Experimental prostate carcinogenesis - rodent models

A number of rodent models of prostate carcinoma development have been established to study mechanisms and modifying potential. All except for transgenic mouse models need long experimental periods for generation of a high yield of cancers. Spontaneous prostate tumor models, while not practical in terms of time and tumor incidences, allow the natural course of multistep neoplasia to be followed without a need for chemical exposure. Carcinogens, especially in combination with testosterone, can induce prostate carcinomas in rats, but none are prostate-specific, so that tumor development in other organs is a complicating factor. Induction of invasive prostate carcinomas in the rat frequently requires long-term administration of a pharmacological dose of testosterone with or without application of a chemical carcinogen. While there are several transgenic mouse models, each also has strong and weak points, and it is therefore necessary to select the best model for the purpose of any experimental study.     

Animal models for radiation injury, protection and therapy

Current events throughout the world underscore the growing threat of different forms of terrorism, including radiological or nuclear attack. Pharmaceutical products and other approaches are needed to protect the civilian population from radiation and to treat those with radiation-induced injuries. In the event of an attack, radiation exposures will be heterogeneous in terms of both dose and quality, depending on the type of device used and each victim's location relative to the radiation source. Therefore, methods are needed to protect against and treat a wide range of early and slowly developing radiation-induced injuries. Equally important is the development of rapid and accurate biodosimetry methods for estimating radiation doses to individuals and guiding clinical treatment decisions. Acute effects of high-dose radiation include hematopoietic cell loss, immune suppression, mucosal damage (gastrointestinal and oral), and potential injury to other sites such as the lung, kidney and central nervous system (CNS). Long-term effects, as a result of both high- and low-dose radiation, include dysfunction or fibrosis in a wide range of organs and tissues and cancer. The availability of appropriate types of animal models, as well as adequate numbers of animals, is likely to be a major bottleneck in the development of new or improved radioprotectors, mitigators and therapeutic agents to prevent or treat radiation injuries and of biodosimetry methods to measure radiation doses to individuals.     

Mechanistic models for radiation carcinogenesis and the atomic bomb survivor data

Recently, Heidenreich et al. (Radiat. Res., 158, 607-617, 2002) suggested that the Radiation Effects Research Foundation (RERF) A-bomb survivor cohort study is not large enough to discriminate between various possible carcinogenic mechanisms. At least with the current follow-up, this is true to some extent, but I think the specific issues are rather different than they suggest. In particular, I do not think it is true-as they further indicate-that various models fit the data about equally well while estimating very different patterns of excess risk, which would imply that these patterns cannot be reasonably well characterized. I will point to specific criticisms of their approach to the data and offer some more general comments on mechanistic modeling approaches. Although there are important distinctions, I suggest on a very optimistic note that the two major approaches may be converging, and soon the main differences may not be in the assumptions made but in the aims of the modeling.     

Molecular models in nickel carcinogenesis

Nickel compounds are known human carcinogens, but the exact molecular mechanisms of nickel carcinogenesis are not known. Due to their abundance, histones are likely targets for Ni(II) ions among nuclear macromolecules. This paper reviews our recent studies of peptide and protein models of Ni(II) binding to histones. The results allowed us to propose several mechanisms of Ni(II)-inflicted damage, including nucleobase oxidation and sequence-specific histone hydrolysis. Quantitative estimations of Ni(II) speciation, based on these studies, support the likelihood of Ni(II) binding to histones in vivo, and the protective role of high levels of glutathione. These calculations indicate the importance of histidine in the intracellular Ni(II) speciation.     

Predicting lichen hydration using biophysical models

Two models for predicting the hydration status of lichens were developed as a first step towards a mechanistic lichen productivity model. A biophysical model included the water potential of the air, derived from measurements of air temperature, relative humidity and species-specific rate constants for desiccation and rehydration. A reduced physical model, included only environmental parameters, assuming instantaneous equilibration between the lichen and the air. These models were developed using field and laboratory data for three green algal lichens: the foliose epiphytic Platismatia glauca (L.) W. Culb., the fruticose epiphytic Alectoria sarmentosa (Ach.) Ach. and the fruticose, terricolous and mat-forming Cladina rangiferina (L.) Weber ex Wigg. The models were compared and validated for the same three species using data from a habitat with a different microclimate. Both models predicted the length and timing of lichen hydration periods, with those for A. sarmentosa and P. glauca being highly accurate—nearly 100% of the total wet time was predicted by both the biophysical and physical models. These models also predicted an accurate timing of the total realized wet time for A. sarmentosa and P. glauca when the lichens were wet. The model accuracy was lower for C. rangiferina compared to the epiphytes, both for the total realized wet time and for the accuracy of the timing for the hydration period. These results demonstrate that the stochastic and continually varying hydration status of lichens can be simulated from biophysical data. Further development of these models to also include water-related activity, light and temperature conditions during the hydration events will then be a potent tool to assess potential lichen productivity in landscapes and habitats of various microclimatic conditions.     

