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Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients

Authors: Stina Garvin, Charlotta Dabrosin

Published in: BMC Cancer | Issue 1/2008

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Abstract

Background

Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue.

Methods

Microdialysis was used to sample VEGF and estradiol in tumors and adjacent normal breast tissue in postmenopausal breast cancer patients. VEGF and estradiol were also measured in plasma, and immunohistochemical staining for VEGF was performed on tumor sections.

Results

We show that in vivo levels of extracellular VEGF were significantly higher in breast cancer tumors than in normal adjacent breast tissue. There was a significant positive correlation between estradiol and extracellular VEGF in normal breast tissue. However, no correlation was detected between estradiol and VEGF in tumors or between tumor VEGF and plasma VEGF.

Conclusion

We conclude that VEGF and estradiol correlates significantly in normal breast tissue. Microdialysis may be used to provide novel insight in breast tumor biology and the regulation of molecules in the extracellular space of human breast tumors in vivo.
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Literature
1.
go back to reference Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995, 1: 27-31. 10.1038/nm0195-27.CrossRefPubMed Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995, 1: 27-31. 10.1038/nm0195-27.CrossRefPubMed
2.
go back to reference Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R: Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol. 2000, 18: 1423-1431.PubMed Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R: Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol. 2000, 18: 1423-1431.PubMed
3.
go back to reference Linderholm B, Tavelin B, Grankvist K, Henriksson R: Vascular endothelial growth factor is of high prognostic value in node- negative breast carcinoma. J Clin Oncol. 1998, 16: 3121-3128.PubMed Linderholm B, Tavelin B, Grankvist K, Henriksson R: Vascular endothelial growth factor is of high prognostic value in node- negative breast carcinoma. J Clin Oncol. 1998, 16: 3121-3128.PubMed
4.
go back to reference Toi M, Inada K, Suzuki H, Tominaga T: Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat. 1995, 36: 193-204. 10.1007/BF00666040.CrossRefPubMed Toi M, Inada K, Suzuki H, Tominaga T: Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat. 1995, 36: 193-204. 10.1007/BF00666040.CrossRefPubMed
5.
go back to reference Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev. 1997, 18: 4-25. 10.1210/er.18.1.4.CrossRefPubMed Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev. 1997, 18: 4-25. 10.1210/er.18.1.4.CrossRefPubMed
6.
go back to reference Dabrosin C: Positive correlation between estradiol and vascular endothelial growth factor but not fibroblast growth factor-2 in normal human breast tissue in vivo. Clin Cancer Res. 2005, 11: 8036-8041. 10.1158/1078-0432.CCR-05-0977.CrossRefPubMed Dabrosin C: Positive correlation between estradiol and vascular endothelial growth factor but not fibroblast growth factor-2 in normal human breast tissue in vivo. Clin Cancer Res. 2005, 11: 8036-8041. 10.1158/1078-0432.CCR-05-0977.CrossRefPubMed
7.
go back to reference Dabrosin C, Margetts PJ, Gauldie J: Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer. Int J Cancer. 2003, 107: 535-540. 10.1002/ijc.11398.CrossRefPubMed Dabrosin C, Margetts PJ, Gauldie J: Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer. Int J Cancer. 2003, 107: 535-540. 10.1002/ijc.11398.CrossRefPubMed
8.
go back to reference Garvin S, Dabrosin C: Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo. Cancer Res. 2003, 63: 8742-8748.PubMed Garvin S, Dabrosin C: Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo. Cancer Res. 2003, 63: 8742-8748.PubMed
9.
go back to reference Garvin S, Nilsson UW, Huss FR, Kratz G, Dabrosin C: Estradiol increases VEGF in human breast studied by whole-tissue culture. Cell Tissue Res. 2006, 325: 245-251. 10.1007/s00441-006-0159-7.CrossRefPubMed Garvin S, Nilsson UW, Huss FR, Kratz G, Dabrosin C: Estradiol increases VEGF in human breast studied by whole-tissue culture. Cell Tissue Res. 2006, 325: 245-251. 10.1007/s00441-006-0159-7.CrossRefPubMed
10.
