Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2010

Open Access 01-12-2010 | Research

Higher expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) and metalloproteinase-9 (MMP-9) in a rat model of peritoneal endometriosis is similar to cancer diseases

Authors: Daniel E Machado, Plínio T Berardo, Celia Y Palmero, Luiz E Nasciutti

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2010

Login to get access

Abstract

Background

Endometriosis is a common disease characterized by the presence of a functional endometrium outside the uterine cavity, causing pelvic pain, dysmenorrheal, and infertility. This disease has been associated to development of different types of malignancies; therefore new blood vessels are essential for the survival of the endometrial implant. Our previous observations on humans showed that angiogenesis is predominantly found in rectosigmoid endometriosis, a deeply infiltrating disease. In this study, we have established the experimental model of rat peritoneal endometriosis to evaluate the process of angiogenesis and to compare with eutopic endometrium.

Methods

We have investigated the morphological characteristics of these lesions and the vascular density, VEGF and its receptor Flk-1 and MMP-9 expression, and activated macrophage distribution, using immunohistochemistry and RT-PCR.

Results

As expected, the auto-transplantation of endometrium pieces into the peritoneal cavity is a well-established method for endometriosis induction in rats. The lesions were cystic and vascularized, and demonstrated histological hallmarks of human pathology, such as endometrial glands and stroma. The vascular density and the presence of VEGF and Flk-1 and MMP-9 were significantly higher in endometriotic lesions than in eutopic endometrium, and confirmed the angiogenic potential of these lesions. We also observed an increase in the number of activated macrophages (ED-1 positive cells) in the endometriotic lesions, showing a positive correlation with VEGF.