Animal models in ocular toxocariasis

Ocular toxocariasis is a clearly defined disease. However, much remains to be learned concerning the migratory route, ocular changes, diagnosis and treatment. Studies in paratenic hosts have contributed to our understanding and will yield more information. Various experimental animals have been used, such as mice, rabbits, guinea pigs, primates, hamsters and gerbils. Of these, the last appear to be the most appropriate model due to their high susceptibility to ocular infection. Results obtained from different animal models are often not comparable due to the fact that dose and routes of inoculation are diverse. Early stages in the pathogenesis of ocular toxocariasis are manifested by haemorrhages in the anterior chamber and iris, replaced in time by accumulations of white cells. Ocular migration produces an early cell reaction, formed by an infiltration of neutrophils accompanied by vasculitis and retinal microinfarcts. Over a period of time, an increase of macrophages and the distribution of the infiltrates is observed. Later, granulomatous lesions are formed. These do not necessarily contain a larva and their appearance varies in different animal models. Local production of IgE and the presence of specific IgG have been described.     

Mouse models of K-ras-initiated carcinogenesis

Activating mutations of the oncogene K-ras are found in one third of all human cancers. Much of our knowledge on K-ras signal transduction and its influence on tumor initiation and progression comes from in vitro studies with cell lines. However, mouse models of human cancer allow a much more faithful recapitulation of the human disease, and the in vivo perspective is crucial for our understanding of neoplasia. In recent years, several new murine models for K-ras-induced tumorigenesis have been described. They allow new insights into the specific role that oncogenic K-ras proteins play in different solid tumors, and they permit the molecular dissection of the pathways that are initiated by somatic mutations in subsets of cells. Key advances have been made by the use of tissue-specific and inducible control of expression, which is achieved by the Cre/LoxP technology or the tetracycline system. from these sophisticated models, a common picture emerges: The effects of K-ras on tumor initiation depend strongly on the cellular context, and different tissues vary in their susceptibility to K-ras transformation.     

Mouse models of prostate carcinogenesis

In recent years, numerous mouse models have been generated that recapitulate salient features of prostate carcinogenesis in humans. Here we review progress in the generation and validation of mouse models for prostate cancer, discuss current limitations of these models, and highlight directions of future research.     

Animal models relevant to human prostate carcinogenesis underlining the critical implication of prostatic stem/progenitor cells

Recent development of animal models relevant to human prostate cancer (PC) etiopathogenesis has provided important information on the specific functions provided by key gene products altered during disease initiation and progression to locally invasive, metastatic and hormone-refractory stages. Especially, the characterization of transgenic mouse models has indicated that the inactivation of distinct tumor suppressor proteins such as phosphatase tensin homolog deleted on chromosome 10 (PTEN), Nkx3.1, p27(KIP1), p53 and retinoblastoma (pRb) may cooperate for the malignant transformation of prostatic stem/progenitor cells into PC stem/progenitor cells and tumor development and metastases. Moreover, the sustained activation of diverse oncogenic signaling elements, including epidermal growth factor receptor (EGFR), sonic hedgehog, Wnt/β-catenin, c-Myc, Akt and nuclear factor-kappaB (NF-κB) also may contribute to the acquisition of more aggressive and hormone-refractory phenotypes by PC stem/progenitor cells and their progenies during disease progression. Importantly, it has also been shown that an enrichment of PC stem/progenitor cells expressing stem cell-like markers may occur after androgen deprivation therapy and docetaxel treatment in the transgenic mouse models of PC suggesting the critical implication of these immature PC cells in treatment resistance, tumor re-growth and disease recurrence. Of clinical interest, the molecular targeting of distinct gene products altered in PC cells by using different dietary compounds has also been shown to counteract PC initiation and progression in animal models supporting their potential use as chemopreventive or chemotherapeutic agents for eradicating the total tumor cell mass, improving current anti-hormonal and chemotherapies and preventing disease relapse.     

Realization of biophysical models of cardiac electrical activity

Considered are the principles of realization of biophysical models of heart ventricle electrical activity in the form of a double electric layer on the surface of the electrically active myocardium (epicardium and endocardium) and the boundary surfaces dividing the model compartments with different electrophysiological characteristics. The model parameters are the electrophysiological and anatomical characteristics of the heart such as the geometry of the ventricles and the specialized His-Purkinje conduction system, the velocity of depolarization spread over myocardium, the ratio of the velocities of excitation transmission through the Myocardium / His / Purkinje elements of the model, the shape of transmembrane action potentials on the boundary surfaces, the orientation of the intrinsic anatomical axes of the heart relative to the initial set of coordinates, and some other biophysical characteristics of the myocardium. This model is the main unit of a computer simulation system, which includes databases of real and simulated electrocardiosignals.     

Animal models of fibromyalgia

Animal models of disease states are valuable tools for developing new treatments and investigating underlying mechanisms. They should mimic the symptoms and pathology of the disease and importantly be predictive of effective treatments. Fibromyalgia is characterized by chronic widespread pain with associated co-morbid symptoms that include fatigue, depression, anxiety and sleep dysfunction. In this review, we present different animal models that mimic the signs and symptoms of fibromyalgia. These models are induced by a wide variety of methods that include repeated muscle insults, depletion of biogenic amines, and stress. All potential models produce widespread and long-lasting hyperalgesia without overt peripheral tissue damage and thus mimic the clinical presentation of fibromyalgia. We describe the methods for induction of the model, pathophysiological mechanisms for each model, and treatment profiles.     

Animal models of cholangiocarcinoma

Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with a poor overall prognosis. There is a critical need to develop effective targeted therapies for the treatment of this lethal disease. In an effort to address this challenge, preclinical in vivo studies have become paramount in understanding CCA carcinogenesis, progression, and therapy. Various CCA animal models exist including carcinogen-based models in which animals develop CCA after exposure to a carcinogen, genetically engineered mouse models in which genetic changes are induced in mice leading to CCA, murine syngeneic orthotopic models, as well as xenograft tumors derived from xenotransplantation of CCA cells, organoids, and patient-derived tissue. Each type has distinct advantages as well as shortcomings. In the ideal animal model of CCA, the tumor arises from the biliary tract in an immunocompetent host with a species-matched tumor microenvironment. Such a model would also be time-efficient, recapitulate the genetic and histopathological features of human CCA, and predict therapeutic response in humans. Recently developed biliary tract transduction and orthotopic syngeneic transplant mouse models encompass several of these elements. Herein, we review the different animal models of CCA, their advantages and deficiencies, as well as features which mimic human CCA.     

Animal models of osteoarthritis

Animal models have proved to be of considerable importance in elucidating mechanisms underlying joint damage in osteoarthritis (OA) and providing proof of concept in the development of pharmacologic and biologic agents that may modify structural damage in the OA joint. The utility of animal models in predicting the response to an intervention with a drug or biologic agent in humans, however, can be established only after evidence is obtained of a positive effect of the agent in humans. To date, no agent has been shown unequivocally to have such an effect, although diacerhein and glucosamine have recently been reported to lower the rate of loss of articular cartilage in patients with hip OA and knee OA, respectively, based on measurements of the rate of joint space narrowing in plain radiographs. Furthermore, the predominant manifestation of OA - and the feature that leads people with radiographic changes of the disease to decide to seek medical attention and contributes to the enormous medicoeconomic and socioeconomic burden imposed by the disease - is joint pain. Notably, none of the animal models of OA is a good indicator of the analgesic effects of pharmacologic agents. Indeed, it should not be assumed a priori that reduction in the rate of progression of joint damage in OA will be associated with a reduction in joint pain.     

Animal models of pheochromocytoma

Pheochromocytomas are neuroendocrine tumors of adrenal chromaffin cells. They are rare in all species except rats but occur with increased frequency in several human familial tumor syndromes. Concurrence of pheochromocytoma with other tumors sometimes parallels these human syndromes in rats, bovines, horses and dogs but a shared genetic basis for human and spontaneously occurring animal pheochromocytomas has thus far not been established. Pheochromocytomas are inducible in rats by a variety of non-genotoxic substances that may act indirectly by stimulating chromaffin cell proliferation. They are not known to be similarly inducible in other species but arise with increased frequency in transgenic and knockout mice that to varying degrees recapitulate human tumor syndromes. Preliminary evidence suggests that homologous somatic genetic changes might contribute to pheochromocytoma development in humans and some mouse models. The nerve growth factor-responsive PC12 cell line, established from a rat pheochromocytoma, has for almost 30 years served as a research tool for many aspects of neurobiology involving normal and neoplastic conditions. Recently developed pheochromocytoma cell lines from neurofibromatosis knockout mice supplement the PC12 line and have generated additional applications. Advantages of the mouse lines include expression of substantial levels of the epinephrine-synthesizing enzyme, phenylethanolamine N-methyltransferase and expression of high levels of the receptor tyrosine kinase, Ret, which is characteristic of sporadic and familial human pheochromocytomas but not of PC12 cells. Disadvantages include an apparently less stable phenotype. It is difficult to establish pheochromocytoma cell lines from any species, although the tumor cells persist in culture for many months. Understanding of factors that permit pheochromocytoma cells to proliferate might itself provide important insights for tumor biology.