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Pamela A. Davol, 76 Mildred Avenue, Swansea, MA  02777-1620.
pdavol@labbies.com


Cancer In The Canine

Part 1. The Basics of Cancer Biology

 

The Origin of Cancer

    In the body, growth of cells is a tightly regulated process. The moment that a single sperm fertilizes an ovum, cellular multiplication through division, the process responsible for growth and maintenance of the dog, is initiated and will continue until the eventual death of that dog. In the beginning of life, cells divide rapidly and the dog increases in size. Some cells may die, however, cell division proceeds more quickly, not only replacing dying cells but producing new cells. Eventually, the dog will reach mature size and internal mechanisms will slow cellular growth so that cell division will only occur in organs or systems of the body requiring normal replacement for dying cells or in cases of cellular injury. If the balance between cell growth and cell death is disturbed, a state of disease occurs. Occasionally, the imbalance occurs because factors that regulate cell growth of a single cell are inhibited and this single cell and its daughter cells begin to multiply beyond the death rate of other cells that make up the system of which it is a part. In such an instance, one cell will give rise to a mass of un-needed cells, all of which will continue to multiply without regulation. This condition results in what is known as a tumor.

    When the cells composing a tumor, which inhabits an organ of the body, closely resemble the normal cells of that organ, they are said to be well-differentiated and may even function as the normal cells. Such tumor cells usually remain localized to the site from which they originated and have a very good long-term prognosis. That is, they are considered benign tumors (they produce no harm to the dog). In contrast, some tumors are composed of cells that have lost their resemblance to the original cell type. Such cells are said to be undifferentiated and have a greater likelihood of spreading to other parts of the body, a process known as metastasis. These latter tumors are considered malignant tumors and are responsible for various forms of cancer.

 

Characteristics of Benign and Malignant Tumors

    For the most part, it is impossible to determine if a tumor is benign or malignant by its outward appearance. Therefore, when a tumor is discovered, the usual plan of action is to obtain a sample for examination under a microscope. This procedure is referred to as a biopsy. Benign tumors are usually encapsulated by fibrous tissue, which makes it easy for surgical removal of the entire tumor in-tact. Under microscopic examination, the cells of a benign tumor closely resemble the normal surrounding cells. However, compared to normal cells that show a high percentage of cells in a growth-arrested, or quiescent stage in the cell cycle, benign tumor cells usually show a greater percentage of cells in the mitotic (dividing) stage of the cell cycle. In contrast, although some malignant tumors may be encapsulated in early stages of their development, advanced malignant tumors exhibit no clear boundaries but usually show invasion into the surrounding normal tissues. Additionally, they can be clearly discerned from normal cells and benign tumor cells because in addition to being predominantly in a mitotic stage of the cell cycle, they usually have an abnormal number of chromosomes (aneuploidy).

 

Classification of Malignant Tumor Types

    Though there are many kinds of cancer (i.e. lung, mammary, stomach, skin, etc.), malignant tumors are classified based on the embryonic origin of the normal cells from which they have developed. Normal cells of animals develop from one of three embryonic layers: the endoderm, the ectoderm or the mesoderm.

    The endoderm gives rise to the gastrointestinal system, salivary glands, pancreas, liver and lungs. The ectoderm gives rise to the skin, skin organs, lens of the eye, and central nervous system. Malignant tumors derived from normal cells originating from the endoderm and the ectoderm are classified as carcinomas.

    The mesoderm gives rise to the dermis of the skin, the musculoskeletal system and connective tissues including tendons and bones, the heart and blood vessels, the blood cells, the urogenital tract and fat cells. Malignant tumors derived from normal cells originating in these organ systems are called sarcomas. The leukemias, cancer originating from components of the blood, are actually a subdivision of sarcomas because they grow as individual cells within the blood rather than as solid tumors.

 

Cancer Metastasis

    The tendency of some cancers to spread to distant sites in the body from the site of the original tumor presents the greatest challenge to successful treatment of cancer in the dog. Treatment failure is most often associated with metastasis, and in many cases, death is usually a result of organ failure due to metastatic invasion rather than from complications caused by the primary tumor.

    Growth of a tumor is dependent on penetration of blood vessels into the mass; therefore, malignant tumors usually secrete chemicals that induce new blood vessel formation. This process is known as angiogenesis. As tumor cells continue to divide, some will penetrate the walls of adjacent blood vessels or may invade the nearby lymphatic vessels and will be carried with the flow of blood or lymphatic drainage to distant sites within the body. Many of these circulating tumor cells will be destroyed in the blood stream or in the lymphatics, or will die once they become deposited at a new organ site because they are not self-sufficient enough to colonize the new location. In contrast, a small percentage of these cells will have become independent because of their ability to produce factors for which their growth is dependent upon. These autonomous cells are the seeds from which new tumors begin.

