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Y C Wong - One of the best experts on this subject based on the ideXlab platform.

  • Sex hormone-induced mammary carcinogenesis in female Noble Rats: detection of differentially expressed genes.
    Breast Cancer Research and Treatment, 2020
    Co-Authors: Gabriel M. Leung, Sw W. Tsao, Y C Wong
    Abstract:

    Breast cancer is the most common cancer and the second most frequent cause of cancer death in women. Epidemiological data has recognized that an increased cumulative exposure to estrogen is the common tie linking most of the established risk factors for breast cancer. Sex hormone-induced mammary gland carcinogenesis of the Noble Rat (using testosterone and 17β-estradiol) resembles that of the human counterpart in its growth pattern as well as the histopathology of the tumors induced. This model may provide a paradigm for examination of genetic alteRations and changes in gene expression between different histological groups and to make inferences about the role of known and putative oncogenes and tumor suppressor genes. We studied the gene expression profile during sex hormone-induced mammary carcinogenesis using a cDNA array technique; the results were further confirmed by RT-PCR, western blotting and immunohistochemical analyses. From the 10 differentially expressed genes identified, we have studied four highly overexpressed genes, two cell cycle/growth control regulators, the cyclins D1 and D2, a growth factor, IGF-2 and a cytokine TNF-α. Cyclins D1 and D2 were highly expressed in the nuclei of carcinoma cells but at low levels in the nuclei of the hyperplastic and normal mammary tissue. IGF-2 was found to expressed in the cytoplasm of the carcinoma cells but not in the stromal cells. Western blot showed expression of big IGF-2 consistent with the tumor derived truncated forms of pro-IGF-2. The matured circulating IGF-2 at 7.5 kDa identified in the serum was not expressed in any of the breast tissue samples. TNF-α expression was found not only in the macrophages but also in the mammary carcinoma cells. The result of the present study provides some information on the molecular basis of this sex hormone-induced mammary carcinogenesis and the role of these proteins in tumor progression.

  • enhanced induction of prostatic dysplasia and carcinoma in Noble Rat model by combination of neonatal estrogen exposure and hormonal treatments at adulthood
    International Journal of Oncology, 2005
    Co-Authors: Mongting Yuen, Y C Wong, Laikwok Leung, Jun Wang, Franky L Chan
    Abstract:

    : Estrogens have been implicated to play certain but yet undefined roles in the normal and neoplastic growth of prostate gland. Studies of perinatal exposure in rodents demonstRate that effects of perinatal estrogenization are permanent and carcinogenic in prostate gland. In the Noble (Nb) Rat model, prostatic dysplasia and neoplastic lesions can be induced by a chronic treatment with both testosterone and estrogen at adulthood. However, by this conventional protocol, neoplastic lesions are mostly confined to the lateral (LP) and ventral (VP) prostates, while gross prostatic tumors are rarely induced. Based on these two experimental models, we developed a modified treatment protocol for the enhancement of prostate cancer induction in Nb Rat model by combining neonatal estrogen exposure of male offspring followed by the hormonal treatment at adulthood (NeoE + T-E2). Using this modified protocol, we were able to induce more extensive development of neoplastic lesions in all three prostatic lobes and also gross tumors at relatively high incidence within 6-9 months. Western blottings and immunohistochemistry showed that ERalpha expression was increased in the hypertrophic peri-acinar and -ductal smooth muscle cells while ERbeta and AR expressions are markedly decreased in dysplastic and neoplastic lesions in NeoE + T-E2-treated prostates. Immunohistochemistry showed that expression of three tumor suppressors (BRCA2, PTEN, and Rap1) and tubulin-alpha are markedly decreased in dysplastic and neoplastic lesions. In addition, loss of expression of smooth muscle differentiation markers (desmin, alpha-actin, and vinculin) and defects of basement membranes were also seen in the reactive stroma. These results suggest that exposure to high levels of estrogens, either endogenous or exogenous, in early life could play a role in the development of prostate cancer in later life.

  • no effect of a high fat diet on promotion of sex hormone induced prostate and mammary carcinogenesis in the Noble Rat model
    British Journal of Nutrition, 2002
    Co-Authors: Gina Leung, Iris F F Benzie, Annie L M Cheung, S W Tsao, Y C Wong
    Abstract:

    Results of international correlation and migrant studies suggest that dietary fat promotes carcinogenesis in hormone-sensitive sites, but this is disputed. In the present study, we used a Noble Rat model of sex hormone-induced cancers to examine the effect of a high-fat diet on the incidence and latency of prostate and mammary cancer in male (n 139) and female (n 72) animals respectively. We also measured α-tocopherol levels in female breast tissue to determine whether a high intake of polyunsatuRated fatty acids depletes antioxidant defence in target tissues, providing a possible potentiating mechanism for carcinogenesis. Results showed a very high incidence of hormone-induced adenocarcinomas of prostate and mammary gland, irrespective of diet. There was no difference in the pattern of carcinogenesis in different prostatic locations, weight of the prostate, or weight gain between male Rats on the high-fat diet compared with the control (standard, low-fat) diet. In female Rats, the incidence of mammary cancer and the body-weight gain were the same in both dietary groups, and breast α-tocopherol was also unaffected by dietary fat intake. Our present results are supportive of recent cohort studies that reported no significant association between intake of fat and the development of human prostate and breast cancer, and do not support a role for dietary fat in promoting sex hormone-induced prostate and mammary carcinogenesis.

