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TIMP-1 is under reg...
TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells : A potential novel approach to the treatment of metastatic colorectal cancer
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- Tarpgaard, Line S. (author)
- Odense Univ Hosp, Dept Oncol, Odense, Denmark.;Univ Southern Denmark, Odense, Denmark.
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- Orum-Madsen, Maj Sofie (author)
- Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
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- Christensen, Ib J. (author)
- Rigshosp, Finsen Lab, Copenhagen, Denmark.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark.
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- Nordgaard, Cathrine (author)
- Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
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- Noer, Julie (author)
- Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
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- Guren, Tormod K. (author)
- Oslo Univ Hosp Oslo, Dept Oncol, Oslo, Norway.;Oslo Univ Hosp Oslo, KG Jebsen Ctr Colorectal Canc Res, Oslo, Norway.
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- Glimelius, Bengt (author)
- Uppsala universitet,Experimentell och klinisk onkologi,Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden.
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- Sorbye, Halfdan (author)
- Haukeland Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway.
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- Ikdahl, Tone (author)
- Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
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- Kure, Elin H. (author)
- Oslo Univ Hosp, Dept Genet, Oslo, Norway.
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- Tveit, Kjell M. (author)
- Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
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- Nielsen, Hans J. (author)
- Copenhagen Univ Hosp, Dept Surg Gastroenterol, Hvidovre, Denmark.
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- Pfeiffer, Per (author)
- Odense Univ Hosp, Dept Oncol, Odense, Denmark.;Univ Southern Denmark, Odense, Denmark.
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- Brunner, Nils (author)
- Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
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- Moreira, Jose M. A. (author)
- Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
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Odense Univ Hosp, Dept Oncol, Odense, Denmark;Univ Southern Denmark, Odense, Denmark. Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. (creator_code:org_t)
- 2016-08-08
- 2016
- English.
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:37, s. 59441-59457
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https://urn.kb.se/re...
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Abstract
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- It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5-fluorouracil and oxaliplatin) +/- cetuximab (NORDIC VII study). Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels, KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level (> 3rd quartile) showing a significantly longer overall survival if treated with cetuximab (HR, 0.48; 95% CI, 0.25 to 0.93). To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines. We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated cells. The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP-1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- metastatic colorectal cancer
- plasma TIMP-1
- KRAS mutations
- prognosis
- prediction
Publication and Content Type
- ref (subject category)
- art (subject category)
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Tarpgaard, Line ...
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Orum-Madsen, Maj ...
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Christensen, Ib ...
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Nordgaard, Cathr ...
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Noer, Julie
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Guren, Tormod K.
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Glimelius, Bengt
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Sorbye, Halfdan
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Ikdahl, Tone
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Kure, Elin H.
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Tveit, Kjell M.
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Nielsen, Hans J.
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Pfeiffer, Per
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Brunner, Nils
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Moreira, Jose M. ...
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- MEDICAL AND HEALTH SCIENCES
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Oncotarget
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Uppsala University
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Karolinska Institutet