    Interestingly, in past years, it was often observed that many times when surgery was performed to remove a primary cancer, despite successful surgery, the patient would die within a short interval following the procedure due to widespread invasion of cancer. Many individuals believed that exposure of the cancer to air during the surgical procedure had caused the disease to spread rapidly. Recent findings, however, indicate that this phenomenon of rapid spread is associated with metastatic growth. It has been found that the primary tumor secretes factors into the bloodstream that actually inhibit the angiogenic process at metastatic sites thereby slowing the growth of these new tumors. When the primary tumor is removed, cell division and tumor growth at these distant sites increase in the absence of these inhibitory factors. As a result, cancer may appear to spread quickly throughout the body, when in actuality, it had been subclinically present.

    In light of these findings, it is clear that successful therapy of cancer in the dog will depend on both thorough evaluation of the primary tumor and consideration of the presence of secondary sites of metastatic disease.

 

Factors Responsible for the Transformation of a Normal Cell to a Cancerous Cell

    There is no single element or condition that causes cancer. Rather, cancer usually occurs as a result of numerous factors that interact over an extended period of time. The observation that cancer occurs with a higher frequency in older patients supports the concept that passage of time allows for the series of events required for a normal cell to transform into a cancer cell. However, each of these events increases the likelihood for development of cancer, and therefore, scientists refer to such events as risk factors. A prime example of a risk factor in the development of human lung cancer is cigarette smoking. Cigarette smoking alone does not cause lung cancer, as evidenced by the many smokers who will never develop lung cancer. However, when cigarette smoking is combined with other factors, such as genetic composition or exposure to certain viruses, an individual's risk for developing cancer will be compounded. Additionally, it is very common for the public to hear, on what seems like a monthly basis, frequent reports of "new evidence linking such-and-such to development of cancer." Whenever evaluating the role of such agents in the development of cancer, important factors to consider prior to applying this data to everyday-life-risk for developing cancer are both the amount of exposure (dose) and duration of exposure to the particular element used in the study. In many of these studies, amount and duration of exposure far exceed what the average individual can expect to receive in in his/her lifetime.

    The importance of risk factors in the development of cancer lies in their ability to effect the genes within a cell. Genes are responsible for controlling the normal functions of cells. Frequently, alterations in the DNA (deoxyribonucleic acid) composing these genes occur: these alterations are called mutations and may effect normal cellular processes. Alterations in DNA information may occur randomly, as a result of infectious agents, or as a result of agents that cause DNA damage. In many cases, cells are capable of detecting and repairing mutations before cellular damage can occur. For example, tumor suppressor genes encode special cellular proteins that will stop a cell from replicating if its DNA is damaged. When functional, this surveillance system prohibits a cell with mutated DNA from passing on the faulty genetic material to daughter cells. In cases of mild damage, once the DNA damage is repaired, the cell will continue through its growth cycle. If damage is too extensive, a process known as programmed cell-death, called apoptosis, will occur which will cause the cell to self-destruct. However, if tumor suppressor genes (which encode proteins that suppress DNA synthesis, cell growth and division) undergo mutation, cell growth will proceed unrestricted. Because cells inherit two copies of each tumor suppressor, one from each parent forming a chromosome-pair, loss of function of a single copy of the tumor suppressor usually has very little effect on the cell. However, if both copies of the gene are lost, the original cell and all its daughter cells will grow out-of-control.

    Other equally important genes are the protooncogenes that promote DNA synthesis, cell growth and division. These genes are required during the development of the individual and subsequently to promote new cell growth during normal replacement of old cells or damaged cells. If, however, these genes are activated by mutation, they become oncogenes and they will drive the cells to grow and divide needlessly.