go back to reference Hyder SM, Murthy L, Stancel GM: Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Cancer Res. 1998, 58: 392-395.PubMed Hyder SM, Murthy L, Stancel GM: Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Cancer Res. 1998, 58: 392-395.PubMed
11.
go back to reference Hyder SM, Nawaz Z, Chiappetta C, Stancel GM: Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Res. 2000, 60: 3183-3190.PubMed Hyder SM, Nawaz Z, Chiappetta C, Stancel GM: Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Res. 2000, 60: 3183-3190.PubMed
12.
go back to reference Hulka BS, Stark AT: Breast cancer: cause and prevention. Lancet. 1995, 346: 883-887. 10.1016/S0140-6736(95)92713-1.CrossRefPubMed Hulka BS, Stark AT: Breast cancer: cause and prevention. Lancet. 1995, 346: 883-887. 10.1016/S0140-6736(95)92713-1.CrossRefPubMed
13.
go back to reference Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama. 2002, 288: 321-333. 10.1001/jama.288.3.321.CrossRefPubMed Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama. 2002, 288: 321-333. 10.1001/jama.288.3.321.CrossRefPubMed
14.
go back to reference Vermeulen A, Deslypere JP, Paridaens R, Leclercq G, Roy F, Heuson JC: Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. Eur J Cancer Clin Oncol. 1986, 22: 515-525. 10.1016/0277-5379(86)90121-5.CrossRefPubMed Vermeulen A, Deslypere JP, Paridaens R, Leclercq G, Roy F, Heuson JC: Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. Eur J Cancer Clin Oncol. 1986, 22: 515-525. 10.1016/0277-5379(86)90121-5.CrossRefPubMed
15.
go back to reference van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH: Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res. 1985, 45: 2900-2906.PubMed van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH: Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res. 1985, 45: 2900-2906.PubMed
16.
go back to reference Geisler J: Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol. 2003, 86: 245-253. 10.1016/S0960-0760(03)00364-9.CrossRefPubMed Geisler J: Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol. 2003, 86: 245-253. 10.1016/S0960-0760(03)00364-9.CrossRefPubMed
17.
go back to reference Gunnarsson C, Olsson BM, Stal O: Abnormal expression of 17beta-hydroxysteroid dehydrogenases in breast cancer predicts late recurrence. Cancer Res. 2001, 61: 8448-8451.PubMed Gunnarsson C, Olsson BM, Stal O: Abnormal expression of 17beta-hydroxysteroid dehydrogenases in breast cancer predicts late recurrence. Cancer Res. 2001, 61: 8448-8451.PubMed
18.
go back to reference Pasqualini JR, Chetrite GS: Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol. 2005, 93: 221-236. 10.1016/j.jsbmb.2005.02.007.CrossRefPubMed Pasqualini JR, Chetrite GS: Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol. 2005, 93: 221-236. 10.1016/j.jsbmb.2005.02.007.CrossRefPubMed
19.
go back to reference Dabrosin C: Increase of free insulin-like growth factor-1 in normal human breast in vivo late in the menstrual cycle. Breast Cancer Res Treat. 2003, 80: 193-198. 10.1023/A:1024575103524.CrossRefPubMed Dabrosin C: Increase of free insulin-like growth factor-1 in normal human breast in vivo late in the menstrual cycle. Breast Cancer Res Treat. 2003, 80: 193-198. 10.1023/A:1024575103524.CrossRefPubMed
20.
go back to reference Dabrosin C: Increased extracellular local levels of estradiol in normal breast in vivo during the luteal phase of the menstrual cycle. J Endocrinol. 2005, 187: 103-108. 10.1677/joe.1.06163.CrossRefPubMed Dabrosin C: Increased extracellular local levels of estradiol in normal breast in vivo during the luteal phase of the menstrual cycle. J Endocrinol. 2005, 187: 103-108. 10.1677/joe.1.06163.CrossRefPubMed
21.
go back to reference Dabrosin C: Variability of Vascular Endothelial Growth Factor in Normal Human Breast Tissue in Vivo during the Menstrual Cycle. J Clin Endocrinol Metab. 2003, 88: 2695-2698. 10.1210/jc.2002-021584.CrossRefPubMed Dabrosin C: Variability of Vascular Endothelial Growth Factor in Normal Human Breast Tissue in Vivo during the Menstrual Cycle. J Clin Endocrinol Metab. 2003, 88: 2695-2698. 10.1210/jc.2002-021584.CrossRefPubMed
22.
go back to reference Ungerstedt U: Microdialysis – principles and applications for studies in animals and man. J Intern Med. 1991, 230: 365-373.CrossRefPubMed Ungerstedt U: Microdialysis – principles and applications for studies in animals and man. J Intern Med. 1991, 230: 365-373.CrossRefPubMed
