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  • 1.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundberg, Erik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Plasma micro-RNA alterations appear late in pancreatic cancer2018In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 267, no 4, p. 775-781Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. Background: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. Methods: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19–9 (Ca 19–9) levels were measured in all samples for comparison. Results: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19–9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19–9 levels were significantly higher in the cases at <5 years before diagnosis. Conclusion: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease.

  • 2. Frentzas, Sophia
    et al.
    Simoneau, Eve
    Bridgeman, Victoria L.
    Vermeulen, Peter B.
    Foo, Shane
    Kostaras, Eleftherios
    Nathan, Mark R.
    Wotherspoon, Andrew
    Gao, Zu-Hua
    Shi, Yu
    Van den Eynden, Gert
    Daley, Frances
    Peckitt, Clare
    Tan, Xianming
    Salman, Ayat
    Lazaris, Anthoula
    Gazinska, Patrycja
    Berg, Tracy J.
    Eltahir, Zak
    Ritsma, Laila
    van Rheenen, Jacco
    Khashper, Alla
    Brown, Gina
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Laere, Steven
    Loyer, Evelyne
    Dirix, Luc
    Cunningham, David
    Metrakos, Peter
    Reynolds, Andrew R.
    Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases2016In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 22, no 11, p. 1294-1302Article in journal (Refereed)
    Abstract [en]

    The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.

  • 3. Kong, So Yeon
    et al.
    Takeuchi, Masayoshi
    Hyogo, Hideyuki
    McKeown-Eyssen, Gail
    Yamagishi, Sho-Ichi
    Chayama, Kazuaki
    O'Brien, Peter J.
    Ferrari, Pietro
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Bastide, Nadia
    Carbonnel, Franck
    Kuehn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Lagiou, Pagona
    Vasilopoulou, Effie
    Masala, Giovanna
    Pala, Valeria
    De Magistris, Maria Santucci
    Tumino, Rosario
    Naccarati, Alessio
    Bueno-De-Mesquita, H. B.
    Peeters, Petra H.
    Weiderpass, Elisabete
    Quiros, J. Ramon
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Dorronsoro, Miren
    Gavrila, Diana
    Ardanaz, Eva
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Bradbury, Kathryn E.
    Romieu, Isabelle
    Freisling, Heinz
    Stavropoulou, Faidra
    Gunter, Marc J.
    Cross, Amanda J.
    Riboli, Elio
    Jenab, Mazda
    Bruce, W. Robert
    The Association between Glyceraldehyde-Derived Advanced Glycation End-Products and Colorectal Cancer Risk2015In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 12, p. 1855-1863Article in journal (Refereed)
    Abstract [en]

    Background: A large proportion of colorectal cancers are thought to be associated with unhealthy dietary and lifestyle exposures, particularly energy excess, obesity, hyperinsulinemia, and hyperglycemia. It has been suggested that these processes stimulate the production of toxic reactive carbonyls from sugars such as glyceraldehyde. Glyceraldehyde contributes to the production of a group of compounds known as glyceraldehyde-derived advanced glycation end-products (glycer-AGEs), which may promote colorectal cancer through their proinflammatory and pro-oxidative properties. The objective of this study nested within a prospective cohort was to explore the association of circulating glycer-AGEs with risk of colorectal cancer. Methods: A total of 1,055 colorectal cancer cases (colon n = 659; rectal n = 396) were matchced (1: 1) to control subjects. Circulating glycer-AGEs were measured by a competitive ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (95% CI), adjusting for potential confounding factors, including smoking, alcohol, physical activity, body mass index, and diabetes status. Results: Elevated glycer-AGEs levels were not associated with colorectal cancer risk (highest vs. lowest quartile, 1.10; 95% CI, 0.82-1.49). Subgroup analyses showed possible divergence by anatomical subsites (OR for colon cancer, 0.83; 95% CI, 0.571.22; OR for rectal cancer, 1.90; 95% CI, 1.14-3.19; Pheterogeneity = 0.14). Conclusions: In this prospective study, circulating glycer-AGEs were not associated with risk of colon cancer, but showed a positive association with the risk of rectal cancer. Impact: Further research is needed to clarify the role of toxic products of carbohydrate metabolism and energy excess in colorectal cancer development. 

