| 21. |
- Ling, Agnes, 1976-, et al.
(författare)
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The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer
- 2016
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Ingår i: The Journal of Pathology: Clinical Research. - : John Wiley & Sons. - 2056-4538. ; 2:1, s. 21-31
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Tidskriftsartikel (refereegranskat)abstract
- Giving strong prognostic information, T-cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer (CRC). With a view to further improving the tools for prognostic evaluation, we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity, but also by subsite, within CRCs with different molecular characteristics (microsatellite instability, CpG island methylator phenotype status, and BRAF and KRAS mutational status). We evaluated the Th1 marker T-bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC. We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC, irrespective of intratumoural subsite, and that both extent of infiltration and patient outcome differ according to molecular subgroup. In brief, microsatellite instability, CpG island methylator phenotype-high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes, and the most pronounced prognostic effect of Th1 infiltration was found in these tumours. Interestingly, BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours whereas the opposite was seen for KRAS mutated tumours. These differences could be explained at least partly by our finding that BRAF mutated, in contrast to KRAS mutated, CRC cell lines and tumour specimens expressed higher levels of the Th1-attracting chemokine CXCL10, and reduced levels of CCL22 and TGFB1, stimulating Th2/Treg recruitment and polarisation. In conclusion, the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated, and it remained significant in multivariable analyses, indicating that T-bet may be a valuable marker in the clinical setting. Our results also indicate that T-bet is of value when analysed in molecular subgroups of CRC, allowing identification of patients with especially poor prognosis who are in need of extended treatment.
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| 22. |
- Lorenz, Fryderyk, et al.
(författare)
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Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 7920-
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Tidskriftsartikel (refereegranskat)abstract
- The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The aim of fecal calprotectin and alpha-1 antitrypsin testing in our study was to find out whether determination of the concentrations of these proteins may be used as a screening method for enteric GVHD. We studied prospectively 51 patients, 8 of whom developed GI-GVHD. Our data demonstrate that elevated fecal calprotectin levels were significantly associated with presence of GI-GVHD. We found a positive association between high F-calprotectin and severe gastrointestinal GVHD. In bivariate analysis, only calprotectin but not alpha-1 antitrypsin was independently associated with GI-GVHD. Testing for fecal calprotectin after allogeneic stem cell transplantation may be a useful screening tool.
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| 23. |
- Lundberg, Ida, et al.
(författare)
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MicroRNA expression in KRAS- and BRAF-mutated colorectal cancers
- 2018
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Ingår i: Anticancer Research. - : International Institute of Anticancer Research. - 0250-7005 .- 1791-7530. ; 38:2, s. 677-683
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: KRAS and BRAF are two genes commonly mutated in colorectal cancer (CRC). Even though BRAF is a downstream target of KRAS in the MAPK signalling pathway, KRAS- and BRAF-mutated CRCs are found to display several different clinical and histopathological features. We investigated whether a differential expression of microRNAs (miRNAs) could explain the clinicopathological differences seen between KRAS-and BRAF-mutated CRCs.Materials and Methods: Using a PCR array, we analyzed the expression of 84 different miRNAs in CRC cell lines wild-type in KRAS and BRAF, or mutated in KRAS or BRAF.Results: Ten miRNAs were selected for further analyses in tumor tissue specimens (let-7a, let-7i, miR-10a, miR-10b, miR-31, miR-100, miR-181a, miR-181b, miR-372, and miR-373). BRAF-mutated tumors were found to express significantly higher levels of miR-31 as well as significantly lower levels of miR-373, compared to wild-type tumors.Conclusion: Our results suggest that KRAS and BRAF-mutated CRCs may have different miRNA signatures compared to CRC tumors wild-type in KRAS and BRAF. However, no difference in expression levels between KRAS-and BRAF-mutated tumors was evident for the miRNAs analyzed in this study.