23.
go back to reference Rosdahl H, Hamrin K, Ungerstedt U, Henriksson J: Metabolite levels in human skeletal muscle and adipose tissue studied with microdialysis at low perfusion flow. Am J Physiol. 1998, 274: E936-945.PubMed Rosdahl H, Hamrin K, Ungerstedt U, Henriksson J: Metabolite levels in human skeletal muscle and adipose tissue studied with microdialysis at low perfusion flow. Am J Physiol. 1998, 274: E936-945.PubMed
24.
go back to reference Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, Senger DR, Connolly JL, Schnitt SJ: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol. 1995, 26: 86-91. 10.1016/0046-8177(95)90119-1.CrossRefPubMed Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, Senger DR, Connolly JL, Schnitt SJ: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol. 1995, 26: 86-91. 10.1016/0046-8177(95)90119-1.CrossRefPubMed
25.
go back to reference Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP: Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res. 1996, 56: 2013-2016.PubMed Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP: Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res. 1996, 56: 2013-2016.PubMed
26.
go back to reference Zhang HT, Scott PA, Morbidelli L, Peak S, Moore J, Turley H, Harris AL, Ziche M, Bicknell R: The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo. Br J Cancer. 2000, 83: 63-68. 10.1054/bjoc.2000.1279.CrossRefPubMedPubMedCentral Zhang HT, Scott PA, Morbidelli L, Peak S, Moore J, Turley H, Harris AL, Ziche M, Bicknell R: The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo. Br J Cancer. 2000, 83: 63-68. 10.1054/bjoc.2000.1279.CrossRefPubMedPubMedCentral
27.
go back to reference Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R, Moghaddam A, Whitehouse R, Bicknell R, Harris AL: Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997, 57: 963-969.PubMed Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R, Moghaddam A, Whitehouse R, Bicknell R, Harris AL: Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997, 57: 963-969.PubMed
28.
go back to reference Horwitz KB, Koseki Y, McGuire WL: Estrogen control of progesterone receptor in human breast cancer: role of estradiol and antiestrogen. Endocrinology. 1978, 103: 1742-1751.CrossRefPubMed Horwitz KB, Koseki Y, McGuire WL: Estrogen control of progesterone receptor in human breast cancer: role of estradiol and antiestrogen. Endocrinology. 1978, 103: 1742-1751.CrossRefPubMed
29.
go back to reference Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996, 16: 4604-4613.CrossRefPubMedPubMedCentral Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996, 16: 4604-4613.CrossRefPubMedPubMedCentral
30.
go back to reference Pugh CW, Ratcliffe PJ: Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003, 9: 677-684. 10.1038/nm0603-677.CrossRefPubMed Pugh CW, Ratcliffe PJ: Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003, 9: 677-684. 10.1038/nm0603-677.CrossRefPubMed
31.
go back to reference Dabrosin C, Chen J, Wang L, Thompson LU: Flaxseed inhibits metastasis and decreases extracellular vascular endothelial growth factor in human breast cancer xenografts. Cancer Lett. 2002, 185: 31-37. 10.1016/S0304-3835(02)00239-2.CrossRefPubMed Dabrosin C, Chen J, Wang L, Thompson LU: Flaxseed inhibits metastasis and decreases extracellular vascular endothelial growth factor in human breast cancer xenografts. Cancer Lett. 2002, 185: 31-37. 10.1016/S0304-3835(02)00239-2.CrossRefPubMed
32.
go back to reference Lacroix M, Leclercq G: Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat. 2004, 83: 249-289. 10.1023/B:BREA.0000014042.54925.cc.CrossRefPubMed Lacroix M, Leclercq G: Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat. 2004, 83: 249-289. 10.1023/B:BREA.0000014042.54925.cc.CrossRefPubMed
33.
go back to reference Dabrosin C: Microdialysis – an in vivo technique for studies of growth factors in breast cancer. Front Biosci. 2005, 10: 1329-1335. 10.2741/1622.CrossRefPubMed Dabrosin C: Microdialysis – an in vivo technique for studies of growth factors in breast cancer. Front Biosci. 2005, 10: 1329-1335. 10.2741/1622.CrossRefPubMed
Metadata
Title
In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients
Authors
Stina Garvin
Charlotta Dabrosin
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-73

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