  • 4. Murphy, Neil
    et al.
    Cross, Amanda J.
    Abubakar, Mustapha
    Jenab, Mazda
    Aleksandrova, Krasimira
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Racine, Antoine
    Kuehn, Tilman
    Katzke, Verena A.
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Overvad, Kim
    Ramon Quiros, J.
    Jakszyn, Paula
    Molina-Montes, Esther
    Dorronsoro, Miren
    Huerta, Jose-Maria
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Masala, Giovanna
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Bueno-de-Mesquita, H. Bas
    Siersema, Peter D.
    Peeters, Petra H.
    Ohlsson, Bodil
    Ericson, Ulrika
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Weiderpass, Elisabete
    Skeie, Guri
    Freisling, Heinz
    Kong, So Yeon
    Tsilidis, Kostas
    Muller, David C.
    Riboli, Elio
    Gunter, Marc J.
    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)2016In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 13, no 4, article id e1001988Article in journal (Refereed)
    Abstract [en]

    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.

  • 5. Nimptsch, Katharina
    et al.
    Aleksandrova, Krasimira
    Boeing, Heiner
    Janke, Juergen
    Lee, Young-Ae
    Jenab, Mazda
    Kong, So Yeon
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Bueno-de-Mesquita, H. B(As)
    Siersema, Peter D.
    Jansen, Eugene H. J. M.
    Trichopoulou, Antonia
    Tjonneland, Anne
    Olsen, Anja
    Wu, Chunsen
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Freisling, Heinz
    Katzke, Verena
    Kaaks, Rudolf
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Severi, Gianluca
    Naccarati, Alessio
    Mattiello, Amalia
    Palli, Domenico
    Grioni, Sara
    Tumino, Rosario
    Peeters, Petra H.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Brandstedt, Jenny
    Sanchez, Maria-Jose
    Gurrea, Aurelio Barricarte
    Bonet, Catalina Bonet
    Chirlaque, Maria-Dolores
    Dorronsoro, Miren
    Quiros, Jose Ramon
    Travis, Ruth C.
    Khaw, Kay-Tee
    Wareham, Nick
    Riboli, Elio
    Gunter, Marc J.
    Pischon, Tobias
    Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 4, p. 911-920Article in journal (Refereed)
    Abstract [en]

    Fetuin-A, also referred to as alpha 2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 mg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 mg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development.

  • 6.
    Norgren, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ericzon, Bo Goran
    de Tayrac, Marie
    Genin, Emmanuelle
    Plante-Bordeneuve, Violaine
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gene expression profile in hereditary transthyretin amyloidosis: differences in targeted and source organs2014In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 2, p. 113-119Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin amyloidosis (ATTR) is a genetic disease caused by a point mutation in the TTR gene that causes the liver to produce an unstable TTR protein. The most effective treatment has been liver transplantation in order to replace the variant TTR producing liver with one that produces only wild-type TTR. ATTR amyloidosis patients' livers are reused for liver sick patients, i.e. the Domino procedure. However, recent findings have demonstrated that ATTR amyloidosis can develop in the recipients within 7-8 years. The aim of this study was to elucidate how the genetic profile of the liver is affected by the disease, and how amyloid deposits affect target tissue. Methods: Gene expression analysis was used to unravel the genetic profiles of Swedish ATTR V30M patients and controls. Biopsies from adipose tissue and liver were examined. Results and Conclusions: ATTR amyloid patients' gene expression profile of the main source organ, the liver, differed markedly from that of the controls, whereas the target organs' gene expression profiles were not markedly altered in the ATTR amyloid patients compared to those of the controls. An impaired ER/protein folding pathway might suggest ER overload due to mutated TTR protein.

  • 7.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stromal collagens in colorectal cancer and in colorectal liver metastases: tumour biological implications and a source for novel tumour markers2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality. About 50 % of patients with CRC will develop subsequent liver metastases (CLM). The survival for untreated CLM is only a few months and liver resection provides the only chance for a lasting cure. It is therefore essential to detect CLM early, enabling successful surgical resection and achieving a long-term cure. There are no optimal tumour markers for CRC or CLM. The best marker available is Carcinoembryonic Antigen (CEA), a marker found elevated in about 50-60% of patients with CLM, but also in many other conditions. The main focus of cancer research has been on the malignant cancer cell. However, a tumour consists of more than cancer cells. A major part of all solid tumours is made up by the stroma. The tumour stroma is defined as the non-malignant cells of a tumour such as fibroblasts, the cells of the vascular and immune systems as well as the extracellular matrix (ECM). The basement membrane (BM) is a specialized form of the ECM in which type IV collagen is the major protein component. All epithelial cells need a contact to the BM and the definition of an invasive cancer is the degradation of the BM and the spread of cancer cells beyond this structure. Different metastatic growth patterns of CLM have previously been described, namely the desmoplastic, pushing and replacement type of CLM. These differ in their stromal reaction in the border, which separates the tumour from the normal liver. In this thesis the tumour stroma of CRC and CLM is studied with a special emphasis on stromal collagens. The aim is to investigate whether stromal collagens/ circulating type IV collagen can be used as tumour markers for CRC and CLM, and to compare this to the conventional marker CEA. The circulating type IV collagen level is also measured in liver metastases from other primary tumours than CRC. Furthermore, the differences between the stroma of a primary CRC that metastasizes to the liver when compared to a CRC that never spreads are analysed. Additionally, the metastatic growth pattern of CLM is studied in relation to the primary tumour, stromal components and survival. We also sought out to find whether CRC cell lines possess the trait to produce ECM proteins endogenously, and in response to a normal liver stroma in a novel organotypic model for CLM.

