Onco-epidemiology of domestic animals and targeted therapeutic attempts: perspectives on human oncology

Spontaneous canine tumors, such as prostate carcinoma, chondrosarcoma, which accounts for approximately 10 % of all primary bone tumors in dogs (Beveridge and Sobin 1976), axial osteosarcoma, which accounts for 80 % of all primary bone tumors in dogs (Thompson and Pool 2002) and synovial cell sarcoma, have been extensively described representing valuable models to study carcinogenesis (Vail et al. 1994). Most canine prostate carcinomas affect both elderly sexually intact dogs and dogs which had undergone surgical castration after reaching sexual maturity. In 2005–2009, a pilot study evaluated the incidence of spontaneous tumors in dogs living in the neighborhood of Venice and Vicenza (Vascellari et al. 2009). Two thousand five hundred and nine out of 296,318 canine cases of neoplasia were diagnosed during the first three years. The estimated annual tumor incidence rate per 100,000 dogs was 282, with an equal distribution of malignant and benign tumors between male and female dogs. Moreover, in pure breeds, a twofold higher incidence of malignant tumors, with respect to mixed breeds, was observed. The incidence increased with age in both genders. Due to the dissimilar methodologies and variable reference populations of both European and North American veterinary cancer registries, the occurrence of spontaneous tumors in pet animals has been underestimated (Bonnett et al. 1997; Dobson et al. 2002; Dorn et al. 1968; Parkin and Muir 1992; Priester and McKay 1980). The Animal Tumor Registry of Genoa (Italy) retrospectively showed that, from 1985 to 2002, 70 % of all cancer cases in female dogs were located in the breast (Merlo et al. 2008). The overall incidence of cancer was 99.3 per 100,000 dogs per year in male dogs and 272.1 in female dogs. Among domestic animal tumors, spontaneous squamous cell carcinomas provided additional information about the pathology of oral cancer (Gardner 1996). As far as oral tumors affecting dogs are concerned, malignant melanoma accounts for the 4 % of all canine tumors (MacEwen et al. 1999). Canine malignant melanomas and human melanomas are treated similarly using surgery and/or fractionated radiation therapy and immunological therapies (Vail and Thamm 2004; Bergman et al. 2003). Therefore, canine malignant melanomas are suitable models for new immunotherapeutic protocols in humans (Vail and Thamm 2004). Dogs and cats also frequently develop squamous cell carcinomas (Dorn and Priester 1976; Strafuss et al. 1976). Skin and subcutaneous tissue neoplasms are the most frequently recognized neoplastic disorders in domestic animals and can be caused by prolonged and continuous exposure to sunlight (Madewell 1981). Alimentary tract cancer in dogs has lower incidence, with ductal and acinar carcinomas occurring most frequently in females than in males while intranasal tumors account for 1–2 % of all canine neoplasms (Priester 1974). Primary bone cancer is the second most often detected in dogs, and its main risk factors are ionizing radiations, chemical carcinogens and viruses (Madewell 1981). Moreover, preexisting bone defects and skeletal abnormalities increase the risk factors from 60 up to 185 times for large and giant breeds with respect to small dogs (Tjalma 1966). As to primary brain tumors, they account for approximately 2 % of all cancer in human adults (McKinney 2004) and for 0.01 % in dogs (LeCouteur 1999). Specifically, gliomas are more common among brachycephalic breeds of dogs, especially boxers, English bulldogs and Boston terriers (Hayes 1976). High incidence rates were also detected for non-Hodgkin’s lymphoma in bitches and for non-Hodgkin’s lymphoma and skin cancer in male dogs (Merlo et al. 2008). Additionally, the incidence rate of cancer increased with age ranging between 23.7 and 763.2 in bitches and 16.5 and 237.6 in male dogs aged ≤3 and >9–11 years. Hemangiosarcoma, which can affect both cats and dogs, involves the musculoskeletal system, and mean survival time in dogs affected by this condition ranges from 267 (Ogilvie et al. 1996) to 780 days (Ward et al. 1994), depending on the disease stage. The ovarian and epithelial tumors, although quite rare in domestic animals, have been reported mainly in cats, dogs and horses (MacLachlan 1987). A single unique gonadoblastoma tumor affecting human males or females has been observed in the testicle of a dog (Turk et al. 1981). Spontaneous testicular tumors, which are quite common in aged dogs, are mainly seminomas (solitary, unilateral, more frequent in the right testicle and with a reduced possibility to develop metastases, if compared with humans) (Kennedy et al. 1998), Sertoli cell tumors and Leydig cell tumors, which can coexist together along with seminomas (Nielsen and Kennedy 1990) and occur with the same frequency (Maiolino et al. 2004). Maiolino et al. suggested a possible correspondence between human spermatocytic seminomas and most canine seminomas in order to justify their low metastatic behavior, showing a potential predictive model for the development of a treatment protocol (Maiolino et al. 2004). Further, rare dog tumors are fibrosarcoma, rib, vertebral body and pelvis tumors (both in dogs and in cats) (Dernell et al. 1998; Pirkey-Ehrhart et al. 1995; Straw et al. 1992) and multiple myeloma (rare in cats and uncommon in dogs), which accounts for 8 % of all canine hematopoietic tumors and affects older dogs with no breed or sex predilection (Matus et al. 1986) and intracranial central neurocytomas (Russell and Burch 1959). Canine mast cell tumors, which account for 16–21 % in this species (Thamm and Vail 2001), display a molecular alteration in the proto-oncogene c-kit, which is involved in mast cell differentiation, proliferation, survival and activation (London et al. 1999). Specifically, the mutation of exon 11 of c-kit occurs in 30–50 % of advanced mast cell tumors and is similar to that usually occurring in 50–90 % of human gastrointestinal stromal tumors (Heinrich et al. 2002; London et al. 2003). This evidence emphasizes a parallel between human and canine mast cell tumors underlying the possibility of using the canine model to develop new beneficial therapeutics for both species (Pryer et al. 2003). Non-Hodgkin lymphoma, which accounts for 5 % of all malignant tumors and 83 % of all hematopoietic malignancies in dogs (Vail and Thamm 2004), affects mostly middle-aged, older dogs (German shepherds, boxers, basset hounds and Saint Bernards) (MacEwen and Young 1996) and both genders equally and corresponds to intermediate and high-grade non-Hodgkin lymphoma in humans. It is generally associated with a poor prognosis, and in 70–80 % of cases, it is B-cell mediated, whereas in 20–30 %, it is T-cell mediated (MacEwen 1995). Due to its sensitivity to chemotherapy, it is used as a model both for development of new chemotherapy drugs and multiple drug resistance studies (Vail and MacEwen 2000). Moreover, non-Hodgkin lymphoma has been used to develop hypoxic cell markers, study the whole-body hyperthermia effects and evaluate autologous bone transplantation (Vail and Thamm 2004).

