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Antiangiogenic therapy effects on age-associated matrix metalloproteinase-9 (MMP-9) and insulin-like growth factor receptor-1 (IGFR-1) responses: a comparative study of prostate disorders in aged and TRAMP mice

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Abstract

Senescence is associated with hormonal imbalance and prostatic disorders. Angiogenesis is fundamental for the progression of malignant lesions and is a promising target for prostate cancer treatment. The aim was to characterize matrix metalloproteinase-9 (MMP-9) and insulin-like growth factor receptor-1 (IGFR-1) responses in the prostate during senescence and following antiangiogenic and/or androgen ablation therapies, comparing them to cancer progression features in TRAMP mice. Aged male mice (52-week-old FVB) were submitted to antiangiogenic treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c). Finasteride (20 mg/kg; s.c.) was administered alone or associated to both inhibitors. Dorsolateral prostate was collected for light microscopy, and immunohistochemistry and Western blotting collected for MMP-9 and IGFR-1. Senescence led to inflammation and different proliferative lesions in the prostate, as well as to increased MMP-9 and IGFR-1, resembling TRAMP mice prostatic microenvironment. Antiangiogenic therapies promoted recovery and/or interruption of age-associated alterations, presenting differential effects on the molecules studied. SU5416 acted mainly on MMP-9, whereas TNP-470 showed its best influence on IGFR-1 levels. Finasteride administration, alone or in combination with antiangiogenic agents, also resulted in regression of inflammation and neoplastic lesions, besides having a negative modulatory effect on both MMP-9 and IGFR-1. We concluded that stimulated tissue remodeling and proliferative processes during senescence predisposed the prostate to malignant disorders. The combination of different agents was more effective to minimize prostatic imbalance during this period, probably due to the differential action of each drug on factors involved in cell proliferation and extracellular matrix remodeling, resulting in a broader spectrum of effects following the combined treatment.

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References

  • Abdollahi A, Lipson KE, Sckell A, Zieher H, Klenke F, Poerschke D, Roth A, Han X, Krix M, Bischof M, Hahnfeldt P, Grone HJ, Debus J, Hlatky L, Huber PE (2003) Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. Cancer Res 63:8890–8898

    CAS  PubMed  Google Scholar 

  • Anawalt BD, Merriam BR (2001) Neuroendocrine aging in men: andropause and somatopause. Endocrinol Metab Clin North Am 30:647–669

    Article  CAS  PubMed  Google Scholar 

  • Aragon-Ching JB, Dahut WL (2009) VEGF inhibitors and prostate cancer therapy. Curr Mol Pharmacol 2:161–168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bandyopadhyay A, Wang L, López-Casillas F, Mendoza V, Yeh IT, Sun L (2005) Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer. Prostate 63:81–90

    Article  PubMed  Google Scholar 

  • Banerjee PP, Banerjee S, Lai JM, Strandberg JD, Zirkin BR, Brown TR (1998) Age-dependent and lobe-specific spontaneous hyperplasia in the Brown Norway rat prostate. Biol Reprod 59:1163–1170

    Article  CAS  PubMed  Google Scholar 

  • Banerjee PP, Banerjee S, Brown TR (2001) Increased androgen receptor expression correlates with development of age-dependent, lobe-specific spontaneous hyperplasia of the Brown Norway rat prostate. Endocrinology 142:4066–4075

    Article  CAS  PubMed  Google Scholar 

  • Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Berman-Booty LD, Sargeant AM, Rosol TJ, Rengel RC, Clinton SK, Chen CS, Kulp SK (2012) A review of the existing grading schemes and a proposal for a modified grading scheme for prostatic lesions in TRAMP mice. Toxicol Pathol 40:5–17

    Article  PubMed  Google Scholar 

  • Bianchi-Frias D, Vakar-Lopez F, Coleman IM, Plymate SR, Reed MJ, Nelson PS (2010) The effects of aging on the molecular and cellular composition of the prostate microenvironment. PLoS ONE. doi:10.1371/journal.pone.0012501

    PubMed Central  PubMed  Google Scholar 

  • Bosland MC (1992) Animal models for the study of prostate carcinogenesis. J Cell Biochem Suppl 16:89–98