    In addition to inactivation of tumor-suppressor genes or activation of oncogenes, alterations in other genes required for DNA repair or cellular apoptosis are among the primary causes for transforming cells from a normal state to a cancerous state. Risk factors that increase susceptibility of an individual to develop cancer do so because they are either directly or indirectly responsible for effecting these genes. Factors leading to increased risk compose two groups, those occurring in the environment (the carcinogens) and internal genetic factors (genetic defects):

Carcinogens

viruses

chemicals

physical carcinogens

 

Genetic defects

inherited gene defects

acquired chromosomal abnormalities

 

Carcinogens

Tumor Viruses

    Some DNA viruses and RNA (ribonucleic acid) viruses (retroviruses) have the distinction of being called tumor viruses because they have been found to cause cancer in cells that they infect. These viruses accomplish this by integrating their own genetic material into or near the site of a protooncogene in the DNA of the infected cells. This integration of foreign DNA may alter the DNA message of the protooncogene. When this event occurs, the protooncogene becomes an oncogene, and the protein encoded by the effected protooncogene is also changed structurally and functionally thereby beginning a chain of events which may lead to transformation of the normal cell into a cancerous cell. In some instances, the oncogene will be incorporated into the DNA of the virus and will change the virus into a cancer-causing agent that may be transmitted to other cells or animals. In other instances, the oncogene will remain only as a part of the infected cell's genetic material and will only be passed on to daughter cells produced when the infected cell divides.

 

Chemical Carcinogens

    As opposed to viral infections that have been linked to only a fraction of cancers, chemical carcinogens are more strongly implicated as having a role in development of many more forms of cancer. There are two groups of chemical carcinogens, the direct-acting and indirect-acting. The latter group, unlike the former group that are reactive compounds unto themselves, require metabolic activation by enzymes, which are normally present in the body, to become carcinogenic. Indirect-activation usually occurs during the normal process by which the body clears toxic substances from the blood. Many toxic substances to which the body is exposed on a daily basis are insoluble, therefore, it the function of the liver, the primary organ responsible for filtration of the blood, through enzymatic reactions, to change insoluble compounds into soluble compounds so that they may be excreted from the body. Some toxic substances, however, require a longer reaction time to convert them to soluble products. If these compounds are highly reactive molecules, they may bind to and lead to alterations in the cellular DNA before they can be excreted from the body. Interestingly, in many cases the agent itself does not cause the alterations directly to the DNA. Instead, DNA damage occurs when normal mechanisms in the cell attempt to repair the DNA and in doing so, alter the correct sequence of DNA at the site of the bound agent thus activating oncogenes. When this event causes permanent damage, in addition to the compound being considered a carcinogen, it is also termed a mutagen because the damage it produces may be passed on to other cells.

 

Physical Carcinogens (ionizing radiation, ultraviolet radiation, fiber and foreign-body related, and hyperthermia)

    Living things are constantly bombarded by different forms of radiation: atomic particle radiation is given off by many minerals in the environment, and the sun is the source of both x-rays and ultraviolet radiation (UV). Both ionizing radiation and UV radiation modify DNA interfering with its cellular replication and inhibiting its information from being encoded into cellular proteins. Specifically, ionizing radiation (atomic particle and x-rays) causes strand breaks in DNA chains while UV radiation creates chemical changes within the molecules called amino acids that compose the DNA. When much of a cell's DNA is damaged, the cell is often incapable of repairing this damage efficiently or quickly enough because its repair systems are over-extended. Additionally, the nature of the damage produced by ionizing radiation is difficult to repair by cellular mechanisms because when repair does occur, the sequence of DNA at a breakage site may be rejoined to a sequence from another breakage site.

    In addition to the above mentioned environmental carcinogens, certain fibers have also been linked to induction of cancer. The most well-known of these is asbestos. However, glass and some plastics have also been implicated in having a role in the development of certain cancers. These fibers become foreign-bodies when they embed themselves into areas of the body (i.e. in the lungs through inhalation, in the digestive tract through digestion, or in the skin through contact). The cells surrounding the fibers will take-in the longer fibers that have a tendency to accumulate in the nuclei of the cells (the compartment of the cell where the DNA resides). Though the exact mechanism of how these fibers interact with the DNA to bring about oncogene activation is not fully understood, it has been observed that chromosomes of cells harboring these fibers have large areas of missing DNA called chromosomal deletions.

    A condition called "erythema ab igne" manifests as an area of skin discoloration after exposure to heat. This condition is associated with the use of hot water bottles or heating pads used for the purpose of alleviating pain. Chronic cases of this condition have been associated with later development of some skin cancers. As with fiber carcinogenesis, the exact mechanisms in which heat activates oncogenes is not understood, however, researchers believe that chronic application of heat stimulates skin cells to continually divide and multiply.

 

Genetic Defects

Inherited Genetic Defects

    The role of hereditary defects in the development of cancer is very difficult to confirm in the absence of laboratory testing, which specifically identifies inherited mutations in cancer-predisposing genes. This is especially true when there is an absence of other hereditary defects that would provide evidence of a distinct genetic syndrome. However, indications suggestive of a hereditary predisposition may include a family history of cancer and early age of onset.

