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  • 1. Ge, Rongbin
    et al.
    Wang, Zongwei
    Bechis, Seth K
    Otsetov, Alexander G
    Hua, Shengyu
    Wu, Shulin
    Wu, Chin-Lee
    Tabatabaei, Shahin
    Olumi, Aria F
    DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate.2015In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, no 3Article in journal (Refereed)
    Abstract [en]

    5-α Reductase type 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Inhibition of SRD5A2 by finasteride is used commonly for the management of urinary obstruction caused by benign prostatic hyperplasia. Contrary to common belief, we have found that expression of SRD5A2 is variable and absent in one third of benign adult prostates. In human samples, absent SRD5A2 expression is associated with hypermethylation of the SRD5A2 promoter, and in vitro SRD5A2 promoter activity is suppressed by methylation. We show that methylation of SRD5A2 is regulated by DNA methyltransferase 1, and inflammatory mediators such as tumor necrosis factor α, NF-κB, and IL-6 regulate DNA methyltransferase 1 expression and thereby affect SRD5A2 promoter methylation and gene expression. Furthermore, we show that increasing age in mice and humans is associated with increased methylation of the SRD5A2 promoter and concomitantly decreased protein expression. Artificial induction of inflammation in prostate primary epithelial cells leads to hypermethylation of the SRD5A2 promoter and silencing of SRD5A2, whereas inhibition with tumor necrosis factor α inhibitor reactivates SRD5A2 expression. Therefore, expression of SRD5A2 is not static and ubiquitous in benign adult prostate tissues. Methylation and expression of SRD5A2 may be used as a gene signature to tailor therapies for more effective treatment of prostatic diseases.

  • 2.
    Henriksson, Maria L
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Colorectal Cancer Cells Activate Adjacent Fibroblasts Resulting in FGF1/FGFR3 Signaling and Increased Invasion.2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 3, p. 1387-1394Article in journal (Refereed)
    Abstract [en]

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

  • 3.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pietras, Kristian
    Jones, Jonathan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Granfors, Torvald
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy2010In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 177, no 2, p. 1031-1041Article in journal (Refereed)
    Abstract [en]

    Mast cells affect growth in various human tumors, but their role in prostate cancer (PC) is unclear. Here, we identify mast cells as independent prognostic markers in PC using a large cohort of untreated PC patients with a long follow-up. By analyzing mast cells in different tissue compartments, our data indicate that intratumoral and peritumoral mast cells have anti- opposed to protumor properties. Intratumoral mast cells negatively regulate angiogenesis and tumor growth, whereas peritumoral mast cells stimulate the expansion of human prostate tumors. We also observed mast cell recruitment particularly to the peritumoral compartment in men during the formation of castrate-resistant prostate tumors. In our ortothopic rat model, mast cells accumulated in the peritumoral tissue where they enhanced angiogenesis and tumor growth. In line with this, prostate mast cells expressed high levels of the angiogenic factor FGF-2. Similar to the situation in men, mast cells infiltrated rat prostate tumors that relapsed after initially effective castration treatment, concurrent with a second wave of angiogenesis and an up-regulation of FGF-2. We conclude that mast cells are novel independent prognostic markers in PC and affect tumor progression in animals and patients. In addition, peritumoral mast cells provide FGF-2 to the tumor micro environment, which may contribute to their stimulating effect on angiogenesis.

  • 4.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adamo, Hani
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Granfors, Torvald
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Laurent, Anna Engström
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, no 4, p. 1961-1968Article in journal (Refereed)
    Abstract [en]

    Our objective was to investigate whether the presence of a tumor increases hyaluronan (HA) levels in surrounding prostate tissues and whether this extratumoral HA influences tumor growth and outcome. From a series of 287 men diagnosed with prostate cancer at transurethral resection and followed up with watchful waiting, tissue microarrays were constructed, stained, and scored for HA. A high HA staining score in the tumor stroma or in nonmalignant prostate tissue stroma were both associated positively with higher Gleason score and larger tumor volume, and was associated with a poor outcome. HA staining score was not an independent marker for outcome (multivariate Cox, with Gleason score, tumor volume, stage, and HA variables). In an orthotopic rat prostate cancer model, hyaluronic acid synthase-1 mRNA levels and HA staining were increased in normal prostate tissue surrounding prostate cancer. Orthotopic prostate cancer growth was increased by intraprostatic injection of HA. In conclusion, cancer in the prostate apparently stimulates HA synthesis both in tumor stroma and in the surrounding normal tissue. This promoted tumor growth and was associated with an unfavorable outcome.

