Gene Ther Biol Vol 13, 205-213, 2009
A Comparative Study on Different Characteristics between Prostate Cancer Model and BPH Model of BALB/c Mice
Sun Weigui1*, Gan Yiping1, Ye Zhangqun2, Yu Qiangguo1, Mi Zhenguo3*, Song Xiaosong1, Fan Zhaoyin1, Wang Quanhong3, Han Chunzhi3
1Department of Urology, the 2nd People’s Hostipal of Nanhai, Guangdong 528251, China
2Department of Urology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430031, China
3Shanxi Cancer Research Institute, Taiyuan 030013, China.
*Correspondence: Sun Weigui, Ph.D, Professor of Urology. Department of Urology, the 2nd People’s Hostipal of Nanhai, Guangdong 528200, China; email: firstname.lastname@example.org; email@example.com and Mi Zhenguo, Shanxi Cancer Research Institute, Taiyuan 030013, China
Key Words: Mouse, Model, Method, Prostate Cancer, PIN, BPH, and Characteristics
Received: 5 December 2008; Revised: 10 June 2009;
Accepted: 11 June 2009; electronically published: 30 June 2009
Objective: To comparatively study the different characteristics between spontaneous PCa (prostate cancer) and BPH (benign prostatic hyperplasia) of mice, we improved methods to simultaneously build their models. Methods: 75 BALB/c male mice were randomly divided into 5 groups: the control mice (A), the castrated mice (B), the castrated mice with T (testosterone) treatment (C), the castrated mice with MNU (N-methyl-N-nitrosourea) treatment (D), and the castrated mice with both T and MNU treatments (E). As to T treatment, 12.5mg·kg-1 T solution was injected into a mouse’s abdominal cavity once every two days. As regards MNU treatment, 100mg.kg-1 MNU solution was injected into a mouse’s prostate once every two weeks. The whole experiment was finished in the ninth weekend and all mice were sacrificed. Their blood-samples were collected from eyeballs for the purpose of serous proteins, cytokines and sexual hormones analyses, while their prostates were studied on anatomy and pathology. Results: The prostates in-group A were normal whereas those in group B appeared atrophy. The group C showed BPH model which had the highest serous T and T/E2 (testosterone / estradiol) (P>0.05). The group D supplied us with mild PIN (prostatic intraepithelial neoplasia) model of 40% incidence, while the group E provided us with severe PIN and early cancers of 92.86% incidence, which had the highest serous VEGF (vascular endothelial growth factor) (P>0.05). In addition, groups CDE had apparently higher serous T and T/E2 than groups AB (P<0.05), however, serous E2 had no distinct difference among 5 groups (P>0.05). With regard to serous proteins analyses by SELDI-TOF-MS as contrasted with BPH model, 12 abnormal proteins in-group E had been discovered which probably have a lot to do with cancerous. Conclusion: Homeochronous models of prostatic BPH, PIN and early cancer could have been quickly obtained in 9 weeks, which would be possibly helpful for us to comparatively study on their mechanisms, characteristics, relationships and differential diagnoses in future.
At present, prostatic PCa and PIN rates in clinical patients are gradually rising, but the researches on their aetiological agent and pathogenesis are still on the way. Owing to clinical data always have limitations that different patients always have different cancer stages, internal diseases and individual medical conditions, let alone we can not directly perform trial therapies and new medicines on human bodies. So, it is important for us to pursue animal experiments instead. Moreover, more effectual and easier animal models should be tried for than previous ones.
Therefore, we launched the following experiment, not only for building more feasible models, but also for homochronously comparatively studying prostates on normal, atrophy, BPH, PIN and PCa glands.
II. Materials and Methods
A. Animals and Groups
75 BALB/c male mice, SPF-grade, 20±2g, 6 weeks old, were from Beijing Animal Research Institute (CHN). They were completely randomized into 5 groups (Table 1), 15 mice in each group.
Table 1: Methods of animal grouping
Group Castration Testosterone MNU
A － － －
B ＋ － －
C ＋ √ －
D ＋ － ∨
E ＋ √ ∨
“－” : Negative or sham treatment;
“＋” : Surgical castration (the 1st week);
“ √ ” : Intraabdominal testosterone injection;
“∨” : Intraprostatic MNU injection.
