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  • 1.
    Dahlin, Anna M
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor2011In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 24, p. 671-682Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eight-gene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score ≥7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score ≤4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P=0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

  • 2.
    Dahlin, Anna M
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jacobsson, Maria
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status2010In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 6, p. 1845-1855Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation.

    EXPERIMENTAL DESIGN: Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umeå Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry.

    RESULTS: CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMP-negative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected.

    CONCLUSIONS: In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research.

  • 3.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47045-Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Macrophages: Good guys in colorectal cancer2013In: Oncoimmunology, ISSN 2162-4011, Vol. 2, no 2, p. e23038-Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74982-Article in journal (Refereed)
    Abstract [en]

    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.

  • 6.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundgren, David
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The combined diagnostic value of faecal haemoglobin and calprotectin in colorectal cancerManuscript (preprint) (Other academic)
  • 7.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Alexeyev, Oleg
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cancer-associated fecal microbial markers in colorectal cancer detection2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, no 12, p. 2528-2536Article in journal (Refereed)
    Abstract [en]

    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.

  • 8.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Å.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 10, p. 2153-2163Article in journal (Refereed)
    Abstract [en]

    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.

  • 9.
    Forssell, Johan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Jung, Andreas
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    High macrophage infiltration along the tumor front correlates with improved survival in colon cancer.2007In: Clin Cancer Res, ISSN 1078-0432, Vol. 13, no 5, p. 1472-1479Article in journal (Refereed)
  • 10.
    Gustafsson, Sofia B
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Jacobsson, Stig OP
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    High tumour cannabinoid CB(1) receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Background: There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome.

    Methodology/Principal Findings: CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and >= 2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB1IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 8565 and 66+/-8%; tumour interior, 86+/-4% and 63+/-8% for the CB(1)IR<2 and CB(1)IR >= 2 groups, respectively.

    Conclusions/Significance: The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.

  • 11.
    Henriksson, M L
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Telepnev, Maxim
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ras effector pathway activation by epidermal growth factor is inhibited in vivo by exoenzyme S ADP-ribosylation of Ras2000In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 347, no 1, p. 217-222Article in journal (Refereed)
  • 12.
    Henriksson, Maria L
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Colorectal Cancer Cells Activate Adjacent Fibroblasts Resulting in FGF1/FGFR3 Signaling and Increased Invasion.2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 3, p. 1387-1394Article in journal (Refereed)
    Abstract [en]

    Cancer-associated fibroblasts expressing fibroblast activation protein (FAP) have been implicated in the invasive behavior of colorectal cancer. In this study, we use FAP expression as a marker of fibroblast activation and analyze the effect of activated fibroblasts on colorectal cancer migration and invasion in experimental cell studies. We also investigated the expression pattern of FAP in cancer-associated fibroblasts during transformation from benign to malignant colorectal tumors. In immunohistochemical analyses, FAP was expressed in fibroblasts in all colorectal cancer samples examined, whereas all normal colon, hyperplastic polyps, or adenoma samples were negative. In in vitro studies, conditioned medium from colon cancer cells, but not adenoma cells, activated fibroblasts by inducing FAP expression. These activated fibroblasts increased the migration and invasion of colon cancer cells in Boyden chamber experiments and in a three-dimensional cell culture model. We identify fibroblast growth factor 1/fibroblast growth factor receptor 3 (FGF1/FGFR-3) signaling as mediators leading to the increased migration and invasion. Activated fibroblasts increase their expression of FGF1, and by adding a fibroblast growth factor receptor inhibitor, as well as an FGF1-neutralizing antibody, we reduced the migration of colon cancer cells. Our findings provide evidence of a possible molecular mechanism involved in the cross talk between cancer cells and fibroblasts leading to cancer cell invasion.