    Whereas cancers attributed to carcinogens usually increase in occurrence in an age-dependent manner, cancers attributed to inherited genetic defects usually occur in young individuals. Since cancer occurs as a result of more than one genetic event, the latency period between these multiple events may take many years, thus the close association of cancer-risk with advancing-age. However, an inherited gene abnormality simply reduces the latency period because the afflicted individual already has an internal predisposing alteration and may only require a single external "hit" to transform normal cells to cancer.

    Inherited genetic defects usually occur as a germline mutation; that is, either a gene controlling tumor suppression is inactivated or an oncogene is activated in the parental sperm or ovum. Most of these mutations are autosomal dominant traits, so that even though the gene received from one of the parents is normal, all the cells of the offspring's body (the somatic cells) will carry a copy of the defective gene. When the somatic cells receive a second "hit" from an environmental carcinogen, there is an increase in the likelihood that cancer will develop.

    Besides mutations affecting tumor suppressor genes and oncogenes, mutations in genes encoding protein for DNA repair mechanisms or replication have been linked to certain hereditary conditions that are associated with increased cancer risk. Inability to repair even mild damage to the DNA increases the likelihood of a mutation in a tumor suppressor gene or activation of an oncogene, even in the absence of carcinogen exposure. These conditions are usually rare and are most often inherited as autosomal recessive defects. Additionally, mutations in genes encoding detoxifying proteins responsible for metabolizing and eliminating carcinogens from the body may make an individual more susceptible to carcinogens in the environment and increase one's risk to certain cancers.

 

Acquired chromosomal defects

    Germline mutations effecting tumor suppressor genes are more prevalent than those activating oncogenes, at least in human cancers. With a few exceptions, mutations associated with oncogene activation and early cancer development are believed to occur during early events in embryogenesis and therefore, arise as somatic cell mutations as opposed to germline mutations; that is, defects in the chromosomes are not inherited from the parental germ cells (egg and sperm), but occur during development and growth of the fertilized egg into a new individual by the process of mitosis (when cells duplicate their chromosomes in order to pass copies of the genetic information to each new daughter cell). Therefore, cancers associated with somatic mutations are not considered hereditary but, are attributed to acquired chromosomal defects. Implications for acquired chromosomal defects as a predisposing factor for cancer may include early onset of cancer in the absence of family history.

 

Other Internal Factors Suspected of Playing a Role in the Development of Cancer

 

Defects in or Suppression of Immune Response

    In addition to protecting the body from infectious micro-organisms, it is believed that the immune system also plays a role in identifying and eliminating cells that have transformed from normal cells to cancerous cells: a process known as immunosurveillance. There are several observations that have led to the belief that defects in the immune system play a role in the development of cancer. For example, very young and very old animals often have decreased immune-response and members of these age groups also demonstrate an increased susceptibility to effects of carcinogens. Additionally, animals that are purposefully immunosuppressed have demonstrated a greater likelihood of developing cancer when exposed to carcinogens while animals exposed to carcinogens but receiving immunostimulants often do not develop cancer. Furthermore, animals administered oncogenic viruses or chemical carcinogens often become immunosuppressed (similar to observed in animals receiving polyvalent vaccines) immediately following administration of these agents indicating that they stimulate an immune response.

    Though it has been observed that congenital immunodeficiency diseases and acquired immunodeficiency syndromes (associated with immunosuppressive drugs and autoimmune diseases) are associated with increased risk for leukemias, lymphomas, and some sarcomas, these disorders do not increase risk for developing other tumor types. In light of this, it is believed that stimulation of the damaged lymphoid system by carcinogens (particularly oncogenic viruses), rather than a defect in immunosurveillance in these immunodeficient individuals, is responsible for malignant transformation of lymphatic cells that give rise to these tumor types.

 

Hormonal Factors

    Evidence suggests that hormones are another internal factor that play a major role in the development of some cancers, particularly mammary, prostate, ovarian, thyroid, bone and testicular cancers. In the young, hormones provide the means by which the cells are signalled to divide so that growth and development of the organs and the individual can take place. In adults, hormones control cell growth in relation to various aspects of the reproductive cycle in both men and women. In the presence of activated oncogenes or inactivated tumor-suppressor genes within a cell, hormones are the factors that will stimulate the abnormal cell to divide and become tumorigenic. Therefore, it is believed that excessive stimulation of certain organs of the body by hormones increases the likelihood of cancer to develop in these organs.

Copyright 1999, 2000. Pamela A. Davol. All rights reserved. Copyright & disclaimer.

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