    Article  Google Scholar 

  • Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522

    Article  CAS  PubMed  Google Scholar 

  • Castronovo V, Belotti D (1996) TNP-470 (AGM-1470): mechanisms of action and early clinical development. Eur J Cancer 32:2520–2527

    Article  Google Scholar 

  • Condon MS (2005) The role of the stromal microenvironment in prostate cancer. Semin Cancer Biol 15:132–137

    Article  PubMed  Google Scholar 

  • Coppé JP, Kauser K, Campisi J, Beauséjour CM (2006) Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem 281:29568–29574

    Article  PubMed  Google Scholar 

  • Cordeiro RS, Scarano WR, Campos SG, Santos FC, Vilamaior PS, Góes RM, Taboga SR (2008) Androgen receptor in the Mongolian gerbil ventral prostate: evaluation during different phases of postnatal development and following androgen blockage. Micron 39:1312–1324

    Article  CAS  PubMed  Google Scholar 

  • Delella FK, Justulin LA Jr, Felisbino SL (2010) Finasteride treatment alters MMP-2 and -9 gene expression and activity in the rat ventral prostate. Int J Androl 33:e114–e122

    Article  CAS  PubMed  Google Scholar 

  • Djavan B, Waldert M, Seitz C, Marberger M (2001) Insulin-like growth factors and prostate cancer. World J Urol 19:225–233

    Article  CAS  PubMed  Google Scholar 

  • Doll JA, Reiher FK, Crawford SE, Pins MR, Campbell SC, Bouck NP (2001) Thrombospondin-1, vascular endothelial growth factor and fibroblast growth factor-2 are key functional regulators of angiogenesis in the prostate. Prostate 49:293–305

    Article  CAS  PubMed  Google Scholar 

  • Ellis LM, Takahashi Y, Liu W, Shaheen RM (2000) Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist 5:11–15

    Article  CAS  PubMed  Google Scholar 

  • Figg WD, Kruger EA, Price DK, Kim S, Dahut WD (2002) Inhibition of angiogenesis: treatment options for patients with metastatic prostate cancer. Invest New Drugs 20:183–194

    Article  CAS  PubMed  Google Scholar 

  • Folkman J (2006) Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Exp Cell Res 312:594–607

    Article  CAS  PubMed  Google Scholar 

  • Folkman JHP, Hlatky L (1998) The logic of anti-angiogenic gene therapy. In: Friedmann T (ed) The development of gene therapy. Cold Spring Harbor Laboratory Press, New York, pp 1–17

    Google Scholar 

  • Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP, McMahon G (1999) 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. Cancer Res 59:99–106

    CAS  PubMed  Google Scholar 

  • Gennigens C, Menetrier-Caux C, Droz JP (2006) Insulin-like growth factor (IGF) family and prostate cancer. Crit Rev Oncol Hematol 58:124–145

    Article  CAS  PubMed  Google Scholar 

  • Gervaz P, Scholl B, Padrum V, Gillet M (2000) Growth inhibition of liver metastasis by the anti-angiogenic drug TNP-470. Liver 20:108–113

    Article  CAS  PubMed  Google Scholar 

  • Gingrich JR, Barrios RJ, Foster BA, Greenberg NM (1999) Pathologic progression of autochthonous prostate cancer in the TRAMP model. Prostate Cancer Prostatic Dis 2:70–75

    Article  PubMed  Google Scholar 

  • Gonzales GF, Gasco M, Malheiros-Pereira A, Gonzales-Castañeda C (2008) Antagonistic effect of Lepidium meyenii (red maca) on prostatic hyperplasia in adult mice. Andrologia 40:179–185

    Article  CAS  PubMed  Google Scholar 

  • Greenberg NM, Demayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO, Cunha GR, Donjacour AA, Matusik RJ, Rosen JM (1995) Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 92:3439–3443

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Grzmil M, Hemmerlein B, Thelen P, Schweyer S, Burfeind P (2004) Blockade of the type I IGF receptor expression in human prostate cancer cells inhibits proliferation and invasion, up-regulates IGF binding protein-3, and suppresses MMP-2 expression. J Pathol 202:50–59

    Article  CAS  PubMed  Google Scholar 

  • Häggström S, Torring N, Moller K, Jensen E, Lund L, Nielsen JE, Bergh A, Damber JE (2002) Effects of finasteride on vascular endothelial growth factor. Scand J Urol Nephrol 36:182–187