  • Id-1 stimulates serum independent prostate cancer cell prolifeRation through inactivation of p16(INK4a)/pRB pathway.
    Carcinogenesis, 2002
    Co-Authors: Xuesong Ouyang, Xiang Hong Wang, Ming-tat Ling, Hing Lok Wong, Sai Wah Tsao, Y C Wong
    Abstract:

    It has been suggested that the helix–loop–helix protein Id-1 plays an important role in tumourigenesis in certain types of human cancer. Previously, we reported that Id-1 was up-regulated during sex hormone-induced prostate carcinogenesis in a Noble Rat model (Ouyang et al. (2001) Carcinogenesis, 22, 965–973). In the present study, we investigated the direct effect of Id-1 expression on human prostate cancer cell prolifeRation by transfecting an Id-1 expression vector into a prostate cancer cell line LNCaP. Ten stable transfectant clones were isolated and the ectopic Id-1 expression resulted in both increased DNA synthesis Rate and the percentage of S phase cells. To study the possible mechanisms involved in the Id-1 induced prostate cancer cell growth, we examined the expression of several factors responsible for G1 to S phase progression. We found that Id-1 expression induced phosphorylation of RB and down-regulation of p16 INK4a but not p21 Waf1 or p27 Kip1 . Our results indicate that the Id-1 induced inactivation of p16 INK4a /pRB pathway may be responsible for the increased cell prolifeRation in prostate cancer cells. Given the fact that both Id-1 over-expression and inactivation of p16 INK4a /

  • The effect of flutamide and tamoxifen on sex hormone-induced mammary carcinogenesis and pituitary adenoma.
    Breast Cancer Research and Treatment, 2002
    Co-Authors: Gabriel M. Leung, Sw W. Tsao, Y C Wong
    Abstract:

    We have established a female Noble Rat model to explore the mechanisms of hormonal mammary carcinogenesis. Based on the previous finding that the dose of testosterone affects only the latency period of mammary cancer, not the final incidence and that androgen upregulates apoptotic activity in pre-malignant mammary glands, we hypothesised that estrogen is the initiator and androgen the promoter for hormonal mammary carcinogenesis of the Rats. In the present study, Rats were treated with the sex hormones together with flutamide and tamoxifen for both short term (7 and 13 weeks) and long term (12 months) duRations. We showed that tamoxifen could totally inhibit mammary carcinogenesis while flutamide cause a delay and reduction in tumour incidence in the 12 months treatment term. Blocking effect of flutamide and tamoxifen on T + E2 (testosterone and 17β-estradiol) short-terms treatment was demonstRated by the similar histological changes identified in the mammary glands of the T + E2 and drug treated Rats to that of the age matched E2 and T controls, respectively. These findings give further support for the role of estrogen and androgen in mammary carcinogenesis. Autopsy of the tumour bearing Rats showed presence of pituitary macroadenoma causing compression and atrophy of the brain stem. Immunohistochemical staining of these adenomas showed a predominance of prolactin-secreting cells. Serum assay also showed a corre-sponding increase in circulatory prolactin level. Tamoxifen was also effective in blocking the formation of pituitary adenoma in the sex hormone treated Rats. Pituitary size and level of prolactin were higher in the T + E2 +flutamide group than the T + E2 group in both short-term and long-term treatments. It suggests that testosterone may have a role in counteracting estradiol stimulation on the pituitary lactotropes although it is synergistic to estrogen in mammary carcinogenesis. Pituitary adenomas were found in all Rats that developed mammary adenocarcinoma but not vice versa suggesting that prolactin level elevation alone cannot lead to mammary tumorigenesis. The animal model, in addition to mammary carcinogenesis, may be useful for investigation of anti-estrogen therapy in pituitary adenomas.

S W Tsao - One of the best experts on this subject based on the ideXlab platform.

  • no effect of a high fat diet on promotion of sex hormone induced prostate and mammary carcinogenesis in the Noble Rat model
    British Journal of Nutrition, 2002
    Co-Authors: Gina Leung, Iris F F Benzie, Annie L M Cheung, S W Tsao, Y C Wong
    Abstract:

    Results of international correlation and migrant studies suggest that dietary fat promotes carcinogenesis in hormone-sensitive sites, but this is disputed. In the present study, we used a Noble Rat model of sex hormone-induced cancers to examine the effect of a high-fat diet on the incidence and latency of prostate and mammary cancer in male (n 139) and female (n 72) animals respectively. We also measured α-tocopherol levels in female breast tissue to determine whether a high intake of polyunsatuRated fatty acids depletes antioxidant defence in target tissues, providing a possible potentiating mechanism for carcinogenesis. Results showed a very high incidence of hormone-induced adenocarcinomas of prostate and mammary gland, irrespective of diet. There was no difference in the pattern of carcinogenesis in different prostatic locations, weight of the prostate, or weight gain between male Rats on the high-fat diet compared with the control (standard, low-fat) diet. In female Rats, the incidence of mammary cancer and the body-weight gain were the same in both dietary groups, and breast α-tocopherol was also unaffected by dietary fat intake. Our present results are supportive of recent cohort studies that reported no significant association between intake of fat and the development of human prostate and breast cancer, and do not support a role for dietary fat in promoting sex hormone-induced prostate and mammary carcinogenesis.

