Extracellular DNA promotes colorectal tumor cell survival after cytotoxic chemotherapy

Anunobi, Reginald; Boone, Brian A.; Cheh, Nick; Tang, Daolin; Kang, Rui; Loux, Tara; Lotze, Michael T.; Zeh, Herbert J.

doi:10.1016/j.jss.2018.02.042

Cited by 27 publications

(31 citation statements)

References 56 publications

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“…There could also be a more direct link between cfDNA, tumor biology and prognosis. A recent CRC cell line study found that the presence of DNA in the tumor microenvironment promotes tumor cell survival after cytotoxic insults, through induction of autophagy [28]. This suggests that cfDNA could exert a disease-modulating biological function and not only be an innocent bystander.…”

Section: Discussionmentioning

confidence: 99%

Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy

et al. 2019

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Background: Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. Patients and methods: This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). Results: cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio ¼ 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) ¼ 62.7, P < 0.001). Conclusion: cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy

et al. 2019

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“…These signals initiate the inflammatory and subsequent immune response to tumor. [57][58][59][60] Frequently members of the Toll-like receptor (TLR) family, which recognizes conserved microbial and endogenous motifs, 61 constitute the primary means for response to so-called 'danger' or 'stranger' signals. [62][63][64] Dysregulated inflammatory innate immune networks support MPE development and tumor cell immune evasion ( Figure 2).…”

Section: Innate Immunity Within the Mpementioning

confidence: 99%

Making cold malignant pleural effusions hot: driving novel immunotherapies

et al. 2019

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Malignant pleural effusions, arising from either primary mesotheliomas or secondary malignancies, heralds advanced disease and poor prognosis. Current treatments, including therapeutic thoracentesis and tube thoracostomy, are largely palliative. The immunosuppressive environment within the pleural cavity includes myeloid derived suppressor cells, T-regulatory cells, and dysfunctional T cells. The advent of effective immunotherapy with checkpoint inhibitors and adoptive cell therapies for lung cancer and other malignancies suggests a renewed examination of local and systemic therapies for this malady. Prior strategies reporting remarkable success, including instillation of the cytokine interleukin-2, perhaps coupled with checkpoint inhibitors, should be further evaluated in the modern era.

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“…Earlier, we and other authors quoted data related to the influence of cfDNA on tumor therapy. CfDNA favors cancer cell survival under the conditions of deleterious impacts, evoking an adaptive response [18, 32].…”

Section: Discussionmentioning

confidence: 99%

Increased Transfection of the Easily Oxidizable GC-Rich DNA Fragments into the MCF7 Breast Cancer Cell

Kostyuk

Mordkovich

Okorokova

et al. 2019

Oxidative Medicine and Cellular Longevity

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Objective. Easily oxidizable GC-rich DNA (GC-DNA) fragments accumulate in the cell-free DNA (cfDNA) of patients with various diseases. The human oxidized DNA penetrates the MCF7 breast cancer cells and significantly changes their physiology. It can be assumed that readily oxidizable GC-DNA fragments can penetrate the cancer cells and be expressed.Methods. MCF7 cells were cultured in the presence of two types of GC-DNA probes: (1) vectors pBR322 and pEGFP and (2) plasmids carrying inserted human rDNA (pBR322-rDNA and pEGFP-rDNA). pEGFP and pEGFP-rDNA contained a CMV promoter and a fluorescent protein geneEGFP.ROS generation rate, accumulation of the DNA probes in MCF7, 8-oxodG content, expression ofEGFPandNOX4, and localization of EGFP, NOX4, and 8-oxodG in MCF7 were explored. The applied methods were qPCR, fluorescent microscopy (FM), immunoassay, and flow cytometry (FCA).Results. When GC-DNA is added to the cell culture medium, it interacts with the cell surface. At the site of GC-DNA contact with the cell, NOX4 is expressed, and ROS level increases. The ROS oxidize the GC-DNA. When using the plasmids pEGFP and pEGFP-rDNA, an increase in the amount of the DNAEGFP, RNAEGFP, and EGFP proteins was detected in the cells. These facts suggest that GC-DNA penetrates the cells and theEGFPgene is expressed. Insertions of the rDNA significantly increase the GC-DNA oxidation degree as well as the rate of plasmid transfection into the cells and theEGFPexpression level. In the nucleus, the oxidized GC-rDNA fragments, but not the vectors, are localized within the nucleolus.Conclusions. GC-rich cfDNA fragments that are prone to oxidation can easily penetrate the cancer cells and be expressed. The cfDNA should become a target for the antitumor therapy.

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Extracellular DNA promotes colorectal tumor cell survival after cytotoxic chemotherapy

Cited by 27 publications

References 56 publications

Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy

Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy

Making cold malignant pleural effusions hot: driving novel immunotherapies

Increased Transfection of the Easily Oxidizable GC-Rich DNA Fragments into the MCF7 Breast Cancer Cell

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