    Methods: Expression patterns of type I, III and IV collagen were studied by immunofluorescence (IF), chemical staining and immunohistochemistry (IHC) in normal colorectal tissue, normal liver, CRC, CLM, benign liver lesions and in liver metastases of other origin than CRC. Circulating plasma levels of type IV collagen were analysed in healthy controls, patients with CRC (T stage I-III) and in patients with CLM. Samples were analysed at the time of diagnosis, during and after oncological and surgical treatment and at the time of relapsing or progressive disease. Additionally, circulating levels were analysed in patients with benign liver lesions and in liver metastases of other origin than CRC. The metastatic growth pattern of CLM was classified according to earlier descriptions. CRC cell lines were studied regarding their production of type IV collagen. The growth, invasiveness and stromal production in CRC cell lines were also investigated in a new organotypic model for CLM using human liver specimens.

    Results: Circulating type IV collagen levels are increased in patients with CLM and other epithelial-derived liver metastases, and is found normal in patients with primary CRC (stage I-III), with liver metastases from tumours of non-epithelial origin, benign liver lesions and in healthy controls. The type IV collagen levels in patients with CLM reflect the tumour burden in the liver, decreases in response to therapy and is found increased in progressive or relapsing disease. The combination of circulating type IV collagen and CEA increased the sensitivity and specificity for detecting CLM. Livermetastatic CRC displayed an increased stromal production when compared to non-metastatic CRC, with an increased type IV collagen expression in the direct vicinity of the CRC cells. The earlier described growth patterns of CLM were verified, with the pushing type of CLM associated with a short survival and poor outcome. Furthermore, CRC cell lines possess the trait of endogenously producing type IV collagen. The novel organotypic liver model revealed that CRC cell lines grown in the context of normal liver stroma, devoid of other cells, does not elicit a desmoplastic reaction.

    Conclusion: Circulating type IV collagen is a promising tumour marker for CLM, where the levels reflect the hepatic tumour burden and can detect disease relapse after liver surgery. The combination of the tumour markers CEA and type IV collagen is superior to CEA alone. The stromal composition of primary CRC predicts the risk of subsequent CLM and the metastatic growth pattern of CLM is related to survival.

  • 8.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björklund, Moa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nygren, Pia
    Department of Diagnosics and Oral Medicine, University of Oulu, Finland.
    Saalo, Tula
    Department of Diagnostics and Oral Medicine, University of Oulu, Finland.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Increased type IV collagen expression is a feature in liver metastases of epithelial origin and related to invasiveness of CRC cells in a novel organotypic liver metastatic modelArticle in journal (Other academic)
  • 9.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Liver-metastatic potential of colorectal cancer is related to the stromal composition of the tumour2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 12, p. 5183-5191Article in journal (Refereed)
    Abstract [en]

    Background: The tumour stroma is an important modulator of cancer cell behaviour. The aim of this study was to compare the stromal composition between primary colorectal cancer (CRC) and colorectal liver metastases (CLM).

    Materials and Methods: The stromal composition in matched tissue sections of CRC and subsequent CLM was analysed, and related to clinical parameters.

    Results: Differences in the expression pattern of type I collagen and type IV collagen in CRC was related to a higher risk of CLM. Two types of CLM the desmoplastic and pushing type were identified. The time between CRC and diagnosis of CLM was shorter (p=0.047) for desmoplastic CLM. The mortality rate was higher for pushing CLM due to frequent extrahepatic disseminated disease. A difference in the overall survival rate between patients with desmoplastic and those with pushing CLM was seen at follow-up of more than 60 months (p=0.046).

    Conclusion: The liver-metastasizing potential is related to the stromal composition of primary CRC. There are distinct growth patterns in CLM with differences in stromal composition and clinical outcome.