  • up regulation of trpm 2 mmp 7 and id 1 during sex hormone induced prostate carcinogenesis in the Noble Rat
    Carcinogenesis, 2001
    Co-Authors: Xuesong Ouyang, S W Tsao, Xiang Hong Wang, Y C Wong
    Abstract:

    : Prostate cancer is the most frequently diagnosed malignancy in the Western world and changes in the Ratio of testosterone and estrogens with advancing age is one of the potential risk factors in the development of this disease. However, the molecular mechanisms associated with hormone imbalance in prostate carcinogenesis are poorly understood. In this study we induced a high incidence of prostate hyperplasia, dysplasia and adenocarcinoma in the Noble Rat using a combination of testosterone and estradiol-17beta. Using this animal model, we studied the gene expression profile during sex hormone-induced prostate carcinogenesis using a cDNA array technique; the results were further confirmed by RT-PCR, western blotting and immunohistochemical analyses. We found up-regulation of TRPM-2 (testosterone-repressed prostatic message-2), MMP-7 (matrix metalloproteinase-7) and Id-1 (inhibitor of differentiation or DNA binding) during development of sex hormone-induced prostate cancer. Increased expression of TRPM-2 and MMP-7 was observed in both premalignant and malignant tissues after sex hormone treatment, indicating their role in the early stages of hormone response and prostate cancer development. In contrast, Id-1 was expressed at relatively low levels in all premalignant samples but increased in malignant cells, suggesting its potential roles as a biomarker for prostate cancer cells. Furthermore, expression of Id-1 appeared to be stronger in poorly differentiated lesions than in well-differentiated carcinomas, suggesting that the levels of Id-1 expression may be correlated with the malignancy of tumors. Our results provide the first evidence of up-regulation of TRPM-2, MMP-7 and Id-1 during sex hormone-induced prostate carcinogenesis and strongly suggest their association with the development of prostate cancer.

  • isolation and purification of breast carcinoma cell lines from a Noble Rat
    2001
    Co-Authors: Y C Wong, S W Tsao
    Abstract:

    We report here the establishment of a culture of breast epithelial cells derived from breast carcinoma of a male Rat induced by implantation of a combination of 17β-estradiol and testosterone propionate. This serially cultivated cell line has been demonstRated, by a variety of criteria, to be a neoplastic Rat mammary epithelial cell line. The criteria used include morphological and growth characteristics, presence of specific antigens, steroid hormone receptors, hormone responsiveness, and karyotype analysis. These cell lines may be useful for a number of in-vitro studies to explore the mechanism(s) of hormonal carcinogenesis. Inasmuch as the cell line expresses androgen receptor, it may serve as a valuable in vitro model in which to assess the effects of endogenous and exogenous androgens known to play an important role in breast carcinogenesis.

  • correlation of increased apoptosis and prolifeRation with development of prostatic intraepithelial neoplasia pin in ventral prostate of the Noble Rat
    The Prostate, 2000
    Co-Authors: Y C Wong, S W Tsao
    Abstract:

    BACKGROUND Imbalance between cell prolifeRation and cell apoptosis has been considered a key factor in carcinogenesis. Prostatic intraepithelial neoplasia (PIN) is the most likely precancereous lesion and represents the major target for chemoprevention of prostate cancer. The prolifeRative and apoptotic activities involved in the development of PIN remain to be elucidated. METHODS Ventral prostates were removed from Noble Rats that were treated with a combination of testosterone (T) and estradiol (E2) for certain periods of time, and processed for histopathological grading. To evaluate the relationship between cell prolifeRation and apoptosis, immunohistochemistry for prolifeRating cell nuclear antigen (PCNA), Ki-67, and in situ DNA nick labeling (TUNEL) for identifying apoptotic cells, were performed on paraffin sections from prostate samples with PIN lesions. The results were correlated with expression patterns of Bcl-2 and Bax, two proteins related to cell survival and cell apoptosis. RESULTS Pathologically, low-grade PIN (LGPIN) and high-grade PIN (HGPIN) were observed in ducts or alveoli after 3 and 5 months of T + E2 treatment, respectively. Quantitative evaluation of Ki-67 showed an increased prolifeRative activity in HGPIN. In contrast to normal prostatic ducts and alveoli, which showed no positive staining for Ki-67 in the nuclei of luminal cells, 25% Ki-67-positive cells were detected in luminal cells of HGPIN. Only 7.5% Ki-67-positive cells were found belonging to the basal cell type. The Ki-67 index showed a higher growth Rate from normal to HGPIN. The PCNA results showed a similar expression pattern to that of Ki-67 in normal prostate, LGPIN, and HGPIN. Apoptotic index (number of apoptotic cells/total number of cell counted) was significantly higher (P = 0.028) in HGPIN (3.23%) than in control prostate (1.19%). In contrast to control prostate, which showed no definite expression of Bcl-2, an intense positive expression of Bcl-2 in HGPIN was observed. Positive expression of Bax protein was observed in glandular epithelial cells of normal control prostate and HGPIN as well. CONCLUSIONS Overexpression of Bcl-2 and higher Ki-67 or PCNA indices in HGPIN suggest that abnormal growth of premalignant lesions might result from an increase in cell prolifeRation. An increased apoptotic Rate in HGPIN further implicates that active apoptosis may acceleRate cell turnover in the development of premalignant lesions of the prostate. Prostate 44:31–39, 2000. © 2000 Wiley-Liss, Inc.

