A naturally occurring cancer with molecular connectivity to human diseases

As Jessani et al. 1 point out development of cell and animal models that accurately depict human tumorigenesis remains a major goal of cancer research. Clam cancer offers significant advantages over traditional models for genotoxic and non-genotoxic preclinical analysis of treatments for human cancers with a similar molecular basis. The naturally occurring clam model closely resembles an out-breeding, human clinical population and provides both in vitro and in vivo alternatives to those generated from inbred mouse strains or by intentional exposure to known tumor viruses. Fly and worm in vivo models for adult human somatic cell cancers do not exist because their adult somatic cells do not divide. Clam cancer is the best characterized, naturally occurring malignancy with a known molecular basis remarkably similar to those observed in several unrelated human cancers where both genotoxic and non-genotoxic strategies can restore the function of wild-type p53. To further emphasize this point of view, we here demonstrate a p53-induced, mitochondrial-directed mechanism for promoting apoptosis in the clam cancer model that is similar to one recently identified in mammals. Discerning the molecular basis for naturally occurring diseases in non-traditional models and correlating these with related molecular mechanisms responsible for human diseases is a virtually unexplored aspect of toxico-proteomics and genomics and related drug discovery.     

Expression of cyclooxygenase-1 and 2 in naturally-occurring canine cancer

The purpose of this work was to determine cox-1 and cox-2 expression by immunohistochemistry in forms of naturally occurring canine cancer in order to identify animal systems for pre-clinical evaluation of cox inhibitors and cox-2 inhibitors in cancer. Canine lymphoma (LSA), prostatic carcinoma (PCA), osteosarcoma (OSA), oral melanoma (MEL), oral squamous cell carcinoma (SCC), oral fibrosarcoma (FSA), mammary carcinoma (MCA), and normal tissues were included. Cox-2 was expressed in epithelial tumors (17 of 26 SCC, 8 of 13 MCA, 5 of 9 PCA cases) and MEL (9 of 15 cases), but was generally absent in normal tissues. Cox-2 expression was minimal or absent in mesenchymal tumors and LSA. Cox-1 was expressed in normal epithelial tissues and in some osteoclast and osteoblast in bone, but was absent in normal lymph node. In conclusion, forms of canine cancer were identified for in vivo studies of the effects of cox inhibitors and selective cox-2 inhibitors on cancer.     

Targeting radioresistant osteosarcoma cells with parthenolide

Osteosarcoma is a devastating tumor of bone, primarily affecting adolescents. Osteosarcoma tumors are notoriously radioresistant. Radioresistant cancers, including osteosarcoma, typically exhibit a considerable potential for relapse and development of metastases following treatment. Relapse and metastatic potential can, in part, be due to a specific radioresistant subpopulation of cells with stem-like characteristics, cancer stem cells, which maintain the capacity to regenerate entire tumors. In the current study, we have investigated whether in vitro treatments with parthenolide, a naturally occurring small molecule that interferes with NF-κB signaling and has various other effects, will re-sensitize cancer stem cells and the entire cell population to radiotherapy in osteosarcoma. Our results indicate that parthenolide and ionizing radiation synergistically induce cell death in LM7 osteosarcoma cells. Importantly, the combination treatment results in a significant reduction in the viability of both the overall population of osteosarcoma cells and the cancer stem cell subpopulation. This effect is dependent on the ability of parthenolide to induce oxidative stress. Therefore, as a supplement to current multimodal therapy, parthenolide may sensitize osteosarcoma tumors to radiation and greatly reduce the prevalence of relapse and metastatic progression.     

