Prostate cancer in dogs: comparative and clinical aspects

The canine prostate gland shares many morphological and functional similarities with the human prostate and dogs are the only other large mammals that commonly develop spontaneous prostate cancer. However, the incidence of prostate cancer is much lower in dogs and the precise cell of origin is not known. Dogs with prostate cancer usually present with advanced disease that does not respond to androgen deprivation therapy. Similar to humans, affected dogs often develop osteoblastic bone metastases in the pelvis and/or lumbar spine with associated pain and neurological deficits. Other clinical signs include weight loss, lethargy, and abnormal urination and/or defecation. Surgery, chemotherapy, and radiation have been used to treat dogs with prostate cancer, but success has been limited by the location and aggressive nature of the disease. It is evident that better methods of early detection and more effective therapies are needed for prostate cancer in dogs and advanced prostate carcinoma in men. Dogs with naturally-occurring prostate cancer are relevant models for the disease in humans and pre-clinical studies of new diagnostics and therapies in dogs may benefit both humans and dogs with prostate cancer.     

Lung cancer risk in workers in the meat and poultry industries--a review

Laboratory and in vivo studies in primates, and serological evidence in humans, indicate that food animal oncogenic viruses show potential for causing cancer in humans. However, until fairly recently, supporting analytic epidemiologic studies have been lacking and have concentrated on lung cancer. We conducted an extensive Medline search and reviewed 60 studies investigating lung cancer risk in highly exposed workers in the meat and poultry industries. The overwhelming majority of studies of different designs (including all the cohort mortality and cancer incidence studies) indicate at least a 30% excess risk of lung cancer in meat and poultry plant workers, even after controlling for smoking. Evidence points to food animal oncogenic microorganisms as one of the main causes. This has important public health implications because the general population is also widely exposed. Studies carried out thus far have not had sufficient statistical power to investigate other potentially carcinogenic exposures within the industries. Thus, large studies that can adequately control for occupational and non-occupational confounding factors are needed, so that the possible role of food animal oncogenic viruses in the occurrence of human lung cancer can be clearly defined.     

富硒动物产品的研究进展

硒是人体和动物必需的微量元素,具有重要的生理功能。硒能预防心血管疾病、抗肿瘤、维持免疫系统功能。本文就硒的生理功能,富硒产品开发的必要性,有机硒对动物产品硒富集的影响以及开发富硒动物产品存在的问题进行简要综述。     

Identification of hepatic stem/progenitor cells in canine hepatocellular and cholangiocellular carcinoma

Hepatic progenitor cells (HPCs) are bipotential stem cells residing in human and animal livers that are able to differentiate towards the hepatocytic or cholangiocytic lineages. HPCs are present in both hepatocellular (HCC) and cholangiocellular carcinoma (CC) in humans; and a small percentage of HCC can originate from cancer stem cells. However, its distribution in canine liver tumour has not been studied. Herein, we searched for stem/progenitor cells in 13 HCC and 7 CC archived samples by immunohistochemical analysis. We found that both liver tumours presented a higher amount of K19‐positive HPCs. Besides, 61.6% of HCC cases presented immature CD44‐positive hepatocytes. Nevertheless, only two cases presented CD133‐positive cells. As observed in humans, hepatic canine tumours presented activated HPCs, with important differentiation onto hepatocytes‐like cells and minimal role of cancer stem cells on HCC. These findings reiterate the applicability of canine model in the search for new therapies before application in humans.     

