Growth of malignant extracranial tumors alters microRNAome in the prefrontal cortex of TumorGraft mice.

Anna Kovalchuk,Olga Kovalchuk,Bryan Kolb,Rocio Rodriguez-Juarez,Yaroslav Ilnytskyy,David Sidransky,Amanda Katz

doi:10.18632/oncotarget.19835

Abstract

A wide array of central nervous system complications, neurological deficits, and cognitive impairments occur and persist as a result of systemic cancer and cancer treatments. This condition is known as chemo brain and it affects over half of cancer survivors. Recent studies reported that cognitive impairments manifest before chemotherapy and are much broader than chemo brain alone, thereby adding in tumor brain as a component. The molecular mechanisms of chemo brain are under-investigated, and the mechanisms of tumor brain have not been analyzed at all. The frequency and timing, as well as the long-term persistence, of chemo brain and tumor brain suggest they may be epigenetic in nature. MicroRNAs, small, single-stranded non-coding RNAs, constitute an important part of the cellular epigenome and are potent regulators of gene expression. miRNAs are crucial for brain development and function, and are affected by a variety of different stresses, diseases and conditions. However, nothing is known about the effects of extracranial tumor growth or chemotherapy agents on the brain microRNAome.We used the well-established TumorGraft ™ mouse models of triple negative (TNBC) and progesterone receptor positive (PR+BC) breast cancer, and profiled global microRNAome changes in tumor-bearing mice upon chemotherapy, as compared to untreated tumor-bearing mice and intact mice. Our analysis focused on the prefrontal cortex (PFC), based on its roles in memory, learning, and executive functions, and on published data showing the PFC is a target in chemo brain.This is the first study showing that tumor presence alone significantly impacted the small RNAome of PFC tissues. Both tumor growth and chemotherapy treatment affected the small RNAome and altered levels of miRNAs, piRNAs, tRNAs, tRNA fragments and other molecules involved in post-transcriptional regulation of gene expression. Amongst those, miRNA changes were the most pronounced, involving several miRNA families, such as the miR-200 family and miR-183/96/182 cluster; both were deregulated in tumor-bearing and chemotherapy-treated animals. We saw that miRNA deregulation was associated with altered levels of brain-derived neurotrophic factor (BDNF), which plays an important role in cognition and memory and is one of the known miRNA targets. BDNF downregulation has been associated with an array of neurological conditions and could be one of the mechanisms underlying tumor brain and chemo brain. In the future our study could serve as a roadmap for further analysis of cancer and chemotherapy’s neural side effects, and differentially expressed miRNAs should be explored as potential tumor brain and chemo brain biomarkers.

Highlights

Initial reports on the cognitive changes associated with cancer chemotherapies appeared in the late 1970s to the mid-1980s, but received scientific attention starting only in the mid-1990s
Our analysis focused on the prefrontal cortex (PFC), based on its roles in memory, learning, and executive functions, and on published data showing the PFC is a target in chemo brain
While the majority of chemo brain reports come from the analysis of breast cancer survivor cohorts, chemo brain has been reported in lymphoma, leukemia, lung, gastrointestinal, and other cancers, and has been accepted as a form of general post-chemotherapy Central nervous system (CNS) toxicity [4, 9]

Summary

Introduction

Initial reports on the cognitive changes associated with cancer chemotherapies appeared in the late 1970s to the mid-1980s, but received scientific attention starting only in the mid-1990s. Most of the chemotherapyinduced cognitive deficits were reported in breast cancer patients, in which deficits affected up to 50% of survivors and lasted for more than 10 years [2]. These effects were so significant that breast cancer survivors even coined a term for them—“chemo fog” or “chemo brain” [3, 4]. The latter term is widely accepted and used to describe the CNS toxicity of chemotherapy (reviewed in [3,4,5]). While the majority of chemo brain reports come from the analysis of breast cancer survivor cohorts, chemo brain has been reported in lymphoma, leukemia, lung, gastrointestinal, and other cancers, and has been accepted as a form of general post-chemotherapy CNS toxicity [4, 9]

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Results

Conclusion