| 61. |
- Nilsson, Ulrika, et al.
(author)
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Tamoxifen decreases extracellular TGF-beta 1 secreted from breast cancer cells - A post-translational regulation involving matrix metalloproteinase activity
- 2009
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In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 315:1, s. 1-9
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Journal article (peer-reviewed)abstract
- Transforming growth factor-beta 1 (TGF-beta 1) promotes cancer progression by regulating tumor cell growth and angiogenesis and high levels of TGF-beta 1 have been associated with metastatic disease and poor prognosis in breast cancer patients. We have previously reported anti-angiogenic effects of the anti-estrogen tamoxifen in breast cancer, by increased matrix metalloproteinase-9 (MMP-9) activity and generation of endostatin. Here, we show that exposure of tamoxifen to ER-positive breast cancer cells for 7 days, decreased extracellular TGF-beta 1. Intracellular TGF-beta 1 levels were unaffected by tamoxifen treatment, indicating a post-translational regulation of TGF-beta 1. Inhibition of MMP activity restored TGF-beta 1 levels, suggesting an involvement of MMP activities in the down-regulation of TGF-beta 1 by tamoxifen. Moreover, using an in vivo model of solid MCF-7 tumors in nude mice, we analyzed tumor levels of TGF-beta 1 after in vivo treatment with estradiol and tamoxifen. Exposure of tumor-bearing mice to tamoxifen significantly decreased tumor TGF-beta 1 protein levels, tumor growth and angiogenesis. In conclusion, our findings suggest a novel mechanism of action of tamoxifen in breast cancer via sex steroid dependent modulation of the proteolytic tumor microenvironment resulting in reduced extracellular TGF-beta 1 levels.
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| 62. |
- Nilsson, Ulrika W., 1977-
(author)
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Effects of sex steroids and tamoxifen on matrix metalloproteinase activity and generation of endostatin in the breast
- 2007
-
Doctoral thesis (other academic/artistic)abstract
- Sex steroids are inevitable in women. However, long-term exposure to sex steroids increases the risk of breast cancer. A complete understanding of sex steroid control of the breast and how it relates to breast cancer risk is still lacking. Angiogenesis and proteolytic enzyme activity are crucial for the process by which tumors evolve into a vascularized, invasive phenotype. Matrix metalloproteinases are potent matrixdegrading enzymes that affect several steps in tumor progression including angiogenesis. In the female reproductive organs, sex steroids regulate angiogenesis and MMP activity, yet little is known how sex steroids affect these crucial events in normal and malignant breast tissue.This thesis elucidates a link between sex steroids, MMP activity, and angiogenesis. It is shown that estradiol down-regulates while tamoxifen up-regulates the protein expression and activity of MMP-2 and MMP-9 in human breast cancer cells in vitro and in human breast cancer xenografts in vivo. The results further suggest that a biological consequence of this regulation may be modulation of tumor angiogenesis. The net effect of adding tamoxifen to estradiol treatment was an increase in extracellular levels of the endogenous angiogenesis inhibitor endostatin and decreased levels of the tumor promoter TGF-β1 compared to estradiol treatment only. This was accompanied by reduced vasculature and decreased tumor growth. Similarly, a regulatory effect of estradiol and tamoxifen on endostatin generation was observed in normal human breast tissue by whole-tissue culture and microdialysis in human breast tissue in situ.In conclusion, the results presented in this thesis suggest previously unknown mechanisms of action of estradiol and tamoxifen in breast cancer and in normal human breast tissue, and novel means by which estradiol may tip the scale to favor angiogenesis. This knowledge may be important for the understanding of sex steroid dependent breast carcinogenesis and in the future development of tissue-specific preventive as well as therapeutic strategies against breast cancer.
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| 63. |
- Nilsson, Ulrika W., et al.
(author)
-
Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo
- 2006
-
In: Cancer Research. - 0008-5472 .- 1538-7445. ; 66:9, s. 4789-4794
-
Journal article (peer-reviewed)abstract
- Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell–generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.
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| 64. |
- Nilsson, Ulrika W., et al.
(author)
-
MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells
- 2007
-
In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 102:3, s. 253-261
-
Journal article (peer-reviewed)abstract
- Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.
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| 65. |
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| 66. |
- Oliva, Delmy, 1967-
(author)
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Prediction of side effects from anticancer treatment with the purpose of increasing quality of life
- 2019
-
Doctoral thesis (other academic/artistic)abstract
- Cancer and its treatments can cause a variety of symptoms. Some of these symptoms are related to the disease and others are seen as a consequence of the treatment. Since patients experience side effects to different degrees despite undergoing the same treatment, it is hypothesized that there is a genetic factor. The individual variation that exists between different patients regarding nausea triggered by chemotherapy, radiotherapy induced skin reactions as well as sleep disorders associated with cancer could partly be explained by genetic differences. We have in these studies confirmed these individual differences. Previous nursing research has mainly focused on the symptoms themselves. The focus in this thesis are the following three main symptoms; nausea and vomiting related to chemotherapy, acute skin inflammation following radiotherapy and sleep problems associated with cancer diagnosis and -treatment.The aim of this thesis was to find biological markers that can identify the risk of and/or protective factors for nausea and/or vomiting (CINV) as well as understand its heterogeneity (Study 1 and 2). It also aimed to understand the individual factors behind acute radiation skin reactions (ARSR) (Study 3) and sleeping disturbances in patients treated for cancer (Study 4), permitting a more individualized care and optimized health-related quality of life (HRQoL).In Study 1 and 2 the patients themselves had to document in a diary their experience of nausea and vomiting and well-being. Well-being was considered as synonymous with quality of life. We found a variability and heterogeneity of those symptoms (Study 1). Three genetic markers, FAS/CD95, RB1/LPAR6 and CCL2 that could explain the individual differences and assess the risk of chemotherapy-induced nausea were found in Study 2.Acute radiation skin reactions (ARSR) along with itching and burning sensation associated with radiotherapy (RT) was assessed by the patients themselves (Study 3) with help of the VAS- and RTOG scales, scoring for visible redness. We found two possible genetic markers, XRCC2 and IFNG. Also, individual differences in symptoms behavior were found.Sleep disturbances were common and were reported with obvious individual differences [1]. For data collection were used a sleep questionnaire, the Medical Outcomes Study Sleep Scale (MOS), open ended questions and EORTC QLQ- C30 questionnaire of quality of life. Sleep, which is important for all primary body functions, is often affected in connection with cancer diagnosis and -treatment.Through collaboration between nursing staff and specialists in basic science, we have found that biological markers can help in creating individualized care. Knowledge of individual variations in the severity of chemo- or radiotherapy-induced side effects is important in order to better personalize the treatment and care, improve the treatment results and alleviate or prevent the side effects of oncological treatments. By linking symptoms to biological markers, it will hopefully be able to increase the patients’ total health-related quality of life, this being the main goal of this thesis.