    Article  PubMed  Google Scholar 

  • Hetzl AC, Fávaro WJ, Billis A, Ferreira U, Cagnon VH (2012) Steroid hormone receptors, matrix metalloproteinases, insulin-like growth factor, and dystroglycans interactions in prostatic diseases in the elderly men. Microsc Res Tech 75:1197–1205

    Article  CAS  PubMed  Google Scholar 

  • Huss WJ, Barrios RJ, Greenberg NM (2003) SU5416 selectively impairs angiogenesis to induce prostate cancer-specific apoptosis. Mol Cancer Ther 2:611–616

    CAS  PubMed  Google Scholar 

  • Huynh H, Seyam RM, Brock GB (1998) Reduction of ventral prostate weight by finasteride is associated with suppression of insulin-like growth factor I (IGF-I) and IGF-I receptor genes and with an increase in IGF binding protein 3. Cancer Res 58:215–218

    CAS  PubMed  Google Scholar 

  • Junqueira LC, Bignolas G, Brentani RR (1979) Picrossirius staining plus polarization microscopy, a specific method of collagen detection in tissue sections. Histochem J 11:447–455

    Article  CAS  PubMed  Google Scholar 

  • Kawada M, Inoue H, Arakawa M, Ikeda D (2008) Transforming growth factor-beta1 modulates tumor-stromal cell interactions of prostate cancer through insulin-like growth factor-I. Anticancer Res 28:721–730

    CAS  PubMed  Google Scholar 

  • Kong D, Li Y, Wang Z, Banerjee S, Sarkar FH (2007) Inhibition of angiogenesis and invasion by 3,3′-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res 67:3310–3319

    Article  CAS  PubMed  Google Scholar 

  • Koyama H, Nishizawa Y, Hosoi M, Fukumoto S, Kogawa K, Shioi A, Morii H (1996) The fumagillin analogue TNP-470 inhibits DNA synthesis of vascular smooth muscle cells stimulated by platelet-derived growth factor and insulin-like growth factor-I. Possible involvement of cyclin-dependent kinase 2. Circ Res 79:757–764

    Article  CAS  PubMed  Google Scholar 

  • Krieg M, Nass R, Tunn S (1993) Effect of aging on endogenous level of 5 alpha-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate. J Clin Endocrinol Metab 77:375–381

    CAS  PubMed  Google Scholar 

  • Krtolica A, Campisi J (2002) Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int J Biochem Cell Biol 34:1401–1414

    Article  CAS  PubMed  Google Scholar 

  • Lau KM, Tam NN, Thompson C, Cheng RY, Leung YK, Ho SM (2003) Age-associated changes in histology and gene-expression profile in the rat ventral prostate. Lab Invest 83:743–757

    Article  CAS  PubMed  Google Scholar 

  • London CA, Sekhon HS, Arora V, Stein DA, Iversen PL, Devi GR (2003) A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity. Cancer Res Ther 10:823–832

    CAS  Google Scholar 

  • Lynch CC, Matrisian LM (2002) Matrix metalloproteinases in tumor-host cell communication. Differentiation 70:561–573

    Article  CAS  PubMed  Google Scholar 

  • Mañes S, Llorente M, Lacalle RA, Gómez-Moutón C, Kremer L, Mira E, Martinez-A C (1999) The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J Biol Chem 274:6935–6945

    Article  PubMed  Google Scholar 

  • Matsusaka S, Nakasho K, Terada N, Sugihara A, Tsujimura T, Takanashi T, Uematsu K, Okamoto E, Toyosaka A (2000) Inhibition by an angiogenesis inhibitor, TNP-470, of the growth of a human hepatoblastoma heterotransplanted into nude mice. J Pediatr Surg 35:1198–1204

    Article  CAS  PubMed  Google Scholar 

  • Miele C, Rochford JJ, Filippa N, Giorgetti-Peraldi S, Van Obberghen E (2000) Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways. J Biol Chem 275:21695–21702

    Article  CAS  PubMed  Google Scholar 

  • Miller MI, Puchner PJ (1998) Effects of finasteride on hematuria associated with benign prostate hyperplasia: long-term follow-up. Urology 51:237–240

