic destination are both determined by the cell type from which the tumor is derived.
· The word cancer is synonymous with malignant tumor.
Multistep Carcinogenesis
It is not easy for a normal cell to transform into a tumor cell. Transformation into a cancer cell is even more difficult. The process by which normal cells are transformed into cancer cells is called carcinogenesis. Carcinogenesis results from mutations of the DNA of normal cells. More than one mutation is usually necessary for carcinogenesis. In fact, the transformation is called multistep carcinogenesis because a series of mutations is usually required before a normal cell can become a cancer cell. There are three basic steps to multistep carcinogenesis: initiation, promotion, and progression.
Step One: Initiation
The first stage, initiation, results in an irreversible change in the DNA of the cell. This may occur randomly or when a carcinogen damages the cell’s DNA. After a single exposure to an initiating event, if the cell’s repair mechanisms do not repair the DNA damage, then the cell is more prone to becoming a tumor cell. An example of an initiating event might be prolonged exposure to the sun. Because the process of multistep carcinogenesis can take years, the forgotten sunburn you had at summer camp could have initiated a population of skin cells. However, by itself, the initiating event is not sufficient to transform a normal cell into a tumor cell.
Step Two: Promotion
During the second stage, promotion, the initiated cell is stimulated to grow and divide faster. It then becomes a population of cells. Only after repeated exposure to the promoting agent does it induce changes in the cell’s shape and structure, and increase the rate at which it reproduces. In human cancers, cigarette smoking can act as a promoting event. Happily, the promotion stage of multistep carcinogenesis is usually reversible, as evidenced by the fact that lung damage can often be reversed after smoking stops.
Step Three: Progression
The third stage of multistep carcinogenesis is called progression. This step is the “point of no return” for a normal cell. During progression, further irreversible changes are made to the DNA of cells that have undergone the initiation or promotion phases, creating malignant tumor cells. Here is how Hanahan and Weinberg describe the characteristics of malignant tumor cells in their article “The hallmarks of cancer”:
Tumor Cells
· acquire their own growth signals, leading to unchecked replication;
· ignore normal antigrowth signals, also leading to unchecked replication;
· overcome internally programmed cell death signals (apoptosis) in order to continue to grow, despite DNA errors;
· gain the capacity for limitless reproduction (immortality);
· can build blood vessels, which provide oxygen and nutrients, allowing a tumor to expand beyond the limitations of feeding on sidestream nutrients;
· invade neighboring tissues;
· spread to other locations in the body, beyond localized invasion (metastasis); and
· lose their capacity to repair DNA errors, leading to genetic instability, which accelerates all the other changes.
Therefore, in order for a normal cell to transform itself into a tumor, it must go through the complex process of being irreversibly altered at least twice, once in the initiation phase and once again in the progression phase. The promotion phase is reversible but alters an initiated cell in such a way as to increase the likelihood that it will be changed again by the progression phase.
Metastasis
When a malignant tumor (cancer) spreads to other locations in the body, beyond just localized tissue invasion, it is called metastasis. The process of metastasis is a complex game of survival, which rivals any television reality show. The metastasizing tumor cells must survive, overcome a host of challenges, and complete complicated tasks before it can develop a distant offspring. The sequence of events is called the metastatic cascade. For a cancer to succeed, it must overcome all of the body’s defensive strategies and complete all seven necessary steps.
Step One: Detachment
The first step in the metastatic cascade is for the tumor to detach a cell from the primary tumor mass. This cell must be able to survive without contact with its neighbors, which is very difficult for most normal cells.
Step Two: Invasion
Once detached, the tumor cell must find a way to enter either the blood or the lymphatic circulatory system.
Step Three: Evasion of Host Defenses
Within the vascular or lymphatic channels, tumor cells must then withstand the assault by a barrage of cells from the body’s immune system.
Step Four: Arrest
Having survived the immune system’s attack, metastatic tumor cells must come to rest in the small blood vessels and capillaries of their target organs. Different types of cancers have different metastatic target organs.
Step Five: Attachment
Once the metastatic tumor cells have rested, they must find a way to stick to the walls of the vessels where they have been resting.
Step Six: Extravasation
Fully rested and attached, the tumor cells must begin working their way through the protective vascular or lymphatic walls and into the soup of extracellular matrix. This process is similar to step two, but in reverse.
Step Seven: Establishment of New Growth
Once they have emerged through the vessel walls and into the extracellular matrix, the cancer cells must survive and proliferate into another tumor. A lot of replication has occurred before any tumor can be detected. For instance, it requires one billion cells to make a tumor the size of a garbanzo bean (about 1 cm).
Cancer Classifications
Cancers are classified by the type of cell that is presumed to be the origin of the tumor. Common cancer categories in veterinary medicine are carcinomas, sarcomas, and hematopoietic tumors.
