Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica
ilustraciones, gráficas, tablas
- Autores:
-
Rodríguez Castañeda, Sergio Fabián
- Tipo de recurso:
- Fecha de publicación:
- 2022
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/81670
- Palabra clave:
- 610 - Medicina y salud::616 - Enfermedades
Hidroxiprostaglandina Deshidrogenasas
Linfocitos T
Neoplasias de la Próstata
Hydroxyprostaglandin Dehydrogenases
T-Lymphocytes
Prostatic Neoplasms
Microambiente tumoral
Inmunorregulación
Cáncer de próstata
Infiltración linfocitaria
Recurrencia bioquímica
Immunoregulation
Prostate cancer
Lymphocytic infiltration
Biochemical recurrence
Tumor microenvironment
- Rights
- openAccess
- License
- Atribución-NoComercial-CompartirIgual 4.0 Internacional
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repository_id_str |
|
dc.title.spa.fl_str_mv |
Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica |
dc.title.translated.eng.fl_str_mv |
Relationship between HPGD expression levels with the density and phenotype of T lymphocytes in tumor tissue of patients with prostate cancer and its association with biochemical recurrence |
title |
Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica |
spellingShingle |
Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica 610 - Medicina y salud::616 - Enfermedades Hidroxiprostaglandina Deshidrogenasas Linfocitos T Neoplasias de la Próstata Hydroxyprostaglandin Dehydrogenases T-Lymphocytes Prostatic Neoplasms Microambiente tumoral Inmunorregulación Cáncer de próstata Infiltración linfocitaria Recurrencia bioquímica Immunoregulation Prostate cancer Lymphocytic infiltration Biochemical recurrence Tumor microenvironment |
title_short |
Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica |
title_full |
Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica |
title_fullStr |
Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica |
title_full_unstemmed |
Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica |
title_sort |
Relación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímica |
dc.creator.fl_str_mv |
Rodríguez Castañeda, Sergio Fabián |
dc.contributor.advisor.spa.fl_str_mv |
Combita Rojas, Alba Lucía Parra Media, Rafael Santiago |
dc.contributor.author.spa.fl_str_mv |
Rodríguez Castañeda, Sergio Fabián |
dc.subject.ddc.spa.fl_str_mv |
610 - Medicina y salud::616 - Enfermedades |
topic |
610 - Medicina y salud::616 - Enfermedades Hidroxiprostaglandina Deshidrogenasas Linfocitos T Neoplasias de la Próstata Hydroxyprostaglandin Dehydrogenases T-Lymphocytes Prostatic Neoplasms Microambiente tumoral Inmunorregulación Cáncer de próstata Infiltración linfocitaria Recurrencia bioquímica Immunoregulation Prostate cancer Lymphocytic infiltration Biochemical recurrence Tumor microenvironment |
dc.subject.decs.spa.fl_str_mv |
Hidroxiprostaglandina Deshidrogenasas Linfocitos T Neoplasias de la Próstata |
dc.subject.decs.eng.fl_str_mv |
Hydroxyprostaglandin Dehydrogenases T-Lymphocytes Prostatic Neoplasms |
dc.subject.proposal.spa.fl_str_mv |
Microambiente tumoral Inmunorregulación Cáncer de próstata Infiltración linfocitaria Recurrencia bioquímica |
dc.subject.proposal.eng.fl_str_mv |
Immunoregulation Prostate cancer Lymphocytic infiltration Biochemical recurrence Tumor microenvironment |
description |
ilustraciones, gráficas, tablas |
publishDate |
2022 |
dc.date.accessioned.none.fl_str_mv |
2022-06-29T19:07:51Z |
dc.date.available.none.fl_str_mv |
2022-06-29T19:07:51Z |
dc.date.issued.none.fl_str_mv |
2022-06-09 |
dc.type.spa.fl_str_mv |
Trabajo de grado - Maestría |
dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/masterThesis |
dc.type.version.spa.fl_str_mv |
info:eu-repo/semantics/acceptedVersion |
dc.type.content.spa.fl_str_mv |
Text |
dc.type.redcol.spa.fl_str_mv |
http://purl.org/redcol/resource_type/TM |
status_str |
acceptedVersion |
dc.identifier.uri.none.fl_str_mv |
https://repositorio.unal.edu.co/handle/unal/81670 |
dc.identifier.instname.spa.fl_str_mv |
Universidad Nacional de Colombia |
dc.identifier.reponame.spa.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.unal.edu.co/ |
url |
https://repositorio.unal.edu.co/handle/unal/81670 https://repositorio.unal.edu.co/ |
identifier_str_mv |
Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia |
dc.language.iso.spa.fl_str_mv |
spa |
language |
spa |
dc.relation.indexed.spa.fl_str_mv |
Bireme |
dc.relation.references.spa.fl_str_mv |
[1] H. Sung et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA. Cancer J. Clin., vol. 71, no. 3, pp. 209–249, 2021, doi: 10.3322/caac.21660. [2] The Global Cancer Observatory, “GLOBOCAN 2020: International Agency Research on Cancer,” 2020. https://gco.iarc.fr/today/data/factsheets/populations/170-colombia-fact-sheets.pdf. [3] P. Rawla, “Epidemiology of Prostate Cancer,” vol. 10, no. 2, pp. 63–89, 2019, doi: 10.1159/000423644. [4] A. Barsouk et al., “Epidemiology, Staging and Management of Prostate Cancer,” Med. Sci., vol. 8, no. 3, p. 28, 2020, doi: 10.3390/medsci8030028. [5] Z. Wang et al., “The efficacy and safety of radical prostatectomy and radiotherapy in high-risk prostate cancer: A systematic review and meta-analysis,” World Journal of Surgical Oncology, vol. 18, no. 1. BioMed Central Ltd., Feb. 24, 2020, doi: 10.1186/s12957-020-01824-9. [6] X. Zhou et al., “Comparing effectiveness of radical prostatectomy versus external beam radiotherapy in patients with locally advanced prostate cancer: A population-based analysis,” Medicine (Baltimore)., vol. 99, no. 34, p. e21642, 2020, doi: 10.1097/MD.0000000000021642. [7] R. Tourinho-Barbosa et al., “Biochemical recurrence after radical prostatectomy: what does it mean?,” doi: 10.1590/S1677-5538.IBJU.2016.0656. [8] C. L. Amling, E. J. Bergstralh, M. L. Blute, J. M. Slezak, and H. Zincke, “Defining prostate specific antigen progression after radical prostatectomy: What is the most appropriate cut point?,” J. Urol., vol. 165, no. 4, pp. 1146–1151, 2001, doi: 10.1016/S0022-5347(05)66452-X. [9] A. I. Cole et al., “Prognostic Value of Percent Gleason Grade 4 at Prostate Biopsy in Predicting Prostatectomy Pathology and Recurrence,” J. Urol., vol. 196, no. 2, pp. 405–411, Aug. 2016, doi: 10.1016/j.juro.2016.01.120. [10] A. V. D’Amico et al., “Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer,” J. Am. Med. Assoc., vol. 280, no. 11, pp. 969–974, Sep. 1998, doi: 10.1001/jama.280.11.969. [11] I. M. van Oort, C. A. Hulsbergen-vandeKaa, and J. A. Witjes, “Prognostic Factors in Radical Prostatectomy Specimens: What Do We Need to Know from Pathologists?,” European Urology, Supplements, vol. 7, no. 12. Elsevier, pp. 715–722, Nov. 01, 2008, doi: 10.1016/j.eursup.2008.07.002. [12] M. N. Simmons, A. J. Stephenson, and E. A. Klein, “Natural History of Biochemical Recurrence after Radical Prostatectomy: Risk Assessment for Secondary Therapy{A figure is presented},” European Urology, vol. 51, no. 5. Elsevier, pp. 1175–1184, May 01, 2007, doi: 10.1016/j.eururo.2007.01.015. [13] N. Mottet et al., “Highlights on Prostate Cancer from Urological and Oncological Congresses in 2007,” European Urology, Supplements, vol. 7, no. 6. Elsevier, pp. 460–476, Apr. 01, 2008, doi: 10.1016/j.eursup.2008.01.004. [14] A. Pettersson et al., “The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: A cohort study and meta-analysis,” Cancer Epidemiol. Biomarkers Prev., vol. 21, no. 9, pp. 1497–1509, Sep. 2012, doi: 10.1158/1055-9965.EPI-12-0042. [15] S. A. Tomlins et al., “Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer,” Science (80-. )., vol. 310, no. 5748, pp. 644–648, 2005, doi: 10.1126/science.1117679. [16] O. Klezovitch et al., “A causal role for ERG in neoplastic transformation of prostate epithelium,” Proc. Natl. Acad. Sci. U. S. A., vol. 105, no. 6, pp. 2105–2110, Feb. 2008, doi: 10.1073/pnas.0711711105. [17] S. H. Kim et al., “Overexpression of ERG and wild-type PTEN are associated with favorable clinical prognosis and low biochemical recurrence in prostate cancer,” PLoS One, vol. 10, no. 4, Apr. 2015, doi: 10.1371/journal.pone.0122498. [18] H. Tai, H. Cho, M. Tong, and Y. Ding, “NAD+-Linked 15-Hydroxyprostaglandin Dehydrogenase: Structure and Biological Functions,” Curr. Pharm. Des., vol. 12, pp. 955–962, 2006. [19] S. Josson, Y. Matsuoka, L. W. K. Chung, H. E. Zhau, and R. Wang, “Tumor-stroma co-evolution in prostate cancer progression and metastasis,” Seminars in Cell and Developmental Biology, vol. 21, no. 1. Elsevier Ltd, pp. 26–32, 2010, doi: 10.1016/j.semcdb.2009.11.016. [20] R. D. Schreiber, L. J. Old, and M. J. Smyth, “Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion,” Science, vol. 331, no. 6024. Science, pp. 1565–1570, Mar. 25, 2011, doi: 10.1126/science.1203486. [21] Y. Kiniwa et al., “CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer,” Clin. Cancer Res., vol. 13, no. 23, pp. 6947–6958, 2007, doi: 10.1158/1078-0432.CCR-07-0842. [22] L. Schmidleithner et al., “Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction,” Immunity, vol. 50, no. 5, pp. 1232-1248.e14, 2019, doi: 10.1016/j.immuni.2019.03.014. [23] X. Lin et al., “Assessment of