上皮间质转化促乳腺癌机制及药物干预治疗研究进展

乳腺癌是犬、猫等伴侣动物与人类常发疾病,作为人类及动物常患恶性肿瘤和主要致死肿瘤之一,其疾病负担仍呈逐步加重趋势,乳腺癌的预防及治疗形势愈加严峻。上皮间质转化(EMT)是乳腺癌发生发展中重要的生物学过程。EMT还可促进恶性肿瘤的侵袭、扩散及耐药,因此它在肿瘤的研究中日益受到关注,靶向于EMT是治疗乳腺癌的重要研究方向与热点。文章就EMT发生过程中细胞形态功能及标志物的变化、EMT分类及EMT与乳腺癌的关系分别展开论述,详细解析了EMT相关TGF-β/Smad、NF-κB及Wnt信号通路转导途径;随后对乳腺癌治疗药物研究进展,包括TGF-β/Smad通路抑制剂开发,相关药物、基因及细胞因子治疗前景、NF-κB通路与Wnt通路抑制剂的动物试验研究结果进行了详细论述;最后对乳腺癌的治疗发展与趋势进行了展望。深入认识信号通路调控乳腺癌EMT的生物学过程,明确其发生发展机制,寻找关键靶点及开发靶向药物,将为乳腺癌的精准治疗带来曙光。     

上皮间质转化促乳腺癌机制及药物干预治疗研究进展

乳腺癌是犬、猫等伴侣动物与人类常发疾病，作为人类及动物常患恶性肿瘤和主要致死肿瘤之一，其疾病负担仍呈逐步加重趋势，乳腺癌的预防及治疗形势愈加严峻。上皮间质转化（EMT）是乳腺癌发生发展中重要的生物学过程。EMT还可促进恶性肿瘤的侵袭、扩散及耐药，因此它在肿瘤的研究中日益受到关注，靶向于EMT是治疗乳腺癌的重要研究方向与热点。文章就EMT发生过程中细胞形态功能及标志物的变化、EMT分类及EMT与乳腺癌的关系分别展开论述，详细解析了EMT相关TGF-β/Smad、NF-κB及Wnt信号通路转导途径；随后对乳腺癌治疗药物研究进展，包括TGF-β/Smad通路抑制剂开发，相关药物、基因及细胞因子治疗前景、NF-κB通路与Wnt通路抑制剂的动物试验研究结果进行了详细论述；最后对乳腺癌的治疗发展与趋势进行了展望。深入认识信号通路调控乳腺癌EMT的生物学过程，明确其发生发展机制，寻找关键靶点及开发靶向药物，将为乳腺癌的精准治疗带来曙光。     

Diet and cancer prevention in humans: review of the evidence and its application to companion animals