  • 13.
    Henriksson, Maria L.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Sundin, Charlotta
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Jansson, Anna L.
    Forsberg, Åke
    Palmer, Ruth H.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hallberg, Bengt
    Exoenzyme S shows selective ADP-ribosylation and GTPase-activating protein (GAP) activities towards small GTPases in vivo2002In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 367, no 3, p. 617-28Article in journal (Refereed)
    Abstract [en]

    Intracellular targeting of the Pseudomonas aeruginosa toxins exoenzyme S (ExoS) and exoenzyme T (ExoT) initially results in disruption of the actin microfilament structure of eukaryotic cells. ExoS and ExoT are bifunctional cytotoxins, with N-terminal GTPase-activating protein (GAP) and C-terminal ADP-ribosyltransferase activities. We show that ExoS can modify multiple GTPases of the Ras superfamily in vivo. In contrast, ExoT shows no ADP-ribosylation activity towards any of the GTPases tested in vivo. We further examined ExoS targets in vivo and observed that ExoS modulates the activity of several of these small GTP-binding proteins, such as Ras, Rap1, Rap2, Ral, Rac1, RhoA and Cdc42. We suggest that ExoS is the major ADP-ribosyltransferase protein modulating small GTPase function encoded by P. aeruginosa. Furthermore, we show that the GAP activity of ExoS abrogates the activation of RhoA, Cdc42 and Rap1.

  • 14.
    Henriksson, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Trollér, Ulrika
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    14-3-3 proteins are required for the inhibition fo Ras by exoenzyme S2000In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 349, p. 697-701Article in journal (Refereed)
    Abstract [en]

    14-3-3 proteins play a regulatory role and participate in both signal transduction and checkpoint control pathways. 14-3-3 proteins bind phosphoserine ligands, such as Raf-l kinase and Bad, by recognizing the phosphorylated consensus motif, Arg-Ser-Xaa-pSer-Xaa-Pro (where 'Xaa' represents 'any residue', and 'pSer' is 'phosphoserine'). However, 14-3-3 proteins must bind unphosphorylated ligands, such as glycoprotein Ib alpha and Pseudomonas aeruginosa exoenzyme S (ExoS), since it has been suggested that specific residues of 14-3-3 proteins are required for activation of ExoS. Furthermore, an unphosphorylated peptide derived from a phage display library inhibited the binding of both ExoS and Raf-1 to 14-3-3, and bound within the same conserved amphipathic groove on the surface of 14-3-3 as the Raf-derived phosphopeptide (pS-Raf-259). In the present study we identify the interaction site on ExoS for 14-3-3, and show that ExoS and 14-3-3 do indeed interact in vivo. In addition, we show that this interaction is critical for the ADP-ribosylation of Ras by ExoS, both in vitro and in vivo. Loss of the 14-3-3 binding site on ExoS results in an ExoS molecule that is unable to efficiently inactivate Ras, and displays reduced killing activity.

  • 15.
    Isaksson-Mettävainio, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High SMAD4 levels appear in MSI and hypermethylated colon cancers, and indicate a better prognosis2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, p. 779-788Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is one of the most common causes of cancer related deaths in western countries. CRC are commonly divided in cancers showing microsatellite stability (MSS) or microsatellite instability (MSI). A more novel classification is dependent on promoter hypermethylation of CpG islands (the CpG island methylator phenotype, CIMP), where cancers show high, low or negative methylation status. SMAD4, located on chromosome 18q, has been thoroughly investigated during the last years. Loss of SMAD4 expression has been reported to correlate with poor CRC patient prognosis. In this study we analyze the impact of SMAD4 expression on prognosis in relation to MSI screening status and CIMP status. 479 paraffin-embedded specimens of CRC were examined for nuclear SMAD4 expression using immunohistochemistry. The tumors were scored loss (-), moderate (+) and high (++) expressing tumors. Loss of SMAD4 correlated significantly with decreased survival in all colon cancer patients. High SMAD4 expression, on the other hand, was significantly associated with increased survival, especially in colon cancer patients which has undergone potential curative surgery. In addition, in MSI tumors and CIMP-high tumors, high SMAD4 expression was significantly related to increase in survival, while loss of SMAD4 resulted in a significantly poorer prognosis. SMAD4 expression was not correlated to prognosis in rectal cancer cases. We conclude, loss of SMAD4 indicates a poor prognosis in colon cancer patients. The novel findings that high SMAD4 expression predicts a better prognosis suggests that SMAD4 immunohistochemistry could constitute a prognostic marker in combination with CIMP and MSI screening status.