biochemical recurrence of prostate cancer (Review),” International Journal of Oncology, vol. 55, no. 6. Spandidos Publications, pp. 1194–1212, Nov. 30, 2019, doi: 10.3892/ijo.2019.4893. [24] N. Vitkin, S. Nersesian, D. R. Siemens, and M. Koti, “The tumor immune contexture of prostate cancer,” Front. Immunol., vol. 10, no. MAR, pp. 1–10, 2019, doi: 10.3389/fimmu.2019.00603. [25] D. Lin, X. Wang, S. Y. C. Choi, X. Ci, X. Dong, and Y. Wang, “Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell-like transition?,” Asian J. Urol., vol. 3, no. 4, pp. 195–202, 2016, doi: 10.1016/j.ajur.2016.08.002. [26] W. H. Fridman, L. Zitvogel, C. Sautès-Fridman, and G. Kroemer, “The immune contexture in cancer prognosis and treatment,” Nature Reviews Clinical Oncology, vol. 14, no. 12. Nature Publishing Group, pp. 717–734, Dec. 01, 2017, doi: 10.1038/nrclinonc.2017.101. [27] A. M. Miller et al., “ CD4 + CD25 high T Cells Are Enriched in the Tumor and Peripheral Blood of Prostate Cancer Patients ,” J. Immunol., vol. 177, no. 10, pp. 7398–7405, Nov. 2006, doi: 10.4049/jimmunol.177.10.7398. [28] V. Nardone et al., “Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse,” Cancer Biol. Ther., vol. 17, no. 11, pp. 1213–1220, 2016, doi: 10.1080/15384047.2016.1235666. [29] F. Petitprez et al., “PD-L1 Expression and CD8 + T-cell Infiltrate are Associated with Clinical Progression in Patients with Node-positive Prostate Cancer,” Eur. Urol. Focus, vol. 5, no. 2, pp. 192–196, 2019, doi: 10.1016/j.euf.2017.05.013. [30] N. Ness et al., “Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer,” Prostate, vol. 74, no. 14, pp. 1452–1461, 2014, doi: 10.1002/pros.22862. [31] J. A. Joyce and D. T. Fearon, “T cell exclusion, immune privilege, and the tumor microenvironment,” Science, vol. 348, no. 6230. American Association for the Advancement of Science, pp. 74–80, Apr. 03, 2015, doi: 10.1126/science.aaa6204. [32] S. Mariathasan et al., “TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells,” Nature, vol. 554, no. 7693, pp. 544–548, Feb. 2018, doi: 10.1038/nature25501. [33] M. Lundholm et al., “Secreted factors from colorectal and prostate cancer cells skew the immune response in opposite directions,” Sci. Rep., vol. 5, Oct. 2015, doi: 10.1038/srep15651. [34] B. Molon et al., “Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells,” J. Exp. Med., vol. 208, no. 10, pp. 1949–1962, Sep. 2011, doi: 10.1084/jem.20101956. [35] J. A. Taylor et al., “Regulation of the prostaglandin pathway during development of invasive bladder cancer in mice,” Prostaglandins Other Lipid Mediat., vol. 88, no. 1–2, pp. 36–41, Jan. 2009, doi: 10.1016/j.prostaglandins.2008.09.003. [36] J. Heighway et al., “Expression profiling of primary non-small cell lung cancer for target identification,” Oncogene, vol. 21, no. 50, pp. 7749–7763, Oct. 2002, doi: 10.1038/sj.onc.1205979. [37] R. Wu et al., “Association of 15-hydroxyprostaglandin dehydrogenate and poor prognosis of obese breast cancer patients,” 2017. Accessed: May 21, 2020. [Online]. Available: www.impactjournals.com/oncotarget. [38] X. Qi, Y. Wang, J. Hou, and Y. Huang, “A single nucleotide polymorphism in HPGD gene is associated with prostate cancer risk,” J. Cancer, vol. 8, no. 19, pp. 4083–4086, 2017, doi: 10.7150/jca.22025. [39] P. Vainio et al., “Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer,” Am. J. Pathol., vol. 178, no. 2, pp. 525–536, Feb. 2011, doi: 10.1016/j.ajpath.2010.10.002. [40] M. Tong and H. H. Tai, “Induction of NAD+-linked 15-hydroxyprostaglandin dehydrogenase expression by androgens in human prostate cancer cells,” Biochem. Biophys. Res. Commun., vol. 276, no. 1, pp. 77–81, Sep. 2000, doi: 10.1006/bbrc.2000.3437. [41] S. Sun et al., “BAP18 coactivates androgen receptor action and promotes prostate cancer progression,” Nucleic Acids Res., vol. 44, no. 17, pp. 8112–8128, 2016, doi: 10.1093/nar/gkw472. [42] T. H. Kim, J. M. Park, M. Y. Kim, and Y. H. Ahn, “The role of CREB3L4 in the proliferation of prostate cancer cells,” Sci. Rep., vol. 7, no. 1, pp. 1–11, Mar. 2017, doi: 10.1038/srep45300. [43] A. A. Mohamed et al., “ERG oncogene modulates prostaglandin signaling in prostate cancer cells,” Cancer Biol. Ther., vol. 11, no. 4, pp. 410–417, Feb. 2011, doi: 10.4161/cbt.11.4.14180. [44] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA. Cancer J. Clin., vol. 68, no. 6, pp. 394–424, 2018, doi: 10.3322/caac.21492. [45] G. The Global Cancer Observatory, “Prostate 2018,” 2019. [46] I. de C. en Colombia, “Infocancer Incidencia Próstata Edades.” http://www.infocancer.co/portal/#!/filtro_tasas/. [47] E. B. O’Keefe, J. P. Meltzer, and T. N. Bethea, “Health Disparities and Cancer: Racial Disparities in Cancer Mortality in the United States, 2000–2010,” Front. Public Heal., vol. 3, no. April, pp. 1–15, 2015, doi: 10.3389/fpubh.2015.00051. [48] G. K. Panigrahi et al., “Exosome proteomic analyses identify inflammatory phenotype and novel biomarkers in African American prostate cancer patients,” Cancer Med., vol. 8, no. 3, pp. 1110–1123, 2019, doi: 10.1002/cam4.1885. [49] I. J. Powell, C. H. Bock, J. J. Ruterbusch, and W. Sakr, “Evidence Supports a Faster Growth Rate and/or Earlier Transformation to Clinically Significant Prostate Cancer in Black Than in White American Men, and Influences Racial Progression and Mortality Disparity,” J. Urol., vol. 183, no. 5, pp. 1792–1797, May 2010, doi: 10.1016/j.juro.2010.01.015. [50] S. D. Brookman-May et al., “Latest Evidence on the Impact of Smoking, Sports, and Sexual Activity as Modifiable Lifestyle Risk Factors for Prostate Cancer Incidence, Recurrence, and Progression: A Systematic Review of the Literature by the European Association of Urology Section of ,” Eur. Urol. Focus, vol. 5, no. 5, pp. 756–787, 2019, doi: 10.1016/j.euf.2018.02.007. [51] E. Giovannucci, Y. Liu, E. A. Platz, M. J. Stampfer, and W. C. Willett, “Risk factors for prostate cancer incidence and progression in the health professionals follow-up study NIH Public Access,” 2007. [52] F. Islami, D. M. Moreira, P. Boffetta, and S. J. Freedland, “A Systematic Review and Meta-analysis of Tobacco Use and Prostate Cancer Mortality and Incidence in Prospective Cohort Studies HHS Public Access,” Eur Urol, vol. 66, no. 6, pp. 1054–1064, 2014, doi: 10.1016/j.eururo.2014.08.059. [53] J. M. Genkinger et al., “Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer,” Ann. Oncol., vol. 31, no. 1, pp. 103–114, 2020, doi: 10.1016/j.annonc.2019.09.007. [54] N. Shah and V. Ioffe, “The Association Between Hypertension and Prostate Cancer,” Rev. Urol. •, vol. 19, no. 2, pp. 113–118, 2017, doi: 10.3909/riu0758. [55] Z. Liang et al., “Hypertension and risk of prostate cancer: a systematic review and meta-analysis OPEN,” 2016, doi: 10.1038/srep31358. [56] Y. C. Chen, J. H. Page, R. Chen, and E. Giovannucci, “Family history of prostate and breast cancer and the risk of prostate cancer in the PSA era,” Prostate, vol. 68, no. 14, pp. 1582–1591, 2008, doi: 10.1002/pros.20825. [57] O. Bratt, L. Drevin, O. Akre, H. Garmo, and P. Stattin, “Family History and Probability of Prostate Cancer, Differentiated by Risk Category: A Nationwide Population-Based Study,” J. Natl. Cancer Inst., vol. 108, no. 10, pp. 1–7, 2016, doi: 10.1093/jnci/djw110. [58] C. H. Lee, O. Akin-Olugbade, and A. Kirschenbaum, “Overview of Prostate Anatomy, Histology, and Pathology,” Endocrinol. Metab. Clin. North Am., vol. 40, no. 3, pp. 565–575, 2011, doi: 10.1016/j.ecl.2011.05.012. [59] K. H. Hammerich, G. E. Ayala, and T. M. Wheeler, “Anatomy of the prostate gland and surgical pathology of prostate cancer,” in Prostate Cancer, Cambridge University Press, 2008, pp. 1–14. [60] E. Shtivelman, T. M. Beer, and C. P. Evans, “Oncotarget 7217 www.impactjournals.com/oncotarget Molecular pathways and targets in prostate cancer,” 2014. Accessed: May 14, 2020. [Online]. Available: www.impactjournals.com/oncotarget/. [61] P. Y. Tan, C. W. Chang, K. R. Chng, K. D. S. A. Wansa, W.