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  • br The outcome of Notch activation

    2020-08-28


    The outcome of Notch3 activation in breast cancer is in fine balance with at least three other major pathways: The Hedgehog, WNT/β-Catenin, and AKT pathways. We observed that COMP expression leads to the activation of β-Catenin and that Notch inhibition leads to even higher levels of active β-Catenin [47]. The activated intracellular domain of Notch was reported to facilitate the interaction of β-Catenin and Numb leading the protein complex to lysosomal degradation. [48]. We Aldosterone additionally detected crosstalk between COMP and AKT inde-pendently from PTEN activity, and in the previous reports both PTEN-dependent and -independent AKT cross-talk with the Notch pathway have been reported [49,50]. Correspondingly, AKT activation and phos-phorylation are inhibited in the presence of COMP. This observation is in line with our published data that COMP-expressing breast and prostate cancer Aldosterone survive better when exposed to different inducers of apoptosis through interference with calcium homeo-stasis [25,26]. We can infer that AKT is deactivated upon COMP expression in response to another calcium-dependent molecular mechanism of survival that is enhanced (Fig. 7). 
    In conclusion, this study describes a novel molecular mechanism by which COMP affects breast cancer development. The key observation is that COMP enhances the cancer stem cell population in breast tumors by facilitating a Notch3-Jagged1 interaction. COMP also affects other pathways involved in cell stemness, notably WNT/β-Catenin and AKT. The crosstalk between these pathways suggests a com-plex regulatory mechanism for the generation and control of cancer stem cells. This mode of Notch regulation in relation to cancer stem cells may inspire new strategies to modulate Notch signaling for therapeutic purposes.
    Acknowledgments
    We would like to thank Dr. Wouter van Overbeke and Dr. Steven Reid for their contribution in the collection of mouse tissues. Also, we thank prof. Åke Oldberg for kindly providing the COMP knock out mice.
    Funding
    This work was supported by grants to AB from the Cancerfonden, the Swedish Government Funds for Clinical research (ALF), the King Gustav V's 80th anniversary Foundation, and a grant from the Malmö Hospital Cancer Fundation, to KSP from Royal Physiographic Society. KP is the Göran and Birgitta Grosskopf-professor at Lund University and is supported by grants from the Cancerfonden, the Swedish Research Council, ALF, BioCARE, Biltema foundation, ISREC foundation, and Lund University. UL is supported by Cancerfonden.
    Author contributions
    KSP performed experiments, analyzed data, pre-pared figures and contributed to writing the manuscript. MB, CR, CG performed experiments and analyzed data. SBJ, UL contributed with material and methods and writing the manuscript. KP designed the animal experiments and contributed to writing the manuscript. AB designed, supervised the study and wrote the manuscript.
    Declaration of interests
    UL holds research grants from Merck AG and AstraZeneca; no personal remuneration. The rest of the authors declare no potential conflicts of interest.
    120 COMP leads to activation of Notch3
    Keywords:
    COMP;
    Notch3; β-Catenin;
    Cancer stem cells
    References
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    [16] K.E. Happonen, T. Saxne, A. Aspberg, M. Morgelin, D. Heinegard, A.M. Blom, Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis, Arthritis Rheum. 62 (12) (2010) 3574–3583.
    H. Mulder, A. Bjartell, A.M. Blom, Cartilage oligomeric matrix protein promotes prostate cancer progression by enhancing invasion and disrupting intracellular calcium homeostasis, Oncotarget 8 (58) (2017) 98298–98311.
    COMP leads to activation of Notch3 121
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    British Journal of Oral and Maxillofacial Surgery xxx (2019) xxx–xxx
    Case-mix adjustment in audit of length of hospital stay in patients operated on for cancer of the head and neck
    b Dept. of Informatics, King’s College London, London
    Abstract
    Patients treated surgically for squamous cell carcinoma (SCC) of the head and neck form a heterogeneous group, and embryo is difficult to take this variation into account when measuring the quality of care. We have tested the feasibility of mathematical models that allow for the adjustment for case mix when auditing the length of hospital stay as a proxy indicator of the quality of care. We completed a case-note audit of 733 surgical episodes of care for SCC of the head and neck in five cancer networks, and used logistic regression and decision tree analysis to adjust for case mix using pertinent preoperative variables. Risk adjustment models of length of stay included age, alcohol, T classification, performance status, tracheostomy, high-risk status, and complexity of operation. The risk-adjusted length of stay differed significantly between the cancer networks studied (p < 0.001). The models performed acceptably for the purpose of audit when this was under 15 days. Length of stay is a measurable outcome that can be used as a benchmark of surgical care. Audits of this after operations for cancer of the head and neck, if reported in national clinical audits, should take case mix into account.