Review articleModelling human prostate cancer: Rat models
Graphical abstract
Introduction
Prostate cancer is the second most common cancer in men, affecting approximately 1.1 million men worldwide. In the year 2012, prostate cancer was responsible for 307, 000 deaths, being considered the fifth leading cause of death from cancer in men [1].
Although the causes of prostate cancer are not fully understood, many risk factors have been considered for the development of this type of cancer, such as age, race, family history, diet, intrauterine conditions, hormone exposure, particularly to androgens and estrogens, and inflammation [[2], [3], [4], [5]]. Since the prostate gland is an androgen-dependent tissue and consequently the prostate cancer is also androgen-dependent [2,3], the important role of androgenic hormones for prostate cancer development is well recognized [4].
Animal models have been used to study several diseases, like cancer, cerebral palsy, diabetes, Alzheimer, obesity and cardiac disease. The animal models may contribute invaluable information to better understand many aspects involved in disease development, and for the discovery and development of new pharmacological and non-pharmacological therapies (lifestyle) and preventive strategies, which may then be tested in clinical trials.
The animal models may be spontaneous, chemically-induced, transgenic/mutant animals with modifications in targeted genes, or implanted models (syngeneic or xenograft) [[6], [7], [8], [9]]. An ideal animal model of human disease should be simple, not expensive and mimics the Human disease as much as possible. The rodents are commonly used in experimental research as cancer models, because they are relatively easy and cheap to maintain, their physiology and genetics are well known, they are mammals like Humans and the tumor's development is fast (all steps of carcinogenesis - initiation, promotion, progression and metastasis - may be observed) [7,9]. Despite all these advantages, the use of rodent models have some disadvantages, like the anatomic differences with humans (e.g. lobulated prostate in rodents vs. non-lobulated prostate in men), the xenograft cancer models have compromised immune systems and do not represent the behavior of naturally occurring cancer in humans, and the researchers are unable to control the level and pattern of gene expression in genetic-engineered models [10].
This review focused on rat prostate cancer models that have been established over the years for prostate cancer study, highlighting their advantages and disadvantages, as well as, their applications. We also describe the works performed in these prostate cancer models for the evaluation of several drugs and natural compounds.
Section snippets
Rat prostate: Anatomy and histology
Prostate is an accessory gland typically associated with the male reproductive tract. However, it is not exclusive of males, being also present in Mongolian gerbil female [11,12]. Prostate is found below the bladder in front of the rectum. Despite analogies found in prostate morphogenesis in different species, the variability of its anatomy among mammals is remarkable. While the prostate is a compact solitary structure in men and dogs, the prostate of rats and mice consists of distinct lobes.
Rat as a model of prostate carcinogenesis
Despite many research projects in the field of prostate cancer are carried out using cells lines (in vitro studies), which allow the understanding of biological aspects related to the development of this disease, they fail to mimic the complex cellular interaction that occurs in tumor microenvironment. To overcome this limitation, researchers employed their efforts for several years on the development of animal models to study this disease.
In 1937, Moore and Melchionna were the first ones to
Rat models of prostate carcinogenesis
Several animal models are available for the study of prostate cancer: spontaneous tumors, chemically or hormonally-induced, implantation of cancer cells and genetically engineered animals [2,36].
Follow-up of animal models - prostate imaging
Although the prostate cancer remains the fifth cause of death by cancer among men, the mortality associated with this type cancer has decreased in the past decades, mainly due to the widespread use of screening strategies. Despite the only definitive way to confirm prostate cancer is through a prostate biopsy (frequently ultrasound guided biopsy) [87], screening for this kind of cancer includes digital rectal examination (DRE) focused on prostate size and consistency, or more typically, a
Sample collection and histological evaluation
A standardized protocol to collect prostate tumors was not yet established. Some researchers remove accessory sex glands together with urinary bladder and separate the different prostate lobes from urinary bladder after fixation in formalin [23,67,96]. Other researchers remove the accessory sex glands, fix them in formalin and cut them into slices (where include urethra and seminal vesicles) to paraffin inclusion [31,35,66,97,98]. Bosland suggests that the accessory sex glands are best removed
Spectrum of prostate lesions
As mentioned elsewhere, cancer is a multifactorial disease and factors that are responsible for prostate tumorigenesis remain largely unknown. As prostate gland is an endocrine-responsive tissue, many studies focused on the effect of androgens, estrogens and their metabolites on prostate tissues.