What is cancer? Cancer is disease of damaged DNA. DNA in every cell is under constant attack, from by‐products of normal metabolism as well as external factors such as radiation and carcinogens. Humans have evolved complex mechanisms to protect DNA from damage so that affected cells either repair their DNA or die. But under certain conditions, cells with damaged DNA can both survive and gain a growth advantage over surrounding cells. Over many years, these rapidly‐growing cells can accumulate additional DNA damage (called somatic mutations) and eventually, when the damage is quite severe, they can become cancers. There are three abnormal characteristics that cells must acquire to become cancers: (1) independence from normal controls on cell growth (proliferation) and death (apoptosis); (2) the ability to stimulate formation of blood vessels to provide nutrients to support rapid cell growth (angiogenesis); and (3) the ability to grow beyond their normal location first locally (invasion) and eventually in distant sites (metastasis). Although these characteristics are shared by all cancers, the clinical characteristics of cancer vary enormously. Some cancers, for example low‐grade prostate cancer, are very slow growing and take decades to become metastatic; other cancers, such as pancreas cancer, are highly invasive and uniformly and rapidly fatal. How could diet affect cancer? The two key components underlying the development of cancer are damage to DNA and rapid cell proliferation. Many mechanisms that protect DNA from damage are dependent upon dietary intake of antioxidants or are regulated by bioactive compounds found in foods. Cell growth is regulated by many factors, including steroid hormones and growth factors such as the insulin‐like growth factors. Cell growth is also influenced by inflammatory cytokines, which stimulate the replacement of cells damaged by inflammatory reactions. Dietary patterns and diet‐related factors such as obesity affect both the levels of circulating hormones and growth factors, and the levels of pro‐ and anti‐inflammatory cytokines. In laboratory experiments, based on cell cultures and animal models, we can consistently show that bioactive food compounds and dietary manipulation can affect DNA damage and cell growth, and that these effects mediate the development and/or growth of cancer cells. Thus, most scientists believe that diet has an important influence on the risk of developing cancer. What is the evidence that diet affects cancer risk? The strongest evidence that diet affects cancer risk in humans is from comparisons across countries. In these studies, there are strong associations between “food disappearance,” (total food production and imports minus food used as animal feed) and cancer incidence, for example between dietary fat and breast cancer. From these studies we have estimated that about 35% of all cancers are associated with diet. However, more analytically rigorous approaches to examining diet and cancer relationships, such as epidemiological studies and large randomized clinical trials, have not yielded consistent and clear answers. This has been very frustrating to scientists working in the field, and has challenged us to examine both our hypotheses about diet and cancer and the approaches we use to study diet and cancer. We now understand that cancer is a very complex disease which is affected strongly both by an individual's genetic characteristics and their life‐long environmental exposures. We have learned that the standard methods used to measure diet in large epidemiological studies are probably not sufficiently accurate to detect moderate diet/cancer associations. And we have learned that randomized clinical trials to test effects of dietary change or dietary supplements on cancer risk can fail to detect associations. Thus, the entire field is now in flux as the next generation of studies are being designed. What specific diet and diet‐related factors affect cancer risk? Currently, the best evidence that diet affects cancer risk is based on the well‐established associations of obesity with increased cancer incidence and mortality. Obesity increases the risk of cancer mortality by about 30‐50%, but this association is remarkably different across cancers. Obesity appears to have an effect both on the risk of developing cancer and on the risk of dying from cancer after diagnosis and treatment. Alcohol is a direct irritant which, in combination with smoking, causes oral and esophageal cancer. Alcohol also increases the risk of breast cancer by interfering with folate metabolism, and it increases the risk of liver cancer through the inflammatory response to cirrhosis. Other dietary factors for which we have strong evidence are fat, selenium, and vegetables, especially cruciferous vegetables. Studies examining antioxidant intake from either foods or supplements have been most often negative, suggesting that in humans the role of dietary antioxidants and cancer is much more complex than in animal models. Finally, there are a long list of foods and food components that have been picked up by the media and food manufacturers as ‘cancer prevention agents,’ most notably lycopene (tomatoes), resveratrol (red wine), and genistein (soy), however most of these have not stood up to scientific scrutiny. Does studies in humans obtain for domestic animals? The applicability of studies on cancer risk in humans to domestic, companion animals is uncertain. Some mechanisms linking diet and diet‐related factors with cancer, for example the associations of obesity with serum steroids and inflammatory cytokines, the importance of selenium for the antioxidant activity of selenoproteins, and the function of vitamin E as an antioxidant, are likely similar between humans and domestic animals. In contrast, the types, distributions and activity of xenobiotic enzymes differ across species; thus the dietary induction of enzyme activity, the prevalence and types of genetic polymorphisms, and the relative susceptibility to carcinogens will likely differ as well. Finally, requirements for nutrients differ across species, with the most obvious being the requirement of dietary vitamin C that is exclusive to humans and guinea pigs. The very limited research on diet and cancer in dogs suggests that obesity, especially when young, and exposure to table foods increase breast cancer risk, while the relationship of obesity with cancer overall are probably as complex as those seen in humans. Rigorous studies to understand the association of diet with cancer risk in domestic, companion animals will be difficult, primarily because the costs of this research are high.     