  • 5. Kalkunte, Satyan S.
    et al.
    Neubeck, Stefan
    Norris, Wendy E.
    Cheng, Shi-Bin
    Kostadinov, Stefan
    Vu Hoang, Dang
    Ahmed, Aftab
    von Eggeling, Ferdinand
    Shaikh, Zahir
    Padbury, James
    Berg, Goran
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Markert, Udo R.
    Sharma, Surendra
    Transthyretin is dysregulated in preeclampsia, and its native form prevents the onset of disease in a preclinical mouse model2013In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 183, no 5, p. 1425-1436Article in journal (Refereed)
    Abstract [en]

    Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinol, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.

  • 6.
    Li, Jinan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Annelii
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Leonardsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nandakumar, Kutty Selva
    Holmdahl, Rikard
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis.2005In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 166, no 3, p. 783-792Article in journal (Refereed)
    Abstract [en]

    The plasminogen activator (PA) system has been proposed to have important roles in rheumatoid arthritis. Here we have used the autoimmune collagen type II (CII)-induced arthritis (CIA) model and mice deficient for urokinase-type PA (uPA) or plasminogen to investigate the role of the PA system for development of arthritis. Our data revealed that uPA-deficient mice have a lower severity and incidence of CIA than wild-type mice. Furthermore, although >80% of wild-type control mice developed CIA, we found that none of the 50 plasminogen-deficient littermates that were tested developed CIA within a 40-day period. Antibody generation after CII immunization as well as the binding of labeled anti-CII antibodies to the surface of cartilage were similar in wild-type and plasminogen-deficient mice. No sign of inflammation was seen when plasminogen-deficient mice were injected with a mixture of monoclonal antibodies against CII. However, after daily injections of human plasminogen, these mice developed arthritis within 5 days. Our finding that infiltration of inflammatory cells into the synovial joints was impaired in plasminogen-deficient mice suggests that uPA and plasminogen are important mediators of joint inflammation. Active plasmin is therefore essential for the induction of pathological inflammatory joint destruction in CIA.

  • 7.
    Sulniute, Rima
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lindh, Tomas
    Umeå University, Faculty of Medicine, Department of Odontology, Prosthetic Dentistry. Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wilczynska, Malgorzata
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Li, Jinan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasmin is essential in preventing periodontitis in mice2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, no 2, p. 819-828Article in journal (Refereed)
    Abstract [en]

    Periodontitis involves bacterial infection, inflammation of the periodontium, degradation of gum tissue, and alveolar bone resorption, which eventually leads to loss of teeth. To study the role of the broad-spectrum protease plasmin in periodontitis, we examined the oral health of plasminogen (Plg)-deficient mice. In wild-type mice, the periodontium was unaffected at all time points studied; in Plg-deficient mice, periodontitis progressed rapidly, within 20 weeks. Morphological study results of Plg-deficient mice revealed detachment of gingival tissue, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. IHC staining showed massive infiltration of neutrophils in the periodontal tissues. Interestingly, doubly deficient mice, lacking both tissue- and urokinase-type plasminogen activators, developed periodontal disease similar to that in Pig-deficient mice; however, mice lacking only tissue- or urokinase-type plasminogen activator remained healthy. Supplementation by injection of Pig-deficient mice with human plasminogen for 10 days led to necrotic tissue absorption, inflammation subsidence, and full regeneration of gum tissues. Notably, there was also partial regrowth of degraded alveolar bone. Taken together, our results show that plasminogen is essential for the maintenance of a healthy periodontium and plays an important role in combating the spontaneous development of chronic periodontitis. Moreover, reversal to healthy status after supplementation of Pig-deficient mice with plasminogen suggests the possibility of using plasminogen for therapy of periodontal diseases. (Am J Pathol 2011, 179:819-828; DOI: 10.1016/j.ajpath.2011.05.003)

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