| 1. |
- Abrahamsson, Annelie, 1966-, et al.
(författare)
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Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen
- 2020
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Ingår i: Cancer Research. - Philadelphia, PA, United States : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 80:20, s. 4487-4499
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Tidskriftsartikel (refereegranskat)abstract
- Although blocking estrogen-dependent signaling is a cornerstone of adjuvant treatment for breast cancer, 25% of patients experience recurrent disease. Stroma events including innate immune responses are key in cancer progression. How different estrogen receptor (ER)-targeting therapies, including the partial agonist tamoxifen and the pure antagonist fulvestrant, affect the tumor stroma has not yet been elucidated. Fulvestrant is used in only postmenopausal patients, and its effects in the presence of estradiol remain undetermined. Here we observe that fulvestrant decreases ER+ breast cancer growth compared with tamoxifen in the presence of physiologic levels of estradiol in human breast cancer in nude mice and in murine breast cancer in immune-competent mice. Fulvestrant significantly inhibited macrophage and neutrophil infiltration in both models. These effects were corroborated in a zebrafish model where fulvestrant inhibited neutrophil- and macrophage-dependent cancer cell dissemination more effectively than tamoxifen. A comprehensive analysis of 234 human proteins released into the cancer microenvironment by the cancer cells sampled via microdialysis in vivo revealed that 38 proteins were altered following both treatments; 25 of these proteins were associated with immune response and were altered by fulvestrant only. Compared with tamoxifen, fulvestrant significantly affected inflammatory proteins released by murine stroma cells. Importantly, in vivo microdialysis of human ER+ breast cancer revealed that the majority of affected proteins in murine models were upregulated in patients. Together, these results suggest that fulvestrant targets ER+ breast cancer more effectively than tamoxifen even in the presence of estradiol, mainly by attenuation of the innate immune response. Significance: These findings demonstrate novel effects of the pure antiestrogen fulvestrant in ERthorn breast cancer and evaluate its effects under physiologic levels of estradiol, representative of premenopausal patients.
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| 2. |
- Abrahamsson, Annelie, 1966-, et al.
(författare)
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Increased nutrient availability in dense breast tissue of postmenopausal women in vivo
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.
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| 3. |
- Andersson, Bengt-Åke
(författare)
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Circulating Biomarkers in Patients with Head and Neck Cancer and the Influence of Cigarette Smoking
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Head and neck cancer (HNC) is a collective name for heterogeneous tumors located in the head and neck regions for which smoking, alcohol and human papillomavirus (HPV) are documented risk factors. The survival of HNC patients has only improved marginally during the last decade. The most important prognostic factors are tumor size, local spread and distant metastases, tumor node metastasis (TNM) staging. Prognostic biomarkers are needed as a complement to TNM staging.The aim for this thesis was to investigate rapid and low cost blood based biomarkers which could indicate the risk of HNC, recurrence of the disease or the survival of HNC patients. Furthermore, the aim was to examine how cigarette smoking influences the levels of biomarkers.In paper I, a possible role of plasma cytokines or proteins associated with immune response or inflammation, as biomarkers for the survival of HNC patients was investigated. Higher levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) were detected in plasma of the patients compared with the levels in the controls. The elevated levels of these two biomarkers detected in patients were associated with decreased survival.In paper II, the influence of 45 single nucleotide polymorphisms (SNPs) located in 41 genes associated with cell cycle progression, cell death, DNA repair or immune response on cancer risk, tumor recurrence and survival in HNC patients were investigated. SNPs in immune response genes were associated with risk for HNC, an elevated risk for recurrence and a decreased survival in HNC patients.In paper III, the influence of cigarette smoking on levels of inflammatory cells, proteins or cytokines/chemokines, microRNAs (miRNAs) and SNPs was analysed in healthy smokers and non-smokers. Higher levels of total white blood cells (WBCs), neutrophils, monocytes, lymphocytes, neutrophil to lymphocyte ratio (NLR), CRP, monocyte chemoattractant protein- 1 (MCP-1) and interferon gamma (IFN-γ) were detected in smokers compared to non-smokers and indicate an inflammatory response. Also, a lower level of oncomiRNA miR-21was detected in smokers. This alteration, in combination with the elevated levels of IFN-γ in smokers could be a protective response to cigarette smoke. The higher levels of IFN-γ in smokers compared to non-smokers were however only detected in individuals with SNP rs2069705 genotype AG/GG. This indicates a genetic association of the levels of IFN-γ.In paper IV, the separate effects of cigarette smoking and HNC on inflammatory or immune biomarkers and the impact of high risk human papillomavirus, age and gender were investigated. Comparisons of circulating levels of WBCs and its subpopulations, plasma proteins or cytokines/chemokines between smoking and non-smoking patients, smoking and non-smoking controls and between the patient and control groups were analysed. Smoking had highest impact on elevated levels of WBCs, IFN-γ and MCP-1, and HNC had highest impact on elevated levels of neutrophils, monocytes, NLR, CRP, macrophage inflammatory protein 1 beta and TNF-α.In conclusion, host immune response associated parameters could be suitable as biomarkers for the risk of HNC, risk of recurrence or in predicting survival of HNC patients. This thesis show that HNC are associated with systemic inflammatory response and upregulated CRP and TNF-α is related to shorter survival in HNC patients. Additionally, SNPs in immune response genes such as rs1800629 in the TNF-α gene indicates a risk for HNC or an elevated risk for recurrence and a decreased survival in HNC patients. These rapid and low cost blood based biomarkers could be used in combination or as a supplement to established biomarkers in the clinic for a more personalized treatment modality.
