Our understanding of how radiation kills normal and tumour cells has been based on an intimate knowledge of the direct induction of DNA damage and its cellular consequences. What has become clear is that, as well as responses to direct DNA damage, cell–cell signalling — known as the bystander effect — mediated through gap junctions and inflammatory responses may have an important role in the response of cells and tissues to radiation exposure and also chemotherapy agents. This Review outlines the key aspects of radiation-induced intercellular signalling and assesses its relevance for existing and future radiation-based therapies.

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Radiation-induced bystander signalling in cancer therapy

Background
MicroRNAs (miRNAs) are small, highly conserved, non-coding RNA that alter protein expression and regulate multiple intracellular processes, including those involved in the response to cellular stress. Alterations in miRNA expression may occur following exposure to several stress-inducing anticancer agents including ionizing radiation, etoposide, and hydrogen peroxide (H2O2).

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Ionizing radiation-induced oxidative stress alters miRNA expression.

Insights into new mechanisms and models of cancer stem cell multidrug resistance

A trip to the National Railway Museum in York always produces a frisson but last month was special. Coinciding with the jubilee celebrations was Railfest 2012, billed as Britain’s biggest ever gathering of rail record breakers. Historic locomotives large and small awaited informed homage from the nation’s trainspotters.⇑

Yes, we were all wearing anoraks (in fairness, it was an outdoor exhibition) and yes, sales of dry white wine were outstripped by a beer called Flying Scotsman, but the crowds …

https://www.bmj.com/content/bmj/345/bmj.e4620.full.pdf

A golden age

METTL3 and N6-Methyladenosine Promote Homologous Recombination-Mediated Repair of DSBs by Modulating DNA-RNA Hybrid Accumulation

Micronuclei (MN) are extranuclear bodies that contain damaged chromosome fragments and/or whole chromosomes that were not incorporated into the nucleus after cell division. MN can be induced by defects in the cell repair machinery and accumulation of DNA damages and chromosomal aberrations. A variety of genotoxic agents may induce MN formation leading to cell death, genomic instability or cancer development. In this review, the genetic and epigenetic mechanisms of MN formation after various clastogenic and aneugenic effects on cell division and cell cycle are described. The knowledge accumulated in literature on cytotoxicity of various genotoxins is precisely reflected and individual sensitivity to MN formation due to single gene polymorphisms is discussed. The importance of rapid MN scoring with respect to the cytokinesis-block micronucleus assay is also evaluated.

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Micronuclei in genotoxicity assessment: from genetics to epigenetics and beyond.

The bystander effect is a phenomenon that occurs when exposed cells signal distress to their naive, unexposed neighbors. It is now accepted as a ubiquitous consequence of radiation exposure. It is well documented to occur in cultured cells, 3D tissue models, and in organs and organisms. Notwithstanding, the exact mechanisms of the bystander effect remain unclear. Recent studies hinted that bystander effects may, in part, be distinct in males and females, and possibly mediated via short non-coding RNAs, specifically, microRNAs. MicroRNAs are small, abundant and capable of regulating the expression of a wide variety of targets. Yet, their roles in bystander effects have not been analyzed in detail. The mechanisms behind sex differences observed in in vivo bystander effects also remain to be uncovered. We hypothesized that the radiation-induced expression of microRNAs in exposed and bystander tissue may be distinct in males and females. Using a well-establish bystander mouse model when the animal's head is exposed, while the body is completely protected by a medical-grade shield, we have for the first time shown that radiation exposure triggers a significant and sex-specific deregulation of the microRNAome in the non-exposed bystander spleen. The altered miRNA levels were paralleled by sex-specific changes in the levels of the miRNA processing enzyme Dicer and components of the RNA-induced silencing complex (RISC). Sterilization of animals resulted in drastic microRNAome alterations and significantly affected radiation and bystander miRNA responses. Our data may provide a roadmap for further analysis of the role of microRNAome in genotoxic stress responses and may help us explain sex specificity of radiation-induced carcinogenesis.