-K. Sung, and E. Cheung, “Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival,” Mol. Cell. Biol., vol. 32, no. 2, pp. 399–414, Jan. 2012, doi: 10.1128/mcb.05958-11. [62] S. A. Tomlins et al., “Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer,” Nature, vol. 448, no. 7153, pp. 595–599, 2007, doi: 10.1038/nature06024. [63] M. J. Linja and T. Visakorpi, “Alterations of androgen receptor in prostate cancer,” J. Steroid Biochem. Mol. Biol., vol. 92, no. 4, pp. 255–264, 2004, doi: 10.1016/j.jsbmb.2004.10.012. [64] P. Lonergan and D. Tindall, “Androgen receptor signaling in prostate cancer development and progression,” J. Carcinog., vol. 10, 2011, doi: 10.4103/1477-3163.83937. [65] M. E. Grossmann, H. Huang, and D. J. Tindall, “Androgen Receptor Signaling in Androgen-Refractory Prostate Cancer.” Accessed: May 15, 2020. [Online]. Available: https://academic.oup.com/jnci/article-abstract/93/22/1687/2519589. [66] J. Seidenfeld et al., “Single-therapy androgen suppression in men with advanced prostate cancer: A systematic review and meta-analysis,” Annals of Internal Medicine, vol. 132, no. 7. American College of Physicians, pp. 566–577, Apr. 04, 2000, doi: 10.7326/0003-4819-132-7-200004040-00009. [67] P. Koivisto et al., “Androgen receptor gene amplification: A possible molecular mechanism for androgen deprivation therapy failure in prostate cancer,” Cancer Res., vol. 57, no. 2, pp. 314–319, 1997. [68] P. A. Koivisto and I. Rantala, “Amplification of the androgen receptor gene is associated with P53 mutation in hormone-refractory recurrent prostate cancer,” J. Pathol., vol. 187, no. 2, pp. 237–241, 1999, doi: 10.1002/(SICI)1096-9896(199901)187:2<237::AID-PATH224>3.0.CO;2-I. [69] M. E. Taplin et al., “Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer,” N. Engl. J. Med., vol. 332, no. 21, pp. 1393–1398, May 1995, doi: 10.1056/NEJM199505253322101. [70] M. J. McPhaul, “Mechanisms of prostate cancer progression to androgen independence,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 22, no. 2. pp. 373–388, Apr. 2008, doi: 10.1016/j.beem.2008.02.006. [71] S. Araki et al., “Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer,” Cancer Res., vol. 67, no. 14, pp. 6854–6862, Jul. 2007, doi: 10.1158/0008-5472.CAN-07-1162. [72] Z. Culig et al., “Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-1, keratinocyte growth factor and epidermal growth factor,” Eur. Urol., vol. 54, no. 20, pp. 5474–5478, 1994, doi: 10.1159/000475232. [73] A. Hobisch et al., “Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor,” Cancer Res., vol. 58, no. 20, pp. 4640–4645, Oct. 1998. [74] O. L. Soo, E. Pinder, Y. C. Jae, W. Lou, M. Sun, and A. C. Gao, “Interleukin-4 stimulates androgen-independent growth in LNCaP human prostate cancer cells,” Prostate, vol. 68, no. 1, pp. 85–91, Jan. 2008, doi: 10.1002/pros.20691. [75] G. J. Wise, V. K. Marella, G. Talluri, and D. Shirazian, “Cytokine variations in patients with hormone treated prostate cancer,” J. Urol., vol. 164, no. 3 I, pp. 722–725, 2000, doi: 10.1097/00005392-200009010-00024. [76] V. M. Velonas, H. H. Woo, C. G. Dos Remedios, and S. J. Assinder, “Current Status of Biomarkers for Prostate Cancer,” Int. J. Mol. Sci, vol. 14, pp. 11034–11060, 2013, doi: 10.3390/ijms140611034. [77] J. I. Epstein, L. Egevad, M. B. Amin, B. Delahunt, J. R. Srigley, and P. A. Humphrey, “The 2014 international society of urological pathology (ISUP) consensus conference on gleason grading of prostatic carcinoma definition of grading patterns and proposal for a new grading system,” Am. J. Surg. Pathol., vol. 40, no. 2, pp. 244–252, 2016, doi: 10.1097/PAS.0000000000000530. [78] N. Lawrentschuk, G. Trottier, C. Kuk, and A. Zlotta, “Role of surgery in high-risk localized prostate cancer,” vol. 17, no. 2, pp. 25–32, 2010. [79] A. J. Hayden, C. Catton, and T. Pickles, “Radiation therapy in prostate cancer: A risk-adapted strategy,” Curr. Oncol., vol. 17, no. SUPPL. 2, p. S18, 2010, doi: 10.3747/co.v17i0.704. [80] M. A. Perlmutter and H. Lepor, “Androgen deprivation therapy in the treatment of advanced prostate cancer.,” Rev. Urol., vol. 9 Suppl 1, no. Suppl 1, pp. S3-8, 2007, Accessed: May 15, 2020. [Online]. Available: http://www.ncbi.nlm.nih.gov/pubmed/17387371. [81] F. Z. Chen and X. K. Zhao, “Prostate cancer: Current treatment and prevention strategies,” Iranian Red Crescent Medical Journal, vol. 15, no. 4. Iranian Red Crescent Society, pp. 279–284, 2013, doi: 10.5812/ircmj.6499. [82] Y. Lotan and C. G. Roehrborn, “Clearance rates of total prostate specific antigen (PSA) after radical prostatectomy in African-Americans and Caucasians,” Prostate Cancer Prostatic Dis., vol. 5, no. 2, pp. 111–114, Jun. 2002, doi: 10.1038/sj.pcan.4500567. [83] O. Yossepowitch et al., “Positive surgical margins after radical prostatectomy: A systematic review and contemporary update,” European Urology, vol. 65, no. 2. Elsevier, pp. 303–313, Feb. 01, 2014, doi: 10.1016/j.eururo.2013.07.039. [84] P. H. Lange, C. J. Ercole, D. J. Lightner, E. E. Fraley, and R. Vessella, “The value of serum prostate specific antigen determinations before and after radical prostatectomy,” J. Urol., vol. 141, no. 4 I, pp. 873–879, Apr. 1989, doi: 10.1016/S0022-5347(17)41037-8. [85] D. A. Leach and G. Buchanan, “Stromal androgen receptor in prostate cancer development and progression,” Cancers (Basel)., vol. 9, no. 1, pp. 1–24, 2017, doi: 10.3390/cancers9010010. [86] P. G. Corn, “The tumor microenvironment in prostate cancer: elucidating molecular pathways for therapy development,” Cancer Manag. Res., vol. 4, pp. 183–193, 2012, doi: 10.2147/CMAR.S32839. [87] D. A. Leach et al., “Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome,” Oncotarget, vol. 6, no. 18, pp. 16135–16150, 2015, doi: 10.18632/oncotarget.3873. [88] S. L. Shiao, G. C.-Y. Chu, and L. W. K. Chung, “Regulation of Prostate Cancer Progression by the Tumor Microenvironment,” Cancer Lett., vol. 380, no. 1, pp. 340–348, 2016, doi: 0.1016/j.canlet.2015.12.022. [89] D. W. Powell, R. C. Mifflin, J. D. Valentich, S. E. Crowe, J. I. Saada, and A. B. West, “Myofibroblasts. I. Paracrine cells important in health and disease,” American Journal of Physiology - Cell Physiology, vol. 277, no. 1 46-1. American Physiological SocietyBethesda, MD , 1999, doi: 10.1152/ajpcell.1999.277.1.c1. [90] A. Desmouliere, C. Guyot, and G. Gabbiani, “The stroma reaction myofibroblast: a key player in the control of tumor cell behavior,” Int. J. Dev. Biol., vol. 48, no. 5–6, pp. 509–517, Sep. 2004, doi: 10.1387/ijdb.041802ad. [91] J. A. Tuxhorn, G. E. Ayala, and D. R. Rowley, “Reactive stroma in prostate cancer progression,” Clin. Cancer Res., vol. 8, no. 9, pp. 2912–2923, 2002, doi: 10.1016/S0022-5347(05)65620-0. [92] B. Bagalad, K. Mohan Kumar, and H. Puneeth, “Myofibroblasts: Master of disguise,” Journal of Oral and Maxillofacial Pathology, vol. 21, no. 3. Medknow Publications, pp. 462–463, Sep. 01, 2017, doi: 10.4103/jomfp.JOMFP_146_15. [93] S. Hendry et al., “Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasi,” Advances in Anatomic Pathology, vol. 24, no. 5. Lippincott Williams and Wilkins, pp. 235–251, 2017, doi: 10.1097/PAP.0000000000000162. [94] K. S. Sfanos, S. Yegnasubramanian, W. G. Nelson, and A. M. De Marzo, “The inflammatory microenvironment and microbiome in prostate cancer development,” Nat. Rev. Urol., vol. 15, no. 1, pp. 11–24, 2018, doi: 10.1038/nrurol.2017.167. [95] A. M. De Marzo and Elizabeth A. Platz, “Inflammation in prostate carcinogenesis,” Nat Rev Cancer, vol. 7, no. 4, pp. 256–269, 2007, doi: 10.1038/nrc2090. [96] R. S. Mani, Mohammad A. Amin, X. Li, and S. Kalyana-Sundaram, “Inflammation induced oxidative stress mediates gene fusion formation in prostate cancer,” Cell Rep, vol. 17, no. 10, pp. 2620–2631, 2016, doi: 10.1016/j.celrep.2016.11.019. [97] G. J. L. H. Van Leenders et al., “Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy,” Am. J. Pathol., vol. 162, no. 5, pp. 1529–1537, 2003, doi: 10.1016/S0002-9440(10)64286-1. [98] W. H. Fridman, F. Pagès, C. Saut̀s-Fridman, and J. Galon, “The immune contexture in human tumours: Impact on clinical outcome,” Nature Reviews Cancer, vol. 12, no. 4. Nat Rev Cancer, pp. 298–306, Apr. 2012, doi: 10.1038/nrc3245. [99] J. Galon et al., “Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours,” J. Pathol., vol. 232, no. 2, pp. 199–209, 2014, doi: 10.1002/path.4287. [100] M. Capone et al., “Immunoscore: a new possible approach for melanoma classification,” J. Immunother. Cancer, vol. 2, no. S3, pp. 2–3, 2014, doi: 10.1186/2051-1426-2-s3-p193. [101] I. F. Lissbrant, P. Stattin, P. Wikstrom, J. E. Damber, L. Egevad, and A. Bergh, “Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival.,” Int. J. Oncol., vol. 17, no. 3, pp. 445–451, 2000, doi: 10.3892/ijo.17.3.445. [102] W. Wang, A. Bergh, and J. E. Damber, “Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human prostate cancer,” Clin. Cancer Res., vol. 11, no. 9, pp. 3250–3256, 2005, doi: 10.1158/1078-0432.CCR-04-2405. [103] N. Nonomura et al., “Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer,” BJU Int., vol. 107, no. 12, pp. 1918–1922, 2011, doi: 10.1111/j.1464-410X.2010.09804.x. [104] E. Richardsen, R. D. Uglehus, J. Due, C. Busch, and L. T. R. Busund, “The prognostic impact of M-CSF, CSF-1 receptor, CD68 and CD3 in prostatic carcinoma,” Histopathology, vol. 53, no. 1, pp. 30–38, 2008, doi: 10.1111/j.1365-2559.2008.03058.x. [105] J. Irani et al., “High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy,” Urology, vol. 54, no. 3, pp. 467–472, 1999, doi: 10.1016/S0090-4295(99)00152-1. [106] P. A. McArdle, K. Canna, D. C. McMillan, A. H. McNicol, R. Campbell, and M. A. Underwood, “The relationship between T-lymphocyte subset infiltration and survival in patients with prostate cancer,” Br. J. Cancer, vol. 91, no. 3, pp. 541–543, 2004, doi: 10.1038/sj.bjc.6601943. [107] M. Lanciotti et al., “The role of M1 and M2 macrophages in prostate cancer in relation to extracapsular tumor extension and biochemical recurrence after radical prostatectomy,” Biomed Res. Int., vol. 2014, 2014, doi: 10.1155/2014/486798. [108] K. S. Sfanos, T. C. Bruno, A. K. Meeker, A. M. De Marzo, W. B. Isaacs, and