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| 4. |
- Bendrik, Christina, 1964-, et al.
(författare)
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Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo
- 2008
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 68:9, s. 3405-3412
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinases (MMP) are important regulators of angiogenesis and tumor progression by degradation of extracellular matrix. Clinical trials using MMP inhibitors have failed and recent studies suggest that MMPs may in contrast suppress tumor growth. It is not known, however, if MMPs or their inhibitors, tissue inhibitor of metalloproteinases (TIMP), can be used as therapy of established cancer. Here, adenovirus vectors carrying the human genes for MMP-9, TIMP-1, or empty controls were injected intratumorally in breast cancers established in mice supplemented with estradiol and treated with tamoxifen. Microdialysis was used to quantify MMP activity and sampling of endostatin and vascular endothelial growth factor (VEGF) in situ. We show that AdMMP-9 increased MMP activity in vivo, decreased tumor growth rate, and decreased microvessel area significantly. AdMMP-9 therapy resulted in significantly increased levels of endostatin in vivo, whereas VEGF levels were unaffected. As previously shown, tamoxifen exposure by itself increased MMP activity in all treatment groups. Moreover, the combined therapy with AdMMP-9 and tamoxifen further reduced tumor growth and increased the endostatin levels compared with either treatment alone. Gene transfer of TIMP-1 had no effects on tumor progression and counteracted the therapeutic effect of tamoxifen in our breast cancer model. This is the first report showing that overexpression of MMP-9 results in increased generation of antiangiogenic fragments, decreased angiogenesis, and therapeutic effects of established breast cancer.
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| 5. |
- Bergman, Malin, 1967-, et al.
(författare)
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Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:3, s. 1061-1067
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, which is crucial in cancer progression. We have previously shown that estradiol (E2) increases VEGF in breast cancer. Phytoestrogens are potential compounds in breast cancer prevention and treatment by poorly understood mechanisms. The main phytoestrogens in Western diet are lignans, and flaxseed is a rich source of the mammalian lignans enterodiol and enterolactone.Experimental Design: In the present study, ovariectomized mice were treated with continuous release of E2. MCF-7 tumors were established and mice were fed with basal diet or 10% flaxseed, and two groups that were fed basal diet received daily injections with enterodiol or enterolactone (15 mg/kg body weight).Results: We show that flaxseed, enterodiol, and enterolactone counteracted E2-induced growth and angiogenesis in solid tumors. Extracellular VEGF in vivo, sampled using microdialysis, in all intervention groups was significantly decreased compared with tumors in the basal diet group. Our in vivo findings were confirmed in vitro. By adding enterodiol or enterolactone, E2-induced VEGF secretion in MCF-7 cells decreased significantly without agonistic effects. The increased VEGF secretion by E2 in MCF-7 cells increased the expression of VEGF receptor-2 in umbilical vein endothelial cells, suggesting a proangiogenic effect by E2 by two different mechanisms, both of which were inhibited by the addition of lignans.Conclusions: Our results suggest that flaxseed and its lignans have potent antiestrogenic effects on estrogen receptor-positive breast cancer and may prove to be beneficial in breast cancer prevention strategies in the future.
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| 6. |
- Dabrosin, Charlotta, 1961-, et al.
(författare)
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Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen : Mediated by the mannose-6-phosphate/IGF-II receptor?
