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Lundin, Christina
Publications (10 of 15) Show all publications
Holsti, M., Wanhainen, A., Lundin, C., Björck, M., Tegler, G., Svensson, J. & Sund, M. (2018). Circulating Vascular Basement Membrane Fragments are Associated with the Diameter of the Abdominal Aorta and Their Expression Pattern is Altered in AAA Tissue. European Journal of Vascular and Endovascular Surgery, 56(1), 110-118
Open this publication in new window or tab >>Circulating Vascular Basement Membrane Fragments are Associated with the Diameter of the Abdominal Aorta and Their Expression Pattern is Altered in AAA Tissue
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2018 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 56, no 1, p. 110-118Article in journal (Refereed) Published
Abstract [en]

Objective: Abdominal aortic aneurysm (AAA) is characterised by enhanced proteolytic activity, and extracellular matrix (ECM) remodelling in the vascular wall. Type IV and XVIII collagen/endostatin are structural proteins in vascular basement membrane (VBM), a specialised ECM structure. Here the association between plasma levels of these collagens with the aortic diameter and expansion rate is studied, and their expression in aortic tissue characterised. Methods: This was a retrospective population based cohort study. Type IV and XVIII collagen/endostatin were analysed in plasma by ELISA assay in 615 men, divided into three groups based on the aortic diameter: 1) normal aorta <= 25 mm, 2) sub-aneurysmal aorta (SAA) 26-29 mm, and 3) AAA >= 30 mm. Follow up data were available for 159 men. The association between collagen levels and aortic diameter at baseline, and with the expansion rate at follow up were analysed in ordinal logistic regression and linear regression models, controlling for common confounding factors. Tissue expression of the collagens was analysed in normal aorta (n = 6) and AAA (n = 6) by immunofluorescence. Results: Plasma levels of type XVIII collagen/endostatin (136 ng/mL [SD 29] in individuals with a normal aorta diameter, 154 ng/ml [SD 45] in SAA, and 162 ng/ml [SD 46] in AAA; p = .001) and type IV collagen (105 ng/mL [SD 42] normal aorta, 124 ng/ml [SD 46] SAA, and 127 ng/ml [SD 47] AAA; p = .037) were associated with a larger aortic diameter. A significant association was found between the baseline levels of type XVIII/endostatin and the aortic expansion rate (p = .035), but in the multivariable model, only the initial aortic diameter remained significantly associated with expansion (p = .005). Altered expression patterns of both collagens were observed in AAA tissue. Conclusion: Plasma levels of circulating type IV and XVIII collagen/endostatin increase with AAA diameter. The expression pattern of VBM proteins is altered in the aneurysm wall.

Place, publisher, year, edition, pages
Saunders Elsevier, 2018
Keywords
Abdominal aortic aneurysm, Collagen, Basement membrane, Extracellular matrix, Circulation
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-152282 (URN)10.1016/j.ejvs.2018.03.002 (DOI)000444270700019 ()29656960 (PubMedID)
Funder
Västerbotten County Council, VLL-582791Västerbotten County Council, VLL-680121Västerbotten County Council, VLL-764621Swedish Research Council, K2013-64X-2040607-3Swedish Heart Lung Foundation, 2012-0353
Available from: 2018-10-01 Created: 2018-10-01 Last updated: 2019-02-18Bibliographically approved
Franklin, O., Jonsson, P., Billing, O., Lundberg, E., Öhlund, D., Nyström, H., . . . Sund, M. (2018). Plasma micro-RNA alterations appear late in pancreatic cancer. Annals of Surgery, 267(4), 775-781
Open this publication in new window or tab >>Plasma micro-RNA alterations appear late in pancreatic cancer
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2018 (English)In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 267, no 4, p. 775-781Article in journal (Refereed) Published
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.

Keywords
blood samples, early detection, micro-RNA, miRNA, pancreatic cancer
National Category
Clinical Laboratory Medicine Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-127998 (URN)10.1097/SLA.0000000000002124 (DOI)000435846900046 ()28425921 (PubMedID)2-s2.0-85044257717 (Scopus ID)
Note

Originally included in thesis in manuscript form.

Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2018-09-27Bibliographically approved
Franklin, O., Öhlund, D., Lundin, C., Öman, M., Naredi, P., Wang, W. & Sund, M. (2015). Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma. Cancer Biomarkers, 15(1), 1-10
Open this publication in new window or tab >>Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma
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2015 (English)In: Cancer Biomarkers, ISSN 1574-0153, Vol. 15, no 1, p. 1-10Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. OBJECTIVE: To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort.