  • Sex hormone-induced mammary carcinogenesis in the female Noble Rats: Expression of Bcl-2 and Bax in hormonal mammary carcinogenesis
    Breast Cancer Research and Treatment, 2000
    Co-Authors: S W Tsao, Y C Wong
    Abstract:

    We have established a Noble Rat model to explore the mechanisms of hormonal mammary carcinogenesis, in which the role of androgen in promoting mammary carcinogenesis was highlighted. We have also established that stromal-epithelial interactions may be responsible for the promotional effects of testosterone in mammary carcinogenesis. Based on these understandings, in the present study we examined the expression of Bcl-2 and Bax in pre-malignant mammary glands from Rats treated with different protocols of sex hormones for 7 weeks as well as sex hormone induced mammary tumours. We observed that Bcl-2 was strongly expressed in most of mammary tumour cells, whereas weak or negative in adjacent normal or hyperplastic ductal structures. On the contrary, Bax immunoreactivity was weak in mammary tumour cells while strongly expressed in adjacent normal or hyperplastic ductal structures. More importantly, the results from compaRative study of ‘pre-malignant’ glands further showed that when animals were treated with 17β-oestradiol, the mammary epithelial cells expressed high levels of Bcl-2. The results from Rats treated with testosterone, either alone or in combination with oestrogen, give rise to high levels of Bax expression in ‘pre-malignant’ mammary glands. These observations indicate that in ‘pre-malignant’ mammary glands, treatment with testosterone, either alone or in combination with 17β-oestradiol, may induce high apoptotic activities. However, in fully developed mammary tumours, the apoptotic activities apparently decrease in tumour cells. TUNEL assay provides further data to support this conclusion. Our study, thus, suggests that androgens may play a promoting role in mammary carcinogenesis by upregulation of Bax expression and induction of high apoptotic activities in ‘pre-malignant’ stage, which would provide a selective pressure favouring the expansion of the initiated cells.

Shukmei Ho - One of the best experts on this subject based on the ideXlab platform.

  • differential proteomics in the aging Noble Rat ventral prostate
    Proteomics, 2008
    Co-Authors: James E Evans, Karin M Green, Xiang Zhang, Shukmei Ho
    Abstract:

    Incidence of prostatic diseases increases dramatically with age which may be related to a decline in androgen support. However, the key mechanisms underlying prostate aging remain unclear. In the present study, we investigated the aging process in the ventral prostate of Noble Rats by identifying differentially expressed prostate proteins between 3- and 16-month-old animals using ICAT and MS. In total, 472 proteins were identified with less than a 1% false positive Rate, among which 34 were determined to have a greater than 2-fold increase or 1.7-fold decrease in expression in the aged VPs versus their younger counterparts. The majority of the differentially expressed proteins identified have not been previously reported to be associated with prostate aging, and they fall into specific functional categories, including oxidative stress/detoxification, chaperones, protein biosynthesis, vesicle transport and intracellular trafficking. The expression of glutathione S-transferase, ferritin, clusterin, kininogen, oxygen regulated protein 150, spermidine synthase, ADP ribosylation factor and cyclophilin B was verified by Western blot analyses on samples used for the ICAT study, as well as on those obtained from an independent group of animals comprised of three age groups. To our knowledge, this is the first study on the proteome of the aging Rat prostate.

  • sex hormones induce direct epithelial and inflammation mediated oxidative nitrosative stress that favors prostatic carcinogenesis in the Noble Rat
    American Journal of Pathology, 2007
    Co-Authors: Irwin Leav, Shukmei Ho
    Abstract:

    Oxidative and nitrosative stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administRation of testosterone plus 17β-estradiol to Noble Rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2′-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/nitrosative stress in epithelium. We concluded that the oxidative/nitrosative damage resulting from the testosterone-plus-17β-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the up-regulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus, we link alteRations in the hormonal milieu with oxidative/nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis.

