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Publications (10 of 19) Show all publications
Borgmästars, E., Jacobson, S., Simm, M., Johansson, M., Billing, O., Lundin, C., . . . Sund, M. (2024). Metabolomics for early pancreatic cancer detection in plasma samples from a Swedish prospective population-based biobank. Journal of Gastrointestinal Oncology, 15(2), 755-767
Open this publication in new window or tab >>Metabolomics for early pancreatic cancer detection in plasma samples from a Swedish prospective population-based biobank
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2024 (English)In: Journal of Gastrointestinal Oncology, ISSN 2078-6891, E-ISSN 2219-679X, Vol. 15, no 2, p. 755-767Article in journal (Refereed) Published
Abstract [en]

Background: Pancreatic ductal adenocarcinoma (pancreatic cancer) is often detected at late stages resulting in poor overall survival. To improve survival, more patients need to be diagnosed early when curative surgery is feasible. We aimed to identify circulating metabolites that could be used as early pancreatic cancer biomarkers.

Methods: We performed metabolomics by liquid and gas chromatography-mass spectrometry in plasma samples from 82 future pancreatic cancer patients and 82 matched healthy controls within the Northern Sweden Health and Disease Study (NSHDS). Logistic regression was used to assess univariate associations between metabolites and pancreatic cancer risk. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to design a metabolite-based risk score. We used receiver operating characteristic (ROC) analyses to assess the discriminative performance of the metabolite-based risk score.

Results: Among twelve risk-associated metabolites with a nominal P value <0.05, we defined a risk score of three metabolites [indoleacetate, 3-hydroxydecanoate (10:0-OH), and retention index (RI): 2,745.4] using LASSO. A logistic regression model containing these three metabolites, age, sex, body mass index (BMI), smoking status, sample date, fasting status, and carbohydrate antigen 19-9 (CA 19-9) yielded an internal area under curve (AUC) of 0.784 [95% confidence interval (CI): 0.714–0.854] compared to 0.681 (95% CI: 0.597–0.764) for a model without these metabolites (P value =0.007). Seventeen metabolites were significantly associated with pancreatic cancer survival [false discovery rate (FDR) <0.1].

Conclusions: Indoleacetate, 3-hydroxydecanoate (10:0-OH), and RI: 2,745.4 were identified as the top candidate biomarkers for early detection. However, continued efforts are warranted to determine the usefulness of these metabolites as early pancreatic cancer biomarkers.

Place, publisher, year, edition, pages
AME Publishing Company, 2024
Keywords
biomarkers, hyperglycemia, Pancreatic neoplasms, risk, survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-224962 (URN)10.21037/jgo-23-930 (DOI)2-s2.0-85192826642 (Scopus ID)
Funder
Umeå UniversitySwedish Cancer Society, 19 0273Swedish Cancer Society, 2017-557Swedish Cancer Society, CAN 2017/332Swedish Cancer Society, CAN 2017/827Swedish Research Council, 2019-01690Swedish Research Council, 2016-02990Swedish Research Council, 2017-01531Region Västerbotten, RV-583411Region Västerbotten, RV-549731Region Västerbotten, RV-841551Region Västerbotten, RV-930167Region Västerbotten, VLL-643451
Available from: 2024-05-27 Created: 2024-05-27 Last updated: 2024-05-27Bibliographically approved
Borgmästars, E., Ulfenborg, B., Johansson, M., Jonsson, P., Billing, O., Franklin, O., . . . Sund, M. (2024). Multi-omics profiling to identify early plasma biomarkers in pre-diagnostic pancreatic ductal adenocarcinoma: a nested case-control study. Translational Oncology, 48, Article ID 102059.
Open this publication in new window or tab >>Multi-omics profiling to identify early plasma biomarkers in pre-diagnostic pancreatic ductal adenocarcinoma: a nested case-control study
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2024 (English)In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 48, article id 102059Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor survival. Novel biomarkers are urgently needed to improve the outcome through early detection. Here, we aimed to discover novel biomarkers for early PDAC detection using multi-omics profiling in pre-diagnostic plasma samples biobanked after routine health examinations.

A nested case-control study within the Northern Sweden Health and Disease Study was designed. Pre-diagnostic plasma samples from 37 future PDAC patients collected within 2.3 years before diagnosis and 37 matched healthy controls were included. We analyzed metabolites using liquid chromatography mass spectrometry and gas chromatography mass spectrometry, microRNAs by HTG edgeseq, proteins by multiplex proximity extension assays, as well as three clinical biomarkers using milliplex technology. Supervised and unsupervised multi-omics integration were performed as well as univariate analyses for the different omics types and clinical biomarkers. Multiple hypothesis testing was corrected using Benjamini-Hochberg's method and a false discovery rate (FDR) below 0.1 was considered statistically significant.