人乳腺癌干细胞异种移植动物模型的制备和应用

越来越多的证据显示乳腺癌干细胞是导致乳腺癌发生、发展、复发和转移的根源。因此,模拟出与人乳腺癌发病机制相似的动物模型将对乳腺癌的治疗起着至关重要的作用。本文旨在介绍乳腺癌干细胞异种移植动物模型的制备方法、应用以及近年来的研究进展。     

Anti-Oxidants from Green Tea and Pomegranate for Chemoprevention of Prostate Cancer

Among males, prostate cancer has become the second leading cause of cancer-related deaths in North America, with similar trends in many Western and developing countries. One way to control prostate cancer is through chemoprevention, which refers to the administration of synthetic or naturally occurring agents to block, reverse, or delay the process of carcinogenesis. For a variety of reasons, the most important of which is human acceptance, for chemopreventive intervention, naturally occurring diet-based agents are preferred. Prostate cancer is an ideal candidate disease for chemopreventive intervention, because it grows very slowly, likely for decades, before symptoms arise and a diagnosis is finally established, it has a long latency period, and it is typically diagnosed in men >50 years of age. Most chemopreventive agents are antioxidant in nature. We have been defining the usefulness of dietary anti-oxidants for chemoprevention of prostate and other cancers. It is increasingly appreciated that some of these dietary anti-oxidants are nature’s gift molecules endowed with cancer preventive and therapeutic properties. This review will focus on prostate cancer chemopreventive effects of polyphenolic anti-oxidants derived from green tea and pomegranate. It is a challenge to custom-tailor these gift molecules as cocktails in concentrations that can easily be consumed by humans for delaying prostate and other cancers.     

Tocopherol Transfer Protein Sensitizes Prostate Cancer Cells to Vitamin E

Prostate cancer is a major cause of mortality in men in developed countries. It has been reported that the naturally occurring antioxidant α-tocopherol (vitamin E) attenuates prostate cancer cell proliferation in cultured cells and mouse models. We hypothesized that overexpression of the tocopherol transfer protein (TTP), a vitamin E-binding protein that regulates tocopherol status, will sensitize prostate cancer cells to the anti-proliferative actions of the vitamin. To test this notion, we manipulated the expression levels of TTP in cultured prostate cells (LNCaP, PC3, DU145, and RWPE-1) using overexpression and knockdown approaches. Treatment of cells with tocopherol caused a time- and dose-dependent inhibition of cell proliferation. Overexpression of TTP dramatically sensitized the cells to the apoptotic effects of α-tocopherol, whereas reduction (“knockdown”) of TTP expression resulted in resistance to the vitamin. TTP levels also augmented the inhibitory effects of vitamin E on proliferation in semi-solid medium. The sensitizing effects of TTP were paralleled by changes in the intracellular accumulation of a fluorescent analog of vitamin E and by a reduction in intracellular levels of reactive oxygen species and were not observed when a naturally occurring, ligand binding-defective mutant of TTP was used. We conclude that TTP sensitizes prostate cancer cells to the anti-proliferative effects of vitamin E and that this activity stems from the ability of protein to increase the intracellular accumulation of the antioxidant. These observations support the notion that individual changes in the expression level or activity of TTP may determine the responsiveness of prostate cancer patients to intervention strategies that utilize vitamin E.     

Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models

The dystrophin-glycoprotein complex (DGC) is a multisubunit complex that connects the cytoskeleton of a muscle fiber to its surrounding extracellular matrix. Mutations in the DGC disrupt the complex and lead to muscular dystrophy. There are a few naturally occurring animal models of DGC-associated muscular dystrophy (e.g. the dystrophin-deficient mdx mouse, dystrophic golden retriever dog, HFMD cat and the delta-sarcoglycan-deficient BIO 14.6 cardiomyopathic hamster) that share common genetic protein abnormalities similar to those of the human disease. However, the naturally occurring animal models only partially resemble human disease. In addition, no naturally occurring mouse models associated with loss of other DGC components are available. This has encouraged the generation of genetically engineered mouse models for DGC-linked muscular dystrophy. Not only have analyses of these mice led to a significant improvement in our understanding of the pathogenetic mechanisms for the development of muscular dystrophy, but they will also be immensely valuable tools for the development of novel therapeutic approaches for these incapacitating diseases.     