METHODS: Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls.

RESULTS: The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre-nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival.

CONCLUSIONS: PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology.

Place, publisher, year, edition, pages
IOS Press, 2015
Keywords
Pancreatic ductal adenocarcinoma (PDAC), tumour markers, stroma, type IV collagen, type XVIII llagen, endostatin, osteopontin, tenascin C, TPS, Ca 125, Ca 19-9, CEA
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-97877 (URN)10.3233/CBM-140430 (DOI)000346079800001 ()
Available from: 2015-01-16 Created: 2015-01-08 Last updated: 2018-06-07Bibliographically approved
Palm-Espling, M., Lundin, C., Björn, E., Naredi, P. & Wittung-Stafshede, P. (2014). Interaction between anticancer drug Cisplatin and copper chaperone Atox1 in human melanoma cells. Protein peptide letters, 21(1), 63-68
Open this publication in new window or tab >>Interaction between anticancer drug Cisplatin and copper chaperone Atox1 in human melanoma cells
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2014 (English)In: Protein peptide letters, ISSN 0929-8665, E-ISSN 1875-5305, Vol. 21, no 1, p. 63-68Article in journal (Refereed) Published
Abstract [en]

Cisplatin (CisPt) is one of the most common anticancer drugs used against many severe forms of cancers. However, treatment with this drug causes many side effects and often, it results in the development of cell resistance. A majority of side effects as well as cell resistance are thought to develop due to CisPt interactions with proteins prior to reaching the nucleus and the DNA target. The copper (Cu) transport proteins Ctr1 and ATP7A/B have been implicated in cellular resistance of CisPt, possibly exporting the drug out of the cell. Recent in vitro work demonstrated that CisPt also interacts with the cytoplasmic Cu-chaperone Atox1, binding in or near the Cu-binding site, without expulsion of bound Cu. Whereas Ctr1 and ATP7B interactions with CisPt have been shown in vivo or ex vivo, there is no such information for Atox1-CisPt interactions. To address this, we developed a method to probe if CisPt interacts with Atox1 in human melanoma cells. Atox1-specific antibodies were linked to magnetic beads and used to immune-precipitate Atox1 from melanoma cells that had been pre-exposed to CisPt. Analysis of extracted Atox1 with inductively coupled plasma mass spectrometry demonstrated the presence of Pt in the protein fraction. Thus, CisPt-exposed human melanoma cells contain Atox1 molecules that bind some derivative of CisPt. This study gives the first indication for the intracellular presence of Atox1-CisPt complexes ex vivo.

Keywords
Copper-chaperone, Cisplatin, Atox1, anticancer, resistance
National Category
Biochemistry and Molecular Biology
Research subject
biological chemistry
Identifiers
urn:nbn:se:umu:diva-80714 (URN)10.2174/09298665113209990036 (DOI)000329022400011 ()
Available from: 2013-09-24 Created: 2013-09-24 Last updated: 2018-06-08Bibliographically approved
Öhlund, D., Franklin, O., Lundberg, E., Lundin, C. & Sund, M. (2013). Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop. BMC Cancer, 13, Article ID 154.
Open this publication in new window or tab >>Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop
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2013 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, article id 154Article in journal (Refereed) Published
Abstract [en]

Background: Pancreatic cancer shows a highly aggressive and infiltrative growth pattern and is characterized by an abundant tumor stroma known to interact with the cancer cells, and to influence tumor growth and drug resistance. Cancer cells actively take part in the production of extracellular matrix proteins, which then become deposited into the tumor stroma. Type IV collagen, an important component of the basement membrane, is highly expressed by pancreatic cancer cells both in vivo and in vitro. In this study, the cellular effects of type IV collagen produced by the cancer cells were characterized.

Methods: The expression of type IV collagen and its integrin receptors were examined in vivo in human pancreatic cancer tissue. The cellular effects of type IV collagen were studied in pancreatic cancer cell lines by reducing type IV collagen expression through RNA interference and by functional receptor blocking of integrins and their binding-sites on the type IV collagen molecule.

Results: We show that type IV collagen is expressed close to the cancer cells in vivo, forming basement membrane like structures on the cancer cell surface that colocalize with the integrin receptors. Furthermore, the interaction between type IV collagen produced by the cancer cell, and integrins on the surface of the cancer cells, are important for continuous cancer cell growth, maintenance of a migratory phenotype, and for avoiding apoptosis.

Conclusion: We show that type IV collagen provides essential cell survival signals to the pancreatic cancer cells through an autocrine loop.

