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Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models

Devarajan, Raman (författare)
Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland
Izzi, Valerio (författare)
Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Finnish Cancer Research Institute, Helsinki, Finland
Peltoketo, Hellevi (författare)
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland
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Rask, Gunilla (författare)
Umeå universitet,Patologi
Kauppila, Saila (författare)
Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland; Northern Finland Laboratory Centre, NordLab, Oulu, Finland
Väisänen, Marja-Riitta (författare)
Department of Pathology, Kainuu Central Hospital, Kajaani, Finland
Ruotsalainen, Heli (författare)
Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Martínez-Nieto, Guillermo (författare)
Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Karppinen, Sanna-Maria (författare)
Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Väisänen, Timo (författare)
Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland
Kaur, Inderjeet (författare)
Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Koivunen, Jussi (författare)
Department of Medical Oncology and Radiotherapy and Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
Sasaki, Takako (författare)
Department of Pharmacology, Faculty of Medicine, Oita University, Oita, Japan
Winqvist, Robert (författare)
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit; Biocenter Oulu, University of Oulu, Oulu, Finland; Northern Finland Laboratory Centre, NordLab, Oulu, Finland
Manninen, Aki (författare)
Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Wärnberg, Fredrik (författare)
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Sund, Malin (författare)
Umeå universitet,Institutionen för kirurgisk och perioperativ vetenskap,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Pihlajaniemi, Taina (författare)
Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Heljasvaara, Ritva (författare)
Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
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 (creator_code:org_t)
American Society for Clinical Investigation, 2023
2023
Engelska.
Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 133:18
Relaterad länk:
https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and α6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.

Ämnesord

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)

Nyckelord

Breast cancer
Collagens
Growth factors
Oncology

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