Over the years, several rat prostate models using chemical carcinogens have been established. In 1977, Fingerhut and Veenema [99] reported carcinomas induced by DMBA in gonadectomized animals. Later in
Conclusions
Experimental data concerning to the rat models of prostate carcinogenesis was reviewed in this work. Although several animal models are available to study prostate cancer and a perfect model does not exist, they provide an important tool to study human and animal prostate carcinogenesis, and to evaluate the effects of potential preventive and therapeutic strategies. The model should be chosen by the researchers, taking into account the aims of their studies, the costs, and the advantages and
Acknowledgments
This work was supported by European Investment Funds by FEDER/COMPETE/POCI - Operational Competitiveness and Internationalization Programme, under Project POCI-01-0145-FEDER-006958 and National Funds by FCT - Portuguese Foundation for Science and Technology, under the project UID/AGR/04033/2013, the project PTDC/DES/114122/2009 and the project PTDC/DTP-DES/6077/2014.
Conflict of interest
None to declare.
References (163)
- et al.
Experimental prostate carcinogenesis - rodent models
Mutat. Res. Rev. Mutat. Res.
(2000) A perspective on the role of estrogen in hormone-induced prostate carcinogenesis
Cancer Lett.
(2013)- et al.
The use of animal models for cancer chemoprevention drug development
Semin. Oncol.
(2010) Chemical and hormonal induction of prostate cancer in animal models
Urol. Oncol.
(1996)Prostate development: a historical perspective
Differentiation
(2008)A new prostatic cancer model: systemic induction of prostatic cancer in rats by a nitrosamine
Cancer Lett.
(1981)- et al.
Methylation of hamster DNA by the carcinogen N-Nitroso-Bis (2-oxopropyl) amine
Cancer Lett.
(1981) Development of billiary and hepatic neoplasms in Guinea pigs treated with N-Nitrosobis(2-oxopropyl)amine
Cancer Lett.
(1978)- et al.
Adenocarcinomas of the prostate induced by N-Nitroso-N-Methylurea in rats preteated with cyproterone acetate and testosterone
Cancer Lett.
(1983) - et al.
Promotional effects of testosterone and high fat diet on the development of autochthonous prostate cancer in rats
Cancer Lett.
(1986)
Lack of modifying effects of 4-n-octylphenol on 3,2′-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in rats
Ecotoxicol. Environ. Saf.
Mammary gland carcinogenesis by food-derived heterocyclic amines and studies on the mechanisms of carcinogenesis of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
Mutat. Res. Fundam. Mol. Mech. Mutagen.
Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat prostate and induction of invasive carcinomas by subsequent treatment with testosterone propionate
Cancer Lett.
Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFκB pathway in the Noble rat model
J. Nutr. Biochem.
P-Nonylphenol pretreatment during the late neonatal period has no effect on 3,2′-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in male F344 rats
Cancer Lett.
A perspective on prostate carcinogenesis and chemoprevention
Curr. Pharmacol. Rep.
Development reprogramming of cancer susceptibility
Nat. Rev. Cancer
Workgroup I: rodent models of prostate cancer
Prostate
Challenges in prostate cancer research: animal models for nutritional studies of chemoprevention and disease progression
J. Nutr.
Modelo animal de doença: critérios de escolha e espécies de animais de uso corrente
Acta Cir. Bras.
Animal models and therapeutic molecular targets of cancer: utility and limitations
Drug Des. Devel. Ther.
Female prostate: a review about the biological repercussions of this gland in humans and rodents
Anim. Reprod.
Aging effects on the mongolian gerbil female prostate (Skene's paraurethal glands): structural, ultrastructural, quantitative, and hormonal evaluations
Anat. Rec.
An anatomic and histologic study of the rat prostate
Prostate
Production of tumors of the prostate of the white rat with 1:2-Benzpyrene
Am. Assoc. Cancer Res. J.
Methylcholanthrene squamous cell carcinoma of the rat prostate with skeletal metastases, and failure of the rat liver to respond to the same carcinogen
Cancer Res.
Animal Models for the Study of Prostate Carcinogenesis
Prostate adenocarcinoma in rats: induction by 3,2′-dimethyl-4-aminobiphenyl
J. Natl. Cancer Inst.
The prostate: a targel for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods
Cancer Res.
Prevention of spontaneous prostate-related cancer in Lobund-Wistar rats by a soy protein isolate/isoflavone diet
Prostate
Chemoprevention of rat prostate carcinogenesis by early and delayed Administration of Dehydroepiandrosterone Chemoprevention of rat prostate carcinogenesis by early and delayed Administration of Dehydroepiandrosterone 1
Cancer Res.
Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats
Jpn. J. Cancer Res.
Chemopreventive effects of zinc on prostate carcinogenesis induced by N-methyl-N-nitrosourea and testosterone in adult male Sprague-Dawley rats
J. Cancer Res. Clin. Oncol.
Chemoprevention of MNU and testosterone induced prostate carcinogenesis by calcitriol (vitamin D3) in adult male albino Wistar rats
Ann. Cancer Res. Ther.
Suppression of prostate cancer in a transgenic rat model via gamma-tocopherol activation of caspase signaling
Prostate
Null activity of selenium and vitamin E as cancer Chemopreventive agents in the rat prostate
Cancer Prev. Res.
Inflammatory processes of prostate tissue microenvironment drive rat prostate carcinogenesis: preventive effects of celecoxib
Prostate
Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model
Prostate Cancer Prostatic Dis.
Enhancing effect of cadmiun or rat ventral prostate carcinogenesis induced by 3,2′-Dimethyl-4-aminobiphenyl
Jpn. J. Cancer Res.
Pioglitazone, a peroxisome proliferator-activated receptor γ agonist, suppresses rat prostate carcinogenesis
Int. J. Mol. Sci.
Ellagic acid, a component of pomegranate fruit juice, suppresses androgen-dependent prostate carcinogenesis via induction of apoptosis
Prostate
Pomegranate for prevention and treatment of cancer: an update
Molecules
Lack of effects of post-initiation cholesterol on 3,2′-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis
Prostate
Significance of chemoprevention for prostate cancer development: experimental in vivo approaches to chemoprevention
Pathol. Int.
Spontaneous adenocarcinomas of the ventral prostate of aged a X C rats
J. Natl. Cancer Inst.
Spontaneous prostate adenocarcinomas in aged germfree wistar rats
J. Natl. Cancer Inst.
The dunning model
Prostate
The aging ACI/Seg versus Copenhagen male rat as a model system for the study of prostatic carcinogenesis
Cancer Res.
Effect of N-Nitrosobis (2-Oxopropyl) amine in newborn and suckling hamsters
Br. J. Cancer
Cited by (26)
The anti-inflammatory properties of the methanolic extract of Cucumis melo Linn. against prostate enlargement in Wistar rats
2022, Saudi Journal of Biological SciencesCitation Excerpt :The reduction in paw volume expressed as inhibition in all three test groups were statistically significant (p < 0.01) when compared with the control group. It is challenging to assess nodule formation in rat prostate (Nascimento-Gonçalves et al., 2018; Al-Trad et al., 2019; Palmieri et al., 2019). However, the number of papillae and amount of secretion can assess the cystic change/hyperplasia in the epithelium (De Nunzio et al., 2020).
Impacts of endocrine-disrupting chemicals on prostate function and cancer
2022, Environmental ResearchCitation Excerpt :Compared to humans, in which the prostate is divided into three zones (central, transitional, and peripheral), the prostate in rodents is divided into four lobes (ventral, dorsal, anterior, and lateral). The rat prostate's ventral lobe is commonly preferred because it is easier to harvest, but, unlike the other lobes, it does not have a human homolog (Nascimento-Gonçalves et al., 2018). As such, the use of the entire prostate should be favored to prevent the use of rodent-specific tissues and allow a proper comparison between rodents and humans in the context of PCa.
Targeting Wistar rat as a model for studying benign, premalignant and malignant lesions of the prostate
2020, Life SciencesCitation Excerpt :Given the above background, our results highlight the potential use of aged Wistar rats as a suitable model to study prostatic lesions. Besides its advantages in regard to the higher PCa incidence and shorter latency period over the pre-existent spontaneous and hormonally-induced rodent models [16,44], the proposed animal model could serve as a valuable alternative to identify preventive or therapeutic measures for the prostate gland. Accordingly, a plethora of non-neoplastic and neoplastic lesions was presently described, thereby allowing evaluating, simultaneously, whether a particular target exerts effective actions against one or more histopathological alteration.
Bioprinted research models of urological malignancy
2024, Exploration