  • 16.
    Isaksson-Mettävainio, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    c-Met expression in primary tumors and their corresponding distant metastases2009In: Molecular Medicine Reports, ISSN 1791-2997, Vol. 1, no 6, p. 787-790Article in journal (Refereed)
    Abstract [en]

    c-Met is a receptor tyrosine kinase that has beenimplicated in the pathogenesis and growth of a wide variety ofhuman malignancies, including CRC, but its role in metastasisis largely unknown. We compared c-Met expression in primaryhuman colorectal carcinomas and distant metastases from thesame patients. Formalin-fixed paraffin-embedded tissuesamples from 69 colorectal cancer patients were obtained. Theprotein expression of c-Met was evaluated immunohistochemicallyusing a commercial antibody. The difference inexpression between primary tumors and their correspondingdistant metastases was analyzed using the Wilcoxon signedranktest. c-Met expression was statistically significantlylower in the distant metastases compared to their correspondingprimary tumors (p<0.001), whereas no difference was foundbetween lymph node metastases and their correspondingprimary tumors (p=0.957). The degree of c-Met expressionwas not related to clinicopathological characteristics such astumor grade and Dukes' stage at the time of primary tumordiagnosis, or to the location of the distant metastases. Wedemonstrated that c-Met expression is often reduced in distantmetastases compared to their corresponding primary colorectaltumors. Additional studies of c-Met activation and signaltransduction will increase our knowledge about the role ofc-Met in colorectal cancer metastasis.

  • 17. Lindholm, Cecilia K
    et al.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Welsh, Michael
    Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells.2002In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 269, no 13, p. 3279-3288Article in journal (Refereed)
    Abstract [en]

    This study addresses the interactions between the adaptor protein Shb and components involved in T cell signalling, including SLP-76, Gads, Vav and ZAP70. We show that both SLP-76 and ZAP70 co-immunoprecipitate with Shb in Jurkat T cells and that Shb and Vav co-immunoprecipitate when cotransfected in COS cells. We also demonstrate, utilizing fusion protein constructs, that SLP-76, Gads and Vav associate independently of each other to different domains or regions, of Shb. Overexpression of an SH2 domain-defective Shb causes diminished phosphorylation of SLP-76 and Vav and consequently decreased activation of c-Jun kinase upon T cell receptor (TCR) stimulation. Shb was also found to localize to glycolipid-enriched membrane microdomains (GEMs), also called lipid rafts, after TCR stimulation. Our results indicate that upon TCR stimulation, Shb is targeted to these lipid rafts where Shb aids in recruiting the SLP-76-Gads-Vav complex to the T cell receptor zeta-chain and ZAP70.

  • 18.
    Ling, Agnes
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues2014In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, no 10, p. 2551-2559Article in journal (Refereed)
    Abstract [en]

    Background: To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8(+)) and regulatory T lymphocytes (FoxP3(+)) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status).

    Methods: CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8(+) and FOXP3(+) cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial).

    Results: We found that infiltration of CD8(+) T lymphocytes within the tumour epithelium provided the strongest prognostic information (P < 0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P < 0.001), suggesting FOXP3(+) T-lymphocyte infiltration to be a better prognostic tool than CD8(+) T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3(+) cells at the tumour invasive front, significantly improved prognosis.

    Conclusions: Analyses of intraepithelial infiltration of CD8(+) T lymphocytes, infiltration of FOXP3(+) T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer.

  • 19.
    Ling, Agnes
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundberg, Ida V.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer2016In: The Journal of Pathology: Clinical Research, ISSN 2056-4538, Vol. 2, no 1, p. 21-31Article in journal (Refereed)
    Abstract [en]

    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.