Spontaneous osteosarcomas account for more than 70 % of malignant bone tumors in cats (Thompson and Pool 2002; Brodey and Riser 1969). These tumors are relevant to human cancer biology, due to their relative resistance to chemotherapy (He et al. 2014) and widespread metastatic potential. Injection-site sarcomas in felines, usually fibrosarcomas, are caused by an intense inflammatory reaction or vaccination adjuvants (Carwardine et al. 2013) and have extensively been reviewed (Hauck 2003). They are highly locally invasive and metastasize in up to 23 % of the affected cases (Seguin 2002). Although aggressive surgical resection remains the gold standard therapy, chemotherapy and radiation can prolong the survival times (Hershey et al. 2000; Kobayashi et al. 2002). Uterine tumors, rare in cats, account for 0.29 % of feline neoplasms (Miller et al. 2003), and they include endometrial adenocarcinoma, mixed mullerian tumor, leiomyoma which occurs most frequently (MacLachlan and Kennedy 2002) and myxoid leiomyosarcoma (Cooper et al. 2006). Even if the etiology of nervous system tumors is not well understood, cats are commonly affected by meningiomas (Troxel et al. 2003). However, the biological behavior of such tumor, except for the anaplastic type, is generally considered benign in both humans (Louis et al. 2007) and common pets like dogs and cats (Motta et al. 2012). A pilot study evaluated the incidence of spontaneous tumors in cats living in the neighborhood of Venice and Vicenza (Vascellari et al. 2009). Four hundred and ninety-four out of 214,683 feline cases of neoplasia were diagnosed during the first three years. For all tumors, the estimated annual incidence rate in cats per 100,000 was 77. Furthermore, a 4.6-fold higher incidence of malignant tumors was observed in cats, if compared to benign pathology. Moreover, in pure breed cats, a twofold higher incidence of malignant tumors was observed and it increased with age in both malignant and benign pathologies, if compared with mixed breeds.

In 2009, Wells introduced the potential role of pets in offering a therapeutic value to humans (Wells 2009b, 2012). Previous reports emphasized the role of dogs and cats as preventers of ill-health showing that pet owners are healthier than non-owners (Parslow et al. 2005; Wells 2009a; Wilson 1991; Serpell 1991; Allen et al. 2002; Anderson et al. 1992; Baun et al. 1984; Dembicki and Anderson 1996; Friedmann et al. 1980; Katcher 1981; Katcher et al. 1983; Larson et al. 2010; Sebkova 1977; Siegel 1993; Vormbrock and Grossberg 1988). Furthermore, the ability of pets to facilitate human recovery has been explored (Larson et al. 2010). For instance, Friedmann et al. reported that pet owners were significantly more likely to be alive 1 year after a heart attack than non-owners (Friedmann et al. 1980) and dogs were stronger facilitators to recovery from ill-health than cats (Friedmann and Thomas 1995). Therefore, dogs may contribute indirectly to long-standing human physical health, which is of great importance, especially in immunocompromised patients (Hemsworth and Pizer 2006), possibly due to the increased physical activity which typically characterizes the ownership of a dog (Larson et al. 2010). Dogs have also been used as warning systems for cancer (Williams and Pembroke 1989), epilepsy (Brown and Strong 2001; Dalziel et al. 2003; Strong et al. 1999, 2002) and diabetes (Chen et al. 2000; Lim et al. 1992; McAulay et al. 2001). They have also been used as therapists in nursing homes (Crowley-Robinson et al. 1996; Fick 1993; Kaiser et al. 2002), visitors in pediatric hospital wards (Moody et al. 2002), assistants for the disabled (Davis et al. 2004; Fishman 2003; Sanders 2000), enhancers of psychological welfare (Raina et al. 1999) and rehabilitators for prisoners (Merriam-Arduini 2000; Strimple 2003).