    Article  CAS  PubMed  Google Scholar 

  • Minischetti M, Vacca A, Ribatti D, Iurlaro M, Ria R, Pellegrino A, Gasparini G, Dammacco AF (2000) TNP-470 and recombinant human interferon-alpha2a inhibit angiogenesis synergistically. Br J Haematol 109:829–837

    Article  CAS  PubMed  Google Scholar 

  • Montgomery DC (1991) Design and analysis of experiments, 3rd edn. Wiley, New York

    Google Scholar 

  • Montico F, Hetzl AC, Cândido EM, Fávaro WJ, Cagnon VH (2011) Hormonal therapy in the senescence: prostatic microenvironment structure and adhesion molecules. Micron 42:642–655

    Article  CAS  PubMed  Google Scholar 

  • Morrissey C, Buser A, Scolaro J, O’Sullivan J, Moquin A, Tenniswood M (2002) Changes in hormone sensitivity in the ventral prostate of aging Sprague-Dawley rats. J Androl 23:341–351

    CAS  PubMed  Google Scholar 

  • Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR (1999) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59:5002–5011

    CAS  PubMed  Google Scholar 

  • Pandini G, Genua M, Frasca F, Vigneri R, Belfiore A (2009) Sex steroids upregulate the IGF-1R in prostate cancer cells through a nongenotropic pathway. Ann N Y Acad Sci 1155:263–267

    Article  CAS  PubMed  Google Scholar 

  • Pareek G, Shevchuk M, Armenakas NA, Vasjovic L, Hochberg DA, Basillote JB, Fracchia JA (2003) 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. J Urol 169:20–23

    Article  CAS  PubMed  Google Scholar 

  • Plymate SR, Tennant MK, Culp SH, Woodke L, Marcelli M, Colman I, Nelson PS, Carroll JM, Roberts CT Jr, Ware JL (2004) Androgen receptor (AR) expression in AR-negative prostate cancer cells results in differential effects of DHT and IGF-1 on proliferation and AR activity between localized and metastatic tumors. Prostate 61:276–290

    Article  CAS  PubMed  Google Scholar 

  • Prahalada S, Rhodes L, Grossman SJ, Heggan D, Keenan KP, Cukierski MA, Hoe CM, Berman C, Van Zwieten MJ (1998) Morphological and hormonal changes in the ventral and dorsolateral prostatic lobes of rats treated with finasteride, a 5-alpha reductase inhibitor. Prostate 3:157–164

    Article  Google Scholar 

  • Prins GS, Jung MH, Vellanoweth RL, Chatterjee B, Roy AK (1996) Age-dependent expression of the androgen receptor gene in the prostate and its implication in glandular differentiation and hyperplasia. Dev Genet 18:99–106

    Article  CAS  PubMed  Google Scholar 

  • Retter AS, Figg WD, Dahut WL (2003) The combination of antiangiogenic and cytotoxic agents in the treatment of prostate cancer. Clin Prostate Cancer 2:153–159

    Article  CAS  PubMed  Google Scholar 

  • Reynolds AR, Kyprianou N (2006) Growth factor signalling in prostatic growth: significance in tumour development and therapeutic targeting. Br J Pharmacol 147(Suppl 2):S144–S152

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Roy-Burman P, Wu H, Powell WC, Hagenkord J, Cohen MB (2004) Genetically defined mouse models that mimic natural aspects of human prostate cancer development. Endocr Relat Cancer 11:225–254

    Article  CAS  PubMed  Google Scholar 

  • Rullis I, Shaeffer JA, Lilien OM (1975) Incidence of prostatic carcinoma in the elderly. Urology 6:295–297

    Article  CAS  PubMed  Google Scholar 

  • Ryan CJ, Haqq CM, Simko J, Nonaka DF, Chan JM, Weinberg V, Small EJ, Goldfine ID (2007) Expression of insulin-like growth factor-1 receptor in local and metastatic prostate cancer. Urol Oncol 25:134–140

    Article  CAS  PubMed  Google Scholar 

  • Saikali Z, Setya H, Singh G, Persad S (2008) Role of IGF-1/IGF-1R in regulation of invasion in DU145 prostate cancer cells. Cancer Cell Int 8:10