MNU powders: Sigma Inc (USA). Testosterone (T) propionate solutions: 1ml (25mg T): Tianjin Jinyao Inc (CHN). Rat-anti-mouse testosterone ELISA kit (QRCT-311221EIA\UTL) and Rat-anti-mouse estradiol ELISA kit (QRCT-311303EIA\ UTL): ADL Inc (USA). VEGF ELISA Kit: Biosource Inc (USA). SELDI-TOF-MS, IMAC3-Cu and the software (22.214.171.1244): Ciphergen Biosystems lnc (USA).
Bilateral orchectomy was operated through mouse’s scrotal incision under the anesthesia of intraabdominal pentobarbital sodium (50mg.kg-1) in the first experimental week.
D. MNU Injection
Intraprostatic MNU treatment, 100mg.kg-1per mice for every time, was operated through a 5-mm-long lower-abdominal incision. In the 2nd～9th week (8 weeks), every mouse had suffered 4 times of MNU treatments, once every two weeks.
In every time operation, the MNU-powders were dissolved into sodium citrate solutions (PH6.0, 10mmol.L-1) and the MNU solutions (2mg.ml-1) were prepared beforehand. Because the body weight of each mouse was about 20g, and the MNU dose of 100mg.kg-1 could be approximately calculated as 2mg, so every time MNU treatment on per mouse was 1ml MNU solutions (2mg.ml-1).
The 1ml MNU solutions were evenly injected into both of the paired lobes of the dorsal and ventral prostatic glands with a mini-injector. After injection, the ventral and dorsal lobes were both wholly swollen. It was very important that accurate punctures and mini-invasive injections should be emphasized in case that MNU solution would leak out from prostate.
E. T Injection
Testosterone solutions were directly injected into mouse’s abdominal cavity, once every two days for also continuous 8 weeks (the 2nd～9th week).
However, T injections were given up in the same days of having injected MNU since mouse was very feeble after intraday operation, for fear that T could possibly aggravate acute medicine toxicity of MNU and cause it death.
The dose of every time T injection was 12.5mg.kg-1 per mouse. Since one mouse was weighed as 20±2g, so the dosage could also be calculated as about 0.01ml T solutions (0.25mg, 25mg.ml-1), and we could very easily handled with a 1ml mini-injector owning every 0.01ml marks.
F. Serological Study
Till the 9th weekend, all mice were sacrificed by eyeball-extracted methods and their serous samples were collected, centrifuged (4℃, 3000rpm×5 minutes), stored (－80℃) and studied for serous T, E2, T/E2, VEGF and SELDI-TOF-MS proteomic analyses, etc.
G. Pathological Study
All mice were studied under operative microscope. Their ventral and dorsal prostatic lobes were anatomized and dissected from the other tissues, such as bladder, urethral, coagulating gland, and seminal vesicals. etc, and individually weighed by analytical balance (0.0001g). What’s more, pathological HE and immuno-histochemical stains of prostates were especially studied. Besides, other organs, such as lung, liver, renal, spine and pelvic lymph nodes, etc, were also observed.
The serous samples of all mice were analyzed for proteinic analyses by SELDI instruments, according to the American manual book and instructions.
. Statistical Analysis
All data were statistically analyzed by SPSS 13.0 (One-Way ANOVA).
A. General Situations of Mice
In the early stage, mice in groups CE always had bigger body-weights than the others because of the effect of protein synthesis of overdose T treatments (Table 2), and they were usually more active and aggressive. Three mice (one in group C and two in group E) were died of biting each other. What’s more, one mouse in-group E lost its prostate specimen because it was eaten up by the others except its ghost.
However, in the later experiment, most of the mice in-group E was gradually in lower spirits, and they became thinner and weak with hedgehog-like hairs in the end. Nevertheless, their body-weights were still slightly bigger than the others, because their abdominal cavities usually had some residual T solutions that could increase their total body-weights, owing to their poor conditions could not wholly absorb abdominal T.