C. G. Drake, “Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+,” Prostate, vol. 69, no. 15, pp. 1694–1703, 2009, doi: 10.1002/pros.21020. [109] S. Davidsson et al., “CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3 + regulatory T cells with respect to lethal prostate cancer,” Mod. Pathol., vol. 26, no. 3, pp. 448–455, 2013, doi: 10.1038/modpathol.2012.164. [110] J. Woo et al., “Mp49-03 Tumor Infiltrating B-Cells Are Increased in Prostate Cancer Tissue,” J. Urol., vol. 191, no. 4S, pp. 1–9, 2014, doi: 10.1016/j.juro.2014.02.1104. [111] A. Flammiger et al., “Intratumoral T but not B lymphocytes are related to clinical outcome in prostate cancer,” Apmis, vol. 120, no. 11, pp. 901–908, 2012, doi: 10.1111/j.1600-0463.2012.02924.x. [112] V. Kärjä, S. Aaltomaa, P. Lipponen, T. Isotalo, M. Talja, and R. Mokka, “Tumour-infiltrating lymphocytes: A prognostic factor of psa-free survival in patients with local prostate carcinoma treated by radical prostatectomy,” Anticancer Res., vol. 25, no. 6 C, pp. 4435–4438, 2005. [113] H. A. Hempel et al., “Low Intratumoral Mast Cells Are Associated With a Higher Risk of Prostate Cancer Recurrence,” Prostate, vol. 77, no. 4, pp. 412–424, 2017, doi: 10.1002/pros.23280. [114] B. Gurel et al., “Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial,” Cancer Epidemiol. Biomarkers Prev., vol. 23, no. 5, pp. 847–856, 2014, doi: 10.1158/1055-9965.EPI-13-1126. [115] R. Kennedy, “Multiple roles for CD4 T cells in anti‐tumor immune responses_KennedyCelisImmRev08.pdf,” Immunol. Rev., vol. 222, pp. 129–144, 2008. [116] M. Beyer and J. L. Schultze, “Regulatory T cells in cancer,” Blood, vol. 108, no. 3, pp. 804–811, 2006, doi: 10.1182/blood-2006-02-002774. [117] T. F. Gajewski, H. Schreiber, and Y. X. Fu, “Innate and adaptive immune cells in the tumor microenvironment,” Nature Immunology, vol. 14, no. 10. NIH Public Access, pp. 1014–1022, 2013, doi: 10.1038/ni.2703. [118] K. S. Sfanos et al., “Phenotypic analysis of prostate-infiltrating lymphocytes reveals T H17 and Treg skewing,” Clin. Cancer Res., vol. 14, no. 11, pp. 3254–3261, 2008, doi: 10.1158/1078-0432.CCR-07-5164. [119] B. Samuelsson, R. Morgenstern, and P. J. Jakobsson, “Membrane prostaglandin E synthase-1: A novel therapeutic target,” Pharmacological Reviews, vol. 59, no. 3. American Society for Pharmacology and Experimental Therapeutics, pp. 207–224, Sep. 01, 2007, doi: 10.1124/pr.59.3.1. [120] A. Madrigal-Martínez, V. Constâncio, F. J. Lucio-Cazaña, and A. B. Fernández-Martínez, “PROSTAGLANDIN E 2 stimulates cancer-related phenotypes in prostate cancer PC3 cells through cyclooxygenase-2,” J. Cell. Physiol., vol. 234, no. 5, pp. 7548–7559, May 2019, doi: 10.1002/jcp.27515. [121] K. Yoshimatsu et al., “Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer,” Clin. Cancer Res., vol. 7, no. 12, pp. 3971–3976, Dec. 2001. [122] F. Finetti, C. Travelli, J. Ercoli, G. Colombo, E. Buoso, and L. Trabalzini, “Prostaglandin E2 and cancer: Insight into tumor progression and immunity,” Biology (Basel)., vol. 9, no. 12, pp. 1–26, 2020, doi: 10.3390/biology9120434. [123] R. Parra-Medina and S. Ramírez-Clavijo, “Why not to use punch biopsies in formalin-fixed paraffin-embedded samples of prostate cancer tissue for DNA and RNA extraction?,” African J. Urol., vol. 27, no. 1, 2021, doi: 10.1186/s12301-021-00257-4. [124] L. Collado-Torres et al., “Reproducible RNA-seq analysis using recount2,” Nat. Biotechnol., vol. 35, no. 4, pp. 319–321, Apr. 2017, doi: 10.1038/nbt.3838. [125] E. Afgan et al., “The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update,” Nucleic Acids Res., vol. 44, no. W1, pp. W3–W10, Jul. 2016, doi: 10.1093/nar/gkw343. [126] TheHumanProteinAtlas:HPGD, “Tissue expression of HPGD - The Human Protein Atlas,” Tissue expression of HPD The Human Protein Atlas. [Online]. Available: https://www.proteinatlas.org/ENSG00000164120-HPGD/tissue. [127] D. Lodygin, A. Epanchintsev, A. Menssen, J. Diebold, and H. Hermeking, “Functional epigenomics identifies genes frequently silenced in prostate cancer,” Cancer Res., vol. 65, no. 10, pp. 4218–4227, 2005, doi: 10.1158/0008-5472.CAN-04-4407. [128] H. T. Purayil, Y. Zhang, J. B. Black, R. Gharaibeh, and Y. Daaka, “Nuclear βArrestin1 regulates androgen receptor function in castration resistant prostate cancer,” Oncogene, vol. 40, no. 14, pp. 2610–2620, 2021, doi: 10.1038/s41388-021-01730-8. [129] H. Liu, J. Shi, M. Wilkerson, X. J. Yang, and F. Lin, “Immunohistochemical evaluation of ERG expression in various benign and malignant tissues,” Ann. Clin. Lab. Sci., vol. 43, no. 1, pp. 3–9, 2013. [130] J. Baohong, J. Sedarsky, S. Srivastava, I. Sesterhenn, A. Dobi, and L. Quanlin, “ERG tumor type is less frequent in high grade and high stage prostate cancers of Chinese men,” J. Cancer, vol. 10, no. 9, pp. 1991–1996, 2019, doi: 10.7150/jca.30025. [131] A. D. Darnel, C. J. LaFargue, R. T. Vollmer, J. Corcos, and T. A. Bismar, “TMPRSS2-ERG fusion is frequently observed in gleason pattern 3 prostate cancer in a canadian cohort,” Cancer Biol. Ther., vol. 8, no. 2, pp. 125–130, 2009, doi: 10.4161/cbt.8.2.7134. [132] J. Galon et al., “Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome,” Science (80-. )., vol. 313, no. 5795, pp. 1960–1964, Sep. 2006, doi: 10.1126/science.1129139. [133] M. J. M. Gooden, G. H. de Bock, N. Leffers, T. Daemen, and H. W. Nijman, “The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis,” Br. J. Cancer, vol. 105, no. 1, pp. 93–103, Jun. 2011, doi: 10.1038/bjc.2011.189. [134] K. Ebelt et al., “Dominance of CD4+ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma,” Prostate, vol. 68, no. 1, pp. 1–10, Jan. 2008, doi: 10.1002/pros.20661. [135] C. Sorrentino, P. Musiani, P. Pompa, G. Cipollone, and E. Di Carlo, “Androgen Deprivation Boosts Prostatic Infiltration of Cytotoxic and Regulatory T Lymphocytes and Has No Effect on Disease-Free Survival in Prostate Cancer Patients,” Clin. Cancer Res., vol. 17, no. 6, pp. 1571–1581, Mar. 2011, doi: 10.1158/1078-0432.CCR-10-2804. [136] A. Flammiger et al., “High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer,” Eur. J. Cancer, vol. 49, no. 6, pp. 1273–1279, Apr. 2013, doi: 10.1016/j.ejca.2012.11.035. [137] K. Park et al., “Antibody-Based Detection of ERG Rearrangement-Positive Prostate Cancer,” Neoplasia, vol. 12, no. 7, pp. 590-IN21, Jul. 2010, doi: 10.1593/neo.10726. [138] A. Flammiger et al., “Intratumoral T but not B lymphocytes are related to clinical outcome in prostate cancer,” APMIS, vol. 120, no. 11, pp. 901–908, Nov. 2012, doi: 10.1111/j.1600-0463.2012.02924.x. [139] G. Petrovics et al., “Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome,” Oncogene, vol. 24, no. 23, pp. 3847–3852, May 2005, doi: 10.1038/sj.onc.1208518. [140] R. K. Nam et al., “Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer,” Br. J. Cancer, vol. 97, no. 12, pp. 1690–1695, Dec. 2007, doi: 10.1038/sj.bjc.6604054. [141] A. VALDMAN et al., “Distribution of Foxp3-, CD4- and CD8-positive lymphocytic cells in benign and malignant prostate tissue,” APMIS, vol. 118, no. 5, pp. 360–365, May 2010, doi: 10.1111/j.1600-0463.2010.02604.x. [142] M. H. M. Barros, F. Hauck, J. H. Dreyer, B. Kempkes, and G. Niedobitek, “Macrophage Polarisation: an Immunohistochemical Approach for Identifying M1 and M2 Macrophages,” PLoS One, vol. 8, no. 11, p. e80908, Nov. 2013, doi: 10.1371/journal.pone.0080908. [143] H. Kared, S. Martelli, T. P. Ng, S. L. F. Pender, and A. Larbi, “CD57 in human natural killer cells and T-lymphocytes,” Cancer Immunol. Immunother., vol. 65, no. 4, pp. 441–452, Apr. 2016, doi: 10.1007/s00262-016-1803-z. |
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Atribución-NoComercial-CompartirIgual 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Combita Rojas, Alba Lucía6314d25773a6df920534c402dcbbd1b1Parra Media, Rafael Santiago868f444c86708ae47f4d527ef042e3aeRodríguez Castañeda, Sergio Fabián25cc0b102bdd60ef80d92f5900a3a3ee2022-06-29T19:07:51Z2022-06-29T19:07:51Z2022-06-09https://repositorio.unal.edu.co/handle/unal/81670Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, gráficas, tablasEn este proyecto se planteó determinar la relación entre los niveles de expresión de 15-Hidroxiprostaglandina deshidrogenasa (HPGD) con la densidad y el fenotipo de linfocitos T (LT) en tejido prostático de pacientes con cáncer de próstata (CaP) y su posible asociación con la recurrencia bioquímica (RB). Es un estudio analítico retrospectivo, en tejidos incluidos en parafina de pacientes con CaP tratados en el Instituto Nacional de Cancerología (INC) entre los años 2007 a 2013, intervenidos con prostatectomía radical (PR). Se analizó la expresión de HPGD mediante qRT-PCR e inmunohistoquímica. La población y fenotipo de LT (periféricos e infiltrantes de tumor (TIL)) se determinó mediante inmunohistoquímica a través de la utilización de anticuerpos específicos para cada marcador. Pruebas de χ2 o test exacto de Fisher fueron aplicadas para determinar diferencias estadísticamente significativas entre las variables analizadas con una p<0,05. Se observó una expresión positiva de HPGD en todos los casos, sin embargo, esta