Role of inflammation/wound healing in feline oncogenesis: A commentary

The occurrence of a tumor in the vicinity of an implanted microchip has been reported for the first time in a cat in this issue of JFMS (Daly et al 2008). The authors clearly indicate that in this case they could not prove that the microchip caused the fibrosarcoma because the cat had also been previously vaccinated in this location. A similar situation was described for a microchip-associated fibrosarcoma reported in a dog that had previous vaccinations administered at the neoplastic site (Vascellari et al 2006).

We have known for many years that irritation, inflammation and/or wounds are promoters of tumor development and there are examples in the human and veterinary literature. However, the pathogenesis of inflammation-associated oncogenesis remains poorly understood. This intriguing association between inflammation and cancer continues to drive very important research programs. In fact the 2007 annual meeting of the American College of Veterinary Pathologists devoted a specific session to this very topic. The invited speakers spoke of the role of inflammation in lung neoplasia, colon cancer, and Helicobacter species associated gastric cancer. The role of inflammation in lung neoplasia is currently being investigated and specific subtypes of tumor associated macrophages tend toward a proliferative response. Inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis) in people is associated with an increased risk of colon cancer. Some researchers are hypothesizing that inflammation of ulcerative colitis increases the number of stem cells due to the need for regeneration/repair and these stem cells undergo changes to become cancer stem cells that have the ability to proliferate and form a tumor. Helicobacter species infection involving the stomach is known to be associated with gastric cancer in people, however the precise manner in which infection causes cancer is not known. The present thinking is that gastric cancer is multifactorial, arising through the combination of infection with a virulent organism, permissive environment, and a genetically susceptible host; the most important cofactor in the induction of Helicobacter-related disease is the host immune response (Stoicov et al 2004). It is very interesting that chronic inflammation in this example is necessary for the progression through atrophy to gastric cancer and CD4 T lymphocytes play a crucial role. Interestingly, lymphocytes that have been phenotyped in some vaccine- and microchip-associated sarcomas in cats and dogs are also T lymphocytes. One of the invited speakers (J. Houghton) has also demonstrated that in response to chronic Helicobacter species infection, bone marrow derived cells can home to and repopulate the gastric mucosa, progressing to a malignant cell phenotype and ultimately gastric cancer (Houghton et al 2004).

In the report by Daly et al (2008) the inflammatory response was only found in adipose and connective tissue at the periphery of the mass, rather than within the neoplastic tissue. Although one might expect to see an inflammatory response associated with the microchip, as it is a foreign object, and the presumed mechanism of sarcoma formation is related to the foreign body, in fact the degree of inflammation in previously reported sarcomas is variable. For example, in a report of a liposarcoma at the site of an implanted microchip in a dog, the authors indicate that the microchip was completely embedded within the mass, but only some multinucleate giant cells were found (Vascellari et al 2004). In a fibrosarcoma found at the site of a microchip implant in a dog, the authors describe that the microchip was attached to the mass and there was multifocal random necrosis and peripheral lymphoid aggregates of a T cell phenotype (Vascellari et al 2006). In a report of subcutaneous microchip-associated tumors in 52 B6C3F1 mice, all masses contained the microchip or were adjacent to it and there was a vestigial fibrous capsule and/or a focus of necrosis associated with the microchip (Le Calvez et al 2006). In this study, there were multinucleated giant cells in some tumors and areas of hemorrhage and necrosis with variable amounts of inflammation commonly seen in the larger tumors. In a microchip-associated leiomyosarcoma in an Egyptian fruit bat, the authors only mention multifocal areas of coagulative necrosis and not the presence of an inflammatory response (Siegal-Willott et al 2007). A study involving Fischer 344 rats reported a low incidence (approximately 1%) of microchip-induced sarcomas; scanning electron and light microscopy demonstrated the tumors conforming to the microchip device, with no evidence of active inflammation immediately surrounding the microchip (Elcock et al 2001). These authors present an explanation for these findings based on previous research of foreign body-tumorigenesis. Foreign bodies with smooth, continuous surfaces are more carcinogenic than those with rough, scratched, or porous surfaces. Apparently the formation of a fibrous tissue capsule around the foreign body is a more important factor in carcinogenesis than ongoing active inflammation, and the occurrence of tissue fibrosis is believed to be linked to neoplastic development. The tumors induced by implantation of foreign bodies likely arise from pluripotential mesenchymal cells, thus explaining the morphologic diversity of the tumors found at the implantation site (Tillmann et al 1997). The molecular mechanism that causes neoplastic transformation in a low proportion of animals implanted with microchips is currently unknown, as is the role of the initial inflammatory response at the implantation site.

The location, magnitude and type of inflammatory cells present in feline vaccine-site sarcomas are also variable (Hendrick and Brooks 1994, Doddy et al 1996, Couto et al 2002). Prominent or abundant inflammation was reportedly seen in 59.1% of vaccine-associated sarcomas in cats, consisting of peritumoral lymphoid aggregates or follicles and smaller numbers of macrophages (Couto et al 2002).

The precise histogenesis and pathogenesis of vaccine-associated sarcomas remain obscure. These sarcomas likely arise from pluripotential mesenchymal cells that proliferate in areas of inflammation and/or wound healing. Injection site sarcomas are histologically similar to mesenchymal tumors arising in traumatized eyes of cats suggesting a common pathogenesis of inflammation/wound healing and the development of sarcomas. The finding of inflammatory cells in injection site sarcomas in cats is in contrast to the absence (Couto et al 2002) or decreased incidence (Doddy et al 1996) of inflammation in fibrosarcomas in non-vaccine sites, thus suggesting that inflammatory cells play a role. Studies investigating pathogenesis of vaccine-associated sarcomas have shown immunoreactivity for platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and their receptors, and transforming growth factor-β (TGF-β) (Hendrick 1998). A theory has been proposed that lymphocytes in vaccine-associated sarcomas may secrete PDGF to recruit macrophages, and lead to fibroblast proliferation which in turn may lead to overexpression of c-jun, a proto-oncogene that is associated with cellular proliferation and oncogenesis in vitro (McEntee and Page 2001).

There is great potential for current research in humans and other species to benefit cats and perhaps the precise molecular mechanisms can be defined for vaccine-associated and foreign body associated sarcomas, including those that are microchip-induced.