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Impact of Epithelia...
Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ
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- Strell, Carina (author)
- Karolinska Institutet,Stockholm University,Karolinska Institute,Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden
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- Paulsson, Janna (author)
- Karolinska Institute
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- Jin, Shao-Bo (author)
- Karolinska Institutet,Karolinska Institute
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- Tobin, Nicholas P (author)
- Karolinska Institutet,Karolinska Institute,Lund University
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- Mezheyeuski, Artur (author)
- Uppsala University,Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab,Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden
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- Roswall, Pernilla (author)
- Karolinska Institute
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- Mutgan, Ceren (author)
- Karolinska Institute
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- Mitsios, Nicholas (author)
- Karolinska Institutet,Karolinska Institute
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- Johansson, Hemming (author)
- Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden
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- Wickberg, Sarah Marie (author)
- Karolinska Institute
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- Svedlund, Jessica (author)
- Stockholm University,Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden
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- Nilsson, Mats (author)
- Stockholm University,Stockholms universitet,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylära verktyg,Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Lund University
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- Hall, Per (author)
- Karolinska Institutet,Karolinska Institute
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- Mulder, Jan (author)
- Karolinska Institutet,Karolinska Institute
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- Radisky, Derek C. (author)
- Mayo Clin, Comprehens Canc Ctr, Dept Canc Biol, Jacksonville, FL 32224 USA,Mayo Clinic Florida
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- Pietras, Kristian (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Experimentell onkologi,Forskargrupper vid Lunds universitet,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Experimental oncology,Lund University Research Groups
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- Bergh, Jonas (author)
- Karolinska Institutet,Karolinska Institute
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- Lendahl, Urban (author)
- Karolinska Institutet,Karolinska Institute
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- Wärnberg, Fredrik (author)
- Uppsala University,Uppsala universitet,Endokrinkirurgi
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- Ostman, Arne (author)
- Karolinska Institutet,Karolinska Institute
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(creator_code:org_t)
- 2019-02-28
- 2019
- English.
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:9, s. 983-995
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Abstract
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- Background: A better definition of biomarkers and biological processes related to local recurrence and disease progression is highly warranted for ductal breast carcinoma in situ (DCIS). Stromal-epithelial interactions are likely of major importance for the biological, clinical, and pathological distinctions between high- and low-risk DCIS cases. Methods: Stromal platelet derived growth factor receptor (PDGFR) was immunohistochemically assessed in two DCIS patient cohorts (n = 458 and n = 80). Cox proportional hazards models were used to calculate the hazard ratios of recurrence. The molecular mechanisms regulating stromal PDGFR expression were investigated in experimental in vitro co-culture systems of DCIS cells and fibroblasts and analyzed using immunoblot and quantitative real-time PCR. Knock-out of JAG1 in DCIS cells and NOTCH2 in fibroblasts was obtained through CRISPR/Cas9. Experimental data were validated by mammary fat pad injection of DCIS and DCIS-JAG1 knock-out cells (10 mice per group). All statistical tests were two-sided. Results: PDGFR alpha((low))/PDGFR beta((high)) fibroblasts were associated with increased risk for recurrence in DCIS (univariate hazard ratio = 1.59, 95% confidence interval [CI] = 1.02 to 2.46; P = .04 Wald test; multivariable hazard ratio = 1.78, 95% CI = 1.07 to 2.97; P = .03). Tissue culture and mouse model studies indicated that this fibroblast phenotype is induced by DCIS cells in a cell contact-dependent manner. Epithelial Jagged1 and fibroblast Notch2 were identified through loss-of-function studies as key juxtacrine signaling components driving the formation of the poor prognosis-associated fibroblast phenotype. Conclusions: A PDGFR alpha((low))/PDGFR beta((high)) fibroblast subset was identified as a marker for high-risk DCIS. The Jagged-1/Notch2/PDGFR stroma-epithelial pathway was described as a novel signaling mechanism regulating this poor prognosis-associated fibroblast subset. In general terms, the study highlights epithelial-stromal crosstalk in DCIS and contributes to ongoing efforts to define clinically relevant fibroblast subsets and their etiology.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
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- By the author/editor
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Strell, Carina
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Paulsson, Janna
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Jin, Shao-Bo
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Tobin, Nicholas ...
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Mezheyeuski, Art ...
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Roswall, Pernill ...
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show more...
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Mutgan, Ceren
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Mitsios, Nichola ...
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Johansson, Hemmi ...
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Wickberg, Sarah ...
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Svedlund, Jessic ...
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Nilsson, Mats
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Hall, Per
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Mulder, Jan
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Radisky, Derek C ...
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Pietras, Kristia ...
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Bergh, Jonas
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Lendahl, Urban
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Wärnberg, Fredri ...
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Ostman, Arne
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- MEDICAL AND HEALTH SCIENCES
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and Clinical Medicin ...
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and Basic Medicine
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Uppsala University
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Stockholm University
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Lund University
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Karolinska Institutet