| 1. |
- Aaltonen, Kristina, et al.
(författare)
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Association between insulin-like growth factor-1 receptor (IGF1R) negativity and poor prognosis in a cohort of women with primary breast cancer
- 2014
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 14:794
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Tidskriftsartikel (refereegranskat)abstract
- Background: Resistance towards endocrine therapy is a great concern in breast cancer treatment and may partly be explained by the activation of compensatory signaling pathways. The aim of the present study was to investigate if the insulin-like growth factor-1 receptor (IGF1R) signaling pathway was activated or deregulated in breast cancer patients and to explore if any of the markers were prognostic, with or without adjuvant tamoxifen. This signaling pathway has been suggested to cause estrogen independent cell growth and thus contribute to resistance to endocrine treatment in estrogen receptor (ER) positive breast cancer. Methods: The protein expression of IGF1R, phosphorylated Mammalian Target of Rapamycin (p-mTOR) and phosphorylated S6 ribosomal protein (p-S6rp) were investigated by immunohistochemistry using tissue microarrays in two patient cohorts. Cohort I (N = 264) consisted of mainly postmenopausal women with stage II breast cancer treated with tamoxifen for 2 years irrespective of ER status. Cohort II (N = 206) consisted of mainly medically untreated, premenopausal patients with node-negative breast cancer. Distant disease-free survival (DDFS) at 5 years was used as end-point for survival analyses. Results: We found that lower IGF1R expression was associated with worse prognosis for tamoxifen treated, postmenopausal women (HR = 0.70, 95% CI = 0.52 - 0.94, p = 0.016). The effect was seen mainly in ER-negative patients where the prognostic effect was retained after adjustment for other prognostic markers (adjusted HR = 0.49, 95% CI = 0.29 - 0.82, p = 0.007). Expression of IGF1R was associated with ER positivity (p less than 0.001) in the same patient cohort. Conclusions: Our results support previous studies indicating that IGF1R positivity reflects a well differentiated tumor with low metastatic capacity. An association between lack of IGF1R expression and worse prognosis was mainly seen in the ER-negative part of Cohort I. The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway suggested that the prognostic effect was not due to complete activation of this pathway. Thus, no evidence could be found for a compensatory function of IGF1R signaling in the investigated cohorts.
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| 2. |
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| 3. |
- Akbarshahi, Hamid, et al.
(författare)
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Acute lung injury in acute pancreatitis - Awaiting the big leap.
- 2012
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 106:9, s. 1199-1210
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Forskningsöversikt (refereegranskat)abstract
- Acute lung injury is a severe complication to acute pancreatitis and a significant health problem associated with a considerable mortality. Underlying mechanisms are complex and poorly understood, although recent insights have identified several inflammatory profiles and cellular components involved to varying degrees during different phases of pancreatitis exacerbation and acute lung injury. This review aims to highlight the current understanding of the inflammatory and cellular components involved in and responsible for the associations of acute pancreatitis and acute lung injury, with the hope of thereby providing an increased understanding of the underlying mechanisms. In addition, novel experimental models of modulating the pancreatitis-associated acute lung injury are presented, interventions that may be of potential future clinical value.
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| 4. |
- Akbarshahi, Hamid, et al.
(författare)
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Early Activation of Pulmonary TGF- β 1/Smad2 Signaling in Mice with Acute Pancreatitis-Associated Acute Lung Injury.
- 2014
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Ingår i: Mediators of Inflammation. - : Hindawi Limited. - 0962-9351 .- 1466-1861. ; 2014:Feb 12
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Tidskriftsartikel (refereegranskat)abstract
- Acute lung injury is caused by many factors including acute pancreatitis. There is no specific therapy directed at underlying pathophysiological mechanisms for acute lung injury. Transforming growth factor- β (TGF- β ) is involved in the resolution of lung injury in later phases of the disease. Some evidence exists demonstrating that TGF- β not only is involved in the late stages, but also contributes to lung injury early on in the progress of the disease. Acute pancreatitis was induced using ductal ligation in mice. TGF- β 1, 2, and 3, T β RII, ALK-5, Smad2, 3, 4, and 7, and P-Smad2 expression in the lungs were analyzed at 9 and 24 h. We demonstrate that TGF- β 1 levels in the lungs of mice with acute pancreatitis increase as early as 9 h after induction. We observed an increased expression of ALK-5 in acute pancreatitis at both 9 and 24 h. Inhibitory Smad7 expression was transiently increased at 9 h in acute pancreatitis, but reduced later at 24 h, with a concomitant increased nuclear translocation of phosphorylated Smad2. Our findings demonstrate activation of TGF- β signaling in the lungs as early as 24 h after acute pancreatitis, suggesting that TGF- β may represent a potential therapeutic candidate in acute pancreatitis-induced acute lung injury.
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| 5. |
- Akbarshahi, Hamid, et al.
(författare)
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Enrichment of Murine CD68(+)CCR2(+) and CD68(+)CD206(+) Lung Macrophages in Acute Pancreatitis-Associated Acute Lung Injury.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Acute lung injury (ALI) is an important cause of mortality in critically ill patients. Acute pancreatitis (AP) is one of the risk factors for developing this syndrome. Among the inflammatory cells, macrophages have a key role in determining the severity of the acute lung injury. In the lungs, macrophages constitute a heterogeneous cell population distributed in different compartments. Changes in not only the macrophage count, but also in their phenotype have been seen during the course of lung injury. A murine ductal ligation model of acute pancreatitis showed substantial morphological changes in the pancreas and lungs. Immunohistochemistry showed neutrophil recruitment into both organs after 9 hours and later on. F4/80(+) cells in the pancreas increased in the ligated animals, though there was not a significant difference in their number in the lungs as compared to sham operated animals. Flow cytometry analysis of lung macrophages demonstrated an enrichment of F4/80(-) CD68(+)CCR2(+) and F4/80(-) CD68(+)CD206(+) lung macrophages in ligated animals (AP) as compared to the sham operated group. The level of interleukin-6 in plasma increased 3 hours after ligation compared to the sham operated group, as a first indicator of a systemic inflammatory response.This study suggests a role for F4/80(-) CD68(+) macrophages in the pathogenesis of acute lung injury in acute pancreatitis. Studying lung macrophages for different phenotypic markers, their polarization, activation and recruitment, in the context of acute lung injury, is a novel area to potentially identify interventions which may improve the outcome of acute lung injury.
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| 6. |
- Ansari, Daniel, et al.
(författare)
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Systematic review of immunohistochemical biomarkers to identify prognostic subgroups of patients with pancreatic cancer.
- 2011
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 98, s. 1041-1055
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis. There is a need to identify prognostic subtypes of PDAC to predict clinical and therapeutic outcomes accurately, and define novel therapeutic targets. The purpose of this review was to provide a systematic summary and review of available data on immunohistochemical (IHC) prognostic and predictive markers in patients with PDAC. METHODS: Relevant articles in English published between January 1990 and June 2010 were obtained from PubMed searches. Other articles identified from cross-checking references and additional sources were reviewed. The inclusion was limited to studies evaluating IHC markers in a multivariable setting. RESULTS: Database searches identified 76 independent prognostic and predictive molecular markers implicated in pancreatic tumour growth, apoptosis, angiogenesis, invasion and resistance to chemotherapy. Of these, 11 markers (Ki-67, p27, p53, transforming growth factor β1, Bcl-2, survivin, vascular endothelial growth factor, cyclo-oxygenase 2, CD34, S100A4 and human equilibrative nucleoside transporter 1) provided independent prognostic or predictive information in two or more separate studies. CONCLUSION: None of the molecular markers described can be recommended for routine clinical use as they were identified in small cohorts and there were inconsistencies between studies. Their prognostic and predictive values need to be validated further in prospective multicentre studies in larger patient populations. A panel of molecular markers may become useful in predicting individual patient outcome and directing novel types of intervention.
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| 7. |
- Bengtsson, Ylva, et al.
(författare)
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Zinc and Breast Cancer Survival: A Prospective Cohort Study of Dietary Intake and Serum Levels
- 2022
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Zinc has been suggested to play a role in breast cancer progression; however, no previous study on zinc levels and the potential effect on breast cancer survival has been conducted. This study investigates recurrence-free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS) in relation to zinc levels, in serum and diet, overall and stratified for phosphorus and selenium levels. The Malmö Diet and Cancer Study, a prospective population-based cohort in Sweden including 17,035 women, was used to identify breast cancer patients diagnosed in the period 1991–2013. Diet was assessed by a validated modified diet history method. A Cox regression analysis yielded hazard ratios (HRs) with 95% confidence intervals adjusted for potential confounders. Out of 1062 patients with invasive breast cancer, 268 recurrences, 205 breast cancer deaths and 228 deaths from other causes were recorded. No overall associations were seen between zinc and RFS, BCSS or OS. However, in women with a high phosphorus intake, a higher BCSS and OS were seen in zinc intake Q2 to Q4 versus Q1; the adjusted HR was 0.41 (0.23–0.73) and 0.64 (0.41–1.00), respectively. The results indicate that the combination of intermediate/high zinc intake and high phosphorus intake may lead to a better breast cancer survival.
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| 8. |
- Bergqvist, Malin, et al.
