Antiangiogenic And Finasteride Therapies: Responses Of The Prostate Microenvironment In Elderly Mice

Aims The aim of this study was to evaluate the structural and molecular effects of antiangiogenic therapies and finasteride on the ventral prostate of senile mice. Main methods 90 male FVB mice were divided into: Young (18 weeks old) and senile (52 weeks old) groups; finasteride group: finasteride (20 mg/kg); SU5416 group: SU5416 (6 mg/kg); TNP-470 group: TNP-470 (15 mg/kg,) and SU5416 + TNP-470 group: similar to the SU5416 and TNP-470 groups. After 21 days, prostate ventral lobes were collected for morphological, immunohistochemical and Western blotting analyses. Key findings The results demonstrated atrophy, occasional proliferative lesions and inflammatory cells in the prostate during senescence, which were interrupted and/or blocked by treatment with antiangiogenic drugs and finasteride. Decreased AR and endostatin reactivities, and an increase for ER-α, ER-β and VEGF, were seen in the senile group. Decreased VEGF and ER-α reactivities and increased ER-β reactivity were verified in the finasteride, SU5416 groups and especially in SU5416 + TNP-470 group. The TNP-470 group showed reduced AR and ER-β protein levels. Significance The senescence favored the occurrence of structural and/or molecular alterations suggesting the onset of malignant lesions, due to the imbalance in the signaling between the epithelium and stroma. The SU5416 + TNP-470 treatment was more effective in maintaining the structural, hormonal and angiogenic factor balance in the prostate during senescence, highlighting the signaling of antiproliferation via ER-β. © 2014 Elsevier Inc.10601/02/155870Abdollahi, A., Lipson, K.E., Sckell, A., Zieher, H., Klenke, F., Poerschke, D., Roth, A., Huber, P.E., Combined Therapy with Direct and Indirect Angiogenesis Inhibition Results in Enhanced Antiangiogenic and Antitumor Effects (2003) Cancer Research, 63 (24), pp. 8890-8898Amikura, K., Matsuno, S., Egawa, S., Synergistic antitumor effect of an angiogenesis inhibitor (TNP-470) and tumor necrosis factor in mice (2006) Surgery Today, 36 (12), pp. 1069-1074. , DOI 10.1007/s00595-006-3289-3Andreollo, N.A., Santos, E.F., Araújo, M.R., Lopes, L.R., Rat's age versus human's age: What is the relationship? (2012) Arq Bras Cir Dig, 25 (1), pp. 49-51Aragon-Ching, J.B., Madan, R.A., Dahut, W.L., Angiogenesis inhibition in prostate cancer: Current uses and future promises (2010) J Oncol, 1-7Ban, H.S., Uno, M., Nakamura, H., Suppression of hypoxia-induced HIF-1alpha accumulation by VEGF inhibitors: Different profiles of AAL993 versus SU5416 and KRN633 (2010) Cancer Lett, 296 (1), pp. 17-26Banerjee, S., Banerjee, P.P., Brown, T.R., Castration-induced apoptotic cell death in the Brown Norway rat prostate decreases as a function of age (2000) Endocrinology, 141 (2), pp. 821-832. , DOI 10.1210/en.141.2.821Bavik, C., Coleman, I., Dean, J.P., Knudsen, B., Plymate, S., Nelson, P.S., The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms (2006) Cancer Research, 66 (2), pp. 794-802. , DOI 10.1158/0008-5472.CAN-05-1716Bianchi-Frias, D., Vakar-Lopez, F., Coleman, I.M., Plymate, S.R., Reed, M.J., Nelson, P.S., The effects of aging on the molecular and cellular composition of the prostate microenvironment (2010) PLoS One, 5 (9), pp. 1-16Bruni-Cardoso, A., Augusto, T.M., Pravatta, H., Damas-Souza, D.M., Carvalho, H.F., Stromal remodelling is required for progressive involution of the rat ventral prostate after castration: Identification of a matrix metalloproteinase-dependent apoptotic wave (2010) Int J Androl, 33 (5), pp. 686-695Cai, J., Hong, Y., Weng, C., Tan, C., Imperato-Mcginley, J., Zhu, Y.