Modeling opportunities in comparative oncology for drug development

Successful development of novel cancer drugs depends on well-reasoned scientific drug discovery, rigorous preclinical development, and carefully conceived clinical trials. Failure in any of these steps contributes to poor rates of approval for new drugs to treat cancer. As technological and scientific advances have opened the door to a variety of novel approaches to cancer drug discovery and development, preclinical models that can answer questions about the activity and safety of novel therapies are increasingly necessary. The advance of a drug to clinical trials based on information from preclinical models presupposes that the models convey informative data for future use in human patients with cancer. The study of novel cancer drugs using in vitro models is highly controllable, reproducible, relatively inexpensive, and linked to high throughput. However, these models fail to reproduce many of the complex features of human cancer. Mouse models address some of these limitations but have important biological differences from human cancer. The integration of studies using pet dogs with spontaneously occurring tumors as models in the development path can answer questions not adequately addressed in conventional models and is therefore gaining attention and interest in drug development communities. The study of novel cancer drugs in dogs with naturally occurring tumors allows drug assessment in a cancer that shares many fundamental features with the human cancer condition, and thus provides an opportunity to answer questions that inform the cancer drug development path in ways not possible in more conventional models.     

Curcumin inhibits proliferation and invasion of osteosarcoma cells through inactivation of Notch-1 signaling

The Notch signaling pathway plays critical roles in human cancers, including osteosarcoma, suggesting that the discovery of specific agents targeting Notch would be extremely valuable for osteosarcoma. Curcumin, a naturally occurring phenolic compound found in curcuma longa, has been shown to inhibit proliferation and induce apoptosis of osteosarcoma cells in vitro and tumor growth in xenotransplant or orthotransplant models. However, the precise molecular mechanisms by which curcumin exerts its antitumor activity remain unclear. Here we used multiple molecular approaches, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the invasion assay, gene transfection, real-time RT-PCR, western blot and gelatin zymography, to investigate whether the downregulation of Notch-1 contributes to curcumin-induced inhibition of proliferation and invasion in osteosarcoma cells. The results showed that curcumin caused marked inhibition of osteosarcoma cell growth and G2/M phase cell cycle arrest. This was associated with concomitant attenuation of Notch-1 and downregulation of its downstream genes, such as matrix metalloproteinases, resulting in the inhibition of osteosarcoma cell invasion through Matrigel. We also found that specific downregulation of Notch-1 via small-interfering RNA prior to curcumin treatment resulted in enhanced inhibition of cell growth and invasion. These results suggest that antitumor activity of curcumin is mediated through a novel mechanism involving inactivation of the Notch-1 signaling pathway. Our data provide the first evidence that the downregulation of Notch-1 by curcumin may be an effective approach for the treatment of osteosarcoma.     

Global Gene Expression Analysis of Canine Osteosarcoma Stem Cells Reveals a Novel Role for COX-2 in Tumour Initiation

Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation.     

转基因肺癌动物模型研究进展

肺癌是世界各国常见的恶性肿瘤,肺癌动物模型在人类肺癌病因、诊断、治疗等方面发挥重要的作用。其中转基因肺癌模型能够更好的模拟肺癌,更有利于肺癌病因及发病过程的研究。本文介绍了近年来转基因肺癌模型的研究进展。     

Genetically Engineered Human Cancer Models Utilizing Mammalian Transgene Expression

Cancer models are vital to cancer biology research, and multiple cancer models are currently available that utilize either murine or human cells, each with particular strengths and weaknesses. The ability to transform primary human cells into tumors through the expression of specific transgenes offers many advantages as a cancer model, including genetic malleability and the ability to transform specific cell types. Until recently, the conversion of primary human cells into tumors through transgene expression required the use of viral genetic elements, which unfortunately adds uncertainty regarding which cancer pathways are affected and how they are affected. In recent years multiple reports have described the transformation of primary human cells into tumors using only mammalian transgenes. This review focuses on these five cancer models, comparing the different cell types which were transformed into tumors and which transgenes were expressed, as well as the cancer pathways affected in the disparate models. These genetically-engineered human cancer models offer a valuable tool to complement existing cancer models and further cancer research.     