Conclusion

The present endometriosis model would be useful for investigation of the mechanisms of angiogenesis process involved in the peritoneal attachment of endometrial cells, as well as of the effects of therapeutic drugs, particularly with antiangiogenic activity.
Appendix
Available only for authorised users
Literature
1.
go back to reference Galle PC: Clinical presentation and diagnosis of endometriosis. Obstet Gynecol Clin North Am. 1989, 16: 29-42. Galle PC: Clinical presentation and diagnosis of endometriosis. Obstet Gynecol Clin North Am. 1989, 16: 29-42.
2.
go back to reference Wheeler JM: Epidemiology and prevalence of endometriosis. Infertil Reprod Med Clin North Am. 1992, 3: 545-549. Wheeler JM: Epidemiology and prevalence of endometriosis. Infertil Reprod Med Clin North Am. 1992, 3: 545-549.
3.
go back to reference Giudice LC, Kao LC: Endometriosis. Lancet. 2004, 364: 1789-1799. 10.1016/S0140-6736(04)17403-5.CrossRef Giudice LC, Kao LC: Endometriosis. Lancet. 2004, 364: 1789-1799. 10.1016/S0140-6736(04)17403-5.CrossRef
4.
go back to reference Groothuis PG, Nap AW, Winterhager E, Grümmer R: Vascular development in endometriosis. Angiogenesis. 2005, 8: 147-156. 10.1007/s10456-005-9005-x.CrossRef Groothuis PG, Nap AW, Winterhager E, Grümmer R: Vascular development in endometriosis. Angiogenesis. 2005, 8: 147-156. 10.1007/s10456-005-9005-x.CrossRef
5.
go back to reference Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995, 1 (1): 27-31. 10.1038/nm0195-27.CrossRef Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995, 1 (1): 27-31. 10.1038/nm0195-27.CrossRef
6.
go back to reference Taylor RN, Lebovic DI, Mueller MD: Angiogenic factors in endometriosis. Ann N Y Acad Sci. 2002, 955: 89-100. 10.1111/j.1749-6632.2002.tb02769.x.CrossRef Taylor RN, Lebovic DI, Mueller MD: Angiogenic factors in endometriosis. Ann N Y Acad Sci. 2002, 955: 89-100. 10.1111/j.1749-6632.2002.tb02769.x.CrossRef
7.
go back to reference Olson JE, Cerhan JR, Janney CA, Anderson KE, Vachon CM, Sellers TA: Postmenopasual cancer risk after self-reported endometriosis diagnosis in the Iowa women's health study. Cancer. 2002, 94: 1612-1618. 10.1002/cncr.10370.CrossRef Olson JE, Cerhan JR, Janney CA, Anderson KE, Vachon CM, Sellers TA: Postmenopasual cancer risk after self-reported endometriosis diagnosis in the Iowa women's health study. Cancer. 2002, 94: 1612-1618. 10.1002/cncr.10370.CrossRef
8.
go back to reference Melin A, Sparen P, Bergqvist A: Endometriosis and the risk of cancer with special emphasis on ovarian cancer. Hum Reprod. 2006, 21: 1237-1242. 10.1093/humrep/dei462.CrossRef Melin A, Sparen P, Bergqvist A: Endometriosis and the risk of cancer with special emphasis on ovarian cancer. Hum Reprod. 2006, 21: 1237-1242. 10.1093/humrep/dei462.CrossRef
9.
go back to reference Patan S: Vasculogenesis and angiogenesis. Cancer Treat Res. 2004, 117: 3-32.CrossRef Patan S: Vasculogenesis and angiogenesis. Cancer Treat Res. 2004, 117: 3-32.CrossRef
10.
go back to reference Chen QH, Qu JU, Xu YY, Qiu NX, Zhuang YZ, Zhong S, Fang QQ: Expressions of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in ectopic and eutopic endometrium. Zhonghua Fu Chan Ke Za Zhi. 2004, 39: 809-812. Chen QH, Qu JU, Xu YY, Qiu NX, Zhuang YZ, Zhong S, Fang QQ: Expressions of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in ectopic and eutopic endometrium. Zhonghua Fu Chan Ke Za Zhi. 2004, 39: 809-812.
11.
go back to reference Risau W: Mechanisms of angiogenesis. Nature. 1997, 386 (6626): 671-674. 10.1038/386671a0.CrossRef Risau W: Mechanisms of angiogenesis. Nature. 1997, 386 (6626): 671-674. 10.1038/386671a0.CrossRef
12.
go back to reference McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Müller KH, Sharkey AM, et al: Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest. 1996, 98: 482-489. 10.1172/JCI118815.CrossRef McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Müller KH, Sharkey AM, et al: Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest. 1996, 98: 482-489. 10.1172/JCI118815.CrossRef
