Immunohistochemical Expression of Potential Therapeutic Targets in Canine Thyroid Carcinoma

Abstract

BackgroundThyroid carcinoma is a common endocrine tumor in the dog. Local invasive growth frequently precludes surgical excision and, in up to 38% of dogs, the tumor has already metastasized by the time of diagnosis. Therefore, it is important to investigate new treatment modalities that may be useful for the large number of dogs with inoperable tumors or metastatic disease.Hypothesis/ObjectivesTo investigate the immunohistochemical expression of potential therapeutic targets in canine thyroid tumors.Animals74 dogs with thyroid neoplasia.MethodsImmunohistochemistry was performed for thyroglobulin, calcitonin, vascular endothelial growth factor (VEGF), p53, cycloxygenase‐2 (cox‐2), and P‐glycoprotein (P‐gp).ResultsFifty‐four (73%) tumors were classified as follicular cell thyroid carcinomas (FTCs) and 20 (27%) as medullary thyroid carcinomas (MTCs). Eighty percent of FTCs and all MTCs had a high percentage (76–100%) of neoplastic cells immunopositive for VEGF. Thirteen percent of FTCs and 50% of MTCs expressed cox‐2. Seven percent of FTCs and 70% of MTCs expressed P‐gp. No tumor was immunopositive for p53 expression. Expression of VEGF (P = .034), cox‐2 (P = .013), and P‐gp (P < .001) was significantly higher in MTCs compared to FTCs.Conclusions and Clinical Importance VEGF is a potential therapeutic target in both FTC and MTC in dogs. Cox‐2 and P‐gp may be useful molecular targets in canine MTC.

Immunohistochemical detection of P-glycoprotein in various subtypes of canine lymphomas

“…This staining pattern have been described in canine tumors of different origin (Hifumi et al 2010, Kim et al 2012, Teng et al 2012, Campos et al 2014 including lymphomas (Bergman et al 1996, Ginn 1996, Lee et al 1996. However, in our study, except typical cytoplasmic reaction, a dot-like staining pattern was found.…”

“…However, the P-gp is highly conserved across species and the monoclonal antibody clone C494 used in our study is known to cross-react with canine tissues (Ginn 1996). This antibody has been frequently used during the last two decades in studies on P-gp expression in dogs in normal tissues (Ginn 1996), pathological conditions ( Van der Heyden et al 2011) and in various types of tumors (Ginn 1996, Lee et al 1996, Hifumi et al 2010, Campos et al 2014). Clone C219 is another most widely used monoclonal antibody for P-gp detection in canine tissues (Bergman et al 1996, Lee et al 1996, Uozurmi et al 2005, Van der Heyden et al 2011, Kim et al 2012, Teng et al 2012, Flood-Knapik et al 2013).…”

“…Single papers focused on expression of P-gp in mast cell tumors (Teng et al 2012), mammary tumors (Kim et al 2012), thyroid carcinoma (Campos et al 2014) and pulmonary carcinoma (Hifumi et al 2010) are available. More attention is given to canine lymphomas.…”

“…A breed-related sensitvity to ivermectin in collies and several other dog breeds is also caused by mutation in MDR1 gene coding P-gp (Martinez et al 2008). Moreover, P-gp prevents the entry of chemotherapeutics into the neoplastic cells by effluxing them out of these cells decreasing the intracellular concentration of anticancer drugs, thereby limiting cytotoxicity at their target site (Campos et al 2014). Overexpression of P-gp is associated with resistance to different types of chemotherapeutical agents including doxorubicin, mitoxantrone, etoposide, vinblastine, paclitaxel, actinomycin B, vinca alkaloids and glucocorticosteroids (Arceci 1993).…”

Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs

“…Therefore, a better understanding of the molecular mechanisms and intracellular networks associated with oncogenesis may help discover new therapeutic options for these malignancies (Malaguarnera et al, 2012). Alterations in the expression of growth factors such as insulin-like growth factor (IGF)-1, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2, and their receptors, play a role in the progression of thyroid cancer in humans and dogs (de Araujo-Filho et al, 2009;Redler et al, 2013;Campos et al, 2014). The activation of the IGF system is associated with the pathogenesis of a variety of human neoplasias because of the mitogenic and anti-apoptotic properties of its cognate receptor (Vella et al, 2001;Ciampolillo et al, 2007).…”