  • Sex hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the Noble Rat.
    American Journal of Pathology, 2007
    Co-Authors: Irwin Leav, Shukmei Ho
    Abstract:

    Oxidative and nitrosative stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administRation of testosterone plus 17β-estradiol to Noble Rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2′-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/nitrosative stress in epithelium. We concluded that the oxidative/nitrosative damage resulting from the testosterone-plus-17β-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the up-regulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus, we link alteRations in the hormonal milieu with oxidative/nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis.

  • Sex hormone-induced alteRations in the activities of antioxidant enzymes and lipid peroxidation status in the prostate of Noble Rats.
    The Prostate, 2003
    Co-Authors: Shibnath Ghatak, Shukmei Ho
    Abstract:

    BACKGROUND Oxidative stress has been implicated in prostate carcinogenesis. In the Noble Rat model, treatment of Rats with testosterone (T) plus 17β-estradiol (E2) induced dysplasia and adenocarcinoma. Previous reports from us and other have indicated a linkage between steroid hormones and oxidative status in prostate cells in vivo and in vitro. Here, we provide further evidence that androgens and estrogens could induce a lobe-specific shift of prooxidant–antioxidant balance and alteRations in antioxidant enzyme activities, leading to oxidative stress in the Rat prostate gland in vivo. METHODS Male Noble Rats were subjected to single (T, E2, or diethylstilbestrol [DES] alone) or combined (T + E2 or T + DES) hormone treatments. Lipid peroxidation status and antioxidant enzyme activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD) were assayed spectrophotometrically. RESULTS Treatment of Rats with T did not alter lipid peroxidation in either the ventral prostate (VP) or the dorsolateral prostate (DLP). In contrast, exposure of Rats to DES or E2 modestly elevated lipid peroxidation in Rat VP or DLP, respectively. Of importance, T + DES and T + E2 treatments of Rats induced marked increases in lipid peroxidation in the VP and the DLP, respectively. Antioxidant enzyme activities in the VP and DLP exhibited differential responses to sex hormone challenges. The activities of catalase, GPx, GR, and G6PD were mostly suppressed in either single or dual hormone-treated DLP, whereas there is a general increase of GR and G6PD activities in the VP after hormonal exposures. The changes in T + DES-treated VP were most dramatic with a marked activation of GPx (by one-fold), GR (by one-fold), and G6PD (by five-fold). CONCLUSION The lobe-specific differential responses of hormone-induced oxidative stress and modulations of antioxidant enzymatic defenses in the Rat prostate suggest that reactive oxygen species may play a role in hormone-induced prostate carcinogenesis. Prostate 55:1–8, 2003. © 2003 Wiley-Liss, Inc.

  • altered expression of extracellular matrix and proteinases in Noble Rat prostate gland after long term treatment with sex steroids
    The Prostate, 2001
    Co-Authors: S C Li, G F Chen, Peter S F Chan, H L Choi, Shukmei Ho, Franky L Chan
    Abstract:

    BACKGROUND Interactions between the epithelial cells and stromal tissues, which include the epithelial basement membrane, extracellular matrix, inducible factors, and various cell types, are believed to play a significant role in prostate gland carcinogenesis. Remodeling of extracellular matrix and degradation of basement membrane are the prerequisites for tumor cell invasion, and these changes are correlated with the expression of various proteinases. METHODS The present study examined the alteRations of epithelial basement membrane, extracellular matrix, and proteinase activities in the Noble Rat prostate gland after long-term treatments with androgen and estrogen (T+DES or T+E2 for 4–12 months) by histochemistry, immunohistochemistry, electron microscopy, and gelatin-gel zymography. RESULTS After hormonal treatments, defects of epithelial basement membranes, such as focal disruption, diffuse staining and multilayering, were observed by histochemistry and immunohistochemistry in the dysplastic and neoplastic lesions induced in the lateral (LP) and ventral prostates (VP) but not in dorsal prostate (DP). An increase in the amount of extracellular matrix components, including hyaluronan (HA), chondroitin sulfate proteoglycan (CSPG) and tenascin, in the stroma of hormone-treated LP and VP was revealed by histochemistry and immunohistochemistry. Positive immunolabeling of matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) was detected in the fibromuscular layer surrounding the adenoma and adenocarcinoma induced in LP and VP after treatments with steroids for over 9–12 months. Zymography also detected an increase in activities of proteinases of apparent MW 120, 90, 86 and 68 kDa in the hormone-treated LP and VP, and these proteinases were characterized as metalloproteinases. In addition, two serine proteinases of MW 100 and 30 kDa were identified as being overexpressed in the hormone-treated LP and VP. Compared to LP and VP, there was no significant change in the proteinase activities in the hormone-treated DP. CONCLUSIONS The present study demonstRated that the epithelial basement membrane and stromal extracellular matrix were altered in dysplastic and neoplastic Noble Rat prostates. Since HA and CSPG (or their complexes) are highly anionic molecules, their increased accumulation in the altered prostatic stroma would tend to hydRate this tissue. This would create an environment more favorable for tumor growth and invasion. These morphological changes were also correlated with the concurrent increase in gelatinolytic proteinase activities induced in these prostates. The results suggest that the remodeling of the stromal tissue might play a role in the early stage of prostate carcinogenesis as shown in the Noble Rat model. Prostate 49:58–71, 2001. © 2001 Wiley-Liss, Inc.