  • 20.
    Ling, Agnes
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 11, article id e1356143Article in journal (Refereed)
    Abstract [en]

    The anti-tumor immune response has been shown to be of great prognostic importance in colorectal cancer (CRC) and so has the tumors ability for immune evasion. Our aim of this study was to investigate tumor factors that influence immunity. We used a gene expression array to search for potential mechanisms of tumor immune escape. One candidate gene identified was TAP1, involved in antigen presentation by MHC class I. TAP1 protein expression was evaluated by immunohistochemistry in 436 CRC patients of the Colorectal Cancer in Umeå Study cohort. We found a significant association between a downregulated expression of TAP1 and low infiltration of various subtypes of lymphocytes as well as macrophages. A downregulated expression of TAP1 was further found to be independent of molecular characteristics, suggesting TAP1 down-regulation to reach beyond the well described highly immunogenic MSI CRCs. A low expression of TAP1 was also significantly associated with poor prognosis in patients with CRC, a result that stayed significant in tumor front of early stage tumors (stage I-II) through multivariable analyses. Furthermore, we found that TAP1 expression was inversely correlated with methylation at sites in close proximity to the promoter region. In summary, our results show down-regulation of TAP1 to be a general mechanism of tumor immune escape in CRC and a poor prognostic factor in stage I-II CRC patients. We also suggest that methylation of the TAP1 gene may be a putative mechanism for TAP1 downregulation.

  • 21.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Increased epidermal growth factor receptor expression at the invasive margin is a negative prognostic factor in colorectal cancer2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 9, p. 2031-2037Article in journal (Refereed)
    Abstract [en]

    The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is often expressed in solid malignant tumours, and the expression has been correlated to disease progression. Multiple new agents targeted against the EGFR have been developed during the last decade, but treatment selecting criteria are still not clear. This immunohistochemical study includes 386 colorectal cancer patients and focuses on EGFR expression variations within the tumour, comparing central parts to the invasive margin. Positive immunostaining for EGFR was evident in the central part in 176/386 (46%) of analyzed primary tumours. The invasive margin was positive in 222/386 (58%). A similar expression in both the central part and the invasive front was evident in 286/386 (74%). An increased score at the invasive margin compared to central parts (EGFR(i)) was evident in 97/386 (25%) of the tumours. Moreover, the results show a significant survival disadvantage for the EGFR(i) group, both in potentially curatively resected colon cancer patients (n = 170, p = 0.01) and in potentially curatively resected colon and rectal cancer patients combined (n = 273, p = 0.013). Multivariate survival analysis adjusted for age, gender, bowel localisation, grade, stage and tumour type showed an increased risk of cancer death for EGFR(i) tumours (HR, 1.53; 95% CI, 1.04-2.23; p = 0.029). A significant correlation between EGFR expression at the invasive margin and the presence of budding was seen (p = 0.0001). This investigation of a large patient material implies that EGFR immunohistochemical analysis still has a role in risk evaluation of colorectal cancer patients.

  • 22.
    Lundberg, Ida V.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer2016In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, article id 471Article in journal (Refereed)
    Abstract [en]

    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.

  • 23.
    Lundberg, Ida V
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e101957Article in journal (Refereed)
    Abstract [en]

    Sporadic colorectal cancer (CRC) is a common malignancy and also one of the main causes of cancer deaths worldwide. Aberrant expression of the transcription factor SOX2 has recently been observed in several cancer types, but its role in CRC has not been fully elucidated. Here we studied the expression of SOX2 in 441 CRC patients by immunohistochemistry and related the expression to clinicopathological and molecular variables and patient prognosis. SOX2 was expressed in 11% of the tumors and was significantly associated to BRAF(V600E) mutation, but not to KRAS mutations (codon 12 and 13). SOX2 positivity was correlated to poor patient survival, especially in BRAF(V600E) mutated cases. In vitro studies showed that cells expressing the constitutively active BRAF(V600E) had increased SOX2 expression, a finding not found in cells expressing KRAS(G12V). Furthermore, blocking downstream BRAF signalling using a MEK-inhibitor resulted in a decreased expression of SOX2. Since SOX2 overexpression has been correlated to increased migration and invasion, we investigated the SOX2 expression in human CRC liver metastasis and found that a SOX2 positive primary CRC also had SOX2 expression in corresponding liver metastases. Finally we found that cells overexpressing SOX2 in vitro showed enhanced expression of FGFR1, which has been reported to correlate with liver metastasis in CRC. Our novel findings suggest that SOX2 expression is partly regulated by BRAF signalling, and an increased SOX2 expression may promote CRC metastasis and mediate a poor patient prognosis.

