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Cell Rep. 2018 Dec 26;25(13):3721-3732.e6. doi: 10.1016/j.celrep.2018.11.093.

Mutations in an Innate Immunity Pathway Are Associated with Poor Overall Survival Outcomes and Hypoxic Signaling in Cancer.

Author information

1
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA. Electronic address: molcina@stanford.edu.
2
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA.
3
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
4
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
6
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA. Electronic address: giaccia@stanford.edu.

Abstract

Complement-mediated cytotoxicity may act as a selective pressure for tumor overexpression of complement regulators. We hypothesize that the same selective pressure could lead to complement alterations at the genetic level. We find that, when analyzed as a pathway, mutations in complement genes occur at a relatively high frequency and are associated with changes in overall survival across a number of cancer types. Analysis of pathways expressed in patients with complement mutations that are associated with poor overall survival reveals crosstalk between complement and hypoxia in colorectal cancer. The importance of this crosstalk is highlighted by two key findings: hypoxic signaling is increased in tumors harboring complement mutations, and hypoxic tumor cells are resistant to complement-mediated cytotoxicity due, in part, to hypoxia-induced expression of complement regulator CD55. The range of strategies employed by tumors to dysregulate the complement system testifies to the importance of this pathway in tumor progression.

KEYWORDS:

cancer; complement system; complement-mediated cytotoxicity; hypoxia; innate immunity; mutations

PMID:
30590044
DOI:
10.1016/j.celrep.2018.11.093
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