| 1. |
- Edin, Sofia, et al.
(författare)
-
Macrophages : Good guys in colorectal cancer
- 2013
-
Ingår i: Oncoimmunology. - : Informa UK Limited. - 2162-4011 .- 2162-402X. ; 2:2, s. e23038-
-
Tidskriftsartikel (refereegranskat)abstract
- Macrophages play a complex role in tumor progression since they can exert both tumor-preventing (M1 macrophages) and tumor-promoting (M2 macrophages) activities. In colorectal carcinoma (CRC), at odds to many other cancers, macrophage infiltration has been correlated with an improved patient survival. In a recent study, we have evaluated the distribution of M1 and M2 macrophage subtypes in CRC and their impact on patient prognosis.
|
|
| 2. |
- Edin, Sofia, et al.
(författare)
-
Opposing roles by KRAS and BRAF mutation on immune cell infiltration in colorectal cancer : possible implications for immunotherapy
- 2024
-
Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The immune response has important clinical value in colorectal cancer (CRC) in both prognosis and response to immunotherapy. This study aims to explore tumour immune cell infiltration in relation to clinically well-established molecular markers of CRC.Methods: Multiplex immunohistochemistry and multispectral imaging was used to evaluate tumour infiltration of cytotoxic T cells (CD8+), Th1 cells (T-bet+), T regulatory cells (FoxP3+), B cells (CD20+), and macrophages (CD68+) in a cohort of 257 CRC patients.Results: We found the expected association between higher immune-cell infiltration and microsatellite instability. Also, whereas BRAF-mutated tumours displayed increased immune-cell infiltration compared to BRAF wild-type tumours, the opposite was seen for KRAS-mutated tumours, differences that were most prominent for cytotoxic T cells and Th1 cells. The opposing relationships of BRAF and KRAS mutations with tumour infiltration of cytotoxic T cells was validated in an independent cohort of 608 CRC patients. A positive prognostic importance of cytotoxic T cells was found in wild-type as well as KRAS and BRAF-mutated CRCs in both cohorts.Conclusion: A combined evaluation of MSI status, KRAS and BRAF mutational status, and immune infiltration (cytotoxic T cells) may provide important insights to prognosis and response to immunotherapy in CRC.
|
|
| 3. |
- Edin, Sofia, et al.
(författare)
-
Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells
- 2013
-
Ingår i: PLOS ONE. - : PLoS, Public Library of Science. - 1932-6203. ; 8:9, s. e74982-
-
Tidskriftsartikel (refereegranskat)abstract
- Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a "mixed" M1/M2 phenotype, which in turn could contribute to a "good inflammatory response". This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer.
|
|
| 4. |
- Edin, Sofia, et al.
(författare)
-
The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer
- 2012
-
Ingår i: PLOS ONE. - : PLoS One. - 1932-6203. ; 7:10, s. e47045-
-
Tidskriftsartikel (refereegranskat)abstract
- High macrophage infiltration has been correlated to improved survival in colorectal cancer (CRC). Tumor associated macrophages (TAMs) play complex roles in tumorigenesis since they are believed to hold both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we have applied an immunohistochemical approach to determine the degree of infiltrating macrophages with a M1 or M2 phenotype in clinical specimens of CRC in relation to prognosis, both in CRC in general but also in subgroups of CRC defined by microsatellite instability (MSI) screening status and the CpG island methylator phenotype (CIMP). A total of 485 consecutive CRC specimens were stained for nitric oxide synthase 2 (NOS2) (also denoted iNOS) as a marker for the M1 macrophage phenotype and the scavenger receptor CD163 as a marker for the M2 macrophage phenotype. The average infiltration of NOS2 and CD163 expressing macrophages along the invasive tumor front was semi-quantitatively evaluated using a four-graded scale. Two subtypes of macrophages, displaying M1 (NOS2(+)) or M2 (CD163(+)) phenotypes, were recognized. We observed a significant correlation between the amount of NOS2(+) and CD163(+) cells (P<0.0001). A strong inverse correlation to tumor stage was found for both NOS2 (P<0.0001) and CD163 (P<0.0001) infiltration. Furthermore, patients harbouring tumors highly infiltrated by NOS2+ cells had a significantly better prognosis than those infiltrated by few NOS2+ cells, and this was found to be independent of MSI screening status and CIMP status. No significant difference was found on cancer-specific survival in groups of CRC with different NOS2/CD163 ratios. In conclusion, an increased infiltration of macrophages with a M1 phenotype at the tumor front is accompanied by a concomitant increase in macrophages with a M2 phenotype, and in a stage dependent manner correlated to a better prognosis in patients with CRC.
|
|
| 5. |
- Edin, Sofia, et al.