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| 24. |
- Lundberg, Ida, 1987-
(författare)
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Molecular understanding of KRAS- and BRAF-mutated colorectal cancers
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is the third most commonly diagnosed malignancy in both men and women, and one of the leading causes of cancer-related deaths worldwide. One frequently mutated pathway involved in oncogenesis in CRC is the RAS/RAF/MAP kinase pathway. Oncogenic activation of KRAS and BRAF occur in 30‒40% and 5‒15% of all CRCs, respectively, and the mutations are mutually exclusive. Even though KRAS and BRAF are known to act in the same pathway, KRAS- and BRAF-mutated CRCs have different clinical and histopathological features. For example, BRAF mutation in CRC is tightly linked to microsatellite instability (MSI) and a CpG island methylator phenotype (CIMP), which is not seen in KRAS-mutated tumours. BRAF-mutated CRCs are also more often found in right-sided tumours. However, the underlying molecular reasons for these differences have not yet been defined.The overall aim of this thesis was to investigate molecular differences between KRAS- and BRAF-mutated CRCs to understand how KRAS and BRAF mutations differentially affect tumour progression. We used an in vitro cell culture system to explore molecular differences between KRAS- and BRAF-mutated CRCs and verified our findings using CRC tissue specimens from the Colorectal Cancer in Umeå Study (CRUMS).We found that BRAF mutation, but not KRAS mutation, was associated with expression of the stem cell factor SOX2. Furthermore, SOX2 was found to be correlated to a poor patient prognosis, especially in BRAF-mutated cancers. We further investigated the role of BRAF in regulation of SOX2 expression and found that SOX2 is at least partly regulated by BRAF in vitro. We continued by investigating the functional role of SOX2 in CRC and found that SOX2-expressing cells shared several characteristics with cancer stem cells, and also had down-regulated expression of the intestinal epithelial marker CDX2. There was a strong correlation between loss of CDX2 expression and poor patient prognosis, and patients with SOX2 expression were found to have a particularly poor prognosis when CDX2 levels were down-regulated. In conclusion, in these studies we identified a subgroup of BRAF-mutated CRCs with a particularly poor prognosis, and having a cancer stem cell-like appearance with increased expression of SOX2 and decreased expression of CDX2.Tumour progression is regulated by interactions with cells of the immune system. We found that BRAF-mutated CRCs were more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours, while the opposite was true for KRAS-mutated CRCs. Interestingly, we found that part of this difference is probably caused by differences in secreted chemokines and cytokines between KRAS- and BRAF-mutated CRCs, stimulating different arms of the immune response.Altered levels of expression of miRNAs have been seen in several malignancies, including CRC. We found that BRAF- and KRAS-mutated CRCs showed miRNA signatures different from those of wild-type CRCs, but the expression of miRNAs did not distinguish KRAS-mutated tumours from BRAF-mutated tumours.In summary, our findings have revealed possible molecular differences between KRAS- and BRAF-mutated CRCs that may explain some of the differences in their clinical and histopathological behaviour.
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| 25. |
- Lundberg, Ida V., et al.
(författare)
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SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer
- 2016
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: To improve current treatment strategies for patients with aggressive colorectal cancer (CRC), the molecular understanding of subgroups of CRC with poor prognosis is of vast importance. SOX2 positive tumors have been associated with a poor patient outcome, but the functional role of SOX2 in CRC patient prognosis is still unclear. Methods: An in vitro cell culture model expressing SOX2 was used to investigate the functional role of SOX2 in CRC. In vitro findings were verified using RNA from fresh frozen tumor tissue or immunohistochemistry on formalin fixed paraffin embedded (FFPE) tumor tissue from a cohort of 445 CRC patients. Results: Using our in vitro model, we found that SOX2 expressing cells displayed several characteristics of cancer stem cells; such as a decreased proliferative rate, a spheroid growth pattern, and increased expression of stem cell markers CD24 and CD44. Cells expressing SOX2 also showed down-regulated expression of the intestinal epithelial marker CDX2. We next evaluated CDX2 expression in our patient cohort. CDX2 down-regulation was more often found in right sided tumors of high grade and high stage. Furthermore, a decreased expression of CDX2 was closely linked to MSI, CIMP-high as well as BRAF mutated tumors. A decreased expression of CDX2 was also, in a stepwise manner, strongly correlated to a poor patient prognosis. When looking at SOX2 expression in relation to CDX2, we found that SOX2 expressing tumors more often displayed a down-regulated expression of CDX2. In addition, SOX2 expressing tumors with a down-regulated CDX2 expression had a worse patient prognosis compared to those with retained CDX2 expression. Conclusions: Our results indicate that SOX2 expression induces a cellular stem cell state in human CRC with a decreased expression of CDX2. Furthermore, a down-regulated expression of CDX2 results in a poor patient prognosis in CRC and at least part of the prognostic importance of SOX2 is mediated through CDX2 down-regulation.
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| 26. |
- Lundgren, David, et al.