  • 24.
    Lundberg, Ida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    MicroRNA expression in KRAS- and BRAF-mutated colorectal cancers2018In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 38, no 2, p. 677-683Article in journal (Refereed)
    Abstract [en]

    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.

  • 25.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. anders.bergh@umu.se.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15651Article in journal (Refereed)
    Abstract [en]

    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.

  • 26.
    Palmqvist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ling, Agnes
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The assiciation of immune cell infiltration and prognosis in colorectal cancer2013In: Current colorectal cancer reports, ISSN 1556-3790, Vol. 9, no 4, p. 372-379Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. The tumor microenvironment is of great biological importance in cancer development and progression and harbors several different immune cells representing both the innate and the adaptive immune response. These inflammatory cells may have both tumor-promoting and tumor-suppressing effects, and they have been shown to be of prognostic importance. This review summarizes the recent evidence regarding the prognostic significance of the host response to colorectal cancer.

  • 27.
    Van Guelpen, Bethany
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cullman, Inger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case-referent study2010In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, no 4, p. 557-566Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: We related prediagnostic plasma folate, vitamin B12, and total homocysteine concentrations, and the MTHFR 677C>T and 1298A>C polymorphisms, to the risk of colorectal cancer with and without the CpG island methylator phenotype (CIMP).

    METHODS: This was a nested case-referent study of 190 cases and double, matched referents from the large, population-based Northern Sweden Health and Disease Study. Using archival tumor tissue, promoter methylation in an eight-gene panel was analyzed by MethyLight.

    RESULTS: A reduced risk of CIMP-low/CIMP-high CRC (>/=1 gene methylated) was observed in subjects with very low plasma folate concentrations [multivariate odds ratio 2.96 (95% CI 1.24-7.08) for quintiles two to five versus one (lowest)]. With the exception of a reduced risk in MTHFR 677 TT-homozygotes, none of the other one-carbon variables were associated with the risk of CIMP-low/CIMP-high CRC. For CIMP-negative CRC, only the MTHFR polymorphisms were statistically significantly related to risk, inversely for 677C>T and positively for 1298A>C, but a tendency toward a reduced risk was observed in subjects with an adequate methyl availability, combining the plasma variables [multivariate odds ratio 0.61 (95% CI 0.32-1.15)].

    CONCLUSION: Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.

  • 28.
    Vernersson, Emma
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Khoo, Nelson K S
    Henriksson, Maria
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Palmer, Ruth
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Characterization of the expression of the ALK receptor tyrosine kinase in mice.2006In: Gene Expression Patterns, ISSN 1567-133X, E-ISSN 1872-7298, Vol. 6, no 5, p. 448-461Article in journal (Refereed)
  • 29.
    Wikberg, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundberg, Ida V.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.2013In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 34, no 2, p. 1013-1020Article in journal (Refereed)
    Abstract [en]

    -An active stroma is important for cancer cell invasion and metastasis. We investigated the expression of fibroblast activation protein (FAP) in relation to patient prognosis in colorectal cancer. Colorectal cancer specimens from 449 patients were immunohistochemically stained with a FAP antibody and evaluated in the tumor center and tumor front using a semiquantitative four-level scale. FAP was expressed by fibroblasts in 85-90 % of the tumors examined. High versus no/low expression in the tumor center was associated with poor prognosis (multivariate hazard ratio, HR = 1.72; 95 % CI 1.07-2.77, p = 0.025). FAP expression in the tumor front, though more frequent than in the tumor center, was not associated with prognosis. FAP expression in the tumor center was more common in specimens with positive microsatellite instability (MSI) screening status and in patients with high CpG island methylator phenotype (CIMP) status. However, inclusion of MSI screening status and CIMP status in the multivariate analysis strengthened the risk estimates for high FAP expression in the tumor center (HR = 1.89; 95 % CI 1.13-3.14; p = 0.014), emphasizing the role of FAP as an independent prognostic factor. Stromal FAP expression is common in colorectal cancer, and we conclude that high FAP expression in the tumor center, but not the tumor front, is an independent negative prognostic factor.