Association between Waste Management and Cancer in Companion Animals

Background: Increased cancer rates have been documented in people residing in areas around Naples characterized by illegal dumping and incineration of waste.
Hypothesis: Risk of cancer in dogs and cats is associated with waste management.
Animals: Four hundred and fifty-three dogs and cats with cancer and 1,554 cancer-free animals.
Methods: Hospital-based case-control study in Naples (low danger) and nearby cities having a history of illegal waste dumping (high danger). Odds ratio (OR) between high- and low-danger areas was calculated for all tumors and various malignancies in dogs and cats.
Results: An increased risk for cancer development was identified in dogs but not in cats residing in high-danger areas (OR: 1.55; 95% confidence interval: 1.18–2.03; P < .01). A 2.39-fold increased risk of lymphoma ( P < .01) accounted for the greater tumor frequency in dogs residing in high-danger areas. The risk of mast cell tumor and mammary cancer did not differ in dogs residing in high- or low-danger areas.
Conclusions and Clinical Importance: Waste emission from illegal dumping sites increases cancer risk in dogs residing in high-danger areas. An increased prevalence of lymphoma has been previously recognized in humans living close to illegal waste dumps. Thus, epidemiological studies of spontaneous tumors in dogs might suggest a role for environmental factors in canine and human carcinogenesis and can predict health hazards for humans.     

Telomeres and telomerase: Biological and clinical importance in dogs

In recent years in human oncology the enzyme telomerase has emerged as an ideal target for cancer therapy. This has led to the assessment of telomerase in cancers in companion animals, mainly dogs and these studies confirm that in dogs, like humans, telomere maintenance by telomerase is the primary mechanism by which cancer cells overcome their mortality and extend their lifespan. This review aims to provide an introduction to the biology of telomeres and telomerase and to discuss some of the telomere/telomerase directed therapeutic methodologies currently under development which may be of benefit to the canine cancer patient.     

Serum biomarker profiling in cancer studies: a question of standardisation?

Companion animals are exposed to similar environmental conditions and carcinogens as humans. In some animal cancers, there also appears to be the same genetic changes associated as in humans. However, little work has been carried out in cancer biomarker identification in animals. The recent dramatic advances in molecular medicine, genomics, proteomics and translational research will allow biomarker identification, which may provide the best strategies for veterinarians and clinicians to combat disease by early diagnosis and administration of effective treatments. Proteomics may have important applications in cancer diagnosis, prognosis and predictive clinical outcome that could directly change clinical practice by affecting critical elemen‐ts of care and management. This review summarizes the advances in proteomics that has propelled us to this exciting age of clinical proteomics, and highlights the future work that is required for this to become a reality. In this review, we will discuss the available proteomic technologies and their limitations, and highlight the key areas of research and how they have been used to discover cancer biomarkers. The principles described here are equally applicable to human and animal disease, but implementation of ‘omic’ technologies requires stringent guidelines for collection of clinical material, the application of analytical techniques and interpretation of the data.     

Production and characterization of monoclonal antibodies specific for canine CD138 (syndecan‐1) for nuclear medicine preclinical trials on spontaneous tumours

We isolated 11 antibodies specific for canine CD138 (cCD138) to validate the interest of CD138 antigen targeting in dogs with spontaneous mammary carcinoma. The affinity of the monoclonal antibodies in the nanomolar range is suitable for immunohistochemistry and nuclear medicine applications. Four distinct epitopes were recognized on cCD138 by this panel of antibodies. CD138 expression in canine healthy tissues is comparable to that reported in humans. CD138 is frequently expressed in canine mammary carcinomas corresponding to the human triple negative breast cancer subtype, with cytoplasmic and membranous expression. In canine diffuse large B‐cell lymphoma, CD138 expression is associated with the ‘non‐germinal center’ phenotype corresponding to the most aggressive subtype in humans. This homology of CD138 expression between dogs and humans confirms the relevance of tumour‐bearing dogs as spontaneous models for nuclear medicine applications, especially for the evaluation of new tumour targeting strategies for diagnosis by phenotypic imaging and radio‐immunotherapy.     