13.
go back to reference Pupo-Nogueira A, de Oliveira RM, Petta CA, Podgaec S, Dias JÁ, Abrão MS: Vascular Endothelial Growth Factor concentrations in the serum and peritoneal fluid of women with endometriosis. Int J Gynecol Obstet. 2007, 99 (1): 33-37. 10.1016/j.ijgo.2007.04.033.CrossRef Pupo-Nogueira A, de Oliveira RM, Petta CA, Podgaec S, Dias JÁ, Abrão MS: Vascular Endothelial Growth Factor concentrations in the serum and peritoneal fluid of women with endometriosis. Int J Gynecol Obstet. 2007, 99 (1): 33-37. 10.1016/j.ijgo.2007.04.033.CrossRef
14.
go back to reference Ferrara N: Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol. 2001, 280: 1358-1366. Ferrara N: Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol. 2001, 280: 1358-1366.
15.
go back to reference Bourlev V, Volkov N, Pavlovitch S, Lets N, Larsson A, Olovsson M: The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction. 2006, 132 (3): 501-509. 10.1530/rep.1.01110.CrossRef Bourlev V, Volkov N, Pavlovitch S, Lets N, Larsson A, Olovsson M: The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction. 2006, 132 (3): 501-509. 10.1530/rep.1.01110.CrossRef
16.
go back to reference Machado DE, Abrão MS, Berardo PT, Takiya CM, Nasciutti LE: Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril. 2008, 90 (1): 148-155. 10.1016/j.fertnstert.2007.05.076.CrossRef Machado DE, Abrão MS, Berardo PT, Takiya CM, Nasciutti LE: Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril. 2008, 90 (1): 148-155. 10.1016/j.fertnstert.2007.05.076.CrossRef
17.
go back to reference Grümmer R: Animals models in endometriosis research. Hum Reprod Update. 2006, 5 (12): 641-649. 10.1093/humupd/dml026.CrossRef Grümmer R: Animals models in endometriosis research. Hum Reprod Update. 2006, 5 (12): 641-649. 10.1093/humupd/dml026.CrossRef
18.
go back to reference Vernon MW, Wilson EA: Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985, 44 (5): 684-694. Vernon MW, Wilson EA: Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985, 44 (5): 684-694.
19.
go back to reference Nap AW, Griffioen AW, Dunselman GA, Bouma-Ter JC, Thijssen VL, Evers JL, et al: Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab. 2004, 89: 1089-1095. 10.1210/jc.2003-031406.CrossRef Nap AW, Griffioen AW, Dunselman GA, Bouma-Ter JC, Thijssen VL, Evers JL, et al: Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab. 2004, 89: 1089-1095. 10.1210/jc.2003-031406.CrossRef
20.
go back to reference Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M: Vascular endothelial growth factor in endometriosis. Hum Reprod. 1998, 13: 1686-1690. 10.1093/humrep/13.6.1686.CrossRef Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M: Vascular endothelial growth factor in endometriosis. Hum Reprod. 1998, 13: 1686-1690. 10.1093/humrep/13.6.1686.CrossRef
21.
go back to reference Sampson JA: Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927, 14: 422-469.CrossRef Sampson JA: Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927, 14: 422-469.CrossRef
22.
go back to reference Nap AW, Groothuis PG, Demir AY, Evers JL, Dunselman GA: Pathogenesis of endometriosis. Bet Pract Res Clin Obstet Gynaecol. 2004, 18: 233-244. 10.1016/j.bpobgyn.2004.01.005.CrossRef Nap AW, Groothuis PG, Demir AY, Evers JL, Dunselman GA: Pathogenesis of endometriosis. Bet Pract Res Clin Obstet Gynaecol. 2004, 18: 233-244. 10.1016/j.bpobgyn.2004.01.005.CrossRef
23.
go back to reference Brosens I: Endometriosis and the outcome of in vitro fertilization. Fertil Steril. 2004, 81: 1198-1200. 10.1016/j.fertnstert.2003.09.071.CrossRef Brosens I: Endometriosis and the outcome of in vitro fertilization. Fertil Steril. 2004, 81: 1198-1200. 10.1016/j.fertnstert.2003.09.071.CrossRef
24.