expresión fue de bajo nivel den la mayoría. Adicional, no se encontraron diferencias significativas con respecto a los desenlaces de RB ni los grupos grado Gleason (p>0,05). La expresión proteica de HPGD en tejido prostático no tumoral se encontró en alta frecuencia a bajo nivel mientras que, en tejido tumoral se halló una baja frecuencia y bajo nivel (p<0,001). La infiltración de LT se presentó en mayor densidad en la región tumoral vs periférica (p<0,001). La densidad alta de TIL se asoció a mayor infiltración CD4 que CD8 y ambos casos se relacionaron con un riesgo de desarrollo de RB (P<0,05). La razón CD8/CD4 se presentó principalmente en mayor frecuencia en tejido periférico de pacientes sin RB. Por otro lado, la expresión alta de HPGD se encontró casi exclusivamente en tejido tumoral en un número reducido de casos y en estos se relacionó con una tendencia de expresión negativa de ERG y sin RB. Aunque no se pudo establecer una asociación entre la densidad ni la razón TIL CD4/CD8 con los niveles de expresión de HPGD y los desenlaces de RB, nuestros resultados resaltan los hallazgos de que la expresión de ERG podría desregular la expresión de HPGD y esta baja expresión podría explicar la baja actividad de los TIL explicando las características de un tumor frío inmunológicamente. Sin embargo, es necesario realizar otros ensayos que permita establecer un mejor fenotipo de las poblaciones celulares y en un número poblacional mayor. (Texto tomado de la fuente).This project aimed to determine the relationship between the expression levels of 15-Hydroxyprostagladine dehydrogenase (HPGD) with the density and phenotype of T lymphocytes (Tcell) in prostatic tissue from patients with prostate cancer (PCa) and its possible association with biochemical recurrence (BCR). It is a retrospective analytical study, in paraffin-embedded tissues of patients with PCa treated at the National Cancer Institute (INC) between 2007 and 2013, who underwent radical prostatectomy (PR). HPGD expression was analyzed by qRT-PCR and immunohistochemistry. The population and phenotype of LT (peripheral and tumor infiltrating (TIL)) was determined by immunohistochemistry through the use of specific antibodies for each marker. χ2 tests or Fisher's exact test were applied to determine statistically significant differences between the variables analyzed with a p<0.05. Positive expression of HPGD was observed in all cases, however this expression was low level in the majority. Additionally, no significant differences were found regarding the outcomes of BR or the Gleason grade groups (p>0.05). The protein expression of HPGD in non-tumorous prostate tissue was found in high frequency at a low level, while in tumor tissue a low frequency and low level was found (p<0.001). LT infiltration was found to be more dense in the tumor vs. peripheral region (p<0.001). High TIL density was associated with greater CD4 than CD8 infiltration, and both cases were associated with a risk of BR development (P<0.05). The CD8/CD4 ratio was mainly present in higher frequency in peripheral tissue of patients without BR. On the other hand, the high expression of HPGD was found almost exclusively in tumor tissue in a small number of cases and in these it was related to a trend of negative expression of ERG and without RB. Although an association between density and TIL CD4/CD8 ratio with HPGD expression levels and RB outcomes could not be established, our results highlight the findings that ERG expression could dysregulate HPGD expression and this low expression could explain the low activity of TILs, explaining the characteristics of an immunologically cold tumor. However, it is necessary to carry out other tests that allow establishing a better phenotype of the cell populations and in a larger population number.Maestría en Inmunología Departamento de Microbiología Facultad de Medicina Universidad Nacional de ColombiaMaestríaMagíster en InmunologíaEs un estudio analítico retrospectivo, para la caracterización de densidad y fenotipos específicos de linfocitos infiltrantes de tumor asociados a los niveles de expresión del gen HPGD y al riesgo de RB.xvi, 74 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Maestría en InmunologíaDepartamento de MicrobiologíaFacultad de MedicinaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::616 - EnfermedadesHidroxiprostaglandina DeshidrogenasasLinfocitos TNeoplasias de la PróstataHydroxyprostaglandin DehydrogenasesT-LymphocytesProstatic NeoplasmsMicroambiente tumoralInmunorregulaciónCáncer de próstataInfiltración linfocitariaRecurrencia bioquímicaImmunoregulationProstate cancerLymphocytic infiltrationBiochemical recurrenceTumor microenvironmentRelación entre niveles de expresión de HPGD con la densidad y el fenotipo de linfocitos T en tejido tumoral de pacientes con cáncer de próstata y su asociación con recurrencia bioquímicaRelationship between HPGD expression levels with the density and phenotype of T lymphocytes in tumor tissue of patients with prostate cancer and its association with biochemical recurrenceTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMBireme[1] H. Sung et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA. Cancer J. Clin., vol. 71, no. 3, pp. 209–249, 2021, doi: 10.3322/caac.21660.[2] The Global Cancer Observatory, “GLOBOCAN 2020: International Agency Research on Cancer,” 2020. https://gco.iarc.fr/today/data/factsheets/populations/170-colombia-fact-sheets.pdf.[3] P. Rawla, “Epidemiology of Prostate Cancer,” vol. 10, no. 2, pp. 63–89, 2019, doi: 10.1159/000423644.[4] A. Barsouk et al., “Epidemiology, Staging and Management of Prostate Cancer,” Med. Sci., vol. 8, no. 3, p. 28, 2020, doi: 10.3390/medsci8030028.[5] Z. Wang et al., “The efficacy and safety of radical prostatectomy and radiotherapy in high-risk prostate cancer: A systematic review and meta-analysis,” World Journal of Surgical Oncology, vol. 18, no. 1. BioMed Central Ltd., Feb. 24, 2020, doi: 10.1186/s12957-020-01824-9.[6] X. Zhou et al., “Comparing effectiveness of radical prostatectomy versus external beam radiotherapy in patients with locally advanced prostate cancer: A population-based analysis,” Medicine (Baltimore)., vol. 99, no. 34, p. e21642, 2020, doi: 10.1097/MD.0000000000021642.[7] R. Tourinho-Barbosa et al., “Biochemical recurrence after radical prostatectomy: what does it mean?,” doi: 10.1590/S1677-5538.IBJU.2016.0656.[8] C. L. Amling, E. J. Bergstralh, M. L. Blute, J. M. Slezak, and H. Zincke, “Defining prostate specific antigen progression after radical prostatectomy: What is the most appropriate cut point?,” J. Urol., vol. 165, no. 4, pp. 1146–1151, 2001, doi: 10.1016/S0022-5347(05)66452-X.[9] A. I. Cole et al., “Prognostic Value of Percent Gleason Grade 4 at Prostate Biopsy in Predicting Prostatectomy Pathology and Recurrence,” J. Urol., vol. 196, no. 2, pp. 405–411, Aug. 2016, doi: 10.1016/j.juro.2016.01.120.[10] A. V. D’Amico et al., “Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer,” J. Am. Med. Assoc., vol. 280, no. 11, pp. 969–974, Sep. 1998, doi: 10.1001/jama.280.11.969.[11] I. M. van Oort, C. A. Hulsbergen-vandeKaa, and J. A. Witjes, “Prognostic Factors in Radical Prostatectomy Specimens: What Do We Need to Know from Pathologists?,” European Urology, Supplements, vol. 7, no. 12. Elsevier, pp. 715–722, Nov. 01, 2008, doi: 10.1016/j.eursup.2008.07.002.[12] M. N. Simmons, A. J. Stephenson, and E. A. Klein, “Natural History of Biochemical Recurrence after Radical Prostatectomy: Risk Assessment for Secondary Therapy{A figure is presented},” European Urology, vol. 51, no. 5. Elsevier, pp. 1175–1184, May 01, 2007, doi: 10.1016/j.eururo.2007.01.015.[13] N. Mottet et al., “Highlights on Prostate Cancer from Urological and Oncological Congresses in 2007,” European Urology, Supplements, vol. 7, no. 6. Elsevier, pp. 460–476, Apr. 01, 2008, doi: 10.1016/j.eursup.2008.01.004.[14] A. Pettersson et al., “The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: A cohort study and meta-analysis,” Cancer Epidemiol. Biomarkers Prev., vol. 21, no. 9, pp. 1497–1509, Sep. 2012, doi: 10.1158/1055-9965.EPI-12-0042.[15] S. A. Tomlins et al., “Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer,” Science (80-. )., vol. 310, no. 5748, pp. 644–648, 2005, doi: 10.1126/science.1117679.[16] O. Klezovitch et al., “A causal role for ERG in neoplastic transformation of prostate epithelium,” Proc. Natl. Acad. Sci. U. S. A., vol. 105, no. 6, pp. 2105–2110, Feb. 2008, doi: 10.1073/pnas.0711711105.[17] S. H. Kim et al., “Overexpression of ERG and wild-type PTEN are associated with favorable clinical prognosis and low biochemical recurrence in prostate cancer,” PLoS One, vol. 10, no. 4, Apr. 2015, doi: 10.1371/journal.pone.0122498.[18] H. Tai, H. Cho, M. Tong, and Y. Ding, “NAD+-Linked 15-Hydroxyprostaglandin Dehydrogenase: Structure and Biological Functions,” Curr. Pharm. Des., vol. 12, pp. 955–962, 2006.[19] S. Josson, Y. Matsuoka, L. W. K. Chung, H. E. Zhau, and R. Wang, “Tumor-stroma co-evolution in prostate cancer progression and metastasis,” Seminars in Cell and Developmental Biology, vol. 21, no. 1. Elsevier Ltd, pp. 26–32, 2010, doi: 10.1016/j.semcdb.2009.11.016.