Effects of luteolin on canine osteosarcoma: Suppression of cell proliferation and synergy with cisplatin

Canine osteosarcoma is characterized by aggressiveness, easy metastasis to the lungs, and high mortality after standard therapy. Luteolin is a flavonoid found in vegetables and fruits and has diverse functions. Elucidation of the biological mechanisms of luteolin on canine osteosarcoma will enhance the efficacy of chemotherapeutic agents in canine tumors. In this study, we examined the effects of luteolin in the canine osteosarcoma cell lines, D17 and DSN. The results of this study show that luteolin inhibited canine osteosarcoma cell proliferation and induced apoptosis by altering cell-cycle proportion, producing reactive oxygen species, increasing the loss of mitochondrial membrane potential, and reducing cytosolic Ca²⁺ concentration. In addition, luteolin activated ERK1/2 and inactivated phosphoinositide 3-kinase/AKT signaling in canine osteosarcoma cells. Moreover, luteolin showed synergistic effects with cisplatin to reduce cell proliferation. In summary, luteolin induced cell death by initiating mitochondrial dysfunction and regulating intracellular signal transduction in canine osteosarcoma cells.     

Cancer resistance in amphibians

While spontaneous tumours may occasionally develop in inbred and isogenic strains of Xenopus laevis, the South African clawed toad, they are extremely rare in natural and laboratory populations. Only two amphibian neoplasms, the renal adenocarcinoma of Rana pipiens and the lymphosarcoma of Xenopus laevis, have been extensively explored. Amphibians are resistant to the development of neoplasia, even following exposure to "direct-acting" chemical carcinogens such as N-methyl-N-nitrosourea, that are highly lymphotoxic, thus diminishing immune reactivity. Regenerative capacity in adults, and a dramatic metamorphosis which remodels much of the larval body to produce the adult form, are unique to amphibian vertebrates, and the control mechanisms involved may protect against cancer. For example, naturally rising corticosteroid titres during metamorphosis will impair some T-cell functions, and the removal of T-regulatory (suppressor) functions inhibits the induction of altered-self tolerance. Altered-self tolerance is not as effectively induced in adult Xenopus laevis as in mammals, so cancer cells with new antigenicity are more likely be rejected in amphibians. Amphibian immunocytes tend to undergo apoptosis readily in vitro, and, unlike mammalian immunocytes, undergo apoptosis without entering the cell cycle. Cells not in the cell cycle that die from nuclear damage (apoptosis), will have no opportunity to express genetic instability leading to cell transformation. We suggest that all these factors, rather than any one of them, may reduce susceptibility to cancer in amphibians.     

Prevention of prostate cancer through custom tailoring of chemopreventive regimen

One practical way to control cancer is through chemoprevention, which refers to the administration of synthetic or naturally occurring agents to block, reverse or delay the process of carcinogenesis. For a variety of reasons, the most important of which is human acceptance, for chemopreventive intervention naturally occurring diet-based agents are preferred over synthetic agents. For a long time, the prevailing mantra of cancer chemoprevention has been: "Find effective agents with acceptable or no toxicity and use them in preventing cancer in relatively healthy people or individuals at high risk for developing cancer". In pursuing this goal many naturally occurring phytochemicals capable of affording protection against carcinogenesis in preclinical settings in experimental animals have been described. However, clinical trials of single agents have yielded disappointing results. Since carcinogenesis is a multistage phenomenon in which many normal cellular pathways become aberrant, it is unlikely that one agent could prove effective in preventing cancer. This review underscores the need to build an armamentarium of naturally occurring chemopreventive substances that could prevent or slow down the development and progression of prostate cancer. Thus, the new effective approach for cancer prevention "building a customized mechanism-based chemoprevention cocktail of naturally occurring substances" is advocated.     

Computed Tomography Imaging of Solid Tumors Using a Liposomal-Iodine Contrast Agent in Companion Dogs with Naturally Occurring Cancer

Objectives

Companion dogs with naturally occurring cancer serve as an important large animal model in translational research because they share strong similarities with human cancers. In this study, we investigated a long circulating liposomal-iodine contrast agent (Liposomal-I) for computed tomography (CT) imaging of solid tumors in companion dogs with naturally occurring cancer.