Yongchuan Wong - One of the best experts on this subject based on the ideXlab platform.

  • Prostate cancer: The Id1 story
    Acta Histochemica Et Cytochemica, 2020
    Co-Authors: Yongchuan Wong, Xuesong Ouyang, Xiang Hong Wang, M T Ling, Franky L Chan
    Abstract:

    Id (inhibitor of differentiation or DNA binding) gene encodes a helix-loop helix protein which dimerizes and blocks the basic HLH protein from binding DNA. It expresses mainly in actively dividing cells and was first reported to be involved in hormone-induced prostate cancer in the Noble Rat model. It was subsequently confirmed also in human prostate cancer. Through functional studies under in vitro system, they have further demonstRated the role of Id1 in prostate cancer progression. They have shown that Id1 transfection stimulated prostate cancer cell prolifeRation through downregulation of p16/Rb, while inducing activation of MAPK and NFκB pathways. Activation of the latter pathways by ectopic transfection of Id1 to LNCaP cells, an androgen dependent line, also resulted in reduced sensitivity of prostate cancer cells to androgen on the one hand and upregulating the expression of EGFR and PSA on the other hand, which are both hallmarks of androgen independent prostate cancer. This review shows the crucial role played by Id1 in the conversion of prostate cancer from androgen dependent to androgen independent stage.

  • aberrant expression of hepatocyte growth factor and its receptor c met during sex hormone induced prostatic carcinogenesis in the Noble Rat
    Carcinogenesis, 2000
    Co-Authors: S S M Chung, Yongchuan Wong
    Abstract:

    : Hepatocyte growth factor (HGF) is a multifunctional cytokine which acts as a mitogen, motogen, morphogen and angiogenic factor of epithelial cells. HGF receptor is encoded by a proto-oncogene, c-met, which is overexpressed in various cancers. The role of HGF and c-Met in prostate carcinogenesis, especially in the early stages, is undefined. In this study, prostatic dysplasia and carcinomas were induced by testosterone propionate and 17 beta-estradiol in Noble Rats. The expression of HGF and c-Met was assessed at a protein level by immunohistochemistry and western blot analysis. Intense immunostaining for HGF alpha and c-Met beta-chain was co-localized in dysplastic lesions and in primary and metastatic cancer cells. The levels of HGF alpha expression were similar among normal control, dysplastic and cancerous prostate tissues, as determined by western blot analysis. Immunoblot study for c-Met under reducing conditions identified two bands at 145 kDa (beta-subunit of c-Met) and 170 kDa (precursor form of c-Met) in Rat liver extracts. However, two bands at approximately 220 and 245 kDa were detected in hormone-treated dysplastic prostate tissues and primary tumors. Overexpression of the 220 kDa band was observed in long-term (10-12 months) hormone-treated prostate and primary tumor extracts. Metastatic tumors consistently exhibited up-regulation of a single 245 kDa band. Under non-reducing conditions, however, protein bands of 220, 280 or 300 kDa were seen in the blots. The hormone-treated prostate tissues and metastatic tumors expressed the 220 and 300 kDa proteins, respectively. The majority of primary tumors expressed the 280 kDa protein. In summary, HGF and its receptor, c-Met, were co-expressed in dysplastic and tumor cells, suggesting that an autocrine mode of action may be involved in prostate carcinogenesis. The close correlation of expression of the high-molecular-weight isoforms of c-Met with different stages of carcinogenesis implicates that they might play differential roles in the onset, progression, growth and metastasis in prostate cancer.

  • changes in serum and tissue zinc levels in sex hormone induced prostatic carcinogenesis in the Noble Rat
    Tumor Biology, 2000
    Co-Authors: Yongchuan Wong, Yuzhuo Wang
    Abstract:

    We investigated the changes in serum and tissue zinc levels in the Noble Rat prostate gland under different pathological conditions induced by the administRation of a combination of testosterone and 17β-estradiol. The results showed that there were significant differences in serum zinc values between normal and hormone-treated Rats with prostatic hyperplasia, dysplasia and prostatic carcinoma (p

  • co expression of vascular endothelial growth factor vegf and its receptors flk 1 and flt 1 in hormone induced mammary cancer in the Noble Rat
    British Journal of Cancer, 1999
    Co-Authors: S W Tsao, Yongchuan Wong
    Abstract:

    Vascular endothelial growth factor (VEGF) is recognized to play a predominant role in breast cancer prognosis. The action of VEGF is mediated by two high-affinity receptors with ligand-stimulated tyrosine kinase activity: VEGFR-1/flt-1 and VEGFR-2/flk-1, which are expressed mainly in vascular endothelial cells. To the best of our knowledge, no previous studies on the expression of these receptors in breast cancer cells has been made. We have established a new animal model for breast cancer, using a combination of 17β-oestradiol and testosterone as ‘carcinogens’. Taking advantage of the animal model, we have demonstRated that mammary cancer cells expressed not only high levels of VEGF but also, surprisingly, its receptors (flt-1 and flk-1) in mammary cancer cells. Intense reactivities to VEGF, flt-1 and flk-1 were observed in mammary cancer cells, especially in invasive mammary carcinoma. Western blot analysis confirmed the increase in flk-1 and flt-1 proteins in induced mammary cancers. Based on these observations, we hypothesize that in mammary cancer, VEGF regulates, in addition to endothelial prolifeRation and angiogenesis, also growth of cancer cells by an autocrine mechanism mediated through its receptors. To further verify this hypothesis, we investigated the correlation between cellular prolifeRation and the expression of VEGF, flt-1 and flk-1. Using double-labelling immunocytochemistry, we have shown a correlation between high VEGF activity and Ki-67 expression. The Ki-67 indices in the areas of strong and weak VEGF reactivities were 58.3% and 3.7% respectively. Similarly, there was also a correlation of strong flk-1 and Ki-67 reactivity. The Ki-67 indices for areas of strong and weak flk-1 reactivities were 53.9% and 3.1% respectively. On the other hand, there was a reverse correlation between flt-1 and Ki-67 activities. These results indicate that overexpression of VEGF and flk-1 is correlated with high Ki-67 index. The data, therefore, suggest that VEGF may act as an autocrine growth factor for mammary cancer cells in vivo and this autocrine regulatory role may be mediated through flk-1. The present study is the first report showing that VEGF may act as a growth stimulator for mammary cancer cells. © 1999 Cancer Research Campaign

  • The prostate gland and prostate carcinogenesis.
    Italian journal of anatomy and embryology, 1998
    Co-Authors: Yongchuan Wong, Yuzhuo Wang, Tam Nn
    Abstract:

    : Despite extensive research, the mechanisms of prostate carcinogenesis are not well understood. The slow progress in this area is due, at least in part, to lack of a suitable animal model for prostate carcinogenesis. We have developed an animal model, based on the existing sex hormone-induced prostate carcinogenesis in the Noble Rat, by substantially increasing the dosage of testosterone while keeping the level of estrogen unchanged. Using the modified method of combination of testosterone and estradiol-17beta (T+E2), it has been shown in Noble Rats that prostate carcinogenesis followed a multi-step process involving hyperplasia, dysplasia, and carcinoma. We have demonstRated the importance of TGF-alpha, TGF-beta1 and bFGF in the development of prostate carcinogenesis. This study also established the roles of VEGF and IGF-1, initially as paracrine factors in epithelial-stromal interactions during the process of carcinogenesis and subsequently switching over to an autocrine mode during the establishment of carcinoma.

Irwin Leav - One of the best experts on this subject based on the ideXlab platform.

  • sex hormones induce direct epithelial and inflammation mediated oxidative nitrosative stress that favors prostatic carcinogenesis in the Noble Rat
    American Journal of Pathology, 2007
    Co-Authors: Irwin Leav, Shukmei Ho
    Abstract:

    Oxidative and nitrosative stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administRation of testosterone plus 17β-estradiol to Noble Rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2′-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/nitrosative stress in epithelium. We concluded that the oxidative/nitrosative damage resulting from the testosterone-plus-17β-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the up-regulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus, we link alteRations in the hormonal milieu with oxidative/nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis.

  • Sex hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the Noble Rat.
    American Journal of Pathology, 2007
    Co-Authors: Irwin Leav, Shukmei Ho
    Abstract:

    Oxidative and nitrosative stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administRation of testosterone plus 17β-estradiol to Noble Rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2′-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/nitrosative stress in epithelium. We concluded that the oxidative/nitrosative damage resulting from the testosterone-plus-17β-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the up-regulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus, we link alteRations in the hormonal milieu with oxidative/nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis.

  • lack of association between enhanced trpm 2 clusterin expression and increased apoptotic activity in sex hormone induced prostatic dysplasia of the Noble Rat
    American Journal of Pathology, 1998
    Co-Authors: Shukmei Ho, Irwin Leav, Shibnath Ghatak, Frederick B Merk, Vehda S Jagannathan, Kevin Mallery
    Abstract:

    Although the functional role of TRPM-2/clusterin in the prostate remains controversial, it has been postulated that transcriptional activation of the gene is an important mechanism in castRation-induced prostatic involution and perhaps is a means for prostatic cells to escape apoptotic induction. In the present study, we have measured expression levels of TRPM-2/clusterin and apoptotic activities in the prostates of castRated Noble (NBL) Rats and those treated with testosterone (T) and estradiol-17β (E2) for 16 weeks. We have previously shown that the combined sex hormone treatment (T+E2) induces dysplasia, a purported preneoplastic lesion, exclusively in the dorsolateral prostates (DLPs) of all treated Rats. In the present study, we demonstRate that, as expected, castRation readily induced enhanced TRPM-2/clusterin expression, which was accompanied by increased apoptotic activity in the epithelia of DLP and ventral prostate (VP). The increase in TRPM-2/clusterin expression appeared earlier and was more dramatic in the VP than in the DLP. In sharp contrast, treatment of Rats with T+E2 for 16 weeks induced augmentation of TRPM-2/clusterin expression selectively in the dysplastic lesions of the DLP but not in the lesion-free VP. The enhanced expression of TRPM-2/clusterin in the dysplastic epithelium was, however, not attended by an increase in apoptotic activity within the lesion. Thus, the observed up-regulation of TRPM-2/clusterin expression in the dysplastic foci of T+E2-treated Rats occurred in animals whose androgen status remained normal and, despite the increased level of expression of this gene, apoptotic activity in these lesions was unchanged from basal values measured in the DLPs of untreated Rats. These findings suggest that TRPM-2/clusterin expression in dysplastic lesions was no longer repressed by androgen nor was it associated with apoptosis. We propose that overexpression of the gene is likely a phenotype of neoplastic transformation. In addition, we speculate that TRPM-2/clusterin may serve as a survival factor, which could favor accumulation of transformed cells in dysplastic foci and thus promote the carcinogenic process.

