Christina Hägglöf

Umeå University, Umeå, Västerbotten, Sweden

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Publications (10)34.82 Total impact

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    ABSTRACT: To elucidate if the density of inflammatory cells expressing S100A9 in malignant and surrounding non-malignant prostate tissues is a prognostic marker for outcome in prostate cancer patients. Tissue was obtained from 358 men diagnosed with prostate cancer at transurethral resection of the prostate due to obstructive voiding problems, of which 260 were then followed with watchful waiting. Tissue microarrays of both malignant and non-malignant tissues were stained with an antibody against S100A9. The number of stained inflammatory cells was scored and related to clinical outcome and histopathological parameters of known prognostic value. A high number of inflammatory cells expressing S100A9 in both malignant and surrounding non-malignant tissues were associated with significantly shorter cancer-specific survival. This association remained significant when Gleason score and local tumour stage were analysed together with S100A9 in a Cox regression model. Low number of S100A9 positive cells in non-malignant stroma was correlated to significantly longer cancer-specific survival also in patients with Gleason score 8-10 tumours. S100A9 positive cells in tumour stroma were correlated with Gleason score, hyaluronan, platelet-derived growth factor receptor beta (PDGFR-β), and androgen receptor (inverse correlation) in tumour stroma. S100A9 positive cells in non-malignant stroma correlated with androgen receptor in this tissue compartment (inverse correlation). A high number of S100A9 positive inflammatory cells in tumour stroma and in non-malignant stroma were associated with shorter cancer-specific survival in prostate cancer patients.
    European journal of cancer (Oxford, England: 1990) 04/2014; · 4.12 Impact Factor
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    ABSTRACT: Purpose To elucidate if the density of inflammatory cells expressing S100A9 in malignant and surrounding non-malignant prostate tissues is a prognostic marker for outcome in prostate cancer patients. Experimental design Tissue was obtained from 358 men diagnosed with prostate cancer at transurethral resection of the prostate due to obstructive voiding problems, of which 260 were then followed with watchful waiting. Tissue microarrays of both malignant and non-malignant tissues were stained with an antibody against S100A9. The number of stained inflammatory cells was scored and related to clinical outcome and histopathological parameters of known prognostic value. Results A high number of inflammatory cells expressing S100A9 in both malignant and surrounding non-malignant tissues were associated with significantly shorter cancer-specific survival. This association remained significant when Gleason score and local tumour stage were analysed together with S100A9 in a Cox regression model. Low number of S100A9 positive cells in non-malignant stroma was correlated to significantly longer cancer-specific survival also in patients with Gleason score 8–10 tumours. S100A9 positive cells in tumour stroma were correlated with Gleason score, hyaluronan, platelet-derived growth factor receptor beta (PDGFR-β), and androgen receptor (inverse correlation) in tumour stroma. S100A9 positive cells in non-malignant stroma correlated with androgen receptor in this tissue compartment (inverse correlation). Conclusions A high number of S100A9 positive inflammatory cells in tumour stroma and in non-malignant stroma were associated with shorter cancer-specific survival in prostate cancer patients.
    European Journal of Cancer. 01/2014;
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    ABSTRACT: The TMPRSS2-ERG gene fusion is found in approximately half of all prostate cancers. The functional and prognostic significance of TMPRSS2-ERG is, however, not fully understood. Based on a historical watchful waiting cohort, an association between TMPRSS2-ERG, evaluated as positive immune staining, and shorter survival of prostate cancer patients was identified. Expression of ERG was also associated with clinical markers such as advanced tumor stage, high Gleason score, presence of metastasis and prognostic tumor cell markers such as high Ki67, pEGFR and pAkt. Novel associations between TMPRSS2-ERG and alterations in the tumor stroma, for example, increased vascular density, hyaluronan and PDGFRβ and decreased Caveolin-1, all known to be associated with an aggressive disease, were found. The present study suggests that the TMPRSS2-ERG fusion gene is associated with a more aggressive prostate cancer phenotype, supported by changes in the tumor stroma.
    PLoS ONE 01/2014; 9(2):e86824. · 3.53 Impact Factor
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    ABSTRACT: PDGF receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAFs). Elevated expression of PDGF receptors on stromal CAFs are associated with metastasis and poor prognosis, but mechanism(s) that underlie this these connections are not understood. Here report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of co-cultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis.
    Cancer Research 12/2012; · 9.28 Impact Factor
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    Christina Hägglöf, Anders Bergh
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    ABSTRACT: Prostate cancer is a very common and highly unpredictable form of cancer. Whereas many prostate cancers are slow growing and could be left without treatment, others are very aggressive. Additionally, today there is no curative treatment for prostate cancer patients with local or distant metastasis. Identification of new, improved prognostic and diagnostic biomarkers for prostate cancer and the finding of better treatment strategies for metastatic prostate cancer is therefore highly warranted. Interactions between epithelium and stroma are known to be important already during prostate development and this interplay is critical also in development, progression of primary tumors and growth of metastases. It is therefore reasonable to expect that future biomarkers and therapeutic targets can be identified in the prostate tumor and metastasis stroma and this possibility should be further explored.