- 2004
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Ingår i: Breast Cancer Research and Treatment. - 0167-6806 .- 1573-7217. ; 85:3, s. 229-238
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Tidskriftsartikel (refereegranskat)abstract
- The lysosomal protease Catliepsin D (Cath D) is associated with increased invasiveness and metastasis in breast cancer. Both estrogen and tamoxifen have been reported to increase Cath D, which seems to contradict the efficacy of tamoxifen as an adjuvant for estrogen dependent breast cancer. Cath D is bioactive in the extracellular space but very little is known about hormonal regulation of secreted Cath D in vivo. In this study we used microdialysis to sample the extracellular fluid in estrogen receptor positive MCF-7 tumors in nude mice. We show that tamoxifen in combination with estradiol decreased secreted Cath D compared with estradiol treatment only in solid tumors in situ. Cell culture of MCF-7 cells revealed that estradiol and tamoxifen increased intracellular proteolytic activity of Cath D in a similar fashion whereas secretion of Cath D was increased by estradiol and inhibited by tamoxifen. Immunofluorescence showed that estradiol located Cath D to the cell surface, while tamoxifen accumulated Cath D to dense lysosomes in perinuclear regions. Moreover, tamoxifen increased the intracellular transporter of Cath D, the mannose 6-phosphate/IGF-II receptor (M6P/IGF2R). In contrast, estradiol decreased the levels of this receptor. Thus, secretion of Cath D is hormone dependent and may be mediated by altered expression of the M6P/IGF2R. Our results highlight the importance of measurements of proteins in all compartments where they are biological active and show that microdialysis is a viable technique for sampling of Cath D in vivo.
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| 7. |
- Dabrosin, Charlotta, 1961-, et al.
(författare)
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Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer
- 2003
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 107:4, s. 535-540
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis is essential for tumor growth and metastasis and an important prognostic factor in breast cancer. VEGF, a key factor for angiogenesis, has been correlated with tumor vessel density in breast cancer. Estrogen, another crucial factor in breast cancer, stimulates VEGF, and an ERE in the VEGF gene has been defined. VEGF is bioactive in the extracellular fluid, where it becomes available to endothelial cells. Whether E2 affects VEGF levels in the extracellular fluid is not known. We show, using intratumoral microdialysis in vivo, that E2 treatment increased tumor extracellular levels of VEGF in an estrogen-dependent breast cancer model. Moreover, extracellular levels of VEGF in the tumor showed a strong correlation with total tumor VEGF, contrary to plasma levels of VEGF. Ninety-three percent of measured VEGF in the extracellular fluid in the tumor was tumor-derived, while only 45% of VEGF in circularing plasma originated from the tumor. We conclude that E2 increases extracellular VEGF and that microdialysis is a sensitive method for measurement of local VEGF production in vivo. Our results have potential application to the assessment of tumor characteristics in vivo in human tumors for individualized cancer therapy.
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| 8. |
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| 9. |
- Dabrosin, Charlotta, 1961-
(författare)
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Increase of free insulin-like growth factor-1 in normal human breast in vivo late in the menstrual cycle
- 2003
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Ingår i: Breast Cancer Research and Treatment. - 0167-6806 .- 1573-7217. ; 80:2, s. 193-198
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Tidskriftsartikel (refereegranskat)abstract
- Prolonged exposure to endogenous and exogenous sex steroids increases the risk of breast cancer but the mechanisms are poorly understood. Increased levels of circulating insulin-like growth factor-1 (IGF-1) and low levels of IGF binding protein are associated with increased risk of breast cancer suggesting that IGF-1 has to be in its free form to be biologically active. Little is known about sex steroid regulation of IGF-1 locally in the breast. In this study microdialysis was used to determine the local levels of free IGF-1 in normal human breast tissue in healthy female volunteers during the menstrual cycle. The results showed that the extracellular levels of free IGF-1 locally in the breast were doubled in the luteal phase, when estradiol and progesterone levels were elevated, compared with the follicular phase. In plasma, free IGF-1 levels also exhibited a cyclic variation but to a less extent. The increased local levels of the tree form of IGF-1 may promote proliferation in the breast epithelium. This could be important in sex steroid dependent breast cancer development.
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| 10. |
- Dabrosin, Charlotta, 1961-
(författare)
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Increased extracellular local levels of estradiol in normal breast in vivo during the luteal phase of the menstrual cycle
- 2005
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Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 187:1, s. 103-108
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen exposure is a major risk factor for breast cancer. Tissue estrogen originates from the ovaries but a significant portion is also produced by enzyme activity locally in the breast itself. How these enzymes are regulated is not fully understood. The extracellular space, where the metabolic exchange and cell interactions take place, reflects the environment that surrounds the epithelium but there has been no previous study of hormone concentrations in this compartment. In the present study microdialysis was used to measure extracellular estrogen concentrations in breast tissue and abdominal subcutaneous fat in 12 healthy women in vivo. It was found that women with high plasma progesterone levels had significant increased levels of estradiol in breast tissue compared with fat tissue (breast tissue 168 ± 6 pM, subcutaneous fat, 154 ± 5 pM, P<0.05), whereas women with low plasma progesterone exhibited no difference. Moreover, there was a significant correlation between local breast tissue estradiol and plasma progesterone levels (r=0.709, P<0.01). There was no difference in estrone sulphate in breast and fat tissue regardless of progesterone levels. Estrone was not detectable. The results in this study suggest that progesterone may be one regulator in the local conversion of estrogen precursors into potent estradiol in normal breast tissue. © 2005 Society for Endocrinology.
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