Carcinoma
Carcinomas are malignant tumors that arise from epithelial cells. In the body, epithelial cells either cover a surface, line a cavity, or form glands. Examples of epithelial cells are skin cells and cells that line the intestines, as well as cells that form the mammary and salivary glands. Carcinomas represent the most common cancers seen in humans and generally spread (metastasize) first to the lymph nodes draining the tumor area, and then beyond. Common human carcinomas include cancers of the breast, prostate, lungs, and colon.
Sarcoma
Sarcomas are malignant tumors derived from connective tissues, such as fat, muscle, cartilage, and bone. Sarcomas usually metastasize through the circulatory system. Common examples in veterinary medicine include osteosarcoma, hemangiosarcoma, and fibrosarcoma.
Hematopoietic Tumors
These are malignant tumors derived from blood-forming cells. These include lymphoma, leukemias, and mast cell tumors.
Generally speaking, benign tumors and malignant tumors use different suffixes in their names, giving visual clues of their risks of spreading. For instance, names of benign tumors most often contain the suffix -oma. Therefore, if a patient presents with a large tumor diagnosed as a lipoma, you can tell by virtue of the name that the tumor is benign. Malignant tumors are generally named using -carcinoma or –sarcoma as a suffix. So, a diagnosis of osteosarcoma gives you the visual clue that the disease is malignant. Unfortunately, some names do not follow these rules. For instance, melanoma and lymphoma use the benign suffix -oma, but are, in fact, malignant tumors.
Grade and Stage
Cancer is further classified using grade and stage to help predict its behavior, its rate of spread, and the prognosis for the patient. Having a pathologist grade a tumor and determining the stage of the disease both significantly impact the plan for treatment.
Grade
The grade of a tumor indicates how closely it resembles the tissue from which it is derived. The more a tumor cell microscopically resembles the normal cells of its “parent” tissue, the more likely it will act like its parent tissue. The extent of resemblance to parent tissue is called differentiation. The more differentiated the tumor cells appear, the more they resemble their parent tissue.
Based on the microscopic appearance, pathologists commonly describe tumor grade by four degrees of severity: Grades 1, 2, 3, and sometimes 4. Cells of a Grade 1 tumor are well differentiated. With a close resemblance to their parent tissue, they are likely to grow slowly and only minimally invade surrounding tissues. The cells of a similar tumor with a higher grade would display poorly defined cell architecture and would be considered undifferentiated. This tumor would likely grow rapidly and aggressively invade normal tissues. Generally, a lower grade indicates a better prognosis.
Stage
The grade of a cancer is often confused with the stage of a cancer. Cancer stage refers to the extent of the cancer based on the location of the primary tumor, the tumor size, the number of tumors, and the degree of tumor spread into the lymph nodes or beyond.
Roman numerals I, II, III, and sometimes IV are used to describe the stages of cancer. The higher the numeral, the more advanced the disease has progressed. For instance, Stage I disease indicates the cancer has remained localized to only one part of the body. In Stage IV, the disease has progressed to other organs, or metastasized throughout the body. Naturally, a Stage I disease carries a better prognosis.
Conclusion
Cancer describes many malignant tumors, which destroy normal tissue and impair normal function. To the veterinary professional, cancer is simply a word used to describe a variety of conditions of uncontrolled cell growth. We study it, categorize it, and classify it by a number of criteria. However, few words create more fear in the imagination of pet owners. To the layperson, cancer is the beginning of the end of a relationship with a loved one. It is an uncle who lost a leg or a cousin whose hair fell out. It is a grandmother who has had too many surgeries or a father who lost the battle entirely. Most people’s perception of cancer, surgery, and chemotherapy is colored with fear and hopelessness. When treating an animal patient with cancer, overcoming the owners’ fear and guilt is the first job for every member of the veterinary team. We must approach the topic of cancer in an educated, encouraging, and compassionate manner.
Additional Reading
Argyle DJ, Khanna C. 2007. Tumor biology and metastasis. In: Withrow SJ, Vail DM (eds.), Small Animal Clinical Oncology (4th Ed.). St. Louis, MO: Saunders Elsevier, pp. 31–53.
Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100(1):57–70.
Henry CJ. 2007. The etiology of cancer: Chemical, physical and hormonal factors. In: Withrow SJ, Vail DM (eds.), Small Animal Clinical Oncology (4th Ed.). St. Louis, MO: Saunders Elsevier, pp. 12–9.
Modiano J, Breen M. 2007. The etiology of cancer: Genetic factors. In: Withrow SJ, Vail DM (eds.), Small Animal Clinical Oncology (4th Ed.). St. Louis, MO: Saunders Elsevier, pp. 3–12.
Onn A, Fidler IJ. 2002. Metastatic potential of human neoplasms. In Vivo 16(6):423–9.