A
IM OF THE STUDYThe aim of this study was to investigate the role iron serum status, serum vascular endothelial growth factor and oxidative stress pattern in canine cancer patients with particular attention on cutaneous mast cell tumour.
Mast cell tumors (MCTs) are the most common cutaneous tumor in the dog, accounting for 16% to 21% of cutaneous tumors (Bostock,1986; Finnie,1979; Rothwell, 1987; Brodey,1970). MCTs are primarily a disease of older dogs (mean age,9 years)
(Davis,1992; Patnaik,1984). Most occur in mixed breeds, although boxers, Boston terriers, Labrador retrievers, beagles, and schnauzers all have been reported to be predisposed to these tumors (Bostock,1986; Rothwell,1987; Patnaik,1984; Peters,1969).
Cutaneous MCTs are thought to arise from tissue mast cells in the dermis and subcutaneous tissues (Carpenter,1987). Well differentiated mast cells contain cytoplasmic granules that become larger as the cell matures. These granules contain a large number of bioactive constituents, including histamine and heparin, which stain metachromatically with toluidine blue. Wide variation is seen in the histologic pattern of canine MCT, and the histologic grade has been clearly established as a strong prognostic factor that is highly predictive of biologic behavior and clinical outcome. Several investigators have applied histologic grading systems to canine mast cell tumors based on the degree of differentiation (Table 19-1). The number grades used in these studies are at odds; therefore, for the sake of clarity, the three differentiation groups should be referred to simply as undifferentiated (high) grade, intermediate grade, and well-differentiated (low) grade. The true metastatic potential of canine MCT is not known for certain. The
histologic grade appears to be very predictive of metastatic behavior. Early necropsy reports state that the metastatic rate of MCT can be as high as 96%.35 However, this is an overestimation, because the necropsy subjects in this generally untreated series either died or were euthanized as a direct result of their tumors; therefore most of the dogs in the series probably had anaplastic, undifferentiated tumors, which have a worse prognosis. The clinical experience of the authors and others suggests that the metastatic potential of well-differentiated tumors is low (less than 10%) and that of intermediate grades is low to moderate
(Cahalane,2004; Michels,2002; Mullins,2006; Murphy,2004; Seguin,2001; Weisse,2002). The metastatic rate for undifferentiated tumors ranges from 55% to 96% (Bostock,1973).
Most of these tumors disseminate first to the local lymph nodes and then to the spleen and liver. Other visceral organs may be involved, although lung involvement is uncommon. Neoplastic mast cells may be observed in the bone marrow and peripheral blood in cases of widespread systemic dissemination. Bone marrow involvement occurs in as many as half of the cases of anaplastic visceral MCT (O’Keefe,1987). Complications related to the release of the bioactive constituents of mast cell granules can occur with MCTs where for example gastrointestinal ulceration is common, reported to occur in 35% to 83%, usually followed by status of chronic anaemia and serum iron depletion (Fox,1990; Howard,1969). Plasma histamine concentrations are increased in dogs with MCTs,
(Ishiguro,2003) and preliminary data indicate that monitoring of plasma histamine concentrations may be useful for monitoring disease progression (Ishiguro,2003).
These dogs also have decreased concentrations of plasma gastrin, which normally is released by antral G-cells in response to an increased concentration of gastric hydrochloric acid, acting as a negative feedback loop. Increased gastric acid
secretion combined with vascular damage likely is the cause of gastric ulceration
(Fox,1990). Perioperative degranulation of MCTs and subsequent release of
histamine and other, less characterized vasoactive substances may also result in potentially life-threatening hypotensive events during surgery. Some researchers believe that prostaglandins in the D series secreted by tumor cells may mediate the hypotensive effects observed in humans with mast cell diseases (Roberts,1980; Scott,1983). Coagulation abnormalities, also reported in dogs with MCTs, likely are caused by heparin release from mast cell granules (O’Keefe,1987; Hottendorf,1965).
Clinical evidence of hemorrhage is not typically associated with this phenomenon; however, localized hemorrhage at the time of surgery, caused by degranulation resulting from tumor manipulation, can be a serious complication, even if presurgical coagulation parameters are normal. Delayed wound healing at the site of removal of a MCT has been attributed to the local effects of proteolytic enzymes and vasoactive amines released by the tumor. Studies in mice suggest that histamine released from the tumor binds to H1 and H2 receptors on macrophages,
resulting in release of a fibroblastic suppressor factor that decreases normal fibroplasia and delays wound healing (Kenyon,1983). Also, histamine and human mast cell leukemia lysates have been shown to reduce keratinocyte proliferation, further inhibiting wound epithelialisation (Huttunen,2001) has been also demonstrated
that mast cells and mast cells tumour can express, produce and release the Vascular endothelial growth factor (VEGF) has been implicated to contribute tissue edema through its effect on vascular permeability (Paturno, 2009; Mederle, 2010).
Studies performed in vitro and in vivo (rats) on Mast cells, showed also how VEGF expression was regulated by hypoxiainducible factor-1a (HIF-1a) activation through the phosphatidylinositol 3-kinase (PI3K)–HIF-1a pathway (Lee, 2008).
Systemic hypoxia produces an inflammatory response characterized by increases in reactive O2 species (ROS), venular leukocyte-endothelial adherence and
emigration, and vascular permeability. Inflammation is typically initiated by mediators released from activated perivascular cells that generate the chemotactic gradient responsible for extravascular leukocyte accumulation. Mast cell degranulation, ROS levels, leukocyte adherence and emigration, and vascular permeability were studied in the mesenteric microcirculation by using intravital microscopy of anesthetized rats. The main findings were 1) activation of mast cells in normoxia produced microvascular effects similar, but not identical, to those of hypoxia; 2) systemic hypoxia resulted in rapid mast cell degranulation; 3) blockade of mast cell degranulation with cromolyn prevented or attenuated the hypoxia-induced increases in ROS, leukocyte adherence/emigration, and vascular permeability; and 4) mast cell degranulation during hypoxia was prevented by administration of the antioxidant lipoic acid and of nitric oxide. These results showed that mast cells could play a key role in hypoxia-induced inflammation and suggested that alterations in the ROS-nitric oxide balance may be involved in mast cell activation during hypoxia (Steiner, 2003). Studies performed in vitro on mast cells have also demonstrated the role of the antioxidant barrier, especially of the vitamin E, in prevent degranulation of mast cells and proliferation of tumour cell lines (Gueck, 2002; Reiter, 2003).
Most of these study have been performed in vitro and, except for the VEGF (which has been often investigated in the last years for his role in the anticancer target therapy in veterinary medicine), there are just few data on the role of oxidative stress pattern and iron profile in canine patients affected by mast cell tumour, as well as in several other neoplastic disease. In dogs the role of these parameters in
tumour development, response to the treatment and progression of the disease is often just anecdotal. These data are just assumed from human studies where both in vitro and in vivo a network between iron serum profile, VEGF and oxidative stress pattern has been established as they are involved in the progression of neoplastic diseases as well as in the body’s response to the tumour. So the aim of this study was to investigate the role of this network in canine oncology patients through different tumour time and clinical substage focusing on mast cell tumour.