[20] R. D. Schreiber, L. J. Old, and M. J. Smyth, “Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion,” Science, vol. 331, no. 6024. Science, pp. 1565–1570, Mar. 25, 2011, doi: 10.1126/science.1203486.[21] Y. Kiniwa et al., “CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer,” Clin. Cancer Res., vol. 13, no. 23, pp. 6947–6958, 2007, doi: 10.1158/1078-0432.CCR-07-0842.[22] L. Schmidleithner et al., “Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction,” Immunity, vol. 50, no. 5, pp. 1232-1248.e14, 2019, doi: 10.1016/j.immuni.2019.03.014.[23] X. Lin et al., “Assessment of biochemical recurrence of prostate cancer (Review),” International Journal of Oncology, vol. 55, no. 6. Spandidos Publications, pp. 1194–1212, Nov. 30, 2019, doi: 10.3892/ijo.2019.4893.[24] N. Vitkin, S. Nersesian, D. R. Siemens, and M. Koti, “The tumor immune contexture of prostate cancer,” Front. Immunol., vol. 10, no. MAR, pp. 1–10, 2019, doi: 10.3389/fimmu.2019.00603.[25] D. Lin, X. Wang, S. Y. C. Choi, X. Ci, X. Dong, and Y. Wang, “Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell-like transition?,” Asian J. Urol., vol. 3, no. 4, pp. 195–202, 2016, doi: 10.1016/j.ajur.2016.08.002.[26] W. H. Fridman, L. Zitvogel, C. Sautès-Fridman, and G. Kroemer, “The immune contexture in cancer prognosis and treatment,” Nature Reviews Clinical Oncology, vol. 14, no. 12. Nature Publishing Group, pp. 717–734, Dec. 01, 2017, doi: 10.1038/nrclinonc.2017.101.[27] A. M. Miller et al., “ CD4 + CD25 high T Cells Are Enriched in the Tumor and Peripheral Blood of Prostate Cancer Patients ,” J. Immunol., vol. 177, no. 10, pp. 7398–7405, Nov. 2006, doi: 10.4049/jimmunol.177.10.7398.[28] V. Nardone et al., “Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse,” Cancer Biol. Ther., vol. 17, no. 11, pp. 1213–1220, 2016, doi: 10.1080/15384047.2016.1235666.[29] F. Petitprez et al., “PD-L1 Expression and CD8 + T-cell Infiltrate are Associated with Clinical Progression in Patients with Node-positive Prostate Cancer,” Eur. Urol. Focus, vol. 5, no. 2, pp. 192–196, 2019, doi: 10.1016/j.euf.2017.05.013.[30] N. Ness et al., “Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer,” Prostate, vol. 74, no. 14, pp. 1452–1461, 2014, doi: 10.1002/pros.22862.[31] J. A. Joyce and D. T. Fearon, “T cell exclusion, immune privilege, and the tumor microenvironment,” Science, vol. 348, no. 6230. American Association for the Advancement of Science, pp. 74–80, Apr. 03, 2015, doi: 10.1126/science.aaa6204.[32] S. Mariathasan et al., “TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells,” Nature, vol. 554, no. 7693, pp. 544–548, Feb. 2018, doi: 10.1038/nature25501.[33] M. Lundholm et al., “Secreted factors from colorectal and prostate cancer cells skew the immune response in opposite directions,” Sci. Rep., vol. 5, Oct. 2015, doi: 10.1038/srep15651.[34] B. Molon et al., “Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells,” J. Exp. Med., vol. 208, no. 10, pp. 1949–1962, Sep. 2011, doi: 10.1084/jem.20101956.[35] J. A. Taylor et al., “Regulation of the prostaglandin pathway during development of invasive bladder cancer in mice,” Prostaglandins Other Lipid Mediat., vol. 88, no. 1–2, pp. 36–41, Jan. 2009, doi: 10.1016/j.prostaglandins.2008.09.003.[36] J. Heighway et al., “Expression profiling of primary non-small cell lung cancer for target identification,” Oncogene, vol. 21, no. 50, pp. 7749–7763, Oct. 2002, doi: 10.1038/sj.onc.1205979.[37] R. Wu et al., “Association of 15-hydroxyprostaglandin dehydrogenate and poor prognosis of obese breast cancer patients,” 2017. Accessed: May 21, 2020. [Online]. Available: www.impactjournals.com/oncotarget.[38] X. Qi, Y. Wang, J. Hou, and Y. Huang, “A single nucleotide polymorphism in HPGD gene is associated with prostate cancer risk,” J. Cancer, vol. 8, no. 19, pp. 4083–4086, 2017, doi: 10.7150/jca.22025.[39] P. Vainio et al., “Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer,” Am. J. Pathol., vol. 178, no. 2, pp. 525–536, Feb. 2011, doi: 10.1016/j.ajpath.2010.10.002.[40] M. Tong and H. H. Tai, “Induction of NAD+-linked 15-hydroxyprostaglandin dehydrogenase expression by androgens in human prostate cancer cells,” Biochem. Biophys. Res. Commun., vol. 276, no. 1, pp. 77–81, Sep. 2000, doi: 10.1006/bbrc.2000.3437.[41] S. Sun et al., “BAP18 coactivates androgen receptor action and promotes prostate cancer progression,” Nucleic Acids Res., vol. 44, no. 17, pp. 8112–8128, 2016, doi: 10.1093/nar/gkw472.[42] T. H. Kim, J. M. Park, M. Y. Kim, and Y. H. Ahn, “The role of CREB3L4 in the proliferation of prostate cancer cells,” Sci. Rep., vol. 7, no. 1, pp. 1–11, Mar. 2017, doi: 10.1038/srep45300.[43] A. A. Mohamed et al., “ERG oncogene modulates prostaglandin signaling in prostate cancer cells,” Cancer Biol. Ther., vol. 11, no. 4, pp. 410–417, Feb. 2011, doi: 10.4161/cbt.11.4.14180.[44] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA. Cancer J. Clin., vol. 68, no. 6, pp. 394–424, 2018, doi: 10.3322/caac.21492.[45] G. The Global Cancer Observatory, “Prostate 2018,” 2019.[46] I. de C. en Colombia, “Infocancer Incidencia Próstata Edades.” http://www.infocancer.co/portal/#!/filtro_tasas/.[47] E. B. O’Keefe, J. P. Meltzer, and T. N. Bethea, “Health Disparities and Cancer: Racial Disparities in Cancer Mortality in the United States, 2000–2010,” Front. Public Heal., vol. 3, no. April, pp. 1–15, 2015, doi: 10.3389/fpubh.2015.00051.[48] G. K. Panigrahi et al., “Exosome proteomic analyses identify inflammatory phenotype and novel biomarkers in African American prostate cancer patients,” Cancer Med., vol. 8, no. 3, pp. 1110–1123, 2019, doi: 10.1002/cam4.1885.[49] I. J. Powell, C. H. Bock, J. J. Ruterbusch, and W. Sakr, “Evidence Supports a Faster Growth Rate and/or Earlier Transformation to Clinically Significant Prostate Cancer in Black Than in White American Men, and Influences Racial Progression and Mortality Disparity,” J. Urol., vol. 183, no. 5, pp. 1792–1797, May 2010, doi: 10.1016/j.juro.2010.01.015.[50] S. D. Brookman-May et al., “Latest Evidence on the Impact of Smoking, Sports, and Sexual Activity as Modifiable Lifestyle Risk Factors for Prostate Cancer Incidence, Recurrence, and Progression: A Systematic Review of the Literature by the European Association of Urology Section of ,” Eur. Urol. Focus, vol. 5, no. 5, pp. 756–787, 2019, doi: 10.1016/j.euf.2018.02.007.[51] E. Giovannucci, Y. Liu, E. A. Platz, M. J. Stampfer, and W. C. Willett, “Risk factors for prostate cancer incidence and progression in the health professionals follow-up study NIH Public Access,” 2007.[52] F. Islami, D. M. Moreira, P. Boffetta, and S. J. Freedland, “A Systematic Review and Meta-analysis of Tobacco Use and Prostate Cancer Mortality and Incidence in Prospective Cohort Studies HHS Public Access,” Eur Urol, vol. 66, no. 6, pp. 1054–1064, 2014, doi: 10.1016/j.eururo.2014.08.059.[53] J. M. Genkinger et al., “Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer,” Ann. Oncol., vol. 31, no. 1, pp. 103–114, 2020, doi: 10.1016/j.annonc.2019.09.007.[54] N. Shah and V. Ioffe, “The Association Between Hypertension and Prostate Cancer,” Rev. Urol. •, vol. 19, no. 2, pp. 113–118, 2017, doi: 10.3909/riu0758.[55] Z. Liang et al., “Hypertension and risk of prostate cancer: a systematic review and meta-analysis OPEN,” 2016, doi: 10.1038/srep31358.[56] Y. C. Chen, J. H. Page, R. Chen, and E. Giovannucci, “Family history of prostate and breast cancer and the risk of prostate cancer in the PSA era,” Prostate, vol. 68, no. 14, pp. 1582–1591, 2008, doi: 10.1002/pros.20825.[57] O. Bratt, L. Drevin, O. Akre, H. Garmo, and P. Stattin, “Family History and Probability of Prostate Cancer, Differentiated by Risk Category: A Nationwide Population-Based Study,” J. Natl. Cancer Inst., vol. 108, no. 10, pp. 1–7, 2016, doi: 10.1093/jnci/djw110.[58] C. H. Lee, O. Akin-Olugbade, and A. Kirschenbaum, “Overview of Prostate Anatomy, Histology, and Pathology,” Endocrinol. Metab. Clin. North Am., vol. 40, no. 3, pp. 565–575, 2011, doi: 10.1016/j.ecl.2011.05.012.[59] K. H. Hammerich, G. E. Ayala, and T. M. Wheeler, “Anatomy of the prostate gland and surgical pathology of prostate cancer,” in Prostate Cancer, Cambridge University Press, 2008, pp. 1–14.[60] E. Shtivelman, T. M. Beer, and C. P. Evans, “Oncotarget 7217 www.impactjournals.com/oncotarget Molecular pathways and targets in prostate cancer,” 2014. Accessed: May 14, 2020. [Online]. Available: www.impactjournals.com/oncotarget/.[61] P. Y. Tan, C. W. Chang, K. R. Chng, K. D. S. A. Wansa, W.-K. Sung, and E. Cheung, “Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival,” Mol. Cell. Biol., vol. 32, no. 2, pp. 399–414, Jan. 2012, doi: 10.1128/mcb.05958-11.[62] S. A. Tomlins et al., “Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer,” Nature, vol. 448, no. 7153, pp. 595–599, 2007, doi: 10.1038/nature06024.[63] M. J. Linja and T. Visakorpi, “Alterations of androgen receptor in prostate cancer,” J. Steroid Biochem. Mol. Biol., vol. 92, no. 4, pp. 255–264, 2004, doi: 10.1016/j.jsbmb.2004.10.012.