Microtomographic characterization of calcifications in canine mammary tumours

The present work describes the microtomographic characterization of macro‐ and microcalcifications present in excised canine mammary glands. In human breast cancer, microcalcifications are highly relevant for diagnosis and prognosis, often being the sole element determining biopsy. Canine mammary tumours are considered a model for human breast cancer, but the morphological features of calcifications had still to be studied in this species. The objective of this research is to contribute to the characterization of the mineralization features of the canine mammary gland. In the present study, the excised mammary glands of 33 bitches underwent fluoroscopic examination. In 30 of the samples, the presence of calcification was suspected, and multiple biopsies were taken of these areas. Biopsy fragments underwent microtomographic scanning. Microcalcifications were found in non‐neoplastic glandular tissue, benign and malign lesions, as it is known to happen in humans. Qualitative evaluation regarding morphology of the imaged calcifications showed similarities to breast cancer findings, based on the BI‐RADS 2013 classification, such as pleomorphism and shape. No differences in the quantitative morphological parameters of volume, surface, surface/volume, SMI and structure thickness were found when macrocalcifications were considered. However, although significant differences existed in these parameters between microcalcifications from malignant canine mammary tumours and the two other groups, none were found between non‐neoplastic and benign tumours. Findings further support the use of this spontaneous animal model for the study of human breast cancer, considering how clinically relevant microcalcifications are in humans.     

Inhibition of canine telomerase in vitro and in vivo using RNAi: further development of a natural canine model for telomerase-based cancer therapies

Despite advances in cancer therapy, cancer related morbidity and mortality among humans and companion animals remains high, and there is a clear need to develop novel targeted therapies. Expression of the enzyme telomerase has emerged as a central unifying mechanism underlying the immortal phenotype of canine cancer cells and has thus become a candidate for targeted molecular therapies. In this study, the value of telomerase inhibition to target telomerase expressing cancer cells was explored using the novel mechanism of RNA interference (RNAi). Using a Lentiviral expression construct, targeting the RNA component of canine telomerase was effective at inhibiting telomerase in vitro and tumour growth in vivo, but possible resistance mechanisms are highlighted. As canine telomerase biology is more closely related to human telomerase biology than the murine system, it is proposed that this study highlights the value of natural canine models to study anti-telomerase therapies for human patients.     

Conduct,Oversight, and Ethical Considerations of Clinical Trials in Companion Animals with Cancer: Report of a Workshop on Best Practice Recommendations

Development of effective and safe treatments for companion animals with cancer requires the collaboration of numerous animal health professionals and the full engagement of animal owners. Establishing ‘Best Practice Recommendations’ for clinical trials in veterinary oncology represents an important step toward meeting the goal of rigorous clinical trial design and conduct that is required to establish valid evidence. Likewise, optimizing patient welfare and owner education and advocacy is crucial to meet the unique ethical obligations to both owners and animals enrolled in these clinical trials and to ensure trust in the team conducting the research. To date, ‘Best Practice Recommendations’ for clinical trial conduct have not been reported for veterinary oncology. This document summarizes the consensus of a workshop held in November, 2014 to identify relevant ethical principles and to ensure responsible conduct of clinical research in companion animals with cancer. It is intended as a working document that will be updated as advances in science and ethical considerations require. To the extent possible, existing guidelines for the conduct and oversight of clinical trials in humans have been adapted for veterinary trials to avoid duplicative effort and to facilitate integration of clinical trials such that translational research with benefits for both companion animals and humans are encouraged.     

Evaluation of telomerase-targeted therapies in canine cancer cell lines

Despite advances in conventional therapeutics, cancer remains an invariably fatal disease, the major challenge being to develop tumour‐specific cancer treatment strategies. Current treatments such as chemotherapy and radiotherapy rely on a crude distinction between cancer cells and normal cells. However, with an increased understanding of the molecular events in the development of cancer, it is possible that far more innovative and targeted approaches can be developed. From studies on humans and dogs, the enzyme telomerase has emerged as a central unifying mechanism underlying the immortal phenotype of cancer and has thus become a candidate for differentiating between normal and cancer cells. The level and frequency of telomerase activity and component gene expression in cancers reinforces this as a potential target for cancer therapies. This article describes two approaches to target cancer by capitalizing on the expression of this enzyme. In the first approach, we target the enzyme itself, the goal being to cause cancer cell death. In the second approach, we utilize the respective gene promoters for telomerase component enzymes to drive expression of a reporter gene in cancer cell lines. The results demonstrated that targeted gene expression using promoter elements can be achieved specifically in telomerase‐positive cell lines. However, targeting the enzyme itself proved less successful and warrants investigations into alternative approaches.     