    Cancers. 01/2012; 4(2):531-48.
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    ABSTRACT: Diagnostic tissue biomarkers for prostate cancer (PC) include basal cell markers and α-methylacyl-coenzyme A-racemase (AMACR), often used in combination. Their sensitivity and specificity are not perfect and there is a need for additional diagnostic biomarkers for PC in cases that are difficult to diagnose on routine stained sections. This study investigated the diagnostic accuracy of three novel tissue biomarkers for PC found through a search in the Human Protein Atlas database ( www.proteinatlas.com ): somatic cytochrome c (CYCS), intestinal cell kinase (ICK) and inhibitor of nuclear factor-κB kinase subunit beta (IKBKB), and compared the results with AMACR. A tissue microarray was constructed from 40 consecutive radical prostatectomy (RP) specimens including benign prostatic tissue, atrophy, high-grade prostatic intraepithelial neoplasia (HGPIN) and PC. Immunoreactivity was scored based on staining intensity and extent. Real-time polymerase chain reaction (PCR) was performed on malignant and benign frozen tissue samples from 32 RP specimens. All four biomarkers showed a stronger expression in PC and HGPIN than in benign tissue (p < 0.001). The highest diagnostic accuracy for PC was achieved with ICK and AMACR at 97%. The area under the curve for CYCS, ICK, IKBKB and AMACR was 0.859, 0.997, 0.865 and 0.983, respectively. The presence of mRNA transcripts of the genes was confirmed by real-time PCR in benign and malignant prostatic tissue. AMACR is an accurate diagnostic tissue marker for PC. However, in some PCs AMACR is false negative and a panel of CYCS, ICK and IKBKB may serve as ancillary diagnostic tool.
    Scandinavian Journal of Urology and Nephrology 11/2010; 45(1):60-7. · 1.01 Impact Factor
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    Martin Augsten, Christina Hägglöf, Cristina Peña, Arne Ostman
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    ABSTRACT: Experimental studies and analyses of clinical material have convincingly demonstrated that tumor formation and progression occurs through a concerted action of malignant cells and the surrounding microenvironment of the tumor stroma. The tumor microenvironment is comprised of various cell types like fibroblasts, immune cells, vascular cells and bone-marrow-derived cells embedded in the extracellular matrix. This review, focusing on recent findings in the context of gastrointestinal tumors, introduces the different stromal cell types and delineates their contributions to cancer initiation, growth and metastasis. By selected examples we also present how the tumor microenvironment is emerging as a promising target for therapeutic intervention.
    Cancer Microenvironment 01/2010; 3(1):167-76.
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    ABSTRACT: The identification of new prognostic markers for prostate cancer is highly warranted, since it is difficult to identify patients requiring curative treatment. Data from both experimental models and clinical samples have identified important functions of PDGFRbeta on pericytes and fibroblasts in the tumor stroma. In this study the prognostic significance of PDGFRbeta in prostate cancer stroma, and in matched non-malignant tissue, was evaluated with immunohistochemistry. PDGFRbeta expression was analyzed in normal and tumor stroma from more than 300 prostate cancer patients. High PDGFRbeta expression in tumor stroma was associated with large tumor size, advanced stage, high Gleason score and high vessel density. Perivascular PDGFRbeta staining in tumors was also correlated with high Gleason score. Correlations were also observed between PDGFRbeta status in tumor stroma and non-malignant stroma. Similarly, high PDGFRbeta expression in adjacent non-malignant tissue stroma correlated with large tumor size, advanced stage, high Gleason score and proliferation in non-malignant epithelium. Interestingly, high levels of PDGFRbeta in the stroma of tumor and non-malignant tissue were associated with shorter cancer specific survival in prostate cancer patients. The study revealed a number of novel associations between stromal PDGFRbeta expression in prostate tumors and several important clinical characteristics, including survival.
    PLoS ONE 01/2010; 5(5):e10747. · 3.53 Impact Factor
  • PLoS ONE 01/2010; 5(5). · 3.53 Impact Factor
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    ABSTRACT: This study explored the role of secreted fibroblast-derived factors in prostate cancer growth. Analyses of matched normal and tumor tissue revealed up-regulation of CXCL14 in cancer-associated fibroblasts of a majority of prostate cancer. Fibroblasts over-expressing CXCL14 promoted the growth of prostate cancer xenografts, and increased tumor angiogenesis and macrophage infiltration. Mechanistic studies demonstrated that autocrine CXCL14-stimulation of fibroblasts stimulate migration and ERK-dependent proliferation of fibroblasts. CXCL14-stimulation of monocyte migration was also demonstrated. Furthermore, CXCL14-producing fibroblasts, but not recombinant CXCL14, enhanced in vitro proliferation and migration of prostate cancer cells and in vivo angiogenesis. These studies thus identify CXCL14 as a novel autocrine stimulator of fibroblast growth and migration, with multi-modal tumor-stimulatory activities. In more general terms, our findings suggest autocrine stimulation of fibroblasts as a previously unrecognized mechanism for chemokine-mediated stimulation of tumor growth, and suggest a novel mechanism whereby cancer-associated fibroblasts achieve their pro-tumorigenic phenotype.
    Proceedings of the National Academy of Sciences 03/2009; 106(9):3414-9. · 9.81 Impact Factor

Publication Stats

129 Citations
34.82 Total Impact Points

Institutions

  • 2012–2014
    • Umeå University
      • Department of Medical Biosciences
      Umeå, Västerbotten, Sweden
    • Hospital Universitario Puerta de Hierro-Majadahonda
      Madrid, Spain
  • 2009–2010
    • Karolinska Institutet
      • Institutionen för onkologi-patologi
      Solna, Stockholm, Sweden