[64] P. Lonergan and D. Tindall, “Androgen receptor signaling in prostate cancer development and progression,” J. Carcinog., vol. 10, 2011, doi: 10.4103/1477-3163.83937.[65] M. E. Grossmann, H. Huang, and D. J. Tindall, “Androgen Receptor Signaling in Androgen-Refractory Prostate Cancer.” Accessed: May 15, 2020. [Online]. Available: https://academic.oup.com/jnci/article-abstract/93/22/1687/2519589.[66] J. Seidenfeld et al., “Single-therapy androgen suppression in men with advanced prostate cancer: A systematic review and meta-analysis,” Annals of Internal Medicine, vol. 132, no. 7. American College of Physicians, pp. 566–577, Apr. 04, 2000, doi: 10.7326/0003-4819-132-7-200004040-00009.[67] P. Koivisto et al., “Androgen receptor gene amplification: A possible molecular mechanism for androgen deprivation therapy failure in prostate cancer,” Cancer Res., vol. 57, no. 2, pp. 314–319, 1997.[68] P. A. Koivisto and I. Rantala, “Amplification of the androgen receptor gene is associated with P53 mutation in hormone-refractory recurrent prostate cancer,” J. Pathol., vol. 187, no. 2, pp. 237–241, 1999, doi: 10.1002/(SICI)1096-9896(199901)187:2<237::AID-PATH224>3.0.CO;2-I.[69] M. E. Taplin et al., “Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer,” N. Engl. J. Med., vol. 332, no. 21, pp. 1393–1398, May 1995, doi: 10.1056/NEJM199505253322101.[70] M. J. McPhaul, “Mechanisms of prostate cancer progression to androgen independence,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 22, no. 2. pp. 373–388, Apr. 2008, doi: 10.1016/j.beem.2008.02.006.[71] S. Araki et al., “Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer,” Cancer Res., vol. 67, no. 14, pp. 6854–6862, Jul. 2007, doi: 10.1158/0008-5472.CAN-07-1162.[72] Z. Culig et al., “Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-1, keratinocyte growth factor and epidermal growth factor,” Eur. Urol., vol. 54, no. 20, pp. 5474–5478, 1994, doi: 10.1159/000475232.[73] A. Hobisch et al., “Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor,” Cancer Res., vol. 58, no. 20, pp. 4640–4645, Oct. 1998.[74] O. L. Soo, E. Pinder, Y. C. Jae, W. Lou, M. Sun, and A. C. Gao, “Interleukin-4 stimulates androgen-independent growth in LNCaP human prostate cancer cells,” Prostate, vol. 68, no. 1, pp. 85–91, Jan. 2008, doi: 10.1002/pros.20691.[75] G. J. Wise, V. K. Marella, G. Talluri, and D. Shirazian, “Cytokine variations in patients with hormone treated prostate cancer,” J. Urol., vol. 164, no. 3 I, pp. 722–725, 2000, doi: 10.1097/00005392-200009010-00024.[76] V. M. Velonas, H. H. Woo, C. G. Dos Remedios, and S. J. Assinder, “Current Status of Biomarkers for Prostate Cancer,” Int. J. Mol. Sci, vol. 14, pp. 11034–11060, 2013, doi: 10.3390/ijms140611034.[77] J. I. Epstein, L. Egevad, M. B. Amin, B. Delahunt, J. R. Srigley, and P. A. Humphrey, “The 2014 international society of urological pathology (ISUP) consensus conference on gleason grading of prostatic carcinoma definition of grading patterns and proposal for a new grading system,” Am. J. Surg. Pathol., vol. 40, no. 2, pp. 244–252, 2016, doi: 10.1097/PAS.0000000000000530.[78] N. Lawrentschuk, G. Trottier, C. Kuk, and A. Zlotta, “Role of surgery in high-risk localized prostate cancer,” vol. 17, no. 2, pp. 25–32, 2010.[79] A. J. Hayden, C. Catton, and T. Pickles, “Radiation therapy in prostate cancer: A risk-adapted strategy,” Curr. Oncol., vol. 17, no. SUPPL. 2, p. S18, 2010, doi: 10.3747/co.v17i0.704.[80] M. A. Perlmutter and H. Lepor, “Androgen deprivation therapy in the treatment of advanced prostate cancer.,” Rev. Urol., vol. 9 Suppl 1, no. Suppl 1, pp. S3-8, 2007, Accessed: May 15, 2020. [Online]. Available: http://www.ncbi.nlm.nih.gov/pubmed/17387371.[81] F. Z. Chen and X. K. Zhao, “Prostate cancer: Current treatment and prevention strategies,” Iranian Red Crescent Medical Journal, vol. 15, no. 4. Iranian Red Crescent Society, pp. 279–284, 2013, doi: 10.5812/ircmj.6499.[82] Y. Lotan and C. G. Roehrborn, “Clearance rates of total prostate specific antigen (PSA) after radical prostatectomy in African-Americans and Caucasians,” Prostate Cancer Prostatic Dis., vol. 5, no. 2, pp. 111–114, Jun. 2002, doi: 10.1038/sj.pcan.4500567.[83] O. Yossepowitch et al., “Positive surgical margins after radical prostatectomy: A systematic review and contemporary update,” European Urology, vol. 65, no. 2. Elsevier, pp. 303–313, Feb. 01, 2014, doi: 10.1016/j.eururo.2013.07.039.[84] P. H. Lange, C. J. Ercole, D. J. Lightner, E. E. Fraley, and R. Vessella, “The value of serum prostate specific antigen determinations before and after radical prostatectomy,” J. Urol., vol. 141, no. 4 I, pp. 873–879, Apr. 1989, doi: 10.1016/S0022-5347(17)41037-8.[85] D. A. Leach and G. Buchanan, “Stromal androgen receptor in prostate cancer development and progression,” Cancers (Basel)., vol. 9, no. 1, pp. 1–24, 2017, doi: 10.3390/cancers9010010.[86] P. G. Corn, “The tumor microenvironment in prostate cancer: elucidating molecular pathways for therapy development,” Cancer Manag. Res., vol. 4, pp. 183–193, 2012, doi: 10.2147/CMAR.S32839.[87] D. A. Leach et al., “Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome,” Oncotarget, vol. 6, no. 18, pp. 16135–16150, 2015, doi: 10.18632/oncotarget.3873.[88] S. L. Shiao, G. C.-Y. Chu, and L. W. K. Chung, “Regulation of Prostate Cancer Progression by the Tumor Microenvironment,” Cancer Lett., vol. 380, no. 1, pp. 340–348, 2016, doi: 0.1016/j.canlet.2015.12.022.[89] D. W. Powell, R. C. Mifflin, J. D. Valentich, S. E. Crowe, J. I. Saada, and A. B. West, “Myofibroblasts. I. Paracrine cells important in health and disease,” American Journal of Physiology - Cell Physiology, vol. 277, no. 1 46-1. American Physiological SocietyBethesda, MD , 1999, doi: 10.1152/ajpcell.1999.277.1.c1.[90] A. Desmouliere, C. Guyot, and G. Gabbiani, “The stroma reaction myofibroblast: a key player in the control of tumor cell behavior,” Int. J. Dev. Biol., vol. 48, no. 5–6, pp. 509–517, Sep. 2004, doi: 10.1387/ijdb.041802ad.[91] J. A. Tuxhorn, G. E. Ayala, and D. R. Rowley, “Reactive stroma in prostate cancer progression,” Clin. Cancer Res., vol. 8, no. 9, pp. 2912–2923, 2002, doi: 10.1016/S0022-5347(05)65620-0.[92] B. Bagalad, K. Mohan Kumar, and H. Puneeth, “Myofibroblasts: Master of disguise,” Journal of Oral and Maxillofacial Pathology, vol. 21, no. 3. Medknow Publications, pp. 462–463, Sep. 01, 2017, doi: 10.4103/jomfp.JOMFP_146_15.[93] S. Hendry et al., “Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasi,” Advances in Anatomic Pathology, vol. 24, no. 5. Lippincott Williams and Wilkins, pp. 235–251, 2017, doi: 10.1097/PAP.0000000000000162.[94] K. S. Sfanos, S. Yegnasubramanian, W. G. Nelson, and A. M. De Marzo, “The inflammatory microenvironment and microbiome in prostate cancer development,” Nat. Rev. Urol., vol. 15, no. 1, pp. 11–24, 2018, doi: 10.1038/nrurol.2017.167.[95] A. M. De Marzo and Elizabeth A. Platz, “Inflammation in prostate carcinogenesis,” Nat Rev Cancer, vol. 7, no. 4, pp. 256–269, 2007, doi: 10.1038/nrc2090.[96] R. S. Mani, Mohammad A. Amin, X. Li, and S. Kalyana-Sundaram, “Inflammation induced oxidative stress mediates gene fusion formation in prostate cancer,” Cell Rep, vol. 17, no. 10, pp. 2620–2631, 2016, doi: 10.1016/j.celrep.2016.11.019.[97] G. J. L. H. Van Leenders et al., “Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy,” Am. J. Pathol., vol. 162, no. 5, pp. 1529–1537, 2003, doi: 10.1016/S0002-9440(10)64286-1.[98] W. H. Fridman, F. Pagès, C. Saut̀s-Fridman, and J. Galon, “The immune contexture in human tumours: Impact on clinical outcome,” Nature Reviews Cancer, vol. 12, no. 4. Nat Rev Cancer, pp. 298–306, Apr. 2012, doi: 10.1038/nrc3245.[99] J. Galon et al., “Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours,” J. Pathol., vol. 232, no. 2, pp. 199–209, 2014, doi: 10.1002/path.4287.[100] M. Capone et al., “Immunoscore: a new possible approach for melanoma classification,” J. Immunother. Cancer, vol. 2, no. S3, pp. 2–3, 2014, doi: 10.1186/2051-1426-2-s3-p193.[101] I. F. Lissbrant, P. Stattin, P. Wikstrom, J. E. Damber, L. Egevad, and A. Bergh, “Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival.,” Int. J. Oncol., vol. 17, no. 3, pp. 445–451, 2000, doi: 10.3892/ijo.17.3.445.[102] W. Wang, A. Bergh, and J. E. Damber, “Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human prostate cancer,” Clin. Cancer Res., vol. 11, no. 9, pp. 3250–3256, 2005, doi: 10.1158/1078-0432.CCR-04-2405.[103] N. Nonomura et al., “Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer,” BJU Int., vol. 107, no. 12, pp. 1918–1922, 2011, doi: 10.1111/j.1464-410X.2010.09804.x.[104] E. Richardsen, R. D. Uglehus, J. Due, C. Busch, and L. T. R. Busund, “The prognostic impact of M-CSF, CSF-1 receptor, CD68 and CD3 in prostatic carcinoma,” Histopathology, vol. 53, no. 1, pp. 30–38, 2008, doi: 10.1111/j.1365-2559.2008.03058.x.[105] J. Irani et al., “High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy,” Urology, vol. 54, no. 3, pp. 467–472, 1999, doi: 10.1016/S0090-4295(99)00152-1.