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Etiology is defined by most medical dictionaries as the "scientific study of the causes/origins of diseases." The cause of vaccine-associated feline sarcoma (VAFS) is unknown, and unfortunately what we don't know vastly overshadows what we do know. To determine the cause of VAFS, we must first understand the cause of cancer as a whole; this predicates the need for better understanding of basic principles in cancer biology.
So what is cancer? Though there are many definitions, one of the foremost is that cancer is a disease of aberrant intracellular signaling. More simply put, there are incoming, outgoing and/or internal messages that lead to loss of cellular homeostasis. These messages principally come from 3 categorical sources: oncogenes, tumor suppressor genes, and programmed cell death (apoptosis) genes. Oncogenes are genes that are derived from proto-oncogenes, which are normal endogenous cellular sequences of DNA involved in growth and differentiation. Proto-oncogenes become oncogenes when there is an alteration in the level of their expression and/or gene product that allows malignant transformation. Tumor suppressor genes can be thought of as anti-oncogenes, and the products of these genes serve to limit or inhibit cellular proliferation.
When tumor suppressor genes are inactivated by a variety of causes, unrestricted proliferation may occur, leading to malignant transformation. Apoptosis, or programmed cell death/suicide, is a physiologic form of cell death present in all nucleated cells of multicellular organisms. Apoptosis serves to keep cell growth in balance, and to keep cells in their normal environment. Modulation of apoptosis can have important implications in cancer biology; decreased apoptosis can lead to an increased numbers of cells, and simultaneously may allow cancer cells to gain global resistance mechanisms and metastatic cancer cells to continue to survive in aberrant locations.
Because most cancers are believed to arise through the process of multistep carcinogenesis (whereby 2 or more genetic changes lead to malignancy), the aforementioned activation of oncogenes and/or inactivation of tumor suppressor genes and/or modulation of apoptosis genes culminates in the malignant phenotype. So what causes these changes? Multistep carcinogenesis can occur through a variety of pathways, including biological agents (eg, viruses, hormones), chemical agents (eg, pesticides, air pollutants), physical agents (eg, foreign bodies, UV radiation), hereditary means (eg, inherited retinoblastoma in children), and passive/spontaneous means (eg, mutations in DNA in normal dividing cells). One can easily see that the multistep carcinogenesis of VAFS could include some or all of these pathways, making elucidation of the cause(s) of VAFS a daunting task.
On the basis of the aforementioned basic cancer biology principles, there are many questions we can ask concerning the cause of VAFS. What factors may be related to the cat, or the population of cats, that has VAFS? This list could include, but not be limited to, the genetic predisposition of certain cats, tumor suppressor gene inactivation or apoptosis gene modulation, immune status differences, variable histocompatability antigens, differences in reactions to inflammation, and lastly, presence of endogenous retroviral elements. What factors may be related to the vaccines? This again could include, but not be limited to, the adjuvants and the severity/type of inflammation induced, the antigens and cell culture products used in vaccine production, and lastly, presence of chemical or viral contaminants. Additionally, during the progression within the multistep carcinogenesis of VAFS, do postvaccinal granulomas inevitably lead to sarcoma and do all VAFS start as palpable granulomas? Unfortunately, we don't know the answer to the most of these questions; however, research studies supported by the VAFS Task Force and the Morris Animal Foundation aim to answer some of these very questions.
So, what do we know about the cause of VAFS? We do know that retroviral elements do not appear to be associated with VAFS. Feline sarcoma virus (FeSV)is a recombinant virus formed when FeLV associates with feline proto-oncogenes leading to sarcoma formation, typically in cats < than 4 years old. Because some VAFS are also seen in cats < 4 years old, all cats with sarcomas, independent of vaccine history, should be tested for FeLV (and feline immunodeficiency virus) because all feline sarcoma virus-positive cats are FeLV positive. We also know that postvaccinal reactions to some rabies and FeLV vaccines may be more common than previously reported and that the size of postvaccinal lesions can be related to certain inflammatory infiltrate types (Macy DW, Bergman PJ, Powers BE, Department of Cell Biology, SRB 173, Houston, Tex: Unpublished data, 1998). Dr. Hendrick will discuss her current research findings concerning the association of tumor suppressor gene alterations and activation of oncogenes in VAFS.
The basic cancer biology principles discussed allow for a logical method in attempting to elucidate the cause(s) of VAFS. The tools of molecular biology now allow us to peek into the windows of cancer on a deeper level than we have ever been able to do previously. It is integral that we approach this formidable task of the elucidation of the cause(s) of VAFS by use of a two-pronged attack. The past can teach us a great deal and plausibly answer some of the aforementioned questions related to factors specific to the cat and the vaccines. In the last 24 months, only 180 cases of VASE have been reported to the USP regulatory agency ( Meyer K, United States Pharmacopeia, Rockville, Md: Personal communication 1998), likely representing a gross under-representation of the number of cases of VAFS in the United States. Following the recommendations of the VAFS Task Force and the American Association of Feline Practitioners for vaccination and reporting cases of VAFS to the USP (1-800-4USP-PRN) and vaccine manufacturers will greatly facilitate future retrospective research studies.
The second prong of the attack is the prospective evaluation of the aforementioned factors by researchers in the field. The combinations of these attack methods will one day lead to elucidation of the cause(s) of VAFS. The aforementioned tools of molecular cancer biology will make the future of cancer diagnostics and therapy bright; in fact, rationally based targeted therapy is the brightest light in cancer therapy's future. Once these causes are found, we will be able to attempt to prevent future VAFS as well as develop novel treatments specifically targeted against the lesion(s) in the cancer cell. We, as a profession, look ardently forward to the day this cancer is eradicated from our animal patients.
References
I. Powis G. Signalling pathways as targets for anticancer development. Pharmarol Ther 1994;62:57-95.
2. Weinberg RA. Oncogenes, antioncogenes and the molecular bases of multistep carcinogenesis. Cancer Res 1989;49:3713-3721.
3. Bergman PJ, Harris D. Radioresistance, chemoresistance, and apoptosis resistance: the past, present, and future. Vet Clin North Am Small Anim Pract 1997;27:47-57.
4. Ellis JA, Jackson ML, Bartsch RC, et al. Use of immunohistochemistry and polymerase chain reaction for detection of oncornaviruses in formalin-fixed, paraffin-embedded fibrosarcomas front cats. J Am Vet Med Assoc1996;209:767-771.
5. Rojko JL, Hardy WD Jr. Feline leukemia virus and other retroviruses. In Sherding RD, ed. The cat: diseases and clinical management. New York: Churchill Livingston Inc, 1994;263-432.
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