-S., Androgen stimulates endothelial cell proliferation via an androgen receptor/VEGF/cyclin A-mediated mechanism (2011) Am J Physiol Heart Circ Physiol, 300, pp. 1210-H1221Candido, E.M., Fávaro, W.J., Montico, F., Hetzl, A.C., Cagnon, V.H.A., Senescence and steroid hormone receptor reactivities in accessory sex glands of elderly rats (Sprague-Dawley) following exogenous hormonal therapy (2012) Tissue Cell, 44 (4), pp. 227-237Castronovo, V., Belotti, D., TNP-470 mechanisms of action and early clinical development (1996) EJC, 32 (14), pp. 2520-2527Chang, B.-D., Broude, E.V., Dokmanovic, M., Zhu, H., Ruth, A., Xuan, Y., Kandel, E.S., Roninson, I.B., A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents (1999) Cancer Research, 59 (15), pp. 3761-3767Cheng, L., Zhang, S., Sweeney, C.J., Kao, C., Gardner, T.A., Eble, J.N., Androgen withdrawal inhibits tumor growth and is associated with decrease in angiogenesis and VEGF expression in androgen-independent CWR22Rv1 human prostate cancer model (2004) Anticancer Research, 24 (4), pp. 2135-2140Christensen, J.G., A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities (2007) Ann Oncol, 18, pp. 3-x10Cordeiro, R.S., Scarano, W.R., Campos, S.G., Santos, F.C., Vilamaior, P.S., Góes, R.M., Androgen receptor in the Mongolian gerbil ventral prostate: Evaluation during different phases of postnatal development and following androgen blockage (2008) Micron, 39 (8), pp. 1312-1324Crawford, E.D., Andriole, G.L., Marberger, M., Rittmaster, R.S., Reduction in the risk of prostate cancer: Future directions after the Prostate Cancer Prevention Trial (2010) Urology, 75 (3), pp. 502-509Cunha, G.R., Hayward, S.W., Wang, Y.Z., Role of stroma in carcinogenesis of the prostate (2002) Differentiation, 70 (9-10), pp. 473-485. , DOI 10.1046/j.1432-0436.2002.700902.xDavalos, A.R., Coppe, J.-P., Campisi, J., Desprez, P.-Y., Senescent cells as a source of inflammatory factors for tumor progression (2010) Cancer Metastasis Rev, 29 (2), pp. 273-283Delongchamps, N.B., Peyromaure, M., Dinh-Xuan, A.T., Role of vascular endothelial growth factor in prostate cancer (2006) Urology, 68 (2), pp. 244-248. , DOI 10.1016/j.urology.2006.03.010, PII S0090429506003542Ellem, S.J., Risbridger, G.P., The dual, opposing roles of estrogen in the prostate (2009) Ann N y Acad Sci, 1155, pp. 174-186Ellem, S.J., Risbridger, G.P., Aromatase and regulating the estrogen: Androgen ratio in the prostate gland (2010) J Steroid Biochem Mol Biol, 118, pp. 246-251Folkman, J., Antiangiogenesis in cancer therapy: Endostatin and its mechanisms of action (2005) Exp Cell Res, 312, pp. 594-606Folkman, J., Hahnfeldt, P., Hlatky, L., The logic of anti-angiogenic gene therapy (1998) The Development of Gene Therapy, pp. 527-543. , T. Friedmann, Cold Spring Harbor Laboratory Press New YorkFong, T.A.T., Shawver, L.K., Sun, L., Tang, C., App, H., Powell, T.J., Kim, Y.H., McMahon, G., SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types (1999) Cancer Research, 59 (1), pp. 99-106Glassman, D.T., Chon, J.K., Borkowski, A., Jacobs, S.C., Kyprianou, N., Combined effect of terazosin and finasteride on apoptosis, cell proliferation, and transforming growth factor-β expression in benign prostatic hyperplasia (2001) Prostate, 46 (1), pp. 45-51. , DOI 10.1002/1097-0045(200101)46:1<45::AID-PROS1007>3.0.CO;2-UGonzales, G.F., Gasco, M., Malheiros-Pereira, A., Gonzales-Castaneda, C., Antagonistic effect of Lepidium meyenii (red maca) on prostatic hyperplasia in adult mice (2008) Andrologia, 40 (3), pp. 179-185. , DOI 10.1111/j.1439-0272.2008.00834.xHäggström, S., Stattin, P., Wikström, P., Bergh, A., Damber, J.E., Castration-induced reduction of vascular endothelial growth factor expression in benign human prostate tissue is lost in advanced prostate cancer (2001) BJU Int, 88 (1), pp. 110-116Hetzl, A.C., Montico, F., Lorencini, R.M., Kido, L.A., Cândido, E.M., Cagnon, V.H., Prostatic microenvironment in senescence: Fibroblastic growth factors × hormonal imbalance (2013) Histochem Cell Biol, , 10.1007/s00418-013-1173-yHochberg, D.A., Basillote, J.B., Armenakas, N.A., Vasovic, L., Shevchuk, M., Pareek, G., Fracchia, J.A., Decreased suburethral prostatic microvessel density in finasteride treated prostates: A possible mechanism for reduced bleeding in benign prostatic hyperplasia (2002) Journal of Urology, 167 (4), pp. 1731-1733Hsing, A.W., Hormones and prostate cancer: What's next? (2001) Epidemiologic Reviews, 23 (1), pp. 42-58Huss, W.J., Barrios, R.J., Greenberg, N.M., SU5416 selectively impairs angiogenesis to induce prostate cancer-specific apoptosis (2003) Mol Cancer Ther, 2, pp. 611-616Justulin, L.A., Della-Coleta, H.H.M., Taboga, S.R., Felisbino, S.L., Matrix metalloproteinase MMP-2 and MMP-9 activity and localization during ventral prostate atrophy and regrowth (2010) Int J Androl, 33 (5), pp. 696-708Kato, T., Sato, K., Kakinuma, H., Matsuda, Y., Enhanced suppression of tumor growth by combination of angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470) and cytotoxic agents in mice (1994) Cancer Research, 54 (19), pp. 5143-5147Krtolica, A., Campisi, J., Cancer and aging: A model for the cancer promoting effects of the aging stroma (2002) International Journal of Biochemistry and Cell Biology, 34 (11), pp. 1401-1414. , DOI 10.1016/S1357-2725(02)00053-5, PII S1357272502000535Lau, K.-M., Tam, N.N.C., Thompson, C., Cheng, R.Y.S., Leung, Y.-K., Ho, S.-M., Age-associated changes in histology and gene-expression profile in the rat ventral prostate (2003) Laboratory Investigation, 83 (5), pp. 743-757Franck-Lissbrant, I., Haggstrom, S., Damber, J.-E., Bergh, A., Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated adult rats (1998) Endocrinology, 139 (2), pp. 451-456. , DOI 10.1210/en.139.2.451Lissbrant, I.F., Hammarsten, P., Lissbrant, E., Ferrara, N., Rudolfsson, S.H., Bergh, A., Neutralizing VEGF Bioactivity with a Soluble Chimeric VEGF-Receptor Protein flt(I-3) IgG Inhibits Testosterone-Stimulated Prostate Growth in Castrated Mice (2004) Prostate, 58 (1), pp. 57-65. , DOI 10.1002/pros.10312Lohmiller, Swing, The laboratory rat (2005) Reproduction and Breeding, pp. 147-164. , Academic Press [Imprint, Charpter 6]Lucia, M.S., Epstein, J.I., Goodman, P.J., Darke, A.K., Reuter, V.E., Civantos, F., Tangen, C.M., Thompson, I.M., Finasteride and high-grade prostate cancer in the prostate cancer prevention trial (2007) Journal of the National Cancer Institute, 99 (18), pp. 1375-1383. , DOI 10.1093/jnci/djm117Masiero, L., Figg, W.D., Kohn, E.C., New anti-angiogenesis agents: Review of the clinical experience with carboxyamido-triazole (CAI), thalidomide, TNP-470 and interleukin-12 (1997) Angiogenesis, 1 (1), pp. 23-35Matsusaka, S., Nakasho, K., Terada, N., Sugihara, A., Tsujimura, T., Takanashi, T., Uematsu, K., Toyosaka, A., Inhibition by an angiogenesis inhibitor, TNP-470, of the growth of a human hepatoblastoma heterotransplanted into nude mice (2000) Journal of Pediatric Surgery, 35 (8), pp. 1198-1204. , DOI 10.1053/jpsu.2000.8726Miki, T., Nonomura, N., Nozawa, M., Harada, Y., Nishimura, K., Kojima, Y., Takahara, S., Okuyama, A., Angiogenesis inhibitor TNP-470 inhibits growth and metastasis of a hormone-independent rat prostatic carcinoma cell line (1998) Journal of Urology, 160 (1), pp. 210-213. , DOI 10.1016/S0022-5347(01)63092-1Montico, F., Hetzl, A.C., Cândido, E.M., Fávaro, W.J., Cagnon, V.H.A., Hormonal therapy in the senescence: Prostatic microenvironment structure and adhesion molecules (2011) Micron, 42 (6), pp. 642-655Morales, A., Androgen replacement therapy and prostate safety (2002) European Urology, 41 (2), pp. 113-120. , DOI 10.1016/S0302-2838(01)00039-2, PII S0302283801000392Nickel, J.C., True, L.D., Krieger, J.N., Berger, R.E., Boag, A.H., Young, I.D., Consensus development of a histopathological classification system for chronic prostatic inflammation (2001) BJU International, 87 (9), pp. 797-805. , DOI 10.1046/j.1464-410X.2001.02193.xO'Donnell, L., Robertson, K.M., Jones, M.E., Simpson, E.R., Estrogen and spermatogenesis (2001) Endocrine Reviews, 22 (3), pp. 289-318. , DOI 10.1210/er.22.3.289Pareek, G., Shevchuk, M., Armenakas, N.A., Vasjovic, L., Hochberg, D.A., Basillote, J.B., Fracchia, J.A., The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density: A possible mechanism for decreased prostatic bleeding in treated patients (2003) Journal of Urology, 169 (1), pp. 20-23Pelletier, G., El-Alfy, M., Immunocytochemical localization of estrogen receptors α and β in the human reproductive organs (2000) Journal of Clinical Endocrinology and Metabolism, 85 (12), pp. 4835-4840. , DOI 10.1210/jc.85.12.4835Quinn, R., Comparing rat's to human's age: How old is my rat in people years? (2005) Nutrition, 21 (6), pp. 775-777. , DOI 10.1016/j.nut.2005.04.002, PII S0899900705001711Reed, M.J., Karres, N., Eyman, D., Cruz, A., Brekken, R.A., Plymate, S., The effects of aging on tumor growth and angiogenesis are tumor-cell dependent (2007) International Journal of Cancer, 120 (4), pp. 753-760. , DOI 10.1002/ijc.22351Reynolds, A.R., Kaprianou, N., Growth factor signaling in prostatic growth: Significance in tumor development and therapeutic targeting (2006) Br J Pharmacol, 147, pp. 144-S152Rittmaster, R.S., Manning, A.P., Wright, A.S., Thomas, L.N., Whitefield, S., Norman, R.W., Evidence for atrophy and apoptosis in the ventral prostate of rats given the 5α-reductase inhibitor finasteride (1995) Endocrinology, 136 (2), pp. 741-748Roy-Burman, P., Wu, H., Powell, W.C., Hagenkord, J., Cohen, M.B., Genetically defined mouse models that mimic natural aspects of human prostate cancer development (2004) Endocrine-Related Cancer, 11 (2), pp. 225-254. , DOI 10.1677/erc.0.0110225Sim, B.K.L., MacDonald, N.J., Gubish, E.R., Angiostatin and endostatin: Endogenous inhibitors of tumor growth (2000) Cancer and Metastasis Reviews, 19 (1-2), pp. 181-190. , DOI 