Sex-specific microRNAome deregulation in the shielded bystander spleen of cranially exposed mice

// Lidiya Luzhna 1 , Anne E. Lykkesfeldt 2 and Olga Kovalchuk 1 1 Department of Biological Sciences, University of Lethbridge, University Drive, Lethbridge, AB, Canada 2 Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden, Copenhagen, Denmark Correspondence: Olga Kovalchuk, email: // Keywords : breast cancer, endocrine therapy, radiation, transcriptomics, apoptosis, treatment resistance Received : July 14, 2014 Accepted : December 01, 2014 Published : December 02, 2014 Abstract Endocrine therapy agents (the selective estrogen receptor (ER) modulators such as tamoxifen or the selective ER down-regulators such as ICI 182,780) are key treatment regimens for hormone receptor-positive breast cancers. While these drugs are very effective in controlling ER-positive breast cancer, many tumors that initially respond well to treatment often acquire drug resistance, which is a major clinical problem. In clinical practice, hormonal therapy agents are commonly used in combination or sequence with radiation therapy. Tamoxifen treatment and radiotherapy improve both local tumor control and patient survival. However, tamoxifen treatment may render cancer cells less responsive to radiation therapy. Only a handful of data exist on the effects of radiation on cells resistant to hormonal therapy agents. These scarce data show that cells that were resistant to tamoxifen were also resistant to radiation. Yet, the existence and mechanisms of cross-resistance to endocrine therapy and radiation therapy need to be established. Here, we for the first time examined and compared radiation responses of MCF-7 breast adenocarcinoma cells (MCF-7/S0.5) and two antiestrogen resistant cell lines derived from MCF-7/S0.5: the tamoxifen resistant MCF-7/TAM R -1 and ICI 182,780 resistant MCF-7/182 R -6 cell lines. Specifically, we analyzed the radiation-induced changes in the expression of genes involved in DNA damage, apoptosis, and cell cycle regulation. We found that the tamoxifen-resistant cell line in contrast to the parental and ICI 182,780-resistant cell lines displayed a significantly less radiation-induced decrease in the expression of genes involved in DNA repair. Furthermore, we show that MCF-7/TAM R -1 and MCF-7/182 R -6 cells were less susceptible to radiation-induced apoptosis as compared to the parental line. These data indicate that tamoxifen-resistant breast cancer cells have a reduced sensitivity to radiation treatment. The current study may therefore serve as a roadmap to the future analysis of the mechanisms of cross-resistance between hormonal therapy and radiation.

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Altered radiation responses of breast cancer cells resistant to hormonal therapy.

Clinical utility of MRI in the neoadjuvant management of early-stage breast cancer

e12595 Background: Neoadjuvant therapy (NAT) in HR+/HER2- tumors is often disputable. While the role of Oncotype DX has been well established in adjuvant settings, its clinical utility and potential implementation for prediction of NAT benefit requires further study. This ongoing study aims to report the feasibility of Oncotype DX testing on core biopsy specimens prior to NAT in patients with operable HR+/HER2- breast cancer. The effect of the recurrence score (RS) on systemic treatment recommendations and its correlation to dynamic markers of proliferation and NAT response will be evaluated. Methods: Participants with clinical T2-T4 and/or node positive HR+/HER2- breast cancer had Oncotype DX testing done prior to NAT. Clinico-pathological information, treatment regimens, clinical, radiologic, and pathological responses were recorded. Results: Of the 48 patients with HR+/HER2- breast cancer referred to BC Cancer Vancouver for consideration of NAT between September 2021 and January 2023, 26 were eligible and enrolled in the study. The success rate of the Oncotype DX on core biopsy samples was 96%. The mean turnaround time from patient consent to RS report was 19 calendar days. Approximately 32% of tumors had a RS equal or higher than 26 while 4% had a score less than 10. Nearly 25% of neoadjuvant treatment recommendations were changed based on the RS. Overall, 33% of patients received neoadjuvant chemotherapy, 54% received neoadjuvant endocrine treatment, and 12.5% proceeded with upfront surgery. Conclusions: The success rate of Oncotype DX testing on core biopsy samples was excellent. There were multiple factors that influenced trial enrollment, highlighting the low uptake and equipoise of NAT use in HR+/HER2- tumors. The Oncotype DX testing resulted in a change in systemic treatment plan in 25% of patients. Analyses are ongoing to correlate the recurrence score to NAT response, dynamic Ki-67 changes and breast MRI changes. Clinical trial information: NCT03790813 .

Lidiya Luzhna

Papers

Micronuclei in genotoxicity assessment: from genetics to epigenetics and beyond.

Sex-specific microRNAome deregulation in the shielded bystander spleen of cranially exposed mice

Altered radiation responses of breast cancer cells resistant to hormonal therapy.

Clinical utility of MRI in the neoadjuvant management of early-stage breast cancer

Informative tools to optimize neoadjuvant therapy in ER positive, HER2 negative breast cancers.