  • 30.
    Wikberg, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Francis, Matthew S.
    Peden, Alex
    Aili, Margareta
    Stefansson, Kristina
    Palmer, Ruth H.
    Aitken, Alastair
    Hallberg, Bengt
    A nonphosphorylated 14-3-3 binding motif on exoenzyme S that is functional in vivo2002In: European Journal of Biochemistry, Vol. 269, no 20, p. 4921-4929Article in journal (Refereed)
  • 31.
    Wikberg, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ling, Agnes
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Neutrophil infiltration is a favorable prognostic factor in early stages of colon cancer2017In: Human Pathology, ISSN 0046-8177, E-ISSN 1532-8392, Vol. 68, p. 193-202Article in journal (Refereed)
    Abstract [en]

    The tumor immune response has been proven critical to prognosis in colorectal cancer (CRC), but studies on the prognostic role of neutrophil infiltration have shown contradictory results. The aim of this study was to elucidate the prognostic role of infiltrating neutrophils at different intratumoral subsites and in different molecular subgroups of CRC. The relations between neutrophil infiltration and infiltration of other immune cells (T-cell and macrophage subsets) were also addressed. Expression of the neutrophil marker CD66b was assessed by immunohistochemistry in 448 archival human tumor tissue samples from patients surgically resected for CRC. The infiltration of CD66b-positive cells was semi-quantitatively evaluated along the tumor invasive front, in the tumor center, and within the tumor epithelium (intraepithelial expression). We found that poor infiltration of CD66b-positive cells in the tumor front indicated a worse patient prognosis. The prognostic significance of CD66b infiltration was found to be mainly independent of tumor molecular characteristics and maintained significance in multivariable analysis of stage I-II colon cancers. We further analyzed the prognostic impact of CD66b-positive cells in relation to other immune markers (NOS2, CD163, Tbet, FOXP3, and CD8) and found that neutrophil infiltration, even though strongly correlated to infiltration of other immune cell subsets, had additional prognostic value. In conclusion, we find that low infiltration of neutrophils in the tumor front is an independent prognostic factor for a poorer patient prognosis in early stages of colon cancers. Further studies are needed to elucidate the biological role of neutrophils in colorectal carcinogenesis.

  • 32.
    Wikberg, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Plasma miRNA can detect colorectal cancer, but how early?2018In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 7, no 5, p. 1697-1705Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is a major cause of deaths worldwide but has a good prognosis if detected early. The need for efficient, preferable non‐ or minimally invasive, inexpensive screening tools is therefore critical. We analyzed 12 miRNAs in pre‐ and postdiagnostic plasma samples to evaluate their potential as CRC screening markers. We used a unique study design with two overlapping cohorts, allowing analysis of pre‐ and postdiagnostic samples from 58 patients with CRC and matched healthy controls. Plasma concentrations of miR‐15b, ‐16, ‐18a, ‐19a, 21, ‐22, ‐25, ‐26a, ‐29c, ‐142‐5p, ‐150, and ‐192 were measured by semi‐quantitative real‐time PCR. Concentrations of miR‐18a, ‐21, ‐22, and ‐25 in plasma from patients with CRC were significantly altered compared to healthy controls. Combined as a multimarker panel, they detected CRC with an AUC of 0.93. Furthermore, levels of these three miRNAs also showed different levels in the prediagnostic case samples close to diagnosis. Only miR‐21‐levels were elevated several years before diagnosis. Plasma levels of miR‐18a, ‐21, ‐22, and ‐25 show promise as screening biomarkers for CRC. However, based on our unique analysis of prediagnostic and postdiagnostic samples from the same patients, we conclude that circulating miRNAs elevated at diagnosis may not automatically be suitable for CRC screening, if the increase occurs too close to clinical diagnosis.

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