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| 67. |
- Rasti Boroojeni, Fatemeh, et al.
(author)
-
Proteolytic remodeling of 3D bioprinted tumor microenvironments
- 2024
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In: Biofabrication. - : IOP Publishing Ltd. - 1758-5082 .- 1758-5090. ; 16:2
-
Journal article (peer-reviewed)abstract
- In native tissue, remodeling of the pericellular space is essential for cellular activities and is mediated by tightly regulated proteases. Protease activity is dysregulated in many diseases, including many forms of cancer. Increased proteolytic activity is directly linked to tumor invasion into stroma, metastasis, and angiogenesis as well as all other hallmarks of cancer. Here we show a strategy for 3D bioprinting of breast cancer models using well-defined protease degradable hydrogels that can facilitate exploration of the multifaceted roles of proteolytic extracellular matrix remodeling in tumor progression. We designed a set of bicyclo[6.1.0]nonyne functionalized hyaluronan (HA)-based bioinks cross-linked by azide-modified poly(ethylene glycol) (PEG) or matrix metalloproteinase (MMP) degradable azide-functionalized peptides. Bioprinted structures combining PEG and peptide-based hydrogels were proteolytically degraded with spatial selectivity, leaving non-degradable features intact. Bioprinting of tumor-mimicking microenvironments using bioinks comprising human breast cancer cells (MCF-7) and fibroblast in hydrogels with different susceptibilities to proteolytic degradation shows that MCF-7 proliferation and spheroid size were significantly increased in protease degradable hydrogel compartments, but only in the presence of fibroblasts. In the absence of fibroblasts in the stromal compartment, cancer cell proliferation was reduced and did not differ between degradable and nondegradable hydrogels. The interactions between spatially separated fibroblasts and MCF-7 cells consequently resulted in protease-mediated remodeling of the bioprinted structures and a significant increase in cancer cell spheroid size, highlighting the close interplay between cancer cells and stromal cells in the tumor microenvironment and the influence of proteases in tumor progression.
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| 68. |
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| 69. |
- Saarinen, Niina M., et al.
(author)
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Estrogen-induced angiogenic factors derived from stromal and cancer cells are differently regulated by enterolactone and genistein in human breast cancer in vivo
- 2010
-
In: International Journal of Cancer. - : John Wiley and Sons, Ltd. - 0020-7136 .- 1097-0215. ; 127:3, s. 737-745
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Journal article (peer-reviewed)abstract
- Angiogenesis is a key in cancer progression and its regulators are released both by the tumor cells and the stroma. Dietary phytoestrogens, such as the lignan enterolactone (ENL) and the isoflavone genistein (GEN), may differently affect breast cancer growth. In this study, human breast cancer cells (MCF-7) were established in mice creating a tumor with species-specific cancer and stroma cells. Ovariectomized athymic mice supplemented with estradiol (E2) were fed basal AIN-93G diet (BD) or BD supplemented with 100 mg/kg ENL, 100 mg/kg GEN or their combination (ENL+GEN). We show that ENL and ENL+GEN inhibited E2-induced cancer growth and angiogenesis, whereas GEN alone did not. Microdialysis was used to sample extracellular proteins in tumors in vivo. ENL and ENL+GEN decreased both stroma- and cancer cell-derived VEGF, whereas cancer cell-derived PlGF increased. In subcutaneous Matrigel plugs in mice, ENL and ENL+GEN decreased E2-induced endothelial cell infiltration, whereas GEN alone did not. In endothelial cells, ENL inhibited E2-induced VEGFR-2 expression, whereas GEN did not. These results suggest that ENL has potent effects on breast cancer growth, even in combination with GEN, by downregulating E2-stimulated angiogenic factors derived both from the stroma and the cancer cells, whereas dietary GEN does not possess any antiestrogenic effects.
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| 70. |
- Svensson, Susanne, et al.
(author)
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CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer
- 2015
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In: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 21:16, s. 3794-3805
-
Journal article (peer-reviewed)abstract
- Purpose: Novel therapeutic targets of estrogen receptor (ER)-positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models. Experimental Design: For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish. Results: ER+ cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment. Conclusions: Our findings shed new light on the mechanisms underlying the progression of ER+ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways. (C)2015 AACR.
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