Carbohydrate antigen (CA) 19-9 was associated with PDAC risk (OR [95 % CI] = 3.09 [1.31–7.29], FDR = 0.03) and increased closer to PDAC diagnosis. Supervised multi-omics models resulted in poor discrimination between future PDAC cases and healthy controls with obtained accuracies between 0.429–0.500. No single metabolite, microRNA, or protein was differentially altered (FDR < 0.1) between future PDAC cases and healthy controls.

CA 19-9 levels increase up to two years prior to PDAC diagnosis but extensive multi-omics analysis including metabolomics, microRNAomics and proteomics in this cohort did not identify novel early biomarkers for PDAC.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Metabolomics, miRNomics, Pancreatic neoplasms, Proteomics, Risk
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-228011 (URN)10.1016/j.tranon.2024.102059 (DOI)39018772 (PubMedID)2-s2.0-85198543877 (Scopus ID)
Funder
Swedish Research Council, 2016-02990Swedish Research Council, 2019-01690Swedish Cancer Society, CAN 2016/643Swedish Cancer Society, 19 0273Region Västerbotten, RV-583411Region Västerbotten, RV-549731Region Västerbotten, RV-583411Region Västerbotten, RV-841551Region Västerbotten, RV 967602Sjöberg FoundationStiftelsen Seth M. Kempes Minnes StipendiefondThe Royal Swedish Academy of Sciences, LM2021-0010The Royal Swedish Academy of Sciences, LM2023-0012Swedish Society of Medicine, SLS-960379Cancerforskningsfonden i Norrland, LP 23-2337Bengt Ihres Foundation, SLS-960529Bengt Ihres Foundation, SLS-986656
Available from: 2024-07-22 Created: 2024-07-22 Last updated: 2024-07-22Bibliographically approved
Jansson, M., Lindberg, J., Rask, G., Svensson, J., Billing, O., Nazemroaya, A., . . . Sund, M. (2024). Stromal type I collagen in breast cancer: correlation to prognostic biomarkers and prediction of chemotherapy response. Clinical Breast Cancer
Open this publication in new window or tab >>Stromal type I collagen in breast cancer: correlation to prognostic biomarkers and prediction of chemotherapy response
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2024 (English)In: Clinical Breast Cancer, ISSN 1526-8209, E-ISSN 1938-0666Article in journal (Refereed) In press
Abstract [en]

Introduction: Fibrillar collagens accumulate in the breast cancer stroma and appear as poorly defined spiculated masses in mammography imaging. The prognostic value of tissue type I collagen remains elusive in treatment-naïve and chemotherapy-treated breast cancer patients. Here, type I collagen mRNA and protein expression were analysed in 2 large independent breast cancer cohorts. Levels were related to clinicopathological parameters, prognostic biomarkers, and outcome.

Method: COL1A1 mRNA expression was analysed in 2509 patients with breast cancer obtained from the cBioPortal database. Type I collagen protein expression was studied by immunohistochemistry in 1395 women diagnosed with early invasive breast cancer.

Results: Low COL1A1 mRNA and protein levels correlated with poor prognosis features, such as hormone receptor negativity, high histological grade, triple-negative subtype, node positivity, and tumour size. In unadjusted analysis, high stromal type I collagen protein expression was associated with improved overall survival (OS) (HR = 0.78, 95% CI = 0.61-0.99, p = .043) and trended towards improved breast cancer–specific survival (BCSS) (HR = 0.65, 95% CI = 0.42-1.01, P = 0.053), although these findings were lost after adjustment for other clinical variables. In unadjusted analysis, high expression of type I collagen was associated with better OS (HR = 0.70, 95% CI = 0.55-0.90, P = .006) and BCSS (HR = 0.55, 95% CI = 0.34-0.88, P = .014) among patients not receiving chemotherapy. Strikingly, the opposite was observed among patients receiving chemotherapy. There, high expression of type I collagen was instead associated with worse OS (HR = 1.83, 95% CI = 0.65-5.14, P = .25) and BCSS (HR = 1.72, 95% CI = 0.54-5.50, P = .357).

