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

Monica M Olcina; Nikolas G Balanis; Ryan K Kim; B Arman Aksoy; Julia Kodysh; Michael J Thompson; Jeff Hammerbacher; Thomas G Graeber; Amato J Giaccia

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

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

Authors

Monica M Olcina¹, Nikolas G Balanis², Ryan K Kim³, B Arman Aksoy⁴, Julia Kodysh⁴, Michael J Thompson⁵, Jeff Hammerbacher⁴, Thomas G Graeber², Amato J Giaccia⁶

Affiliations

¹ Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Antigens, Neoplasm / metabolism
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / immunology*
Colorectal Neoplasms / pathology
Complement System Proteins / genetics
Cytotoxicity, Immunologic / genetics
HCT116 Cells
Humans
Immunity, Innate / genetics*
Male
Mice
Mutation / genetics*
Signal Transduction*
Survival Analysis
Tumor Hypoxia / genetics*

Substances

Antigens, Neoplasm
Complement System Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding