Feline vaccine-associated and FeSV-virus-associated sarcomas

 

© A. Nieto, M. A. Sánchez, E. Martínez and E. Rollán Immunohistochemical Expression of p53, Fibroblast Growth Factor-b, and Transforming Growth Factor in Feline Vaccine-associated Sarcomas Vet Pathol 40:651-658 (2003)

 

Vaccine-associated sarcoma in cats has been investigated since the early 1990s by numerous authors.4,8,15,16,19,24 However, despite an increasing incidence of this disease, the mechanism of tumorigenesis has not been determined nor has a relationship emerged between the occurrence and specific manufacturers of adjuvant or vaccine product.14,15,25

Transition between inflammation or wound healing and tumours has been frequently observed in different animal models of virus- or oncogene-induced tumours, in which inflammatory compounds appear to play a role in carcinogenesis.20,42 In cats, early vaccination sites show persistent inflammatory or foreign-body reactions characterized by areas of necrosis, aggregates of lymphocytes and plasma cells, and granulation tissue formation.4,6,15,19 This reaction is thought to predispose fibroblasts or myofibroblasts to proliferate, leading to neoplastic transformation through different mechanisms including activation of oncogenes and inactivation of tumour suppressor genes.15 On the other hand, agents that promote inflammation such as acidic fibroblast growth factor (FGF-a) and basic FGF (FGF-b) create a favourable environment for expression of oncogenes and subsequent development of tumors.27

The p53 tumour suppressor gene is a transcription factor that regulates the expression of genes involved in cell-cycle control, apoptosis in cells with defective deoxyribonucleic acid (DNA), cellular differentiation, and genetic instability.13,37 Mutations in the p53 gene have been associated with human and animal neoplasms.13,26,37,46 To investigate the role of the p53 gene in oncogenesis in cats, molecular cloning and chromosomal mapping of the feline p53 tumour suppressor gene were carried out.35 p53 genetic aberrations have been observed in codons 180 and 248 from exons 5–7 in two of 10 feline fibrosarcomas (FS).29 Of 60 tumours investigated, missense mutations were also detected in two FS, one malignant fibrous histiocytoma (MFH), one undifferentiated carcinoma of the skin, and one mammary carcinoma. The problematic histopathologic overlap between FS and MFH was also identified by Mayr et al.28 Recently, a single missense mutation in the exons 5 through 8 and intron 5 was found in 5 of the 40 feline vaccine site–associated sarcomas.31

The wild-type p53 protein is not detected by immunohistochemistry because of the short half-life of about 15–20 minutes.37 Missense mutations leading to amino acid substitutions may induce p53 protein stabilization, resulting in accumulations of nuclear p53 proteins that are detectable by immunohistochemistry.17,37 p53 protein was detected using immunohistochemistry in various feline cancer types, including carcinomas and sarcomas.32,33

Recently, different authors have confirmed that growth factors (GFs) not only promote proliferation but also induce malignant transformation and regulation of angiogenesis.10,18,38,40 Overexpression of GFs has been found in different human tumours and is considered to be one of the causes of carcinogenesis.11,45

FGF-b is a prototype member of FGF family that comprises 20 members, with pleiotropic effects in different cells and organ systems.1,12 FGF-b is involved in inflammation and wound healing2,27,36 and in promoting nerve survival and regeneration after central nervous system injury.23 It is also known that FGF-b can activate DNA synthesis in mesenchymal cells such as fibroblasts and smooth muscles, stimulating growth of tumours derived from these cells.2,12 In addition, numerous studies have shown that FGF-b can stimulate division and migration of vascular endothelial cells, essential for sustaining tumour growth and enabling metastasis.10,18

Transforming growth factor-α (TGF-α) is a protein of 50 amino acids belonging to the epidermal growth factor (EGF) family that was initially called sarcoma growth factor because of its profound effects on the morphology of rat fibroblasts.7 TGF-α binds the EGF receptor (EGF-R), triggering a cascade of events that leads to regulation of epithelial and mesenchymal cell growth.21,38 EGF- or TGF-α–induced mutation in the p53 gene with overexpression of the mutant p53 product causes enhanced signalling in vulvar squamous carcinoma cell line.5 Expression of TGF-α can be induced by several viral and cellular oncogenes and causes a mitogenic effect in a variety of cells.34 An increase in TGF-α expression has been detected in several malignant neoplasms in humans, including MFH.11,40,44

  1. Basilico C, Moscatelli D: The FGF family of growth factors and oncogenes. Adv Cancer Res 59:115-165, 1992[ISI][Medline]
  2. Bikfalvi A, Klein S, Pintucci G, Rifkin DB: Biological roles of fibroblast growth factor-2. Endocr Rev 18:26-45, 1997[Abstract/Free Full Text]
  3. Brooks JJ: Fact or fiction: malignant fibrous histiocytoma. Am J Surg Pathol 16:1023-1024, 1992[ISI][Medline]
  4. Burton G, Mason KV: Do postvaccinal sarcomas occur in Australian cats? Aust Vet J 75:102-106, 1997[ISI][Medline]
  5. Carpenter G, Soler C, Baulida J, Beguinot L, Sorkin A: Interaction of signaling and trafficking proteins with the carboxyterminus of the epidermal growth factor receptor. Ann N Y Acad Sci 766:44-51, 1995[ISI][Medline]
  6. Couto SS, Griffey SM, Duarte PC, Madewell BR: Feline vaccine-associated fibrosarcoma: morphologic distinctions. Vet Pathol 39:33-41, 2002[Abstract/Free Full Text]
  7. Derynck R: Transforming growth factor-alpha: structure and biological activities. J Cell Biochem 32:293-304, 1986[CrossRef][ISI][Medline]
  8. Esplin DG, Mcgill LD, Meininger AC, Wilson SR: Postvaccination sarcomas in cats. J Am Vet Med Assoc 202:1245-1247, 1993[ISI][Medline]
  9. Gabbiani G: The biology of the myofibroblast. Kidney Int 41:530-532, 1992[ISI][Medline]
  10. Galy B, Maret A, Prats AC, Prats H: Cell transformation results in the loss of the density-dependent translational regulation of the expression of fibroblast growth factor 2 isoforms. Cancer Res 59:165-171, 1999[Abstract/Free Full Text]
  11. Gerharz CD, Ramp U, Reinecke P, Schardt C, Friebe U, Déjosez M, Nitsch T, Gabbert HE: Analysis of growth factor-dependent signalling in human epithelioid sarcoma cell lines: clues to the role of autocrine, juxtacrine and paracrine interactions in epithelioid sarcoma. Eur J Cancer 36:1171-1179, 2000[CrossRef][ISI][Medline]
  12. Gospodarowicz D, Neufeld G, Schweigerer L: Fibroblast growth factor: structural and biological properties. J Cell Physiol 5: (Suppl) 15-26, 1987[CrossRef]
  13. Greenblatt MS, Bennett WP, Hollstein M, Harris CC: Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855-4878, 1994[ISI][Medline]
  14. Hendrick MJ: Feline vaccine-associated sarcomas: current studies on pathogenesis. J Am Vet Med Assoc 213:1425-1426, 1998[ISI][Medline]
  15. Hendrick MJ, Brooks JJ: Postvaccinal sarcomas in the cat: histology and immunohistochemistry. Vet Pathol 31:126-129, 1994[ISI][Medline]
  16. Hendrick MJ, Goldschmidt MH: Do injection site reactions induce fibrosarcomas in cats? J Am Vet Med Assoc 199:968, 1991
  17. Iggo R, Gatter K, Bartek J, Lane D, Harris AL: Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet 335:675-679, 1990[CrossRef][ISI][Medline]
  18. Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D: Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell 66:1095-1104, 1991[CrossRef][ISI][Medline]
  19. Kass PH, Barnes WG, Spangler WL, Chomel BB, Culbertson MR: Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 203:396-405, 1993[ISI][Medline]
  20. Lacey SW: Oncogenes in retroviruses, malignancy, and normal tissues. Am J Med Sci 291:39-46, 1986[ISI][Medline]
  21. Lee DC, Fenton SE, Berkowitz EA, Hissong MA: Transforming growth factor alpha: expression, regulation, and biological activities. Pharmacol Rev 47:51-85, 1995[Free Full Text]
  22. Linkhart TA, Clegg CH, Hauschika SD: Myogenic differentiation in permanent clonal mouse myoblast cell lines: regulation by macromolecular growth factors in the culture medium. Dev Biol 86:19-30, 1981[CrossRef][ISI][Medline]
  23. Logan A, Frautschy SA, Baird A: Basic fibroblast growth factor and central nervous system injury. Ann N Y Acad Sci 638:474-476, 1991[ISI][Medline]
  24. Macy DW, Hendrick MJ: The potential role of inflammation in the development of postvaccinal sarcomas in cats. Vet Clin North Am Small Anim Pract 26:103-109, 1996[ISI][Medline]
  25. Madewell BR, Griffey SM, McEntee MC, Leppert VJ, Munn RJ: Feline vaccine-associated fibrosarcoma: an ultrastructural study of 20 tumors (1996–1999). Vet Pathol 38:196-202, 2001[Abstract/Free Full Text]
  26. Malkin D, Li FP, Strong LC, Fraumeni JF, Jr Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233-1238, 1990[Abstract/Free Full Text]
  27. Martins-Green M, Boudreau N, Bissell MJ: Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res 54:4334-4341, 1994[ISI][Medline]
  28. Mayr B, Blauensteiner J, Edlinger A, Reifinger M, Alton K, Schaffner G, Brem G: Presence of p53 mutations in feline neoplasms. Res Vet Sci 68:63-70, 2000[CrossRef][ISI][Medline]
  29. Mayr B, Schaffner R, Kurzbauer M, Schneider A, Reifinger M, Loupal G: Mutations in tumor suppressor gene p53 in two feline fibrosarcomas. Br Vet J 151:707-713, 1995[ISI][Medline]
  30. Mentzel T, Fletcher CDM: The emerging role of myofibroblast in soft tissue neoplasia. Am J Clin Pathol 107:2-5, 1997[ISI][Medline]
  31. Nambiar PR, Haines DM, Ellis JA, Kidney BA, Jackson ML: Mutational analysis of tumor suppressor gene p53 in feline vaccine site-associated sarcomas. Am J Vet Res 61:1277-1281, 2000[CrossRef][ISI][Medline]
  32. Nambiar PR, Jackson ML, Ellis JA, Chelack BJ, Kidney BA, Haines DM: Immunohistochemical detection of tumor suppressor gene p53 in feline injection site-associated sarcomas. Vet Pathol 38:236-238, 2001[Abstract/Free Full Text]
  33. Nasir L, Krasner H, Argyle DJ, Williams A: Immunocytochemical analysis of the tumor suppressor protein (p53) in feline neoplasia. Cancer 155:1-7, 2000
  34. Normanno N, Bianco C, De Luca A, Salomon DS: The role of EGF-related peptides in tumor growth. Front Biosci 6:685-707, 2001
  35. Okuda M, Umeda Y, Matsumoto Y, Momoi Y, Watari T, Goitsuka R, Obrien SJ, Tsujimoto H, Hasegawa A: Molecular cloning and chromosomal mapping of feline p53 tumor suppressor gene. J Vet Med Sci 55:801-805, 1993[ISI][Medline]
  36. Ortega S, Ittmann M, Tsang SH, Ehrlich M, Basilico C: Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc Natl Acad Sci USA 95:5672-5677, 1998[Abstract/Free Full Text]
  37. Ozbun MA, Butel JS: p53 suppressor gene: Structure and function. In: Encyclopedia of Cancer, ed. Bertino JR, pp 1240-1257, Academic Press, San Diego, CA 1997
  38. Perosio PM, Brooks JJ: Expression of growth factors and growth factor receptors in soft tissue tumors. Implications for the autocrine hypothesis. Lab Invest 60:245-253, 1989[ISI][Medline]
  39. Roche WR: Myofibroblasts. J Pathol 161:281-282, 1990[CrossRef][ISI][Medline]
  40. Rosenthal A, Lindquist PB, Bringman TS, Goeddel DV, Derynck R: Expression in rat fibroblasts of a human transforming growth factor-alpha cDNA results in transformation. Cell 46:301-309, 1986[CrossRef][ISI][Medline]
  41. Samaniego F, Markham PD, Gendelman R, Watanabe Y, Kao V, Kowalski K, Sonnabend JA, Pintus A, Gallo RC, Ensoli B: Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi's sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular permeability and KS lesion development. Am J Pathol 152:1433-1443, 1998[Abstract]
  42. Schuh AC, Keating SJ, Monteclaro FS, Vogt PK, Breitman ML: Obligatory wounding requirement for tumorigenesis in v-jun transgenic mice. Nature 346:756-760, 1990[CrossRef][ISI][Medline]
  43. Sorrentino V: Growth factors, growth inhibitors and cell cycle control (review). Anticancer Res 9:1925-1935, 1989[ISI][Medline]
  44. Wang D, Patil S, Li W, Humphrey LE, Brattain MG, Howell GM: Activation of the TGFalpha autocrine loop is downstream of IGF-I receptor activation during mitogenesis in growth factor dependent human colon carcinoma cells. Oncogene 21:2785-2796, 2002[CrossRef][ISI][Medline]
  45. Wu X, Xin Y, Yao J, Hasui K, Tsuyama S, Yonezawa S, Murata F: Expression of epithelial growth factor receptor and its two ligands, transforming growth factor-alpha and epithelial growth factor, in normal and neoplastic squamous cells in the vulva: an immunohistochemical study. Med Electron Microsc 34:179-184, 2001[CrossRef][Medline]
  46. Yoo J, Park SY, Kang SJ, Shim SI, Kim BK: Altered expression of G1 regulatory proteins in human soft tissue sarcomas. Arch Pathol Lab Med 126:567-573, 2002[ISI][Medline]