go back to reference Lebovic DI, Kir M, Casey CL: Peroxisome proliferator-activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis. Fertil Steril. 2004, 82 (3): 1008-1013. 10.1016/j.fertnstert.2004.02.148.CrossRef Lebovic DI, Kir M, Casey CL: Peroxisome proliferator-activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis. Fertil Steril. 2004, 82 (3): 1008-1013. 10.1016/j.fertnstert.2004.02.148.CrossRef
25.
go back to reference Dogan E, Saygili U, Posaci C, Tuna B, Caliskan S, Altunyurt S, Saatli B: Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib. Fertil Steril. 2004, 82 (3): 1115-1120. 10.1016/j.fertnstert.2004.06.033.CrossRef Dogan E, Saygili U, Posaci C, Tuna B, Caliskan S, Altunyurt S, Saatli B: Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib. Fertil Steril. 2004, 82 (3): 1115-1120. 10.1016/j.fertnstert.2004.06.033.CrossRef
26.
go back to reference Vinatier D, Dufour P, Oosterlynck D: Immunological aspects of endometriosis. Hum Reprod Update. 1996, 2 (5): 371-384. 10.1093/humupd/2.5.371.CrossRef Vinatier D, Dufour P, Oosterlynck D: Immunological aspects of endometriosis. Hum Reprod Update. 1996, 2 (5): 371-384. 10.1093/humupd/2.5.371.CrossRef
27.
go back to reference Backer CM, D'Amato RJ: Angiogenesis and antiangiogenesis therapy in endometriosis. Microvas Res. 2007, 74: 121-130. 10.1016/j.mvr.2007.04.008.CrossRef Backer CM, D'Amato RJ: Angiogenesis and antiangiogenesis therapy in endometriosis. Microvas Res. 2007, 74: 121-130. 10.1016/j.mvr.2007.04.008.CrossRef
28.
go back to reference Mueller MD, Lebovic DI, Garrett E, Taylor RN: Neutrophils infiltrating the endometrium express vascular endothelial growth factor: potential role in endometrial angiogenesis. Fertil Steril. 2000, 74 (1): 107-112. 10.1016/S0015-0282(00)00555-0.CrossRef Mueller MD, Lebovic DI, Garrett E, Taylor RN: Neutrophils infiltrating the endometrium express vascular endothelial growth factor: potential role in endometrial angiogenesis. Fertil Steril. 2000, 74 (1): 107-112. 10.1016/S0015-0282(00)00555-0.CrossRef
29.
go back to reference Wang HB, Lang JH, Leng JH, Zhu L, Liu ZF, Sun DW: Expression of vascular endothelial growth factor receptors in the ectopic and eutopic endometrium of women with endometriosis. Zhonghua Yi Xue Za Zhi. 2005, 85 (22): 1555-1559. Wang HB, Lang JH, Leng JH, Zhu L, Liu ZF, Sun DW: Expression of vascular endothelial growth factor receptors in the ectopic and eutopic endometrium of women with endometriosis. Zhonghua Yi Xue Za Zhi. 2005, 85 (22): 1555-1559.
30.
go back to reference Lin YJ, Lai MD, Lei HY, Wing LY: Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology. 2006, 147 (3): 1278-1286. 10.1210/en.2005-0790.CrossRef Lin YJ, Lai MD, Lei HY, Wing LY: Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology. 2006, 147 (3): 1278-1286. 10.1210/en.2005-0790.CrossRef
31.
go back to reference Folkman J: Tumor angiogenesis: therapeutic implications. New Engl J Med. 1971, 285 (21): 1182-1186.CrossRef Folkman J: Tumor angiogenesis: therapeutic implications. New Engl J Med. 1971, 285 (21): 1182-1186.CrossRef
32.
go back to reference Prowse AH, Manek S, Varma R, Liu J, Godwin AK, Maher ER, Tomlinson IPM, Kennedy SH: Molecular genetic evidence that endometriosis is a precursor of ovarian cancer. Int J Cancer. 2006, 119: 556-562. 10.1002/ijc.21845.CrossRef Prowse AH, Manek S, Varma R, Liu J, Godwin AK, Maher ER, Tomlinson IPM, Kennedy SH: Molecular genetic evidence that endometriosis is a precursor of ovarian cancer. Int J Cancer. 2006, 119: 556-562. 10.1002/ijc.21845.CrossRef
33.
go back to reference Melin A, Sparen P, Berqvist A: The risk of cancer and the role of parity among women with endometriosis. Hum Reprod. 2007, 22: 3021-3026. 10.1093/humrep/dem209.CrossRef Melin A, Sparen P, Berqvist A: The risk of cancer and the role of parity among women with endometriosis. Hum Reprod. 2007, 22: 3021-3026. 10.1093/humrep/dem209.CrossRef
34.