10.1023/A:1026551202548Strieth, S., Eichhorn, M.E., Sutter, A., Jonczyk, A., Berghaus, A., Dellian, M., Antiangiogenic combination tumor therapy blocking alpha (v)-integrins and VEGF-receptor-2 increases therapeutic effects in vivo (2006) Int J Cancer, 119 (2), pp. 423-431Thompson, I.M., Lucia, M.S., Redman, M.W., Darke, A., La Rosa, F.G., Parnes, H.L., Finasteride decreases the risk of prostatic intraepithelial neoplasia (2007) J Urol, 178 (1), pp. 107-109Thompson, I.M., Tangen, C.M., Goodman, P.J., Lucia, M.S., Klein, E.A., Chemoprevention of prostate cancer (2009) J Urol, 182 (2), pp. 499-507Tomas, D., Kruslin, B., The potential value of (myo)fibroblastic stromal reaction in the diagnosis of prostatic adenocarcinoma (2004) Prostate, 61 (4), pp. 324-331. , DOI 10.1002/pros.20109Toorians, A.W.F.T., Kelleher, S., Gooren, L.J., Jimenez, M., Handelsman, D.J., Estimating the Contribution of the Prostate to Blood Dihydrotestosterone (2003) Journal of Clinical Endocrinology and Metabolism, 88 (11), pp. 5207-5211. , DOI 10.1210/jc.2003-030521Tutrone, Jr.R.F., Ball, R.A., Ornitz, D.M., Leder, P., Richie, J.P., Benign prostatic hyperplasia in a transgenic mouse: A new hormonally sensitive investigatory model (1993) J Urol, 149 (3), pp. 633-699Tuxhorn, J.A., Ayala, G.E., Smith, M.J., Smith, V.C., Dang, T.D., Rowley, D.R., Reactive stroma in human prostate cancer: Induction of myofibroblast phenotype and extracellular matrix remodeling (2002) Clinical Cancer Research, 8 (9), pp. 2912-2923Tuxhorn, J.A., McAlhany, S.J., Dang, T.D., Ayala, G.E., Rowley, D.R., Stromal cells promote angiogenesis and growth of human prostate tumors in a differential reactive stroma (DRS) xenograft model (2002) Cancer Research, 62 (11), pp. 3298-3307Van Moorselaar, R.J.A., Voest, E.E., Angiogenesis in prostate cancer: Its role in disease progression and possible therapeutic approaches (2002) Molecular and Cellular Endocrinology, 197 (1-2), pp. 239-250. , DOI 10.1016/S0303-7207(02)00262-9, PII S0303720702002629Weidner, N., Carroll, P.R., Flax, J., Blumenfeld, W., Folkman, J., Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma (1993) American Journal of Pathology, 143 (2), pp. 401-409Weihua, Z., Makela, S., Andersson, L.C., Salmi, S., Saji, S., Webster, J.I., Jensen, E.V., Gustafsson, J.-A., A role for estrogen receptor β in the regulation of growth of the ventral prostate (2001) Proceedings of the National Academy of Sciences of the United States of America, 98 (11), pp. 6330-6335. , DOI 10.1073/pnas.111150898Yamaoka, M., Yamamoto, T., Masaki, T., Ikeyama, S., Sudo, K., Fujita, T., Inhibition of tumor growth and metastasis of rodent tumors by the angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470AGM- 1470) (1993) Cancer Research, 53 (18), pp. 4262-4267Zar, J.H., (1999) Biostatistical Analysis, , 4th ed. Prentice Hall Upper, New JerseyZhao, H., Patra, A., Yeh, C.-C., Tanaka, Y., Oh, B.R., Dahiya, R., Effects of aging on growth factors gene and protein expression in the dorsal and ventral lobes of rat prostate (2002) Biochemical and Biophysical Research Communications, 292 (2), pp. 482-491. , DOI 10.1006/bbrc.2002.6660Zhong, X.-S., Zheng, J.Z., Reed, E., Jiang, B.-H., SU5416 inhibited VEGF and HIF-1α expression through the PI3K/AKT/p70S6K1 signaling pathway (2004) Biochemical and Biophysical Research Communications, 324 (2), pp. 471-480. , DOI 10.1016/j.bbrc.2004.09.082, PII S0006291X0402116