Keywords
Type IV collagen, Pancreatic cancer, Basement membrane, Integrin receptors, Autocrine loop
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-71100 (URN)10.1186/1471-2407-13-154 (DOI)000317397700001 ()
Available from: 2013-06-12 Created: 2013-05-20 Last updated: 2018-06-08Bibliographically approved
Palm, M. E., Weise, C. F., Lundin, C., Wingsle, G., Nygren, Y., Björn, E., . . . Wittung-Stafshede, P. (2011). Cisplatin binds human copper chaperone Atox1 and promotes unfolding in vitro. Proceedings of the National Academy of Sciences of the United States of America, 108(17), 6951-6956
Open this publication in new window or tab >>Cisplatin binds human copper chaperone Atox1 and promotes unfolding in vitro
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2011 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 17, p. 6951-6956Article in journal (Refereed) Published
Abstract [en]

Cisplatin (cisPt), Pt(NH(3))(2)Cl(2), is a cancer drug believed to kill cells via DNA binding and damage. Recent work has implied that the cellular copper (Cu) transport machinery may be involved in cisPt cell export and drug resistance. Normally, the Cu chaperone Atox1 binds Cu(I) via two cysteines and delivers the metal to metal-binding domains of ATP7B; the ATP7B domains then transfer the metal to the Golgi lumen for loading on cuproenzymes. Here, we use spectroscopic methods to test if cisPt interacts with purified Atox1 in solution in vitro. We find that cisPt binds to Atox1's metal-binding site regardless of the presence of Cu or not: When Cu is bound to Atox1, the near-UV circular dichroism signals indicate Cu-Pt interactions. From NMR data, it is evident that cisPt binds to the folded protein. CisPt-bound Atox1 is however not stable over time and the protein begins to unfold and aggregate. The reaction rates are limited by slow cisPt dechlorination. CisPt-induced unfolding of Atox1 is specific because this effect was not observed for two unrelated proteins that also bind cisPt. Our study demonstrates that Atox1 is a candidate for cisPt drug resistance: By binding to Atox1 in the cytoplasm, cisPt transport to DNA may be blocked. In agreement with this model, cell line studies demonstrate a correlation between Atox1 expression levels, and cisplatin resistance.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-43722 (URN)10.1073/pnas.1012899108 (DOI)21482801 (PubMedID)
Available from: 2011-05-09 Created: 2011-05-09 Last updated: 2018-06-08Bibliographically approved
Ramazani, M., Lundin, C. & Sund, M. (2011). Increased circulating levels of basement-membrane components in patients with abdominal aortic aneurysms: A Pilot Study. European Journal of Vascular and Endovascular Surgery, 42(4), 484-487
Open this publication in new window or tab >>Increased circulating levels of basement-membrane components in patients with abdominal aortic aneurysms: A Pilot Study
2011 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 42, no 4, p. 484-487Article in journal (Refereed) Published
Abstract [en]

Aim: The decision for abdominal aortic aneurysm (AM) repair is based on aneurysm size. However, smaller aneurysms can rupture, while larger ones can remain stable. New variables and markers are needed to better select patients at high rupture risk. The study was done to analyse if AAA patients have increased levels of circulating basement-membrane (BM) fragments.

Design: Circulating levels of BM components type IV and XVIII collagen were measured by enzyme-linked immunosorbent assay (ELISA) in 10 patients with AAA, nine patients with peripheral artery disease (PAD) and 10 healthy controls (CON).

Results: AAA patients had significantly increased levels of type IV and XVIII collagen compared with CON (134.0 +/- 24.8 ng ml(-1) vs. 104.5 +/- 16.4 ng ml(-1); p = 0.005 and 149.0 +/- 56.9 ng ml(-1) vs. 59.6 +/- 8.7 ng ml(-1); p < 0.001, respectively). The PAD patients did not have significantly increased levels of these fragments when compared with CON. In addition, the AAA patients had significantly increased level of type XVIII collagen (149.0 +/- 56.9 ng ml(-1) vs. 58.3 +/- 25.4 ng/ml(-1); p < 0.01) when compared with the PAD group.

Conclusion: Based on this preliminary analysis of a small number of subjects, patients with AAA had significantly increased levels of circulating BM components. BM fragments should be studied further to establish their potential role as biomarkers for AAA.