[106] P. A. McArdle, K. Canna, D. C. McMillan, A. H. McNicol, R. Campbell, and M. A. Underwood, “The relationship between T-lymphocyte subset infiltration and survival in patients with prostate cancer,” Br. J. Cancer, vol. 91, no. 3, pp. 541–543, 2004, doi: 10.1038/sj.bjc.6601943.[107] M. Lanciotti et al., “The role of M1 and M2 macrophages in prostate cancer in relation to extracapsular tumor extension and biochemical recurrence after radical prostatectomy,” Biomed Res. Int., vol. 2014, 2014, doi: 10.1155/2014/486798.[108] K. S. Sfanos, T. C. Bruno, A. K. Meeker, A. M. De Marzo, W. B. Isaacs, and C. G. Drake, “Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+,” Prostate, vol. 69, no. 15, pp. 1694–1703, 2009, doi: 10.1002/pros.21020.[109] S. Davidsson et al., “CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3 + regulatory T cells with respect to lethal prostate cancer,” Mod. Pathol., vol. 26, no. 3, pp. 448–455, 2013, doi: 10.1038/modpathol.2012.164.[110] J. Woo et al., “Mp49-03 Tumor Infiltrating B-Cells Are Increased in Prostate Cancer Tissue,” J. Urol., vol. 191, no. 4S, pp. 1–9, 2014, doi: 10.1016/j.juro.2014.02.1104.[111] A. Flammiger et al., “Intratumoral T but not B lymphocytes are related to clinical outcome in prostate cancer,” Apmis, vol. 120, no. 11, pp. 901–908, 2012, doi: 10.1111/j.1600-0463.2012.02924.x.[112] V. Kärjä, S. Aaltomaa, P. Lipponen, T. Isotalo, M. Talja, and R. Mokka, “Tumour-infiltrating lymphocytes: A prognostic factor of psa-free survival in patients with local prostate carcinoma treated by radical prostatectomy,” Anticancer Res., vol. 25, no. 6 C, pp. 4435–4438, 2005.[113] H. A. Hempel et al., “Low Intratumoral Mast Cells Are Associated With a Higher Risk of Prostate Cancer Recurrence,” Prostate, vol. 77, no. 4, pp. 412–424, 2017, doi: 10.1002/pros.23280.[114] B. Gurel et al., “Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial,” Cancer Epidemiol. Biomarkers Prev., vol. 23, no. 5, pp. 847–856, 2014, doi: 10.1158/1055-9965.EPI-13-1126.[115] R. Kennedy, “Multiple roles for CD4 T cells in anti‐tumor immune responses_KennedyCelisImmRev08.pdf,” Immunol. Rev., vol. 222, pp. 129–144, 2008.[116] M. Beyer and J. L. Schultze, “Regulatory T cells in cancer,” Blood, vol. 108, no. 3, pp. 804–811, 2006, doi: 10.1182/blood-2006-02-002774.[117] T. F. Gajewski, H. Schreiber, and Y. X. Fu, “Innate and adaptive immune cells in the tumor microenvironment,” Nature Immunology, vol. 14, no. 10. NIH Public Access, pp. 1014–1022, 2013, doi: 10.1038/ni.2703.[118] K. S. Sfanos et al., “Phenotypic analysis of prostate-infiltrating lymphocytes reveals T H17 and Treg skewing,” Clin. Cancer Res., vol. 14, no. 11, pp. 3254–3261, 2008, doi: 10.1158/1078-0432.CCR-07-5164.[119] B. Samuelsson, R. Morgenstern, and P. J. Jakobsson, “Membrane prostaglandin E synthase-1: A novel therapeutic target,” Pharmacological Reviews, vol. 59, no. 3. American Society for Pharmacology and Experimental Therapeutics, pp. 207–224, Sep. 01, 2007, doi: 10.1124/pr.59.3.1.[120] A. Madrigal-Martínez, V. Constâncio, F. J. Lucio-Cazaña, and A. B. Fernández-Martínez, “PROSTAGLANDIN E 2 stimulates cancer-related phenotypes in prostate cancer PC3 cells through cyclooxygenase-2,” J. Cell. Physiol., vol. 234, no. 5, pp. 7548–7559, May 2019, doi: 10.1002/jcp.27515.[121] K. Yoshimatsu et al., “Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer,” Clin. Cancer Res., vol. 7, no. 12, pp. 3971–3976, Dec. 2001.[122] F. Finetti, C. Travelli, J. Ercoli, G. Colombo, E. Buoso, and L. Trabalzini, “Prostaglandin E2 and cancer: Insight into tumor progression and immunity,” Biology (Basel)., vol. 9, no. 12, pp. 1–26, 2020, doi: 10.3390/biology9120434.[123] R. Parra-Medina and S. Ramírez-Clavijo, “Why not to use punch biopsies in formalin-fixed paraffin-embedded samples of prostate cancer tissue for DNA and RNA extraction?,” African J. Urol., vol. 27, no. 1, 2021, doi: 10.1186/s12301-021-00257-4.[124] L. Collado-Torres et al., “Reproducible RNA-seq analysis using recount2,” Nat. Biotechnol., vol. 35, no. 4, pp. 319–321, Apr. 2017, doi: 10.1038/nbt.3838.[125] E. Afgan et al., “The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update,” Nucleic Acids Res., vol. 44, no. W1, pp. W3–W10, Jul. 2016, doi: 10.1093/nar/gkw343.[126] TheHumanProteinAtlas:HPGD, “Tissue expression of HPGD - The Human Protein Atlas,” Tissue expression of HPD The Human Protein Atlas. [Online]. Available: https://www.proteinatlas.org/ENSG00000164120-HPGD/tissue.[127] D. Lodygin, A. Epanchintsev, A. Menssen, J. Diebold, and H. Hermeking, “Functional epigenomics identifies genes frequently silenced in prostate cancer,” Cancer Res., vol. 65, no. 10, pp. 4218–4227, 2005, doi: 10.1158/0008-5472.CAN-04-4407.[128] H. T. Purayil, Y. Zhang, J. B. Black, R. Gharaibeh, and Y. Daaka, “Nuclear βArrestin1 regulates androgen receptor function in castration resistant prostate cancer,” Oncogene, vol. 40, no. 14, pp. 2610–2620, 2021, doi: 10.1038/s41388-021-01730-8.[129] H. Liu, J. Shi, M. Wilkerson, X. J. Yang, and F. Lin, “Immunohistochemical evaluation of ERG expression in various benign and malignant tissues,” Ann. Clin. Lab. Sci., vol. 43, no. 1, pp. 3–9, 2013.[130] J. Baohong, J. Sedarsky, S. Srivastava, I. Sesterhenn, A. Dobi, and L. Quanlin, “ERG tumor type is less frequent in high grade and high stage prostate cancers of Chinese men,” J. Cancer, vol. 10, no. 9, pp. 1991–1996, 2019, doi: 10.7150/jca.30025.[131] A. D. Darnel, C. J. LaFargue, R. T. Vollmer, J. Corcos, and T. A. Bismar, “TMPRSS2-ERG fusion is frequently observed in gleason pattern 3 prostate cancer in a canadian cohort,” Cancer Biol. Ther., vol. 8, no. 2, pp. 125–130, 2009, doi: 10.4161/cbt.8.2.7134.[132] J. Galon et al., “Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome,” Science (80-. )., vol. 313, no. 5795, pp. 1960–1964, Sep. 2006, doi: 10.1126/science.1129139.[133] M. J. M. Gooden, G. H. de Bock, N. Leffers, T. Daemen, and H. W. Nijman, “The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis,” Br. J. Cancer, vol. 105, no. 1, pp. 93–103, Jun. 2011, doi: 10.1038/bjc.2011.189.[134] K. Ebelt et al., “Dominance of CD4+ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma,” Prostate, vol. 68, no. 1, pp. 1–10, Jan. 2008, doi: 10.1002/pros.20661.[135] C. Sorrentino, P. Musiani, P. Pompa, G. Cipollone, and E. Di Carlo, “Androgen Deprivation Boosts Prostatic Infiltration of Cytotoxic and Regulatory T Lymphocytes and Has No Effect on Disease-Free Survival in Prostate Cancer Patients,” Clin. Cancer Res., vol. 17, no. 6, pp. 1571–1581, Mar. 2011, doi: 10.1158/1078-0432.CCR-10-2804.[136] A. Flammiger et al., “High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer,” Eur. J. Cancer, vol. 49, no. 6, pp. 1273–1279, Apr. 2013, doi: 10.1016/j.ejca.2012.11.035.[137] K. Park et al., “Antibody-Based Detection of ERG Rearrangement-Positive Prostate Cancer,” Neoplasia, vol. 12, no. 7, pp. 590-IN21, Jul. 2010, doi: 10.1593/neo.10726.[138] A. Flammiger et al., “Intratumoral T but not B lymphocytes are related to clinical outcome in prostate cancer,” APMIS, vol. 120, no. 11, pp. 901–908, Nov. 2012, doi: 10.1111/j.1600-0463.2012.02924.x.[139] G. Petrovics et al., “Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome,” Oncogene, vol. 24, no. 23, pp. 3847–3852, May 2005, doi: 10.1038/sj.onc.1208518.[140] R. K. Nam et al., “Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer,” Br. J. Cancer, vol. 97, no. 12, pp. 1690–1695, Dec. 2007, doi: 10.1038/sj.bjc.6604054.[141] A. VALDMAN et al., “Distribution of Foxp3-, CD4- and CD8-positive lymphocytic cells in benign and malignant prostate tissue,” APMIS, vol. 118, no. 5, pp. 360–365, May 2010, doi: 10.1111/j.1600-0463.2010.02604.x.[142] M. H. M. Barros, F. Hauck, J. H. Dreyer, B. Kempkes, and G. Niedobitek, “Macrophage Polarisation: an Immunohistochemical Approach for Identifying M1 and M2 Macrophages,” PLoS One, vol. 8, no. 11, p. e80908, Nov. 2013, doi: 10.1371/journal.pone.0080908.[143] H. Kared, S. Martelli, T. P. Ng, S. L. F. Pender, and A. Larbi, “CD57 in human natural killer cells and T-lymphocytes,” Cancer Immunol. Immunother., vol. 65, no. 4, pp. 441–452, Apr. 2016, doi: 10.1007/s00262-016-1803-z.Caracterización de perfiles de expresión génica en los grupos de riesgo de recurrencia bioquímica en adenocarcinoma de próstataInstituto Nacional de CancerologíaEstudiantesInvestigadoresMaestrosPúblico generalORIGINALDocumento Final Tesis.pdfDocumento Final Tesis.pdfTesis de Maestría en Inmunologíaapplication/pdf2289574https://repositorio.unal.edu.co/bitstream/unal/81670/1/Documento%20Final%20Tesis.pdf921d374381418a2b102ba4fa8e8c98e2MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-84074https://repositorio.unal.edu.co/bitstream/unal/81670/2/license.txt8153f7789df02f0a4c9e079953658ab2MD52THUMBNAILDocumento Final Tesis.pdf.jpgDocumento Final Tesis.pdf.jpgGenerated Thumbnailimage/jpeg4984https://repositorio.unal.edu.co/bitstream/unal/81670/3/Documento%20Final%20Tesis.pdf.jpg4a189953a803fb8cc0506c476dbaf8baMD53unal/81670oai:repositorio.unal.edu.co:unal/816702024-08-07 23:10:13.79Repositorio 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