Prostates in-group A was normal (Figure1), while those in group B were atrophy covered with a few fats and fasciae (Figure 2). In-group C, prostates were enlarged (BPH), especially in ventral glands (Figure 3). In groups DE, prostates were big, tough and coarse (no visible nodes) in grayish-white colors. No positive changes were found in their pelvic lymph nodes, livers, lungs, and lumbar bones. In addition, most of bladders in groups DE were also white and enlarged in which were full of abundant cloudy urines, urinary sediments and bladder stones (Figure 4). Unlike those in human bladders, the stones were white, smooth and waxy with a few brown blots due to infected urines (Figure 5).
Prostates of groups ABCDE in microscope(40×) were illustrated in Figure 6～12 respectively. Six mice (6/15, 40%) in group D were found Ⅰ～ⅡPIN, while thirteen mice in group E (13/14, 92.86%) (one mouse was eaten up including its prostate by other mice) had suffered Ⅲ～Ⅳ PIN and potentially early-stage cancers. These murine PIN of prostate were usually unifocal in group D, while were mostly multifocal and diffusely present in group E. The method of Ⅰ～Ⅳ PIN- grading was referred to the reports of Jae-Hak Park, etc.【1】
Table 2．Conditions of prostates in five groups（±s）
Group Body weight (g) Appearance Color Surface Texture Ventral (mg) Dorsal (mg) Prostate index
A 22.56±1.08 normal red smooth normal 8.89±1.88 4.83±0.92 0.61±0.09
B 21.33±2.12 atrophy yellow smooth soft 5.35±2.33 3.52±1.09 0.42±0.11
C 23.23±1.68 raised red smooth tough 12.80±1.27* 5.65±1.25 0.79±0.06
D 22.44±1.71 atrophy pale coarse tough 6.03±2.19 4.92±1.22 0.49±0.15
E 23.76±1.25 raised pale coarse tough 15.38±4.20# 6.15±1.58* 0.91±0.21*
*P<0.05, # P<0.01. Prostate index=prostate weight / body weight = (ventral +dorsal) / body weight
Figure 1, 2, 3 and 4 were normal, castrated, BPH and PIN models respectively. Ventral lobe , Dorsal lobe .
Figure 5: Bladder and bladder stones
Figure 6 normal (Group A): The epithelial cells were in Monolayer and the nuclei were in normal size arraying as string beads. The lumens were in normal size and the glandular nipples were in low columns. The fibromuscular sheathes of glands were too slender to be easily found, but a small vessel could be seen
Figure 7-castrated model (Group B): The epithelial cells were intimately crowded and the nuclei were slightly smaller. The lumens had shrunken and the glandular nipples were flat due to castration and atrophy. The fibromuscular sheathes and the small vessel could be found .
Figure 9 PIN model (Grade 1, Groups DE): The epithelial cells had more than one layers of atypical cells and hyper-chromatic and minimally polymorphic nuclei could be found. The nuclei had uneven hyperchromasia with a few heterotypical features. However, these lesions were still mild and local in lumens .
Figure 10 PIN Ⅱmodel (Grade 2, Groups DE): There were larger foci with two or more layers of atypical cells. Nuclear pleomorphism, hyperchromasia and increasing proportions of nuclei could be found. Some nuclei even had vesicular chromatin patterns
Figure 12 PIN Ⅳmodel (Grade 4, Group E): The foci of atypical cells had wholly crowed the lumen of the ducts. The atypical cells were poorly oriented with severe nuclear pleomorphism and hyperchromasia. Moreover, fibromuscular sheath and the basement membrane of lumen became incomplete indicating potentially early-stage cancer.
D. Results of Serology
Table 3: Different serum concentrations in five groups（±s）
Group T (ng.ml-1) E2 (pg.ml-1) T/E2 VEGF (pg.ml-1)
A 0.45±0.21 36.45±46.70 12.35 4.05±0.29
B 0.53±0.10 31.55±28.98 14.11 4.58±0.33
C 3.20±1.31* 25.34±19.88 126.28# 3.08±1.62
D 2.18±1.01* 23.98±13.67 90.83* 4.14±1.48
E 2.59±0.50* 36.44±25.44 71.08* 5.62±1.66
*P<0.05, # P<0.01
E. Results of SELDI-TOF-MS
All SELDI data of five groups were analyzed in Table 4. In group E, 12 proteins owning differential PV (protein value, Da) were mainly located in five sections: 2.0～4.5KDa, 5.5～6KDa, 7.5KDa, 8.5KDa and 15～16KDa (Figure 13). In addition, 8 proteins had higher PI (peak information) whereas 4 proteins had lower PI (Figure 14).
