| 1. |
- Helczynska, Karolina
(författare)
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Hypoxia and Hypoxia-Inducible Factors in Normal and Malignant Breast Epithelium
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer treatment is based on tumor and patient related factors such as tumor stage, grade, hormonal status, HER2 status, patient age, and family history to name a few. It is today widely acknowledged that hypoxia and hypoxia-inducible factors (HIF:s) contribute to tumor progression. We therefore set out to explore the impact of hypoxia on mammary epithelial differentiation and what consequences the hypoxic response might have on breast cancer development and behavior. We found that hypoxia induces a less differentiated, estrogen receptor (ER)-negative/cytokeratin (CK) 19-positive phenotype in mammary cancer cells in vivo and in vitro and suggest that hypoxiainduced dedifferentiation is one of the mechanisms behind hypoxia-driven malignant progression. Hypoxia was also found to significantly impair both morphological and functional differentiation of non-transformed, immortalized epithelial mammary cells grown in three-dimensional cultures. Heterogeneous ER expression in breast cancer was additionally found to be related to cyclin D1, a cell cycle regulator frequently overexpressed in breast cancer. As cyclin D1 expression was not affected by hypoxia, our findings suggest two separate mechanisms behind varied ER expression in breast cancer. The two pivotal regulators of hypoxic response, HIF-1α and HIF-2α, were analyzed in two cohorts of breast cancer patients and found to be un-correlated suggesting HIF-α subtype specific mechanisms of induction. Furthermore, HIF-2α was found to be an independent prognostic factor related to distant recurrence.
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| 2. |
- Helczynska, Karolina, et al.
(författare)
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Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.
- 2008
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Ingår i: Cancer Research. - 1538-7445. ; 68:22, s. 9212-9220
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Tidskriftsartikel (refereegranskat)abstract
- Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.
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| 3. |
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| 4. |
- Hultman, Karolina Helczynska, et al.
(författare)
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Validation of a Swedish version of a short Patient-Reported-Outcome-Measure for superficial venous insufficiency
- 2021
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Ingår i: Journal of Vascular Surgery. - : Elsevier. - 2213-3348 .- 2213-333X. ; 9:2, s. 416-422.e4
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Patient-reported-outcome-measures (PROM) are increasingly used to measure symptoms and treatment effects thereof, and a short PROM is more user friendly. The aim of this study was to test whether a Swedish 7-item version of the PROM used in the Vascular Quality Initiative Varicose Vein Registry can be used to measure quality of life in a Swedish cohort of patients with superficial venous insufficiency (SVI) equally well as the 26-item VEINES-QOL/Sym-S, and measure treatment effect.METHODS: Consecutive patients with SVI and CEAP C-class ≥ 2 were recruited at three private clinics and one county hospital between January 2018 and October 2019. The patients were asked to answer both the VEINES-QOL/Sym-S, and the Swedish 7-item version, called VARIShort, at two assessment points: baseline (Cohort 1, 252 patients) and one week later (Cohort 2, 138 patients), and the VARIShort at baseline and eight weeks after an endovenous procedure (Cohort 3, 106 patients). The mean age was 58.3 (range 20 - 93), 61.4 (range 20-93) and 57.2 (range 20-89) years, the majority were female (59%, 55% and 64%), and most were C4 (39%, 46% and 38%) in Cohorts 1, 2 and 3, respectively. The VARIShort was evaluated with regards to its validity, test-retest reliability, internal consistency reliability, as well as sensitivity and responsiveness.RESULTS: There was a strong correlation between the VEINES-QOL-S and the VARIShort (rs = -.816, p < .001). The VARIShort showed both excellent internal consistency with Cronbach's α = 0.93 and a high response to clinical change as measured with Cohen's d, overall score of 1.17.CONCLUSIONS: The Swedish 7-item PROM, the VARIShort, may be used for assessment of symptoms of SVI and outcome after treatment in Swedish SVI patients. The short PROM shows degree of SVI symptom impact on quality of life in the same manner as the 26-item VEINES-QOL/Sym-S.
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| 5. |
- Kronblad, Åsa, et al.
(författare)
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Regional cyclin D1 overexpression or hypoxia correlate inversely with heterogeneous oestrogen receptor-alpha expression in human breast cancer.
- 2003
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Ingår i: In Vivo. - 0258-851X. ; 17:4, s. 311-8
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Tidskriftsartikel (refereegranskat)abstract
- Substance P (SP) has been implicated in the pathophysiology of ulcerative colitis (UC) and it has been suggested that blocking of its effect would be advantageous in this disease. Eosinophils have also been implicated in the pathophysiology of UC. In the present study, specimens from the sigmoid colon of UC patients were investigated by the use of antisera against SP and the neurokinin-1 receptor (NK-1R) and staining for demonstration of eosinophils. The degrees of SP innervation and NK-1R immunoreaction, as well as the levels of eosinophil infiltration, varied between different patients. Interestingly, NK-1R immunoreaction in the epithelium was often seen to be the most marked where there were numerous eosinophils in the underlying mucosa and where the mucosa showed a marked morphologic derangement. The observations suggest that there are marked fluctuations in effects of SP and eosinophils during the disease. The infiltrating eosinophils may be involved in the destruction of the mucosal tissue. Furthermore, for the majority of cases where there is marked derangement of the mucosa, it is apparent that there is an upregulation of the NK-1 receptor in the epithelium in parallel with the infiltration of the eosinophils.
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| 6. |
- Vaapil, Marica, et al.
(författare)
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Hypoxic conditions induce a cancer-like phenotype in human breast epithelial cells.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Solid tumors are less oxygenated than their tissue of origin. Low intra-tumor oxygen levels are associated with worse outcome, increased metastatic potential and immature phenotype in breast cancer. We have reported that tumor hypoxia correlates to low differentiation status in breast cancer. Less is known about effects of hypoxia on non-malignant cells. Here we address whether hypoxia influences the differentiation stage of non-malignant breast epithelial cells and potentially have bearing on early stages of tumorigenesis.
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