(författare)
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Patients with longstanding ulcerative colitis in remission do not have more irritable bowel syndrome-like symptoms than controls
- 2016
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Ingår i: BMC Gastroenterology. - : Springer Science and Business Media LLC. - 1471-230X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Irritable bowel syndrome (IBS) is more common in patients with ulcerative colitis (UC) than expected. The prevalence of IBS in patients with UC with longstanding disease is not known. We investigated the prevalence of IBS-like symptoms in patients with UC in remission and longstanding disease in comparison to control subjects.METHODS: Sixty-eight patients with UC and 33 patients with hereditary familiar colon cancer and who underwent colonoscopy surveillance were included. Faecal calprotectin (FC), Gastrointestinal Symptoms Rating Scale-Irritable Bowel Syndrome (GSRS-IBS) and Hospital Anxiety and Depression scale were fulfilled prior to endoscopy. UC in remission was define by steroid-free clinical remission, a Mayo Score ≤ 1 on endoscopy, a FC ≤ 200 μg/g and no significant active inflammation on colon biopsies.RESULTS: Fifty-five UC patients met the criteria for being in remission. The median disease duration was 17 years. The patients with UC in remission tended to have lower scores on total GSRS-IBS score (6 vs 10.5; p = 0.062) and lower or equal scores on all specific IBS symptoms in comparison to controls. There was a moderate but significant correlation between diarrhoea scores and FC levels (in the span ≤ 200 μg/g) (rs 0.38; p = 0.004) in the UC in remission group.CONCLUSION: Patients with UC with longstanding disease and in remission do not have more IBS symptoms than controls. In UC patients in remission the FC level in the lower span showed a moderate correlation to symptoms of diarrhoea.
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| 27. |
- Lundgren, David, et al.
(författare)
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Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy
- 2019
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 54:2, s. 152-157
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Faecal Calprotectin (FC) is a sensitive marker for gut inflammation. However, slightly elevated FC levels are also common in subjects without inflammation. We investigated the association between FC and clinical factors including concomitant use of medical therapy in patients with a normal colonoscopy.Material and methods: Out-patients (n=1263) referred for colonoscopy, performed FC test (CALPRO) the day before the start of bowel preparation. All subjects answered questionnaires that included questions on the present and past health history, concomitant medical treatment and gastrointestinal symptoms (GSRS). A medical record chart review was performed to check for concomitant disease, cause of referral and the result of the colonoscopy including biopsies. Inclusion criteria were a normal colonoscopy. Exclusion criteria were inflammatory bowel disease, colon cancer and high-grade dysplasia.Results: Five hundred ninety subjects fulfilled the inclusion criteria and completed the study. Thirty-six per cent of the subjects had a FC >50 mu g/g. In a logistic regression analysis, age (adjusted OR: 1.051; CI: 1.032-1.071), and the use of proton pump inhibitors (adjusted OR: 3.843; CI: 2.338-6.316), non-steroid anti-inflammatory drugs (adjusted OR: 2.411; CI: 1.162-5.002) and acetylsalicylic acid (adjusted OR: 2.934; CI: 1.085-3.448) were significantly associated with an elevated FC (>50 mu g/g).Conclusions: More than one-third of the patients with a normal colonoscopy performed in clinical routine had a slightly elevated FC level. Our results emphasise the need for attention to age, the use of proton pump inhibitors, non-steroid anti-inflammatory drugs and acetylsalicylic acid in the interpretation of FC tests in clinical practice.
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| 28. |
- Lundholm, Marie, et al.
(författare)
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Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions
- 2015
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.
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| 29. |
- Malesci, Alberto, et al.
(författare)
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Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer
- 2017
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-associated macrophages (TAMs) play a role in tumor development and progression. We hypothesized that abundance of TAMs might modify efficacy of 5-fluorouracil chemotherapy in colorectal cancer. We measured the density of CD68+ TAMs at the invasive front of primary tumor of colorectal carcinoma (PT-TAMs; n = 208), at available matched metastatic lymph node (LN-TAMs; n = 149), and in an independent set of primary colorectal cancers (PT-TAMs, n = 111). The hazard ratios for disease-free survival were computed by Cox proportional-hazards model. In exploratory analysis, the interaction between TAMs and 5-fluorouracil adjuvant therapy was significant (PT-TAMs, p=0.02; LN-TAMs, p D 0.005). High TAMs were independently associated with better disease-free survival only in 5-fluorouracil-treated patients (PT-TAMs, HR 0.23; 95% CI, 0.08-0.65; p=0.005; LN-TAMs, HR 0.13; 95% CI, 0.04-0.43; p D 0.001). The independent predictive value of PT-TAMs was replicated in the external set (HR, 0.14; 95% CI 0.02-1.00; p=0.05). In an in vitro experiment, 5-fluorouracil and macrophages showed a synergistic effect and increased colorectal cancer cell death. High densities of TAMs, particularly in metastatic lymph-nodes, identify stage III colorectal cancer patients benefitting from 5-fluorouracil adjuvant therapy.
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| 30. |
- Murphy, Neil, et al.
(författare)
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A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)
- 2016
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Background Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.Methods and Findings The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m(2)), (2) metabolically healthy/overweight (BMI >= 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI >= 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [>= 80 cm for women and >= 94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed.Conclusions These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.
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