go back to reference Baldi A, Campioni M, Signorile PG: Endometriosis: Pathogenesis, diagnosis, therapy and association with cancer. Oncol Reports. 2008, 19: 843-846. Baldi A, Campioni M, Signorile PG: Endometriosis: Pathogenesis, diagnosis, therapy and association with cancer. Oncol Reports. 2008, 19: 843-846.
35.
go back to reference Goumenou AG, Arvanitis DA, Matalliotakis IM, Koumantakis EE, Spandidos DA: Microsatellite DNA assays reveal an allelic imbalance in p16(Ink4), GALT, p53, and APOA2 loci in patients with endometriosis. Fertil Steril. 2001, 75: 160-165. 10.1016/S0015-0282(00)01663-0.CrossRef Goumenou AG, Arvanitis DA, Matalliotakis IM, Koumantakis EE, Spandidos DA: Microsatellite DNA assays reveal an allelic imbalance in p16(Ink4), GALT, p53, and APOA2 loci in patients with endometriosis. Fertil Steril. 2001, 75: 160-165. 10.1016/S0015-0282(00)01663-0.CrossRef
36.
go back to reference Mammas IN, Zafiropoulos A, Spandidos DA: Involvement of the ras genes in female genital tract cancer. Int J Oncol. 2005, 26: 1241-1255. Mammas IN, Zafiropoulos A, Spandidos DA: Involvement of the ras genes in female genital tract cancer. Int J Oncol. 2005, 26: 1241-1255.
37.
go back to reference Chung HW, Wen Y, Chun SH, Nezhat C, Woo BH, Lake PM: Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness. Fertil Steril. 2001, 75 (1): 152-159. 10.1016/S0015-0282(00)01670-8.CrossRef Chung HW, Wen Y, Chun SH, Nezhat C, Woo BH, Lake PM: Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness. Fertil Steril. 2001, 75 (1): 152-159. 10.1016/S0015-0282(00)01670-8.CrossRef
38.
go back to reference Chen QH, Zhou WD, Pu DM, Huang QS, Li T, Chen QX: 15-Epi-lipoxin A(4) inhibits the progression of endometriosis in a murine model. Fertil Steril. 2009. Chen QH, Zhou WD, Pu DM, Huang QS, Li T, Chen QX: 15-Epi-lipoxin A(4) inhibits the progression of endometriosis in a murine model. Fertil Steril. 2009.
39.
go back to reference Kirn-Safran CB, D'Souza SS, Carson DD: Heparan sulfate proteoglycans and their binding proteins in embryo implantation and placentation. Semin Cell Dev Biol. 2008, 19: 187-193. 10.1016/j.semcdb.2007.07.013.CrossRef Kirn-Safran CB, D'Souza SS, Carson DD: Heparan sulfate proteoglycans and their binding proteins in embryo implantation and placentation. Semin Cell Dev Biol. 2008, 19: 187-193. 10.1016/j.semcdb.2007.07.013.CrossRef
40.
go back to reference Berardo PT, Abrão MS, Souza ML, Machado DE, Silva LC, Nasciutti LE: Composition of sulfated glycosaminoglycans and immunodistribution of chondroitin sulfate in deeply infiltrating endometriosis affecting the rectosigmoid. Micron. 2009, 40: 639-45. 10.1016/j.micron.2009.02.005.CrossRef Berardo PT, Abrão MS, Souza ML, Machado DE, Silva LC, Nasciutti LE: Composition of sulfated glycosaminoglycans and immunodistribution of chondroitin sulfate in deeply infiltrating endometriosis affecting the rectosigmoid. Micron. 2009, 40: 639-45. 10.1016/j.micron.2009.02.005.CrossRef
41.
go back to reference Nasciutti LE, Ferrari R, Berardo PT, Souza MLS, Takiya CM, Borojevic R, Abrao MS, Silva LCF: Distribution of chondroitin sulfate in human endometrium. Micron. 2006, 37: 544-550. 10.1016/j.micron.2005.12.005.CrossRef Nasciutti LE, Ferrari R, Berardo PT, Souza MLS, Takiya CM, Borojevic R, Abrao MS, Silva LCF: Distribution of chondroitin sulfate in human endometrium. Micron. 2006, 37: 544-550. 10.1016/j.micron.2005.12.005.CrossRef
Metadata
Title
Higher expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) and metalloproteinase-9 (MMP-9) in a rat model of peritoneal endometriosis is similar to cancer diseases
Authors
Daniel E Machado
Plínio T Berardo
Celia Y Palmero
Luiz E Nasciutti
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2010
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-29-4

Other articles of this Issue 1/2010

Journal of Experimental & Clinical Cancer Research 1/2010 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine