| 1. |
- Al-Haidari, Amr A., et al.
(författare)
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MiR-155-5p positively regulates CCL17-induced colon cancer cell migration by targeting RhoA
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:9, s. 14887-14896
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer is the second most common cause of cancer-related death, which is due to migration of tumor cells to distant sites of metastasis. Accumulating data indicate that mciroRNAs play an important role in several aspects of colon cancer cell biology. Herein, we examined the role of miR-155-5p in colon cancer cell migration induced by the CCL17-CCR4 axis in HT-29 colon cancer cells. We found that miR-155-5p knockdown in serum starved colon cancer cells decreased CCL17-induced cell chemotaxis. Moreover, knocking down miR-155-5p markedly decreased CCL17-provoked activation of RhoA in colon cancer cells. Bioinformatics analysis predicted two putative binding sites in the AU-rich element at the 3'-UTR of RhoA mRNA. MiR-155-5p binding to RhoA mRNA was verified using a target site blocker and functionally validated by RNA immunoprecipitation assays, showing that miR-155-5p-dependent regulation of RhoA mRNA is mediated by AU-rich elements present in the 3'-UTR region. Taken together, these results show that miR-155-5p positively regulates RhoA mRNA levels and translation as well as cell migration in serum starved colon cancer cells and indicate that targeting miR-155-5p might be a useful strategy to antagonize colon cancer metastasis.
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| 2. |
- Al-Haidari, Amr, et al.
(författare)
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MiR-155-5p controls colon cancer cell migration via post-transcriptional regulation of Human Antigen R (HuR)
- 2018
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 421, s. 145-151
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related deaths worldwide. Metastasis is the worst prognostic factor for patients with CRC. HuR (ELAVL1) is overexpressed in CRC and has been reported to promote colon cancer growth by targeting RNA in the cell cytoplasm. Herein, the role of miR-155-5p in regulating HuR expression and cell migration was examined in colon cancer cells. MiR-155-5p knockdown in serum-starved colon cancer cells decreased both colon cancer cell chemotaxis and cytoplasmic expression of HuR. Bioinformatics analysis predicted two putative binding sites in the AU-rich elements (AREs) at the 3′-UTR of HuR mRNA. MiR-155-5p binding to HuR was verified using specific target site blockers and functionally validated by use of RNA immunoprecipitation assays, showing that miR-155-5p-dependent regulation of HuR expression is mediated by AREs. Targeting AREs with a specific blocker inhibited colon cancer cell migration. Taken together, these novel findings demonstrate that AREs mediate miR-155-5p positive regulation of HuR mRNA levels and translation as well as migration in colon cancer cells, suggesting that targeting miR-155-5p and/or Hur might be useful therapeutic strategies against colon cancer metastasis.
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| 3. |
- Al-Haidari, Amr, et al.
(författare)
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Neutrophil extracellular traps promote surgery-induced peritoneal carcinosis of metastatic colorectal cancer via modulation of CXCR2 and αv integrin
- 2017. - Suppl 3
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 28, s. 87-88
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Konferensbidrag (refereegranskat)abstract
- Introduction: Peritoneal carcinosis (PC) is the third common site of metastatic colorectal cancer which characterized by a very low survival rate. Surgical trauma has been identified as an important factor in the progression of PC, postulated to be caused by the inflammatory response to tissue injury. The mechanism behind tumor metastasis remains poorly understood. However, existing evidence indicates that neutrophils, via Neutrophil Extracellular Traps (NETs), are implicated in the development of metastatic disease and recently identified as one of the most significant key players in promoting tumor progression. In this study, we highlight the mechanism by which NETs promote surgery-induced colon cancer cell peritoneal metastasis through regulation of key receptors, CXCR2 and αvβ3 integrin.Methods: We developed a murine model of surgical stress-induced PC by post-surgery inoculation of CT-26 murine colon cancer cell line. Surface expression of CXCR2 and αvβ3 on CT-26 cells were evaluated by flow cytometry live staining. Gene expression of extracellular matrix (ECM) proteins from wound incision wall was quantified using qRT-PCR. Function of CXCR2 and αvβ3 in tumor cell migration, proliferation, and adhesion were assessed by blocking assays using CXCR2 antagonist SB225002 and anti-CD51 in vitro and in vivo. Role of neutrophils in promoting cancer cell migration and adhesion was demonstrated using in vitro co-cultured migration and adhesion assays. NET formation was measured using modified ELISA technique of Histone-DNA complex. Depletion of NETs were achieved by daily intraperitoneal administration of 2mg/kg DNase I to mice for 10 days and tumor growth was evaluated by counting macroscopic nodules number on the peritoneum.Results: Blocking CXCR2 and Targeting αv integrin reduced tumor nodules number in vivo by 70% and 65% respectively and decreased cancer cell migration, proliferation, and adhesion in vitro. Incision wound tissue displayed pronounced reduction in ECM proteins mRNAs in treated mice with both CXCR2 antagonist and αv antibody. Mice treatment with DNase I significantly reduced tumor nodules number more than 90% compared to tumor control. Anti-CD51 decreased NET-induced CT-26 cell adhesion. Neutrophils stimulation with MIP-2 exhibits dose-dependent increase of NETosis. Co-culture of neutrophils and cancer cells provoked NETs formation and increased capacity of colon cancer cell migration while DNase I treatment abolished neutrophils NETs-induced tumor cell migration in vitroConclusion: Our novel findings implicate NETs in the development of PC due to surgical stress, suggesting that blocking NET formation might be an interesting potential therapeutic approach.
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| 4. |
- Cashin, Peter H., et al.
(författare)
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Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases : A randomised trial
- 2016
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 53, s. 155-162
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Tidskriftsartikel (refereegranskat)abstract
- Background: First-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm). Methods: Patients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m(2) /d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity. Results: The study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27-0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5-year PFS. Grade III-IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities. Conclusions: Cytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials. gov nr: NCT01524094).
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| 5. |
- Cashin, Peter, 1984-, et al.
(författare)
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Peritoneal mesothelioma in Sweden : A population-based study
- 2019
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 8:14, s. 6468-6475
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Tidskriftsartikel (refereegranskat)abstract
- The study aim was to report survival and morbidity of all patients in Sweden with peritoneal mesothelioma treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as well as investigate whether the survival has increased on a population level since this treatment was nationalized 2011. Study data were collected from the Swedish HIPEC registry and the Swedish National Cancer Registry. All patients with peritoneal mesothelioma scheduled for CRS/HIPEC treatment in Sweden January 2011 to March 2018 were retrieved from the Swedish HIPEC registry. Clinicopathological and survival data were collected. For population-level analysis, all patients with diffuse malignant peritoneal mesothelioma (DMPM) were identified from the Swedish National Cancer Registry and data were retrieved from two separate 5-year time periods: 1999-2003 and 2011-2015. Thirty-two patients were accepted for CRS/HIPEC. Four were open/close cases. Two-year survival rate was 84% or 59% when excluding borderline peritoneal mesotheliomas (n = 17). Median overall survival was not reached. Grade III-IV Clavien-Dindo events occurred in 22% with no mortality. From the national cancer registry, 102 DMPM cases were retrieved: 40 cases between 1999 and 2003, and 62 cases between 2011 and 2015 (corresponding to an increase from 0.9 to 1.24/million/year, P =.04). Six patients (10%) received CRS/HIPEC in the second period. Median OS increased between periods from 7 to 15 months and 5-year survival from 14% to 29% (P =.03). Peritoneal mesothelioma of both borderline and DMPM subtypes undergoing CRS/HIPEC have good long-term survival. The incidence of DMPM in Sweden has increased. Overall survival has increased alongside the introduction of CRS/HIPEC, which may be a contributing factor.
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| 6. |
- Erlandsson, Johan, et al.
(författare)
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Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial
- 2017
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Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 18:3, s. 336-346
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Tidskriftsartikel (refereegranskat)abstract
- Background Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. Methods In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 x 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 x 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1.7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813. Findings Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33.4 months (range 18.2-62.2) in the short-course radiotherapy group and 19.3 months (8.5-39.5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33.3 months (range 17.8-114.3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1.44 [95% CI 0.41-5.11]; long-course radiotherapy with delay 2.24 [0.71-7.10]; p=0.48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (amp;lt;1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 [50%] of 129 patients in the short-course radiotherapy group; 48 [38%] of 128 patients in the short-course radiotherapy with delay group; 50 [39%] of 128 patients in the long-course radiotherapy with delay group; odds ratio [OR] vs short-course radiotherapy: short-course radiotherapy with delay 0.59 [95% CI 0.36-0.97], long-course radiotherapy with delay 0.63 [0.38-1.04], p=0.075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0.61 [95% CI 0.45-0.83] p=0.001). Interpretation Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery.
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| 7. |
- Hansdotter Andersson, Pernilla, et al.
(författare)
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The COLOFOL trial: study design and comparison of the study population with the source cancer population.
- 2016
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Ingår i: Clinical Epidemiology. - 1179-1349. ; 8, s. 15-21
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Tidskriftsartikel (refereegranskat)abstract
- The COLOFOL trial, a prospective randomized multicenter trial comparing two follow-up regimes after curative surgical treatment for colorectal cancer, focuses on detection of asymptomatic recurrences. This paper aims to describe the design and recruitment procedure in the COLOFOL trial, comparing demographic characteristics between randomized patients and eligible patients not included in the study.
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| 8. |
- Hwaiz, Rundk, et al.
(författare)
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Rac1-dependent secretion of platelet-derived CCL5 regulates neutrophil recruitment via activation of alveolar macrophages in septic lung injury.
- 2015
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Ingår i: Journal of Leukocyte Biology. - 1938-3673. ; 97:5, s. 975-984
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence suggest that platelets play an important role in regulating neutrophil recruitment in septic lung injury. Herein, we hypothesized that platelet-derived CCL5 might facilitate sepsis-induced neutrophil accumulation in the lung. Abdominal sepsis was induced by CLP in C57BL/6 mice. CLP increased plasma levels of CCL5. Platelet depletion and treatment with the Rac1 inhibitor NSC23766 markedly reduced CCL5 in the plasma of septic mice. Moreover, Rac1 inhibition completely inhibited proteasePAR4-induced secretion of CCL5 in isolated platelets. Immunoneutralization of CCL5 decreased CLP-induced neutrophil infiltration, edema formation, and tissue injury in the lung. However, inhibition of CCL5 function had no effect on CLP-induced expression of Mac-1 on neutrophils. The blocking of CCL5 decreased plasma and lung levels of CXCL1 and CXCL2 in septic animals. CCL5 had no effect on neutrophil chemotaxis in vitro, suggesting an indirect effect of CCL5 on neutrophil recruitment. Intratracheal challenge with CCL5 increased accumulation of neutrophils and formation of CXCL2 in the lung. Administration of the CXCR2 antagonist SB225002 abolished CCL5-induced pulmonary recruitment of neutrophils. Isolated alveolar macrophages expressed significant levels of the CCL5 receptors CCR1 and CCR5. In addition, CCL5 triggered significant secretion of CXCL2 from isolated alveolar macrophages. Notably, intratracheal administration of clodronate not only depleted mice of alveolar macrophages but also abolished CCL5-induced formation of CXCL2 in the lung. Taken together, our findings suggest that Rac1 regulates platelet secretion of CCL5 and that CCL5 is a potent inducer of neutrophil recruitment in septic lung injury via formation of CXCL2 in alveolar macrophages.
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| 9. |
- Larsson, Anna, et al.
(författare)
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Water soluble contrast enema examination of the integrity of the rectal anastomosis prior to loop ileostomy reversal may be superfluous
- 2015
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 30:3, s. 381-384
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Tidskriftsartikel (refereegranskat)abstract
- Defunctioning loop ileostomy in low anterior resection (LAR) is routinely used to reduce consequences of anastomotic leakage. The purpose of this study was to analyze which examination technique is optimal for evaluating the integrity of the anastomosis prior to loop ileostomy reversal. Retrospective analysis of 95 patients who had been subjected to LAR at Helsingborg Hospital and SkAyenne University Hospital, Sweden, was undertaken between January 2007 and June 2009. The examination techniques of the rectal anastomosis prior to reversal and the clinical outcome after reversal were studied. Radiologic anastomosis control using water soluble contrast enema, digital rectal examination (DRE), and rectoscopy were performed in 53 % (50/95), 98 % (93/95), and 69 % (66/95), respectively. In two patients, no control of the anastomosis was performed before reversal. Fifty-two percent (49/95) of the patients were examined using all techniques. Six patients demonstrated leakage detected before reversal of which two were only radiological leakages. These two patients underwent loop ileostomy reversal after delay without complications. They were the only ones where the three examination techniques did not prove coherence. Four patients had symptomatic leakage; these were detected with rectoscopy and DRE and verified with enema. Three patients developed anastomotic leakage after loop ileostomy reversal despite normal preoperative examinations. Two of these patients had rectovaginal fistulas (AVFs). This retrospective study indicates that contrast enema does not provide additional information if rectoscopy and DRE are normal. Despite negative examinations, three of nine leakages were diagnosed after loop ileostomy reversal. Especially, AVFs seem difficult to diagnose.
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| 10. |
- Loftås, Per, 1964-
(författare)
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Response to neoadjuvant treatment in rectal cancer surgery
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.
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