  • mitogen activated protein kinase and mitogen activated kinase phosphatase 1 expression in the Noble Rat model of sex hormone induced prostatic dysplasia and carcinoma
    Laboratory Investigation, 1996
    Co-Authors: Irwin Leav, Shukmei Ho, Cristina Magi Galluzzi, Jeffrey Ziar, Philip J S Stork, Massimo Loda
    Abstract:

    : Our recent studies have implicated the TGF-alpha/epidermal growth factor receptor pathway in the genesis of testosterone (T) and estradiol-17 beta (E2)-induced dysplasia in the dorsolateral prostate (DLP) of Noble Rats. This pathway was also found to be markedly up-regulated in the androgen-independent transplantable carcinoma that arose from the DLP of a Noble Rat. In the current study, we investigated the expression of mitogen-activated protein kinase (MAP-kinase) and mitogen-activated kinase phosphatase-1 (MKP-1), key downstream regulators of growth factor-activated signal transduction in the DLP of castRated, castRated T-supplemented, and T+E2-treated Rats and in the androgen-independent transplantable carcinoma. Both MAP-kinase and MKP-1 expression in the DLP were found to be dependent on androgen stimulation. Immunoblots of DLP from T+E2 treated Rats demonstRated a selective decline in MKP-1 levels with no alteRation in MAP-kinase expression. These findings suggest that the dual hormone treatment induces changes in the signal transduction pathway, which favors the protracted mitogenic action of MAP-kinase. In situ hybridization and immunohistochemistry findings corroboRated the immunoblot data but also revealed that both MAP-kinase and MKP-1 were strongly expressed in severely dysplastic lesions, which may indicate the presence of transformed cells in these foci. In this regard, both proteins were strongly expressed in samples of the androgen-independent transplantable carcinoma. Taken together, results from this and our recent study suggest that alteRations in a growth factor-MAP-kinase pathway may be important events in the initiation and progression of prostatic carcinoma.

  • Metabolism of estradiol and estrone in organ cultures of dorsolateral and ventral prostate of untreated and sex hormone-implanted Rats
    Steroids, 1992
    Co-Authors: Peter Ofner, R L Vena, Marie R. Nadeau, Irwin Leav
    Abstract:

    Abstract Since dorsolateral but not ventral prostate undergoes estrogen-induced dysplasia in the androgen-supported Noble Rat in 16 weeks, we studied estrogen metabolism by these tissues from untreated and sex hormone-implanted animals. We incubated 8.5 nM [6,7-3H]-labeled estradiol (E2) and estrone (E1) for 21 hours in serum-free, prostate-lobe cultures and 8.5 nM [2-3H]E2 with expiants from untreated Rats and animals treated with testosterone, 5α-dihydrotestosterone, or E2 plus testosterone. Untreated Rat ventral prostate metabolized 3.7 times as much E2 to E1 as dorsolateral prostate, whereas the latter tissue converted 2.5 times as much E1 to E2 as the former. After dorsolateral prostate culture with 8.5 nM [6,7-3H]-labeled E2 or E1 0.6 M KCl-extracted, Sephadex G25-excluded nuclear protein bound preponderantly E2, whereas the counterpart nuclear protein fraction from ventral prostate explants incubated with E2 bound substRate and E1 almost equally. The combination sex hormone treatment decreased E2 metabolism and increased its uptake by the dysplastic dorsolateral prostate. Implantation of 5α-dihydrotestosterone, but not of testosterone, also decreased E2 metabolism to E1 by dorsolateral prostate cultures. Treatments with E2 plus testosterone and with 5α-dihydrotestosterone changed E2 uptake/E1 retention in dorsolateral prostate expiants from 2.4 to 7.4 and 8.5, respectively. C-2 tritium release marking the 2,3-catechol estrogen pathway was greater for ventral than dorsolateral prostate, but was unaffected by the sex hormone treatments. Nuclear ligand preponderance of E2 could account for the reported presence of type II estrogen-binding sites in the Rat dorsolateral prostate and help to explain induction of lobe-specific dysplasia and adenocarcinoma after chronic androgen/estrogen combination treatment.