    Article  PubMed Central  PubMed  Google Scholar 

  • Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM (1997) The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci USA 94:6099–6103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sprenger CC, Plymate SR, Reed MJ (2008) Extracellular influences on tumour angiogenesis in the aged host. Br J Cancer 98:250–255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Strieth S, Eichhorn ME, Sutter A, Jonczyk A, Berghaus A, Dellian M (2006) Antiangiogenic combination tumor therapy blocking alpha(v)-integrins and VEGF-receptor-2 increases therapeutic effects in vivo. Int J Cancer 119:423–431

    Article  CAS  PubMed  Google Scholar 

  • Sweeney P, Karashima T, Kim SJ, Kedar D, Mian B, Huang S, Baker C, Fan Z, Hicklin DJ, Pettaway CA, Dinney CP (2002) Anti-vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate câncer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production. Clin Cancer Res 8:2714–2724

    CAS  PubMed  Google Scholar 

  • Takamoto T, Sasaki M, Kuno T, Tamaki N (2001) Flk-1 specific kinase inhibitor (SU5416) inhibited the growth of GS-9L glioma in rat brain and prolonged the survival. Kobe J Med Sci 47:181–191

    CAS  PubMed  Google Scholar 

  • Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr (2003) The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215–224

    Article  CAS  PubMed  Google Scholar 

  • Thum T, Hoeber S, Froese S, Klink I, Stichtenoth D, Galuppo P, Jakob M, Tsikas D, Anker S, Poole-Wilson P, Borlak J, Ertl G, Bauersachs J (2007) Age-dependent impairment of endothelial progenitor cells is corrected by growth hormone mediated increase of insulin-like growth factor-1. Circ Res 100:434–443

    Article  CAS  PubMed  Google Scholar 

  • Tsukamoto S, Akaza H, Imada S, Koiso K, Shirai T, Ideyama Y, Kudo M (1995) Chemoprevention of rat prostate carcinogenesis by use of finasteride or casodex. J Natl Cancer Inst 87:842–843

    Article  CAS  PubMed  Google Scholar 

  • Turk BE, Griffith EC, Wolf S, Biemann K, Chang YH, Liu JO (1999) Selective inhibition of amino-terminal methionine processing by TNP-470 and ovalicin in endothelial cells. Chem Biol 6:823–833

    Article  CAS  PubMed  Google Scholar 

  • Tutrone RF Jr, Ball RA, Ornitz DM, Leder P, Richie JP (1993) Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J Urol 149:633–699

    PubMed  Google Scholar 

  • Tuxhorn JA, Ayala GE, Rowley DR (2001) Reactive stroma in prostate cancer progression. J Urol 166:2472–2483

    Article  CAS  PubMed  Google Scholar 

  • Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR (2002) Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res 8:2912–2923

    CAS  PubMed  Google Scholar 

  • Van Moorselaar RJ, Voest EE (2002) Angiogenesis in prostate cancer: its role in disease progression and possible therapeutic approaches. Mol Cell Endocrinol 197:239–250

    Article  PubMed  Google Scholar 

  • Wang YZ, Wong YC (1998) Sex hormone-induced prostatic carcinogenesis in the Noble rat: the role of insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in the development of prostate cancer. Prostate 35:165–177

    Article  CAS  PubMed  Google Scholar 

  • Yoshiji H, Harris SR, Thorgeirsson UP (1997) Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells. Cancer Res 57:3924–3928

    CAS  PubMed  Google Scholar 

  • Zar JH (1999) Biostatistical analysis. Prentice Hall Upper, New Jersey

    Google Scholar 

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Acknowledgments

This work was supported by São Paulo Research Foundation (FAPESP) (2011/01968-3 and 2012/03010-4).

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  1. Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), P.O. Box 6109, Campinas, São Paulo, 13083-865, Brazil

    Fabio Montico, Larissa Akemi Kido, Amanda Cia Hetzl, Raísa Mistieri Lorencini, Eduardo Marcelo Cândido & Valéria Helena Alves Cagnon

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  1. Fabio Montico
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Montico, F., Kido, L.A., Hetzl, A.C. et al. Antiangiogenic therapy effects on age-associated matrix metalloproteinase-9 (MMP-9) and insulin-like growth factor receptor-1 (IGFR-1) responses: a comparative study of prostate disorders in aged and TRAMP mice. Histochem Cell Biol 142, 269–284 (2014). https://doi.org/10.1007/s00418-014-1193-2

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