Conclusion: Low stromal type I collagen mRNA and protein expression are associated with unfavourable tumour characteristics in breast cancer. Stromal type I collagen might predict chemotherapy response.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Breast cancer, Chemotherapy response, Extracellular matrix, Tumour microenvironment, Type I collagen
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-223260 (URN)10.1016/j.clbc.2024.02.015 (DOI)38485557 (PubMedID)2-s2.0-85187983725 (Scopus ID)
Funder
The Breast Cancer FoundationRegion Västerbotten, RV-866131Region Västerbotten, RV-932421Region Västerbotten, RV-764621Visare Norr, VISARENORR931408Visare Norr, VISARENORR750491Percy Falks stiftelse för forskning beträffande prostatacancer och bröstcancer
Available from: 2024-04-18 Created: 2024-04-18 Last updated: 2024-04-18
Jansson, M., Lindberg, J., Rask, G., Svensson, J., Billing, O., Nazemroaya, A., . . . Sund, M. (2022). Prognostic Value of Stromal Type IV Collagen Expression in Small Invasive Breast Cancers. Frontiers in Molecular Biosciences, 9, Article ID 904526.
Open this publication in new window or tab >>Prognostic Value of Stromal Type IV Collagen Expression in Small Invasive Breast Cancers
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2022 (English)In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 9, article id 904526Article in journal (Refereed) Published
Abstract [en]

Breast cancer is the most common cause of cancer death among women worldwide. Localized breast cancer can be cured by surgery and adjuvant therapy, but mortality remains high for tumors that metastasize early. Type IV collagen is a basement membrane protein, and breach of this extracellular matrix structure is the first step of cancer invasion. Type IV collagen is found in the stroma of many cancers, but its role in tumor biology is unclear. Here, expression of type IV collagen in the stroma of small breast cancers was analyzed, correlated to clinically used prognostic biomarkers and patient survival. The findings were further validated in an independent gene expression data cohort. Tissue samples from 1,379 women with in situ and small invasive breast cancers (≤15 mm) diagnosed in 1986-2004 were included. Primary tumor tissue was collected into tissue microarrays. Type IV collagen expression in tissues was visualized using immunohistochemistry. Gene expression data was extracted from the Cancer Genome Atlas database. Out of 1,379 women, 856 had an invasive breast cancer and type IV collagen staining was available for 714 patients. In Kaplan-Meier analysis high type IV collagen expression was significantly associated (p = 0.026) with poorer breast cancer specific survival. There was no correlation of type IV collagen expression to clinically used prognostic biomarkers. High type IV collagen expression was clearly associated to distant metastasis (p = 0.002). In an external validation cohort (n = 1,104), high type IV collagen mRNA expression was significantly (p = 0.041) associated with poorer overall survival, with overexpression of type IV collagen mRNA in metastatic tissue. Stromal type IV collagen expression in the primary tumor correlates to poor breast cancer specific survival most likely due to a higher risk of developing distant metastasis. This ECM protein may function as biomarker to predict the risk of future metastatic disease in patients with breast cancers.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
breast cancer, extracellular matrix, tumor microenvironment, tumor progression, type IV collagen
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-200221 (URN)10.3389/fmolb.2022.904526 (DOI)000807868300001 ()35693557 (PubMedID)2-s2.0-85131874326 (Scopus ID)
Funder
Region Västerbotten, 93242Region Västerbotten, 866131Region Västerbotten, 764621Visare Norr, 931408Visare Norr, 750491The Breast Cancer Foundation
Available from: 2022-10-12 Created: 2022-10-12 Last updated: 2023-09-26Bibliographically approved
Raj, D., Billing, O., Podraza-Farhanieh, A., Kraish, B., Hemmingsson, O., Kao, G. & Naredi, P. (2021). Alternative redox forms of ASNA-1 separate insulin signaling from tail-anchored protein targeting and cisplatin resistance in C. elegans. Scientific Reports, 11(1), Article ID 8678.
Open this publication in new window or tab >>Alternative redox forms of ASNA-1 separate insulin signaling from tail-anchored protein targeting and cisplatin resistance in C. elegans
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 8678Article in journal (Refereed) Published
Abstract [en]