Chronic adrenergic stress and generation of myeloid-derived suppressor cells: Implications for cancer immunotherapy in dogs

Recent studies have highlighted a key role played by the sympathetic nervous system (SNS) and adrenergic stress in mediating immune suppression associated with chronic inflammation in cancer and other diseases. The connection between chronic SNS activation, adrenergic stress and immune suppression is linked in part to the ability of catecholamines to stimulate the bone marrow release and differentiation of myeloid-derived suppressor cells (MDSC). Rodent model studies have revealed an important role for β-adrenergic receptor signalling in suppression of cancer immunity in mice subjected to chronic stresses, including thermal stress. Importantly, therapeutic blockade of beta-adrenergic responses by drugs such as propranolol can partially reverse the generation and differentiation of MDSC, and partly restore tumour immunity. Clinical trials in both humans and dogs with cancer have demonstrated that propranolol blockade can improve responses to radiation therapy, cancer vaccines and immune checkpoint inhibitors. Thus, the SNS stress response has become an important new target to relieve immune suppression in cancer and other chronic inflammatory conditions.     

A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs

Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and Drug Administration (FDA) as Taxol^® for use in advanced ovarian cancer. Two years later, it was approved for the treatment of metastatic breast cancer. Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia in 1971. Taxanes are a family of microtubule inhibitors. As a member of this family, paclitaxel suppresses spindle microtubule dynamics. This activity results in the blockage of the metaphase‐anaphase transitions, and ultimately in the inhibition of mitosis, and induction of apoptosis in a wide spectrum of cancer cells. Additional anticancer activities of paclitaxel have been defined that are independent of these effects on the microtubules and may include the suppression of cell proliferation as well as antiangiogenic effects. Based on its targeting of a fundamental feature of the cancer phenotype, the mitotic complex, it is not surprising that paclitaxel has been found to be active in a wide variety of cancers in humans. This review summarizes the evidence in support of paclitaxel's broad anticancer activity and introduces the rationale for, and the progress in development of novel formulations of paclitaxel that may preferentially target cancers and that are not associated with the risks for hypersensitivity in dogs. Of note, a novel nanoparticle formulation of paclitaxel that substantially limits hypersensitivity was recently given conditional approval by the FDA Center for Veterinary Medicine for use in dogs with resectable and nonresectable squamous cell carcinoma and nonresectable stage III, IV and V mammary carcinoma.     

The Combination of Surgery and Radiation in the Treatment of Cancer A Review

Although radiation and surgery have been combined for the treatment of cancer in humans and animals since the 1920s, little has been written about the methods of combining radiation and surgery and the efficacy of this combination for the treatment of animal tumors. This article reviews the rationale for combining radiation and surgery for the treatment of cancer and the ways in which these two modalities can be combined with emphasis placed on the advantages and disadvantages of preoperative and postoperative radiotherapy. The role of preoperative and postoperative irradiation for the treatment of various animal tumors is discussed. Directions for future clinical trials are pointed out. Finally, the importance of surgeons and radiation oncologists communicating with each other and participating in cooperative treatment methods is stressed.     

Advances in the management of skin cancer

Skin cancer is one of the most commonly diagnosed cancers in the world today in both humans and our pet population. Advances in molecular techniques are now affording us an opportunity to develop therapeutics targeted at specific cancer‐related cellular pathways. However, despite progress in conventional treatments, such as chemotherapy and radiation, and the new targeted therapies, some cancers, such as melanoma and cutaneous lymphoma, continue to cause significant mortality and morbidity. This short synopsis is not complete but is aimed at providing an insight into current advanced treatments and horizon therapies for cutaneous malignancies in dogs and cats with comparative aspects.