(författare)
-
The Prognostic Importance of CD20+ B lymphocytes in Colorectal Cancer and the Relation to Other Immune Cell subsets
- 2019
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- The anti-tumour immune response is critical to patient prognosis in colorectal cancer (CRC). The aim of this study was to investigate infiltration of B lymphocytes into CRC tumours, and their clinical relevance, prognostic value and relation to other immune cell subsets. We used multiplexed immunohistochemistry and multispectral imaging to assay the amount of infiltrating CD20+ B lymphocytes along with infiltration of CD8+ cytotoxic T cells, FOXP3+ T regulatory cells, CD68+ macrophages and CD66b+ neutrophils, in 316 archival CRC tissue specimens. A higher density of infiltrating CD20+ B lymphocytes was associated with tumours of the right colon (P = 0.025) and of lower stages (P = 0.009). Furthermore, patients whose tumours were highly infiltrated by CD20+ B lymphocytes had a significantly improved disease-specific survival (HR = 0.45, 95% CI 0.28-0.73, P = 0.001), which remained significant in multivariable analysis. CD20+ B lymphocytes were highly and positively associated with CD8+ T lymphocytes (P < 0.001), and part of the prognostic role was found to be a cooperative effect between these lymphocyte subsets. Our results support a favourable prognostic value of tumour-infiltrating CD20+ B lymphocytes in CRC. Furthermore, a cooperative prognostic effect between CD20+ B lymphocytes and CD8+ T lymphocytes is suggested.
|
|
| 6. |
- Eklöf, Vincy, 1984-, et al.
(författare)
-
Cancer-associated fecal microbial markers in colorectal cancer detection
- 2017
-
Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 141:12, s. 2528-2536
-
Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota have been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied. We used a nested case-control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harboring the pks pathogenicity island, afa-C+ diffusely adherent Escherichia coli harboring the afa-1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and F. nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and F. nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%. Our findings support a potential value of microbial factors in stool as putative noninvasive biomarkers for CRC detection. We propose that microbial markers may represent an important future screening strategy for CRC, selecting patients with a "high-risk" microbial pattern to other further diagnostic procedures such as colonoscopy.
|
|
| 7. |
|
|
| 8. |
- Eklöf, Vincy, 1984-, et al.
(författare)
-
The Combined Value of Faecal Haemoglobin andCalprotectin in Diagnosis of Colorectal Cancer inSymptomatic Patients Referred to Colonoscopy
- 2019
-
Ingår i: Academic Journal of Gastroenterology & Hepatology (AJGH). - San Fransisco : Iris Publishers. ; 1:3, s. 1-7
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To investigate the diagnostic value of a combined analyses of faecal immunological haemoglobin (FIT) and faecal calprotectin (FC) in detection of colorectal cancer (CRC).Methods: Out-patients (n=1440) referred to the endoscopy unit were analysed for FIT and FC in stool samples collected before the colonoscopy bowel preparation. The samples were collected from one defecation by the patients at home. Patients with IBD were excluded leaving stool samples from 1133 patients for further analyses. FIT was analysed using the immunological Analyse F.O.B Test and FC was analysed using the CALPRO® Calprotectin Elisa Test. Sensitivity and specificity to detect CRC was calculated for the individual tests, as well as for combined FIT/FC tests.Results: Out of the included patients, 38 were diagnosed with CRC, 9 with high grade dysplasia (HGD), and 133 with low grade dysplasia (LGD). FIT was analysed in 673 (59.4%), FC in 1021 (90.1%) and both FIT and FC in 561 (49.5%) patients. A ROC curve analysis showed that the most accurate cut-off level for FC in detecting CRC in our study was 105.5 µg/g. The sensitivity for CRC when using FIT, FC (cut-off > 100 µg/g) and the combination of FIT and FC (at least one positive test) was 65.5%, 74.1% and 94.4%, respectively. The corresponding specificity was 84.8%, 74.9% and 68.3%, respectively.Conclusion: Combined analyses of FIT and FC improved sensitivity for detection of CRC. Further studies in larger cohorts are required to find the optimal cut-off levels for different combinations of tests.
|
|
| 9. |
- Eklöf, Vincy, 1984-, et al.