Place, publisher, year, edition, pages
London: Grune & Stratton, 2011
Keywords
Aortic aneurysm, Collagen, Biomarker, Basement membrane
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-49567 (URN)10.1016/j.ejvs.2011.05.021 (DOI)000296042600016 ()
Available from: 2011-11-22 Created: 2011-11-14 Last updated: 2019-02-18Bibliographically approved
Tran, M. Q., Nygren, Y., Lundin, C., Naredi, P. & Björn, E. (2010). Evaluation of cell lysis methods for platinum metallomic studies of human malignant cells. Analytical Biochemistry, 396(1), 76-82
Open this publication in new window or tab >>Evaluation of cell lysis methods for platinum metallomic studies of human malignant cells
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2010 (English)In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 396, no 1, p. 76-82Article in journal (Refereed) Published
Abstract [en]

Three cell lysis methods-freeze-thaw, osmosis, and a chemical detergent-based method-were evaluated as sample treatment procedures for platinum metallomic studies of in vitro grown human malignant cells exposed to cisplatin. The lysis methods are relatively mild, resemble those commonly used in proteomic studies, and were selected because of the proven reactivity of platinum drug metabolites and indications that platinum in exposed cells and plasma is mainly associated with proteins. The chemical method gave an absolute lysis efficiency of greater than 80%, whereas the freeze-thaw and osmosis methods gave approximately 30% lower efficiency. The within- and between-batch lysis reproducibilities were, for all methods, better than 20 and 24% relative standard deviations, respectively. Total platinum concentration normalized to lysate protein content was statistically the same for all lysis methods. Reagents in the chemical lysis buffer did, however, react with platinum analyte compounds, making this method unsuitable for analysis of reactive compounds or for metallome profiling encompassing analytes with unknown reactivity. Of the lysis methods evaluated here, osmosis gave the highest cisplatin recovery, likely because this protocol is chemically inert and can be carried out at a constant low temperature. Therefore, it is the recommended cell lysis method for the determination of reactive and unknown intracellular platinum compounds.

Place, publisher, year, edition, pages
Elsevier, 2010
Keywords
Cell lysis, Sample preparation, Human malignant cells, Metallomics, Platinum, Cisplatin
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-29753 (URN)10.1016/j.ab.2009.08.044 (DOI)000272406100011 ()19733145 (PubMedID)
Available from: 2009-11-23 Created: 2009-11-23 Last updated: 2018-06-08Bibliographically approved
Öhlund, D., Lundin, C., Ardnor, B., Öman, M., Naredi, P. & Sund, M. (2009). Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer. British Journal of Cancer, 101(1), 91-97
Open this publication in new window or tab >>Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer
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2009 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, no 1, p. 91-97Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Pancreas cancer is a dreaded disease with high mortality, despite progress in surgical and oncological treatments in recent years. The field is hampered by a lack of good prognostic and predictive tumour biomarkers to be used during follow-up of patients.

METHODS: The circulating level of type IV collagen was measured by ELISA in pancreas cancer patients and controls. The expression pattern of type IV collagen in normal pancreas, pancreas cancer tissue and in pancreas cancer cell lines was studied by immunofluorescence and Western blot techniques.

RESULTS: Patients with pancreas cancer have significantly increased circulating levels of type IV collagen. In pancreas cancer tissue high levels of type IV collagen expression was found in close proximity to cancer cells in the tumour stroma. Furthermore, pancreas cancer cells were found to produce and secrete type IV collagen in vitro, which in part can explain the high type IV collagen expression observed in pancreas cancer tissue, and the increased circulating levels in pancreas cancer patients. Of clinical importance, our results show that the circulating level of type IV collagen after surgery is strongly related to prognosis in patients treated for pancreas cancer by pancreatico-duodenectomy with curative intent. Persisting high levels of circulating type IV collagen after surgery indicates a quick relapse in disease and poor survival.

CONCLUSION: Our results most importantly show that stroma related substances can be evaluated as potential cancer biomarkers, and thereby underline the importance of the tumour microenvironment also in this context.

Keywords
extracellular matrix, basement membrane, surgery, circulation, biomarker, pancreas
Identifiers
urn:nbn:se:umu:diva-33778 (URN)10.1038/sj.bjc.6605107 (DOI)19491897 (PubMedID)
Available from: 2010-05-06 Created: 2010-05-06 Last updated: 2018-06-08Bibliographically approved
Holsti, M., Wanhainen, A., Lundin, C., Svensson, J., Björck, M. & Sund, M.Association of inflammatory cytokines to vascular wall remodelling and the aortic diameter.
Open this publication in new window or tab >>Association of inflammatory cytokines to vascular wall remodelling and the aortic diameter
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(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-156522 (URN)
Available from: 2019-02-18 Created: 2019-02-18 Last updated: 2019-02-19
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