Cisplatin is a frontline cancer therapeutic, but intrinsic or acquired resistance is common. We previously showed that cisplatin sensitivity can be achieved by inactivation of ASNA-1/TRC40 in mammalian cancer cells and in Caenorhabditis elegans. ASNA-1 has two more conserved functions: in promoting tail-anchored protein (TAP) targeting to the endoplasmic reticulum membrane and in promoting insulin secretion. However, the relation between its different functions has remained unknown. Here, we show that ASNA-1 exists in two redox states that promote TAP-targeting and insulin secretion separately. The reduced state is the one required for cisplatin resistance: an ASNA-1 point mutant, in which the protein preferentially was found in the oxidized state, was sensitive to cisplatin and defective for TAP targeting but had no insulin secretion defect. The same was true for mutants in wrb-1, which we identify as the C. elegans homolog of WRB, the ASNA1/TRC40 receptor. Finally, we uncover a previously unknown action of cisplatin induced reactive oxygen species: cisplatin induced ROS drives ASNA-1 into the oxidized form, and selectively prevents an ASNA-1-dependent TAP substrate from reaching the endoplasmic reticulum. Our work suggests that ASNA-1 acts as a redox-sensitive target for cisplatin cytotoxicity and that cisplatin resistance is likely mediated by ASNA-1-dependent TAP substrates. Treatments that promote an oxidizing tumor environment should be explored as possible means to combat cisplatin resistance.

Place, publisher, year, edition, pages
Springer, 2021
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-182496 (URN)10.1038/s41598-021-88085-y (DOI)000644202000020 ()33883621 (PubMedID)2-s2.0-85104701525 (Scopus ID)
Available from: 2021-04-23 Created: 2021-04-23 Last updated: 2023-09-05Bibliographically approved
Jacobson, S., Dahlqvist, P., Johansson, M., Svensson, J., Billing, O., Sund, M. & Franklin, O. (2021). Hyperglycemia as a risk factor in pancreatic cancer: A nested case-control study using prediagnostic blood glucose levels. Pancreatology (Print), 21(6), 1112-1118
Open this publication in new window or tab >>Hyperglycemia as a risk factor in pancreatic cancer: A nested case-control study using prediagnostic blood glucose levels
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2021 (English)In: Pancreatology (Print), ISSN 1424-3903, E-ISSN 1424-3911, Vol. 21, no 6, p. 1112-1118Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To determine the risk association between fasting glucose levels and pancreatic cancer using systematically collected prediagnostic blood glucose samples.

METHODS: Prospective nested case-control study of participants from the Northern Sweden Health and Disease Study, including 182 cases that developed pancreatic cancer and four matched controls per case. Blood glucose levels collected up to 24 years before pancreatic cancer diagnosis were analyzed. The association between fasting glucose levels and pancreatic cancer risk was determined using unconditional and conditional logistic regression models. The association between fasting glucose and the time to pancreatic cancer diagnosis, tumor stage and survival was determined using likelihood-ratio test, t-test and log rank test.

RESULTS: The unadjusted risk of developing pancreatic cancer increased with increasing fasting glucose levels (OR 1.30, 95% CI 1.05-1.60, P = .015). Impaired fasting glucose (≥6.1 mmol/L) was associated with an adjusted risk of 1.77 for developing pancreatic cancer (95% CI 1.05-2.99, P = .032). In subgroup analysis, fasting glucose levels were associated with an increased risk in never-smokers (OR 4.02, 95% CI 1.26-12.77, P = .018) and non-diabetics (OR 3.08, 95% CI 1.08-8.79, P = .035) (non-significant for interaction). The ratio between fasting glucose and BMI was higher among future pancreatic cancer patients and an increased ratio was associated with elevated risk of pancreatic cancer (OR 1.66, 95% CI 1.04-2.66, P = .034). Fasting glucose levels were not associated with TNM stage at diagnosis or survival.

CONCLUSIONS: High fasting glucose is associated with an increased risk of being diagnosed with pancreatic cancer.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Early detection, Fasting glucose, Pancreatic ductal adenocarcinoma, Risk analysis
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-184041 (URN)10.1016/j.pan.2021.05.008 (DOI)000727779500013 ()34049822 (PubMedID)2-s2.0-85106561109 (Scopus ID)
Funder
Swedish Cancer Society, 19027Swedish Cancer Society, 2016-643Swedish Research Council, 2016-02990Swedish Research Council, 2019-01690
Available from: 2021-06-08 Created: 2021-06-08 Last updated: 2023-09-26Bibliographically approved
Herdenberg, C., Mutie, P., Billing, O., Abdullah, A., Strawbridge, R. J., Dahlman, I., . . . Hedman, H. (2021). LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes. Communications Biology, 4(1), Article ID 90.
Open this publication in new window or tab >>LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes
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2021 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 90Article in journal (Refereed) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-beta) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease. Herdenberg et al. show that adipogenesis and BMP signaling are altered in mouse cells deficient in LRIG (Leucine-rich repeats and immunoglobulin-like domains) proteins. They find that mutant LRIG/sma-10 variant worms exhibit lipid storage defects and that human LRIG1 variants are associated with higher body mass index, yet protect against type 2 diabetes. This study suggests an evolutionarily conserved role of LRIG proteins for lipid metabolism and BMP signaling.