Figure 13: ABCDE indicated groups ABCDE respectively. The arrows indicated the main locations of abnormal proteins in PIN model: up-expression , low-expression .
Table 4: All proteins results of SELDI in five groups（±s）
Group A Group B Group C Group D Group E
PV PI PV PI PV PI PV PI PV PI
751.1 25.2±2.1 752.2 10.8±0.4 752.2 18.0±0.6 751.3 13.4±0.7 752.1 12.2±0.5
794.4 34.6±2.3 794.5 29.1±2.3 794.5 38.5±0.7 795.1 25.1±3.4 795.3 25.5±2.2
839.6 25.5±1.9 839.6 33.2±2.6 839.6 36.3±4.4 840.0 33.1±2.8 844.3 28.5±2.0
3410.5 21.2±2.0 3496.3 15.2±1.5 974.9 10.8±1.2 885.2 26.2±3.0 1939.3 11.7±2.0
3498.8 24.3±2.0 3749.7 15.8±3.2 1019.9 10.8±2.1 3407.9 14.9±4.4 2105.6 17.2±1.2
4055.2 11.5±0.5 4055.3 12.0±1.1 2429.9 10.5±0.4 3495.1 23.8±1.1 2229.8 12.4±1.2
4094.6 11.3±0.6 4095.1 12.3±0.5 3408.1 11.7±2.3 3746.3 12.1±0.5 2261.1* 31.4±2.2
5835.9 10.9±0.2 4434.6 12.1±1.1 3496.7 41.1±2.0 4053.1 16.3±0.6 2332.2 26.6±2.4
6815.2 75.1±6.5 6019.4 17.4±1.1 3558.8 19.8±1.5 4094.7 12.0±1.4 2388.0 12.2±1.0
6877.6 39.1±2.5 6057.1 21.0±4.0 3747.4 27.0±3.2 4522.8 10.7±0.2 2475.7 12.3±1.0
6936.9 47.0±4.1 6247.2 15.1±0.8 4055.5 10.5±2.1 6815.2 67.8±3.4 2544.6 12.6±1.0
6982.9 51.3±4.0 6815.2 49.6±4.0 4094.2 10.9±0.4 6877.6 36.5±3.2 2587.9 18.1±1.3
7015.1 32.0±3.0 6877.6 23.2±1.0 4434.0 18.0±0.8 6936.9 34.5±2.5 2761.3 12.1±2.0
7104.9 18.2±0.1 6936.9 19.9±0.8 4862.2 11.0±0.2 6982.9 47.4±4.0 2829.5 11.2±3.0
7539.9 13.2±0.2 6982.9 21.0±3.2 5910.3 16.8±0.11 7015.1 24.8±3.0 2984.6 30.2±2.5
7634.1 10.8±0.3 7015.1 14.2±1.0 6055.1 16.1±2.1 7104.9 18.0±2.1 3020.2 16.4±0.4
7839.1 12.0±0.2 7894.0 12.4±2.1 6155.4 13.9±1.2 8109.1 63.1±3.0 3121.5* 39.8±3.9
7894.0 13.0±0.5 8109.1 67.7±4.0 6238.4 11.9±1.0 8191.7 51.7±3.1 3236.1* 57.5±9.9
8109.1 60.7±4.5 8191.7 67.3±2.8 6815.2 67.5±6.2 8244.7 52.3±6.1 3290.5 22.5±7.5
8191.7 46.0±3.5 8244.7 54.5±8.7 6877.6 51.3±3.1 8319.6 42.7±3.1 3409.4 24.9±6.4
8244.7 40.0±3.3 8319.6 53.6±6.2 6936.9 38.5±3.0 8381.5 29.1±1.9 3497.2 32.9±8.1
8319.6 33.1±1.9 8381.5 38.9±1.1 6982.9 44.8±2.0 8441.1 17.1±2.0 3697.8 22.1±5.1
8381.5 18.4±0.2 9050.0 44.3±3.4 7015.1 31.3±4.2 9050.0 46.3±4.3 3749.0 16.0±2.2
9050.0 33.2±3.2 9112.5 42.1±3.1 7104.9 19.1±2.0 9112.5 44.6±2.8 3886.0* 47.6±7.4
9112.5 24.9±2.5 9184.8 38.5±4.0 7894.0 11.2±0.8 9184.8 42.0±3.9 4055.5 39.1±2.6
9184.8 22.6±3.0 9249.6 33.9±4.0 8109.1 66.4±5.9 9249.6 36.9±4.5 4219.1 14.8±1.5
9249.6 18.9±2.0 9319.3 24.6±3.2 8191.7 60.1±10.5 9319.3 29.3±4.0 4435.9 13.7±3.1
11665.8 34.5±1.8 11665.8 17.1±0.7 8244.7 50.2±3.9 9443.0 39.6±3.8 4633.7 27.5±2.8
11840.8 25.0±2.1 11840.8 14.3±0.9 8319.6 38.1±5.1 9500.4 26.8±3.3 4725.3 10.7±1.1
14924.0 24.2±2.1 14924.0 14.8±0.8 8381.5 25.9±1.9 9585.7 25.1±2.2 5074.1 12.4±0.5
15074.8 35.4±3.0 15074.8 21.5±2.1 9050.0 24.3±2.4 9643.0 20.9±3.6 5543.1 10.0±1.2
15207.2 29.0±3.1 15683.6 12.4±1.2 9112.5 30.6±3.3 11665.8 27.0±2.7 5655.2* 51.8±8.7
15683.6 23.7±2.6 15880.3 12.9±0.8 9184.8 29.8±2.7 11840.8 22.4±1.6 5715.4 10.8±4.1
15880.3 20.6±0.5 9249.6 24.6±3.0 5765.5 15.2±3.5
9319.3 20.4±3.0 5838.5 15.2±2.4
11665.8 22.0±3.0 5915.0* 36.5±2.6
11840.8 21.5±1.9 6040.3 15.2±3.6
15074.8 32.6±3.6 6076.6 18.4±2.7
15207.2 30.1±3.0 6111.4 28.6±4.1
15683.6 19.0±1.8 6205.3 26.5±2.5
15880.3 18.3±3.4 6814.2 66.0±7.8
*: In group E, 12 proteins had apparently abnormal PI values (Fig.14).