  • 10.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hafström, Larsolof
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Type IV collagen as a tumour marker for colorectal liver metastases2011In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 37, no 7, p. 611-617Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: About 50% of patients with primary colorectal cancer (CRC) will develop liver metastases (CLM). Currently, carcinoembryonic antigen (CEA) is the most common tumour marker for CRC and CLM. However, the sensitivity and specificity of this marker is not optimal, as almost 50% of patients have tumours that do not produce CEA. Therefore there is a need for better markers for CRC and CLM.

    METHODS: The circulating levels of type IV collagen were measured in patients with CLM, primary CRC and in healthy controls. The expression pattern of type IV collagen was studied by immunofluorescence in CLM and normal liver tissue. The metastatic volume of CLM in the liver was estimated from CT.

    RESULTS: In CLM tissue type IV collagen is highly expressed in the areas of desmoplasia. Patients with primary CRC (Dukes' A-C) did not show any increase in circulating type IV collagen compared to healthy controls. However, patients with CLM have significantly elevated levels of circulating type IV collagen when compared to patients with primary CRC and healthy controls. The levels of type IV collagen decreased during chemotherapy and increased at the time of disease progression. The circulating levels of type IV collagen seem to reflect the tumour burden in the liver.

    CONCLUSIONS: Type IV collagen has the potential to be used as tumour associated biomarker for CLM. These results indicate the importance of interaction between cancer cells and the stroma in the tumour microenvironment.

  • 11.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björklund, Moa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Improved tumor marker sensitivity by combined type IV collagen and CEA measurement in colorectal liver metastasesArticle in journal (Other academic)
  • 12.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björklund, Moa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Improved tumour marker sensitivity in detecting colorectal liver metastases by combined type IV collagen and CEA measurement2015In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 36, no 12, p. 9839-9847Article in journal (Refereed)
    Abstract [en]

    Carcinoembryonic antigen (CEA) is the best circulating tumour marker for colorectal liver metastasis (CLM) but has suboptimal sensitivity and specificity. Circulating type IV collagen (COLIV) is a new potential CLM marker. Here, COLIV and CEA were measured in patients with resectable CLM. COLIV levels were also related to the type of CLM. The prognostic value of these markers and the type of CLM on survival was evaluated. Preoperative plasma samples (n = 94) from patients (n = 85) with CLM undergoing liver resection were used. Seven patients underwent repeated liver resection. Samples from 118 healthy individuals served as control. Samples after liver resection (n = 27) were analysed and related to recurrence. COLIV and CEA levels were analysed, and the type of CLM was classified using paraffinated tissue. Results were analysed by logistic regression and receiver operating characteristic (ROC) curve analysis. CLM patients had significantly elevated levels of COLIV compared to controls (p = 0.001). The sensitivity of COLIV was not better than CEA, but improved sensitivity for detecting CLM was observed with a combination of the two markers compared to using either marker alone (p = 0.001). Circulating COLIV was elevated in 81 % and CEA in 56 % of CLM patients at diagnosis, and high marker levels were related to poor survival. In follow-up samples (n = 27), patients with CLM recurrence (n = 14) had significantly elevated COLIV levels compared to patients without postoperative recurrence (n = 10) (p = 0.001). COLIV is a promising tumour marker for CLM and can possibly be used to detect postoperative CLM recurrence. The combination of COLIV and CEA is superior to either marker alone in detecting CLM.

  • 13. van Dam, Pieter-Jan
    et al.
    van der Stok, Eric P.
    Teuwen, Laure-Anne
    Van den Eynden, Gert G.
    Illemann, Martin
    Frentzas, Sophia
    Majeed, Ali W.
    Eefsen, Rikke L.
    van den Braak, Robert R. J. Coebergh
    Lazaris, Anthoula
    Fernandez, Maria Celia
    Galjart, Boris
    Laerum, Ole Didrik
    Rayes, Roni
    Grunhagen, Dirk J.
    Van de Paer, Michelle
    Sucaet, Yves
    Mudhar, Hardeep Singh
    Schvimer, Michael
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kockx, Mark
    Bird, Nigel C.
    Vidal-Vanaclocha, Fernando
    Metrakos, Peter
    Simoneau, Eve
    Verhoef, Cornelis
    Dirix, Luc Y.
    Van Laere, Steven
    Gao, Zu-hua
    Brodt, Pnina
    Reynolds, Andrew R.
    Vermeulen, Peter B.
    International consensus guidelines for scoring the histopathological growth patterns of liver metastasis2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 117, no 10, p. 1427-1441Article in journal (Refereed)
    Abstract [en]

    Background: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.

    Methods: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.

    Results: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).

