Original ResearchFull Report: Basic and Translational—Alimentary TractNeutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer
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Human Samples
For expression analyses, freshly frozen resected human CRC tissue was obtained from the Northwestern University-Robert H. Lurie Comprehensive Cancer Center Pathology Core Facility with approval by and in accordance with Northwestern University institutional review board protocol. For histological analyses of genomic instability (GI) features, colon cancer tissue arrays CO992a (43 cases/99 cores) and CO962 (48 cases/96 cores) were used (US Biomax Inc, Rockville, MD). For immunofluorescence
Tumor-Infiltrating PMNs Exert Functional Dualism to Temporally Suppress or Promote Tumor Development
PMNs cause genotoxicity in colon epithelium by promoting DSB accumulation, leading to GI.6,8 Because GI is a hallmark of cancer,9 we performed correlative and quantitative analyses of PMN frequency and abundance of key GI markers, micronuclei (MNs), and lagging chromosomes,10 in sporadic CRC. Phenotypic scoring of 70 CRC biopsies (Bio-Matrix tissue microarray) from grades 1 to 3 revealed that formation of MNs and lagging chromosomes was mutually correlated across CRC tissues, and that both GI
Discussion
Distinct PMN populations can mediate anti- and pro-tumorigenic activities1,2; however, we demonstrate for the first time that the anti- or pro-tumorigenic outcomes may respectively arise from the immediate cytotoxic impact of PMNs and the PMN-driven long-term cellular reprogramming in cancer cells. Our findings reconcile seemingly opposing roles of PMNs in cancer and support the idea of potential temporal differences in PMN responses in tumorigenesis. Indeed, PMN presence in low-grade CRC has
Acknowledgments
The authors thank the Northwestern University Center for Advanced Microscopy core (supported by National Cancer Institute CCSG P30 CA060553 awarded to the Lurie Comprehensive Cancer Center) for helping with the imaging experiments, and Lurie Cancer Center Pathology Core Facility for helping with obtaining and processing of CRC tissue.
CRediT Authorship Contributions
Triet M. Bui, BS (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Investigation: Lead; Methodology: Lead; Writing –
References (25)
- et al.
53BP1: pro choice in DNA repair
Trends Cell Biol
(2014) - et al.
DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities
Mol Cell
(2014) - et al.
5-Fluorouracil mediated anti-cancer activity in colon cancer cells is through the induction of adenomatous polyposis coli: implication of the long-patch base excision repair pathway
DNA Repair (Amst)
(2014) - et al.
NICE guidance on olaparib for maintenance treatment of patients with relapsed, platinum-sensitive, BRCA mutation-positive ovarian cancer
Lancet Oncol
(2016) - et al.
Neutrophil diversity and plasticity in tumour progression and therapy
Nat Rev Cancer
(2020) - et al.
Neutrophils in cancer: neutral no more
Nat Rev Cancer
(2016) - et al.
Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer
Br J Cancer
(2011) - et al.
Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients' adverse prognosis
PLoS One
(2012) - et al.
High levels of tumor-associated neutrophils are associated with improved overall survival in patients with stage II colorectal cancer
PLoS One
(2017) - et al.
Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing
J Clin Invest
(2019)
Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis
Nat Rev Mol Cell Biol
Progressing from recurring tissue injury to genomic instability: a new mechanism of neutrophil pathogenesis
DNA Cell Biol
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Conflict of interest The authors disclose no conflicts.
Funding This work was supported by grants from the Digestive Health Foundation, American Cancer Society Research Scholar Award, and Crohn’s & Colitis Foundation Senior Research Award to Ronen Sumagin, and the Department of Defense’s Congressionally Directed Medical Research Program Horizon Award to Triet M. Bui. Lisa Wiesmüller was supported by the German Research Foundation (DFG) Grant Project B3 in Research Training Group GRK 2254 “Heterogeneity and evolution in solid tumors (HEIST).”
Author names in bold designate shared co-first authorship.
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Authors contributed equally.