(författare)
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Adipocytes Under Obese-Like Conditions Change Cell Cycle Distribution and Phosphorylation Profiles of Breast Cancer Cells : The Adipokine Receptor CAP1 Matters
- 2021
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity and associated metabolic conditions impact adipocyte functionality with potential consequences for breast cancer risk and prognosis, but contributing mechanisms remain to be understood. The adipokine receptor adenylyl cyclase-associated protein-1 (CAP1) has been implicated in the progression of breast cancer, but results are conflicting and the underlying molecular mechanisms are still unknown. In this study, molecular and cellular effects in breast cancer cells by stimulation of adipocytes under normal or obese-like conditions, and potential involvement of CAP1, were assessed. Material and Methods: Estrogen receptor (ER)-positive T47D and ER-negative MDA-MB-231 breast cancer cells were exposed to adipocyte-secretome from adipocytes placed under pressures mimicking normal and obese-like metabolic conditions. Changes in phosphorylated kinase proteins and related biological pathways were assessed by phospho-antibody array and PANTHER analysis, cell proliferation were investigated through sulforhodamine B, cell cycle distribution by flow cytometry. Functional effects of CAP1 were subsequently examined following small interfering (si)RNA-mediated knockdown. Results: Protein phosphorylations involved in important biological processes were enriched in T47D breast cancer cells in response to adipocyte secretome from obese-like compared with normal conditions. The obesity-associated adipocyte secretome further stimulated cell proliferation and a shift from cell cycle G1-phase to S- and G2/M-phase was observed. Silencing of CAP1 decreased cell proliferation in both T47D and MDA-MB-231 cells, and reduced the obesity-associated secretome-induction of phosphoproteins involved in cell proliferation pathways. Conclusions: These results indicate that the adipocyte secretome and CAP1 are mechanistically important for the proliferation of both ER-positive and ER-negative breast cancer cells, and potential signaling mediators were identified. These studies provide biological insight into how obesity-associated factors could affect breast cancer.
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| 9. |
- Bergqvist, Malin, et al.
(författare)
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Effects of tumor-specific CAP1 expression and body constitution on clinical outcomes in patients with early breast cancer
- 2020
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity induces molecular changes that may favor tumor progression and metastatic spread, leading to impaired survival outcomes in breast cancer. Adenylate cyclase-associated protein 1 (CAP1), an actin regulatory protein and functional receptor for the obesity-associated adipokine resistin, has been implicated with inferior cancer prognosis. Here, the objective was to investigate the interplay between body composition and CAP1 tumor expression regarding breast cancer outcome through long-term survival analyses. Methods: Among 718 women with primary invasive breast cancer within the large population-based prospective Malmö Diet and Cancer Study, tumor-specific CAP1 levels were assessed following thorough antibody validation and immunohistochemical staining of tumor tissue microarrays. Antibody specificity and functional application validity were determined by CAP1 gene silencing, qRT-PCR, Western immunoblotting, and cell microarray immunostaining. Kaplan-Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of breast cancer-specific survival (BCSS) and overall survival (OS) according to body composition and CAP1 expression. Results: Study participants were followed for up to 25 years (median 10.9 years), during which 239 deaths were observed. Patients with low CAP1 tumor expression were older at diagnosis, displayed anthropometric measurements indicating a higher adiposity status (wider waist and hip, higher body mass index and body fat percentage), and were more prone to have unfavorable tumor characteristics (higher histological grade, higher Ki67, and estrogen receptor (ER) negativity). Overall, patients with CAP1-low tumors had impaired BCSS (adjusted hazard ratio: HRadj = 0.52, 95% CI 0.31-0.88) and OS (HRadj = 0.64, 95% CI 0.44-0.92) compared with patients having high CAP1 tumor expression. Further, analyses stratified according to different anthropometric measures or ER status showed that the CAP1-associated survival outcomes were most pronounced among patients with low adiposity status or ER-positive disease. Conclusions: Low CAP1 tumor expression was associated with higher body fatness and worse survival outcomes in breast cancer patients with effect modification by adiposity and ER status. CAP1 could be a novel marker for poorer survival outcome in leaner or ER-positive breast cancer patients, highlighting the need for considering body constitution in clinical decision making.
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| 10. |
- Bjørge, Tone, et al.
(författare)
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BMI and weight changes and risk of obesity-related cancers : a pooled European cohort study
- 2019
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 1464-3685 .- 0300-5771. ; 48:6, s. 1872-1885
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity is an established risk factor for several cancers. Adult weight gain has been associated with increased cancer risk, but studies on timing and duration of adult weight gain are relatively scarce. We examined the impact of BMI (body mass index) and weight changes over time, as well as the timing and duration of excess weight, on obesity- and non-obesity-related cancers. METHODS: We pooled health data from six European cohorts and included 221 274 individuals with two or more height and weight measurements during 1972-2014. Several BMI and weight measures were constructed. Cancer cases were identified through linkage with national cancer registries. Hazard ratios (HRs) of cancer with 95% confidence intervals (CIs) were derived from time-dependent Cox-regression models. RESULTS: During follow-up, 27 881 cancer cases were diagnosed; 9761 were obesity-related. The HR of all obesity-related cancers increased with increasing BMI at first and last measurement, maximum BMI and longer duration of overweight (men only) and obesity. Participants who were overweight before age 40 years had an HR of obesity-related cancers of 1.16 (95% CI 1.02, 1.32) and 1.15 (95% CI 1.04, 1.27) in men and women, respectively, compared with those who were not overweight. The risk increase was particularly high for endometrial (70%), male renal-cell (58%) and male colon cancer (29%). No positive associations were seen for cancers not regarded as obesity-related. CONCLUSIONS: Adult weight gain was associated with increased risk of several major cancers. The degree, timing and duration of overweight and obesity also seemed to be important. Preventing weight gain may reduce the cancer risk.
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