Microdialysis of Human Breast Tissue during the Menstrual Cycle

Dabrosin, Charlotta; Hallström, Åse; Ungerstedt, Urban; Hammar, Mats

doi:10.1042/cs0920493

Cited by 35 publications

(18 citation statements)

References 6 publications

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“…The secreted cytokine pattern of cells in vivo are difficult to explore with traditional methods such as immunohistochemistry and/or flow sorting of whole tumor tissue not differentiating between intracellular/extracellular molecules. Therefore, we performed microdialysis, which we previously have shown to be an excellent tool for sampling of extracellular proteins in vivo (39)(40)(41)(42)(43)(44). In the tumor model used in this study with human cancer cells in a murine stroma, we were able not only to sample cytokines in vivo, but also to distinguish from which compartment of the tumor microenvironment the secreted cytokines originated.…”

Section: Discussionmentioning

confidence: 99%

Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

Leifler

Svensson

Abrahamsson

et al. 2013

The Journal of Immunology

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Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro- and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell–derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities.

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Section: Discussionmentioning

confidence: 99%

Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

Leifler

Svensson

Abrahamsson

et al. 2013

The Journal of Immunology

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“…Mepivacaine (5 mg/mL) was administrated intracutaneously as a local anesthetic before the insertion of the microdialysis catheters. The microdialysis catheter was placed in the upper lateral quadrant of the left breast and directed toward the nipple as previously described (15,19,21,23). Microdialysis is a technique that allows continuous sampling of the extracellular fluid by passive diffusion of substances over a semipermeable membrane.…”

Section: Methodsmentioning

confidence: 99%

Positive Correlation between Estradiol and Vascular Endothelial Growth Factor but not Fibroblast Growth Factor-2 in Normal Human Breast Tissue In vivo

Dabrosin

2005

Clinical Cancer Research

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Purpose: Angiogenesis is crucial in tumor development and progression. Ovarian hormones regulate angiogenesis in the reproductive tract but very little is known about its regulation in the normal breast. Sex steroids play an important role in breast cancer development by poorly understood mechanisms. Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) are potent stimulators of angiogenesis. Both VEGF and FGF-2 function in autocrine/paracrine pathways and there is a major contribution of bioactive proteins by a posttranslational activation of sequestered molecules in the extracellular space. A direct measurement of these molecules in the extracellular compartment is, therefore, needed. Experimental Design: In this study, microdialysis was used to measure extracellular VEGF and FGF-2 in normal human breast tissue in situ in 11 premenopausal and 5 postmenopausal women. Results: Significantly higher level of VEGF in breast tissue of premenopausal women was found. Plasma as well as local estradiol and breast tissue VEGF exhibited significant correlations, whereas progesterone had no correlation with breast VEGF. FGF-2 did not correlate with either estradiol or progesterone. Conclusion: The result suggests that estradiol is a more potent regulator of free VEGF levels than progesterone in the normal breast. The control of free FGF-2 seems to be independent of sex steroids in the breast. Estrogen induction of free extracellular VEGF may be one mechanism involved in sex steroid–dependent breast carcinogenesis.

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“…In healthy volunteers, the microdialysis catheter was placed in the upper lateral quadrant of the left breast and directed toward the nipple as previously described (24,(30)(31)(32)(33). The breast cancer patients were investigated on the day before or the same day as surgery.…”

Section: Microdialysis Of Healthy Volunteers and Breast Cancer Patientsmentioning

confidence: 99%

Angiogenin Regulation by Estradiol in Breast Tissue: Tamoxifen Inhibits Angiogenin Nuclear Translocation and Antiangiogenin Therapy Reduces Breast Cancer Growth In vivo

Nilsson

Abrahamsson

Dabrosin

2010

Clinical Cancer Research

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Purpose: Angiogenin, a 14.2-kDa polypeptide member of the RNase A superfamily, has potent angiogenic effects. Nuclear accumulation of angiogenin is essential for its angiogenic activity. Increased angiogenin expression has been associated with the transition of normal breast tissue into invasive breast carcinoma. In this article, we investigated whether estradiol (E 2 ) affected angiogenin in breast tissue.Experimental Design: We used microdialysis for sampling of extracellular angiogenin in vivo. In vitro cultures of whole normal breast tissue, breast cancer cells, and endothelial cells were used.Results: We show that extracellular angiogenin correlated significantly with E 2 in normal human breast tissue in vivo and that exposure of normal breast tissue biopsies to E 2 stimulated angiogenin secretion. In breast cancer patients, the in vivo angiogenin levels were significantly higher in tumors compared with the adjacent normal breast tissue. In estrogen receptor-positive breast cancer cells, E 2 increased and tamoxifen decreased angiogenin secretion. Moreover, E 2 -induced angiogenin derived from cancer cells significantly increased endothelial cell proliferation. Tamoxifen reversed this increase as well as inhibited nuclear translocation of angiogenin. In vivo, in experimental breast cancer, tamoxifen decreased angiogenin levels and decreased angiogenesis. Additionally, treating tumor-bearing mice with an antiangiogenin antibody resulted in tumor stasis, suggesting a role for angiogenin in estrogen-dependent breast cancer growth.Conclusion: Our results suggest previously unknown mechanisms by which estrogen and antiestrogen regulate angiogenesis in normal human breast tissue and breast cancer. This may be important for estrogendriven breast cancer progression and a molecular target for therapeutic interventions.

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Microdialysis of Human Breast Tissue during the Menstrual Cycle

Cited by 35 publications

References 6 publications

Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

Positive Correlation between Estradiol and Vascular Endothelial Growth Factor but not Fibroblast Growth Factor-2 in Normal Human Breast Tissue In vivo

Angiogenin Regulation by Estradiol in Breast Tissue: Tamoxifen Inhibits Angiogenin Nuclear Translocation and Antiangiogenin Therapy Reduces Breast Cancer Growth In vivo

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