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Tyrosine Kinase Inhibitors (Tkis) in Human and Pet Tumours with Special Critical Reviews in Oncology/Hematology 88 (2013) 293–308 Tyrosine kinase inhibitors (TKIs) in human and pet tumours with special reference to breast cancer: A comparative review a,∗ b b b Girolamo Ranieri , Marianna Pantaleo , Mariagrazia Piccinno , Maria Roncetti , b c d b Maddalena Mutinati , Ilaria Marech , Rosa Patruno , Annalisa Rizzo , b Raffaele Luigi Sciorsci a Interventional Radiology Unit with Integrated Section of Transational Medical Oncology National Cancer Research Centre, Cancer Institute“Giovanni Paolo II”, Bari, Italy b Department of Emergencies and Organ Transplantation (DETO)-University of Bari “Aldo Moro”, Italy c Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy d Department of Prevention and Animal Ealth, ASL BAT, Barletta, Italy Accepted 17 May 2013 Contents 1. Breast tumours in humans and pets . 294 2. Dysregulation of tyrosine kinase proteins in tumours . 295 3. The TKR type III family and breast cancer . 297 3.1. PDGFRs . 297 3.2. Colony stimulating factor-1 receptor (CSF-1R, c-fms) . 298 3.3. c-KitR . 298 4. Tyrosine kinase inhibitors (TKIs) in the treatment of cancer. 298 4.1. EGFR and HER-2 inhibitors . 298 4.2. VEGFR, PDGFR, c-KitR and CSF-1R inhibitors . 299 5. Concluding remarks . 301 Conflict of interest statement . 301 Reviewers . 302 Acknowledgement . 302 References . 302 Biographies. 307 Abstract Tyrosine kinase receptors (TKRs) play a key role in tumour cell proliferation and survival since they are involved in endothelial cell activation leading to tumour neoangiogenesis. In particular, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-KitR), and colony-stimulating factor 1 (CSF-1) are overexpressed or constitutively activated in human and pet malignancies. A variety of small molecule inhibitors targeting specific tyrosine kinases (known as tyrosine kinase inhibitors or TKIs) have recently been approved, or are under investigation, for the treatment of human cancer. TKI application in animal ∗ Corresponding author at: Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre “Giovanni Paolo II”, via Orazio Flacco 65, 70124, Bari, Italy. Tel.: +39 080 5555561; fax: +39 080 5555563. E-mail addresses: [email protected], [email protected] (G. Ranieri). 1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.05.009 294 G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308 cancer is however relatively recent. This review aims to illustrate the major aspects of tyrosine kinase dysfunctions, with special regard to human and animal cancer of the mammary gland, providing an update on the background of the anti-angiogenic and anti-neoplastic properties of TKIs in human and veterinary cancer. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Tyrosine kinase receptors; Tyrosine kinase inhibitors; Angiogenesis; Breast cancer; Women; Pets; Comparative oncology; Bitch; Queen 1. Breast tumours in humans and pets which tends to be clinically HER-2 positive, and the basal- like subtype, which tends to have a low expression of ER, Breast cancer is the most commonly diagnosed malig- progesterone receptor (PR) and HER-2 [25,26,28]. This clas- nancy and one of the major causes of mortality among women sification is clinically meaningful, leading to distinct tumour worldwide [1]. It is diagnosed in about 1 million women every phenotypes and outcomes [26,27,29]. year, causing the death of over 400,000 of them [2]. In 2010, Moreover, a number of prognostic factors have been iden- breast cancer was the most diagnosed cancer in the USA tified in human breast cancer [30]. (207,090 women) and showed the fourth highest death rate Humans and their pets share the same environment, and (39,840 women) [3]. For this reason, it is one of the most this suggests pets may be considered as an “environmental investigated diseases [1,4]. sentinel” [31], allowing for a much more timely evaluation of Breast cancer is a heterogeneous disease in which genetic carcinogenicity and exposure risk for countless agents [32]. and environmental factors interact to initiate carcinogenesis It is well known that the biological behaviour of some malig- [5]. Many of the breast cancer risk factors are well known: (1) nancies, including breast carcinoma, shares a similar biology age [6,7], (2) early menarche (<12 years); (3) late menopause in dogs and humans [33]. In fact, in both species the tumour (>55 years) [8,9]; (4) family history [6,10,11]; (5) genetic arises spontaneously over a number of years as a result of factors [12]; (6) obesity; (7) use of combined oestrogen and multiple genetic alterations, and is frequently characterized progestin hormones; (8) alcohol consumption; (9) repro- by microscopic metastases at the time of diagnosis [34]. In the ductive behaviour; (10) sedentary lifestyle; (11) radiation canine species, tumour incidence increases around 6 years of exposure; and (12) chronic accidental exposition to endocrine age and peaks in bitches aged 9–11 years [35]. In particular, disrupters [13–15]. Nevertheless, the aetiology of this disease about 50% of all tumours in bitches are mammary tumours remains unclear [16]. Moreover, since breast cancer is influ- [36,37], which clearly show a steroid hormone-dependent enced by hormonal status, its incidence increases with age development [38], as suggested by the protective effects of and doubles every 10 years until menopause [17]. Conversely, early spaying [39]. Some authors have reported that bitches it has been demonstrated that younger age at first full-term spayed before their first estrous cycle have an approximately pregnancy (<30 years), and multiple births rather than no 0.5% chance of developing breast neoplasia which, con- pregnancy, decrease the risk of breast cancer over the long versely, increases if spaying occurs after the first estrus [40]. term [8,18,19]. The protective role against tumour develop- On the other hand, ovariohysterectomy, performed at later ment provided by pregnancy on the mammary gland depends ages, does not seem to play a role in reducing the risk of devel- on the permanent changes to the gland structure determined oping malignant mammary tumours in the canine species by pregnancy itself [20,21]. Interestingly, some researchers [41]. Canine mammary neoplasms are commonly presented have suggested that the increased risk of breast cancer may be as circumscribed nodules with variable size, consistency and due to a decrease in melatonin levels which occurs as a result mobility to the skin and muscle [34]. of exposure to light at night. In fact, melatonin may affect As to the morfo-functional classification system of mam- oestrogen levels as well as acting as a tumour suppressor [22]. mary tumours, both human and animal malignancies are With regard to human breast cancer classification, this disease staged according to the Tumour Node Metastasis (TNM) sys- can be subclassified into preinvasive and invasive stages [23]. tem established by the World Health Organization (WHO). The preinvasive histological phases of common hyperplasia, This system assesses the size of the primary lesion (T), the atypical hyperplasia, and ductal carcinoma in situ (DCIS) extent of its spread to regional lymph nodes (N) and the usually precede neoplastic conversion to invasive cancer [24]. presence or absence of distant metastases (M) [42]. Another criterium of classification of breast cancer is based The grading system most widely used currently in human on gene expression profiles [25,26]. According to this classi- medicine to establish the histological grade of tumour differ- fication, the two major subtypes of ER-positive malignancies entiation is the Nottingham system modified by Elston and are luminal A and luminal B. These subtypes are biolog- Ellis [43]. This system is based on the evaluation of the tubule ically distinct in that luminal A tumours tend to have a formation index. higher expression of ER-related genes and a lower expres- In veterinary medicine this system is not frequently used sion of proliferative genes than luminal B [26,27]. Among [44]. The systems proposed by Gilbertson et al. [45] and the ER-negative tumours, the major subtypes are the human by Misdorp et al. [46] are two of the most popular criteria epidermal growth factor 2 (HER-2) array subtype, most of proposed for the identification of breast tumour type in G. Ranieri et al. / Critical Reviews in Oncology/Hematology 88 (2013) 293–308 295 veterinary medicine. Both are based on the combined evalua- Table 1 Principal classifications of mammary gland tumours in human and pet. tion of cellular and nuclear features as suggested by Misdorp et al. [46]. They classify breast tumours as: (1) non-neoplastic Breast cancer Pet mammary gland tumours epithelial lesions; (2) benign tumours; (3) malignant tumours. Histological Misdorp system • • Non-neoplastic epithelial lesions consist of epithelial Preinvasive Non-neoplastic epithelial - Common hyperplasia lesions hyperplasia, ductal hyperplasia (when these lesions arise - Atypical hyperplasia - Epithelial hyperplasia in the extralobular ducts), lobular hyperplasia (when these - Ductal carcinoma in situ (DCIS) - Ductal hyperplasia lesions arise in the intralobular ducts), adenosis, and colum- - Lobular hyperplasia
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