    Conclusions: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

  • 14. Vaniotis, George
    et al.
    Rayes, Roni F.
    Qi, Shu
    Milette, Simon
    Wang, Ni
    Perrino, Stephanie
    Bourdeau, France
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    He, Yi
    Lamarche-Vane, Nathalie
    Brodt, Pnina
    Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis2018In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 28, p. 3790-3805Article in journal (Refereed)
    Abstract [en]

    Liver metastases remain a major cause of death from gastrointestinal tract cancers as well as from other malignancies such as breast and lung carcinomas and melanoma. Understanding the underlying biology is essential for the design of effective targeted therapies. We previously reported that collagen IV α1/α2 overexpression in non-metastatic lung carcinoma (M27colIV) cells increased their metastatic ability, specifically to the liver and documented high collagen IV levels in surgical resections of liver metastases from diverse tumor types. Here, we aimed to elucidate the functional relevance of collagen IV to metastatic outgrowth in the liver. Gene expression profiling revealed in M27colIVcells significant increases in the expression of chemokines CCL5 (5.7-fold) and CCL7 (2.6-fold) relative to wild-type cells, and this was validated by qPCR and western blotting. Similarly, in human colon carcinoma KM12C and KM12SM cells with divergent liver-colonizing potentials, CCL7 and CCL5 production correlated with type IV collagen expression and the metastatic phenotype. CCL7 silencing by short hairpin RNA (shRNA) reduced experimental liver metastasis in both cell types, whereas CCL5 silencing reduced metastasis of M27colIV cells, implicating these cytokines in metastatic expansion in the liver. Subsequent functional analyses implicated both MEK/ERK and PI3K signaling upstream of CCL7 upregulation and identified CCL7 (but not CCL5) as a critical migration/invasion factor, acting via the chemokine receptor CCR3. Chemokine CCL5 was identified as a regulator of the T-cell immune response in the liver. Loss of CCL7 in KM12SM cells was also associated with altered E-cadherin and reduced vimentin and Snail expression, implicating it in epithelial-to-mesenchymal transition in these cells. Moreover, in clinical specimens of colon cancer liver metastases analyzed by immunohistochemistry, CCL5 and CCL7 levels paralleled those of collagen IV. The results identify the chemokines CCL5 and CCL7 as type IV collagen-regulated genes that promote liver metastasis by distinct and complementary mechanisms.

  • 15. Ward, Heather A.
    et al.
    Murphy, Neil
    Weiderpass, Elisabete
    Leitzmann, Michael F.
    Aglago, Elom
    Gunter, Marc J.
    Freisling, Heinz
    Jenab, Mazda
    Boutron-Ruault, Marie-Christine
    Severi, Gianluca
    Carbonnel, Franck
    Kuehn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Merino, Susana
    Zamora-Ros, Raul
    Rodriguez-Barranco, Miguel
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Perez-Cornago, Aurora
    Trichopoulou, Antonia
    Bamia, Christina
    Lagiou, Pagona
    Masala, Giovanna
    Grioni, Sara
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, Bas
    Vermeulen, Roel
    Van Gils, Carla
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Aune, Dagfinn
    Riboli, Elio
    Cross, Amanda J.
    Gallstones and incident colorectal cancer in a large pan-European cohort study2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 6, p. 1510-1516Article in journal (Refereed)
    Abstract [en]

    Gallstones, a common gastrointestinal condition, can lead to several digestive complications and can result in inflammation. Risk factors for gallstones include obesity, diabetes, smoking and physical inactivity, all of which are known risk factors for colorectal cancer (CRC), as is inflammation. However, it is unclear whether gallstones are a risk factor for CRC. We examined the association between history of gallstones and CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a prospective cohort of over half a million participants from ten European countries. History of gallstones was assessed at baseline using a self‐reported questionnaire. The analytic cohort included 334,986 participants; a history of gallstones was reported by 3,917 men and 19,836 women, and incident CRC was diagnosed among 1,832 men and 2,178 women (mean follow‐up: 13.6 years). Hazard ratios (HR) and 95% confidence intervals (CI) for the association between gallstones and CRC were estimated using Cox proportional hazards regression models, stratified by sex, study centre and age at recruitment. The models were adjusted for body mass index, diabetes, alcohol intake and physical activity. A positive, marginally significant association was detected between gallstones and CRC among women in multivariable analyses (HR = 1.14, 95%CI 0.99–1.31, p = 0.077). The relationship between gallstones and CRC among men was inverse but not significant (HR = 0.81, 95%CI 0.63–1.04, p = 0.10). Additional adjustment for details of reproductive history or waist circumference yielded minimal changes to the observed associations. Further research is required to confirm the nature of the association between gallstones and CRC by sex.

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