(författare)
-
The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer
- 2013
-
Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 108:10, s. 2153-2163
-
Tidskriftsartikel (refereegranskat)abstract
- Background Mutations in KRAS, BRAF, PIK3CA and PTEN expression have been in focus to predict the effect of epidermal growth factor receptor-blocking therapy in colorectal cancer (CRC). Here, information on these four aberrations was collected and combined to a Quadruple index and used to evaluate the prognostic role of these factors in CRC. Patients We analysed the mutation status in KRAS, BRAF and PIK3CA and PTEN expression in two separate CRC cohorts, Northern Sweden Health Disease Study (NSHDS; n = 197) and Colorectal Cancer in Umea Study (CRUMS; n = 414). A Quadruple index was created, where Quadruple index positivity specifies cases with any aberration in KRAS, BRAF, PIK3CA or PTEN expression. Results Quadruple index positive tumours had a worse prognosis, significant in the NSHDS but not in the CRUMS cohort (NSHDS; P = 0.003 and CRUMS; P = 0.230) in univariate analyses but significance was lost in multivariate analyses. When analysing each gene separately, only BRAF was of prognostic significance in the NSHDS cohort (multivariate HR 2.00, 95% CI: 1.16-3.43) and KRAS was of prognostic significance in the CRUMS cohort (multivariate HR 1.48, 95% CI: 1.02-2.16). Aberrations in PIK3CA and PTEN did not add significant prognostic information. Conclusions Our results suggest that establishment of molecular subgroups based on KRAS and BRAF mutation status is important and should be considered in future prognostic studies in CRC.
|
|
| 10. |
- Gkekas, Ioannis, 1981-, et al.
(författare)
-
Colon cancer patients with mismatch repair deficiency are more likely to present as acute surgical cases
- 2021
-
Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 157, s. 1-9
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The effect of the genetic imprint on the emergency presentation of colon cancer remains unclear. The disparity between tumours evolving along different carcinogenetic pathways has not been studied systematically. This retrospective multicenter cohort study evaluates the association between mismatch repair status and the risk for acute surgery of colon cancer.Patients and methods: A retrospective multicenter cohort study including in total 870 patients from three different countries. Scandinavian cohort (Finland and Sweden), including a total of 412 patients operated between January 1, 1995 and December 31, 2010, was validated against a cohort from the Czech Republic, including a total of 458 patients, operated between January 1, 2018 and December 31, 2019. The proficiency or deficiency of mismatch repair was determined by immunohistochemistry. Primary outcome was the risk for acute colon cancer surgery given as the Odds Ratio (OR) in the univariable and multivariable analyses. Acute colon cancer surgery was defined as surgery performed during the same hospital admission as when the diagnosis of colon cancer was made.Results: Of the 870 patients (399 females [46%]) included in the analyses, median age at surgery was 69 [interquartile range, 61–76] years, deficient Mismatch Repair (dMMR) status was found in 190 patients (22%), and 179 patients (21%) underwent acute surgery during the same hospital admission as when the diagnosis of colon cancer was made. In the Scandinavian cohort, a significant association between dMMR status and acute surgery was seen in both the univariable (OR 1.82, 95% CI 1.11–3.02, P = 0.017) and the multivariable (OR = 2.21, 95% CI 1.28–3.95, P = 0.005) analyses. This was confirmed in the Czech validation cohort in both the univariable (OR = 1.94, 95% CI 1.09–3.26, P = 0.022) and the multivariable (OR = 1.77, 95% CI 1.15–3.18, P = 0.021) analyses.Conclusion: This multicenter study reveals a strong association between acute colon cancer surgery and dMMR tumour status.
|
|
