Elsevier

Life Sciences

Volume 203, 15 June 2018, Pages 210-224
Life Sciences

Review article
Modelling human prostate cancer: Rat models

https://doi.org/10.1016/j.lfs.2018.04.014Get rights and content

Abstract

Prostate cancer is the second most common cancer in men, affecting approximately 1.1 million men worldwide. In this way, the study of prostate cancer biopathology and the study of new potential therapies is of paramount importance. Several rat models were developed over the years to study prostate cancer, namely spontaneous models, chemically-induced models, implantation of cancer cell lines and genetically-engineered models. This manuscript aimed to provide the readers with an overview of the rat models of prostate cancer, highlighting their advantages and disadvantages, as well as, their applications.

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)

  • H. Kohno et al.

    Lack of modifying effects of 4-n-octylphenol on 3,2′-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in rats

    Ecotoxicol. Environ. Saf.

    (2002)
  • E.G. Snyderwine et al.

    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.

    (2002)
  • T. Shirai et al.

    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.

    (1999)
  • A. Hsu et al.

    Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFκB pathway in the Noble rat model

    J. Nutr. Biochem.

    (2011)
  • S. Inaguma et al.

    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.

    (2004)
  • Globocan. Estimated Incidence, Mortality and Prevalence Worldwide in 2012, Int. Agency Res. Cancer (Word Heal. Organ)....
  • M.C. Bosland et al.

    A perspective on prostate carcinogenesis and chemoprevention

    Curr. Pharmacol. Rep.

    (2015)
  • C.L. Walker et al.

    Development reprogramming of cancer susceptibility

    Nat. Rev. Cancer

    (2012)
  • M.S. Lucia et al.

    Workgroup I: rodent models of prostate cancer

    Prostate

    (1998)
  • D. Lambe et al.

    Challenges in prostate cancer research: animal models for nutritional studies of chemoprevention and disease progression

    J. Nutr.

    (2005)
  • D.J. Fagundes et al.

    Modelo animal de doença: critérios de escolha e espécies de animais de uso corrente

    Acta Cir. Bras.

    (2004)
  • M. Cekanova et al.

    Animal models and therapeutic molecular targets of cancer: utility and limitations

    Drug Des. Devel. Ther.

    (2014)
  • C.A. Santos et al.

    Female prostate: a review about the biological repercussions of this gland in humans and rodents

    Anim. Reprod.

    (2006)
  • A.M. Custodio et al.

    Aging effects on the mongolian gerbil female prostate (Skene's paraurethal glands): structural, ultrastructural, quantitative, and hormonal evaluations

    Anat. Rec.

    (2008)
  • C.J. Jesik et al.

    An anatomic and histologic study of the rat prostate

    Prostate

    (1982)
  • R.A. Moore et al.

    Production of tumors of the prostate of the white rat with 1:2-Benzpyrene

    Am. Assoc. Cancer Res. J.

    (1937)
  • W.F. Dunning et al.

    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.

    (1946)
  • M.C. Bosland et al.

    Animal Models for the Study of Prostate Carcinogenesis

    (1992)
  • S. Katayama et al.

    Prostate adenocarcinoma in rats: induction by 3,2′-dimethyl-4-aminobiphenyl

    J. Natl. Cancer Inst.

    (1982)
  • T. Shirai et al.

    The prostate: a targel for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods

    Cancer Res.

    (1997)
  • M. Pollard et al.

    Prevention of spontaneous prostate-related cancer in Lobund-Wistar rats by a soy protein isolate/isoflavone diet

    Prostate

    (2000)
  • K.V.N. Rao et al.

    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.

    (1999)
  • M. Onozawa et al.

    Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats

    Jpn. J. Cancer Res.

    (1999)
  • S. Banudevi et al.

    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.

    (2011)
  • Senthilkumar et al.

    Chemoprevention of MNU and testosterone induced prostate carcinogenesis by calcitriol (vitamin D3) in adult male albino Wistar rats

    Ann. Cancer Res. Ther.

    (2006)
  • S. Takahashi et al.

    Suppression of prostate cancer in a transgenic rat model via gamma-tocopherol activation of caspase signaling

    Prostate

    (2009)
  • D.L. McCormick et al.

    Null activity of selenium and vitamin E as cancer Chemopreventive agents in the rat prostate

    Cancer Prev. Res.

    (2010)
  • N.K. Narayanan et al.

    Inflammatory processes of prostate tissue microenvironment drive rat prostate carcinogenesis: preventive effects of celecoxib

    Prostate

    (2009)
  • Y.-M. Cho et al.

    Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model

    Prostate Cancer Prostatic Dis.

    (2007)
  • T. Shirai et al.

    Enhancing effect of cadmiun or rat ventral prostate carcinogenesis induced by 3,2′-Dimethyl-4-aminobiphenyl

    Jpn. J. Cancer Res.

    (1993)
  • S. Suzuki et al.

    Pioglitazone, a peroxisome proliferator-activated receptor γ agonist, suppresses rat prostate carcinogenesis

    Int. J. Mol. Sci.

    (2016)
  • A. Naiki-Ito et al.

    Ellagic acid, a component of pomegranate fruit juice, suppresses androgen-dependent prostate carcinogenesis via induction of apoptosis

    Prostate

    (2015)
  • P. Sharma et al.

    Pomegranate for prevention and treatment of cancer: an update

    Molecules

    (2017)
  • Y. Tagawa et al.

    Lack of effects of post-initiation cholesterol on 3,2′-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis

    Prostate

    (1992)
  • T. Shirai

    Significance of chemoprevention for prostate cancer development: experimental in vivo approaches to chemoprevention

    Pathol. Int.

    (2008)
  • S.A. Shain et al.

    Spontaneous adenocarcinomas of the ventral prostate of aged a X C rats

    J. Natl. Cancer Inst.

    (1975)
  • M. Pollard

    Spontaneous prostate adenocarcinomas in aged germfree wistar rats

    J. Natl. Cancer Inst.

    (1973)
  • T.R. Tennant et al.

    The dunning model

    Prostate

    (2000)
  • J.T. Isaacs

    The aging ACI/Seg versus Copenhagen male rat as a model system for the study of prostatic carcinogenesis

    Cancer Res.

    (1984)
  • M.S. Rao et al.

    Effect of N-Nitrosobis (2-Oxopropyl) amine in newborn and suckling hamsters

    Br. J. Cancer

    (1980)
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