PI: There had no distinct difference of PI values among 5 groups (P>0.05).
At present, spontaneous PCa models usually included old dogs, carcinogenic medicines induction, transgenic engineering animals, etc. The old dogs of 7～17 years-old only had 16% PCa molde-rate.【2】Among carcinogenic medicines, MNU was one of the most commonly used medicines.【3～6】It had been reported that intravenous or oral MNU (30-50mg.kg-1) treatments for 1-2 years could get about 5-15% model-rate in rats or mice.【7～8】In recent years, by increasing MNU dosage to 50-100mg.kg-1 for continuous 10 months treatments, scientists could increase the model-rate to 40% or so.【9～10】However, these rates were not high enough for daily and extensive studies yet.
In order to more effectively and more quickly build the model, after a series of preliminary trials, we suggested to improve the methods as follows: First, SPF-grade BALB/c mice were chosen in our experiment instead of rats, rabbits, dogs or swines, because these mice were pure bred, bulks, cheapness and had few individual variations. Moreover, mice were the most commonly used animals for prostate studies as previous reported. Second, previous models were castrated by antiandrogen medicines such as flutamide or progestogen for 3-4 weeks treatments.【10】We operated bilateral orchiectomy which was more easier and simpler. The mice were all complete recovery in 5-7 days later after the operation, which could apparently shorten experimental period. Third, intravenous or oral MNU treatments would bring out more serious medical toxicites of MNU and result in the other organic cancers besides prostate.【9—13】It might be the reason that previous studies had to use low-dose MNU for the safety of animals. On the contrary, intraprostatic injections of high-dose MNU could not only conspicuously increase intraprostatic MNU density in order to improve the model-rate, but also largely decrease systemic toxicities and avoid the other organic cancers. The intervals of once every two weeks for MNU injection in our experiment were scheduled in order to protect that the mice could have enough time to be wholly recovered after operation. In addition, during our whole experiment, no serious MNU toxicity happened except for temporary lacrimation and single-eye blind in a few mice, which could be naturally recovered by themselves in 3-5 days later. So we called these symptoms of ocular MNU toxicities as “sham-blind”. Forth, the previous methods usually subcutaneously implanted a silastic capsule that contained 25mg T at a interval of once every two months for continuous 6 months.【9】We directly injected T solutions into mice’s abdominal cavities instead, which was easy, simple, cheap, quick and had no abdominal negative effects. Fifth, minimally invasive procedures with ophthalmic apparatuses were adopted throughout 5 times operations (4 MNU intraprostatic injections and 1 castration). Nevertheless, we decided to give up the 6th operation because the mice had been very weak after five operations. Fortunately, no mouse was died from surgical reasons. In short, owing to above five improvements, we not only increased the model-rate but also shortened experimental period from previous 10 months to 9 weeks.
