**2. The carcinogenesis and biological behavior of CTVT**

The carcinogenesis of CTVT remains unclear. This cancer may be caused by many sources, but all CTVT cells share the same genetic rearrangement [12]. Specifically, the long interspersed nuclear element-1 (LINE-1) in CTVT cells shows a difference from normal dog cells or host cells [12]. This evidence demonstrates that CTVT clonal evolution grows along the host, and the genetic instability and numerous mutations of CTVT cells give them contagious abilities [6, 8].

Remarkably, CTVT cells are usually transplanted through physical transmission from one dog to another during sexual intercourse. The violent exertions associated with intercourse in both genders are prone to causing genital mucosal damage, which enables the transmission of viable CTVT cells to susceptible hosts. The tumor starts to grow as solitary or multiple nodules at the glans penis or bulbus glandis area in the male dog and on the mucosa wall of the vagina or vulva in the female dog [13]. Cancer cells can affect the mucosa of the external genital organs, skin, and other sites on the body [14–19]. Transplantation occurs individually across the major histocompatibility complex (MHC) between the cancer cells of the CTVT-infected dog and the damaged mucosa of the susceptible dog [1, 2]. CTVT can evade the host's immunological detection, allowing its worldwide spread as a naturally occurring allograft cancer in dogs because its cells lose the expression of MHC class I and II molecules. The growth of a CTVT mass in the external genital area usually appears within 2–6 months after mating [13]. CTVT was the first tumor to be experimentally transplanted by Novinsky in 1876. The CTVT mass cannot be grown with cells that have been treated with glycerin or cell-free filtrates or cells that have been frozen or heated [13]. Even though this contagious cancer has been described as having only dogs as its specific host, CTVT can be heterotransplanted experimentally by inoculation between dogs (*Canis familiaris*) and other members of the social canids, such as wolves (*Canis lupus*), foxes (genus Vulpes), coyotes (*Canis latrans*), and jackals (*Canis aureus*) [1]. The transplantation of viable CTVT cells has also been successful in irradiated mice and athymic nude mice as xenografts in a murine model [13]. Experimentally transplanted and naturally transplanted CTVT growth patterns are predictable and clinically characterized by an initial aggressive growth or progressive phase (P-phase), followed by a stable population in the host or stationary phase (S-phase), and then slowly diminishing cancer cells in a regression phase (R-phase) [20]. In the P-phase, CTVT has a rapid growth rate and forms a mass-like cauliflower feature with discharge at the genital area. Histologic examination of the predictable growth pattern of CTVT in the P-phase reveals numerous round-to-ovoid-shaped CTVT cells with an abundance of mitotic figures and few tumor-infiltering lymphocytes (TILs). The extracellular matrix in the P-phase is rich in the hyaluronan matrix, which may be advantageous for CTVT growth because the hyaluronan creates hydration for the extracellular matrix, which enhances cell proliferation and shields tumor cells against apoptosis [21]. Moreover, the hyaluronan may mask the tumor-associated antigens and MHC antigens on CTVT cell surfaces from the host's immunosurveillance. Histological

#### *Canine Transmissible Venereal Tumor: An Infectious Neoplasia in Dogs DOI: http://dx.doi.org/10.5772/intechopen.106150*

features of CTVT tissues in the S-phase show a decrease in the population of CTVT cells; there are fewer mitotic figures and more apoptotic cells than in the P-phase. In the S-phase, the growth rate of cancer cells is slow. Moreover, TILs increase in the S-phase. In the R-phase, the main cellular population is TILs, and the tumor stroma structure gradually collapses and is replaced by collagen tissue. A key feature of the R-phase is the disappearance of cancer cells [22, 23]. Moreover, vascular stroma and fibrosis increase in the R-phase [11, 23]. During the R-phase, the number of myofibroblasts is higher than in the P-phase. This increase in fibroblast population and tenascin-C extracellular matrix coincides with the increasing number of TILs. These features may be the consequence of the same factor produced by the tumor cells and their microenvironment. During the R-phase, the tumor parenchyma destroys and remodels the tumor stroma. Myofibroblasts and extracellular matrices are related to the R-phase and tissue remodeling of CTVT, which are related to wound healing and stromal reactions of tumors [23].