Place, publisher, year, edition, pages
Springer Nature, 2021
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-180823 (URN)10.1038/s42003-020-01613-w (DOI)000613509200014 ()33469151 (PubMedID)2-s2.0-85099541477 (Scopus ID)
Available from: 2021-02-26 Created: 2021-02-26 Last updated: 2024-07-02Bibliographically approved
Billing, O., Holmgren, Y., Nosek, D., Hedman, H. & Hemmingsson, O. (2021). LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance. Oncogene, 40, 3707-3718
Open this publication in new window or tab >>LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance
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2021 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 40, p. 3707-3718Article in journal (Refereed) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma.

Place, publisher, year, edition, pages
Springer Nature, 2021
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-182828 (URN)10.1038/s41388-021-01808-3 (DOI)000647099200001 ()33947959 (PubMedID)2-s2.0-85105305447 (Scopus ID)
Available from: 2021-05-06 Created: 2021-05-06 Last updated: 2024-04-18Bibliographically approved
Jansson, M., Billing, O., Herdenberg, C., Lundin, C., Tolockiene, E., Nazemroaya, A. & Sund, M. (2020). Expression and Circulating Levels of Perlecan in Breast Cancer: Implications for Oestrogen Dependent Stromal Remodeling. Journal of mammary gland biology and neoplasia, 25, 69-77
Open this publication in new window or tab >>Expression and Circulating Levels of Perlecan in Breast Cancer: Implications for Oestrogen Dependent Stromal Remodeling
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2020 (English)In: Journal of mammary gland biology and neoplasia, ISSN 1083-3021, E-ISSN 1573-7039, Vol. 25, p. 69-77Article in journal (Refereed) Published
Abstract [en]

Localised breast cancer can be cured by surgery and adjuvant treatments, but mortality remains high as some tumours metastasize early. Perlecan is a basement membrane (BM) protein involved in tumour development and progression. Here, mRNA and protein expression of perlecan, and mRNA expression of matrix degrading enzymes were studied in normal breast and invasive breast cancer, and correlated to prognostic risk factors, in particular oestrogen status. Moreover, plasma levels of perlecan were measured in patients with breast cancer and compared with controls. mRNA data was extracted from the Cancer Genome Atlas database. Perlecan protein expression was visualized using immunofluorescence and plasma levels measured by ELISA assay. Perlecan mRNA levels were twice as high in normal breast compared with breast cancer tissue. A strong correlation was found between mRNA expression of perlecan and several matrix-degrading enzymes in oestrogen receptor positive (ER+) tumours. Perlecan protein was localized to both epithelial and vascular BMs, but absent in the stroma in normal breast. In breast cancer, the expression of perlecan in epithelial BM was fragmented or completely lost, with a marked upregulation of perlecan expression in the stroma. Significantly higher levels of perlecan were found in plasma of ER+ patients when compared with ER- patients. This study shows that perlecan expression and degradation in breast cancer may be linked to the ER status of the tumour.

Keywords
Perlecan, HSPG2, Breast cancer, Oestrogen receptor, extracellular matrix, Matrix metalloproteinases
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-169048 (URN)10.1007/s10911-020-09447-2 (DOI)000517718100001 ()32124140 (PubMedID)2-s2.0-85081637971 (Scopus ID)
Available from: 2020-03-19 Created: 2020-03-19 Last updated: 2024-07-02Bibliographically approved
Franklin, O., Billing, O., Öhlund, D., Berglund, A., Herdenberg, C., Wang, W., . . . Sund, M. (2019). Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer. Journal of Pathology, 5(2), 130-141
Open this publication in new window or tab >>Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer
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2019 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed) Published
Abstract [en]

The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
CD44, biomarkers, hyaluronan, osteopontin, pancreatic cancer, type IV collagen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-154564 (URN)10.1002/cjp2.122 (DOI)000465218700006 ()30456933 (PubMedID)2-s2.0-85064472279 (Scopus ID)
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2024-07-02Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5824-6263

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