The purpose of castration before experiment was to cause prostate to atrophy beforehand.【7～11】After the glands and cells had shrunk to puerilism, their identities of synchronous reactions to T and MNU might be possibly improved. Moreover, it had been reported that castrated mice would have more poor-differentiated cancerations than non-castrated ones,【14～16】which indicated that castration would be beneficial to cancer model. However, the differences between castration and noncastration were also discovered in our experiment: serous T and VEGF of castrated mice were slightly higher than those of noncastrated mice, which might be attributed to the negative feedbacks of hypothalamus-pituitary-adrenal axis after castration.【17～18】Moreover, compared with noncastrated mice, some serous proteins of castrated mice (752.2, 6247.2, 11840.8, 14924.0 and 15683.6Da) were in low-expression, whereas the other proteins (8109.1 and 9080.0Da) were in high-expression.
The similar features between PCa model and BPH model. Firstly, the two models both had high prostatic weights and indexes because of overdose T treatments and prostatic hypertrophy. Secondly, they both had big bladders owing to lower urinary obstruction. Thirdly, their serous T, T/E2 and VEGF were both increased. Fourthly, they both had a few abnormal protein-waves in SELDI results.
However, the obvious differences between PCa model and BPH model were also discovered. First, the predilection site of PCa was always in dorsal lobes whereas that of BPH was mostly in ventral lobes. Second, the appearance of canceration was mostly pale, coarse and tough, while that of BPH was generally red, smooth and soft. Third, the prostatic weight and index of cancerations were slightly higher than those of BPH (P>0.05). Four kinds of human PIN in histopathology were papillary, cribriform, tufting, and flat patterns,【19】all which could be found in our models. Moreover, a few early PCa lesions had been also discovered in our models (Figure 12). Forth, it was reported that some patients with lower serous T and T/E2 would easily occur PCa and have poorer prognosis,【20】whereas higher serous T and T/E2 were apt to BPH instead.【21】In our experiment, serous T and T/E2 of canceration model were lower than those of BPH model, which was similar to the above clinical patients. Fifth, serous VEGF of canceration model was higher than that of BPH model (P>0.05), which suggested that PIN diseases already had the capability of vascular neogenesis and canceration developing.【22～23】Sixth, 12 apparently different proteins (Fig.14 and table 4) between malignant and benign models were found, which might have some possibly values for differential diagnosis. For example, 3236.1Da located in the range of 2803～3319Da which was the heat-shock-protein precursor family. 5655.2Da was very close to mitochondrial precursor (5601Da) that was programmed cell-death protein 8. 5765.5Da was reported that could increase dihydro-testosterone (DHT).【24～26】Nevertheless, their PI values had no apparent difference in comparison (P>0.05) the same as previous studies.【27】
In order to increase the experimental reliability, we had designed two control groups (Group A and B) in advance, so we could easily screen out some nonspecific proteins just like lipoproteins and glycoproteins which were inherent in serum, such as 752.1Da, 795.3Da, 844.3Da, etc. In addition, a few proteins (PI<5.0) due to possibly signal-noises and variances by instruments had been also overlooked.【28】
On the whole, the autochthonous prostatic PIN and early PCa model could be quickly and easily reached in a short period (9 weeks) by some improved methods, which would be very convenient for us to simultaneously study the individual and mutual characteristics among castration, BPH, PIN and PCa models. Moreover, combined with clinical studies and cytological data just like our previous results,【29】it might be probably available for us to further comparatively research the relationships among castration, sexual hormone, BPH, PIN and PCa.
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Dr.Sun Weigui, Ph.D