Materials and Methods

The institutional animal ethics committees approved the study and written informed consent was obtained from all owners. Thirteen dogs (mean age 10.1 years) with a variety of masses including primary and metastatic liver tumors, sarcomas, mammary carcinoma and lung tumors, were enrolled in the study. CT imaging was performed pre-contrast and at 15 minutes and 24 hours after intravenous administration of Liposomal-I (275 mg/kg iodine dose). Conventional contrast-enhanced CT imaging was performed in a subset of dogs, 90 minutes prior to administration of Liposomal-I. Histologic or cytologic diagnosis was obtained for each dog prior to admission into the study.

Results

Liposomal-I resulted in significant (p < 0.05) enhancement and uniform opacification of the vascular compartment. Non-renal, reticulo-endothelial systemic clearance of the contrast agent was demonstrated. Liposomal-I enabled visualization of primary and metastatic liver tumors. Sub-cm sized liver lesions grossly appeared as hypo-enhanced compared to the surrounding normal parenchyma with improved lesion conspicuity in the post-24 hour scan. Large liver tumors (> 1 cm) demonstrated a heterogeneous pattern of intra-tumoral signal with visibly higher signal enhancement at the post-24 hour time point. Extra-hepatic, extra-splenic tumors, including histiocytic sarcoma, anaplastic sarcoma, mammary carcinoma and lung tumors, were visualized with a heterogeneous enhancement pattern in the post-24 hour scan.

Conclusions

The long circulating liposomal-iodine contrast agent enabled prolonged visualization of small and large tumors in companion dogs with naturally occurring cancer. The study warrants future work to assess the sensitivity and specificity of the Liposomal-I agent in various types of naturally occurring canine tumors.     

Neural tube defects: a review of human and animal studies on the etiology of neural tube defects

Although neural tube defects are a common congenital anomaly, their etiology is not known. Human studies have emphasized the pathology and epidemiology of the defects and suggest that in the majority of cases the etiology is multifactorial. Factors which appear possibly to be important are genetic predisposition, maternal illness, and fetal drug exposure. Animal studies have utilized naturally occurring neural tube defects and teratologically induced lesions. No animal model has been convincingly established as the equivalent of human neural tube defects. However, animal models have allowed investigation of the mechanisms of suggested human teratogens and determination of the pathogenesis of naturally occurring animal defects. Their most important contribution has been in furthering the understanding of the normal mechanisms of neural tube closure. It may be through this understanding that the etiology of human neural tube defects will be determined.     

Species differences in tumour responses to cancer chemotherapy

Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies.     

Heat shock proteins in animal neoplasms and human tumours—a comparison

Heat shock proteins (HSPs) are implicated in all phases of cancer from proliferation, impaired apoptosis and sustained angiogenesis to invasion and metastasis. The presence of abnormal HSP levels in several human tumours suggests that these proteins could be used as diagnostic and/or prognostic markers, whilst the direct correlation between HSP expression and drug resistance in neoplastic tissues means they could also be used to predict cancer response to specific treatment. HSPs have also been successfully targeted in clinical trials modifying their expression or chaperone activity. Preliminary studies in veterinary medicine have also demonstrated the presence of altered HSP expression in neoplasms, and the study of carcinogenesis and the role of HSPs in animal models will surely be an additional source of information for clinical cancer research.     

Comparison of Serum and Tissue Levels of Trace Elements in Different Models of Cervical Cancer

Cervical cancer is a leading cause of death by cancer among women worldwide. It is necessary to develop and refine cervical cancer models to more accurately reflect human tumor type. The relevance of cervical cancer to trace element was studied in this paper. By means of quantitative trace element analysis in models and patients with cervical cancer, the tissue and serum levels of trace elements in papillomaviruses-induced cancer models were more similar to that of patients than the levels in models induced by HeLa cell and methylcholanthrene. The results reflect papillomaviruses model most accurately mimic in vivo carcinogenesis of patients with cervical cancer. It will have a superior predictive value over HeLa cell and methylcholanthrene models in pre-clinical trials. The papillomaviruses-induced cervical cancer can provide more reliable models for testing the efficacy of drugs in treating human cancers.