Chemo brain or tumor brain - that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice.

Anna Kovalchuk,Amanda Katz,Rocio Rodriguez-Juarez,Stepan Melnyk,Olga Kovalchuk,Svitlana Shpyleva,Yaroslav Ilnytskyy,David Sidransky,Bryan Kolb,Igor Pogribny

doi:10.18632/aging.101243

Abstract

Cancer chemotherapy causes numerous persistent central nervous system complications. This condition is known as chemo brain. Cognitive impairments occur even before treatment, and hence are referred to as cancer associated cognitive changes, or tumor brain. There is much yet to be learned about the mechanisms of both chemo brain and tumor brain. The frequency and timing of chemo brain and tumor brain occurrence and persistence strongly suggest they may be epigenetic in nature and associated with altered gene expression. Here we used TumorGraftTM models wherein part of a patient's tumor is removed and grafted into immune-deficient mice and conducted global gene expression and DNA methylation analysis. We show that malignant non-central nervous system tumor growth causes profound molecular alterations in the brain. Mice harbouring triple negative or progesterone positive breast cancer TumorGrafts exhibited altered gene expression, decreased levels of DNA methylation, increased levels of DNA hydroxymethylation, and oxidative stress in the prefrontal cortex. Interestingly, chemotherapy did not have any additional synergistic effects on the analyzed processes. The molecular changes observed in this study are known signs of neurodegeneration and brain aging. This study provides an important roadmap for future large-scale analysis of the molecular and cellular mechanisms of tumor brain.

Highlights

Breast cancer is one of the most commonly diagnosed cancers in the world, and it is the most common cause of cancer-related deaths in women
We showed that chemotherapy altered gene expression profiles in the prefrontal cortex (PFC) and HPC tissues; the changes were most prominent in the PFC tissues of females 3 weeks after mitomycin C (MMC) treatment
The principal component analysis based on the entire transcriptome dataset showed good clustering for each group and clear differences between gene expression profiles in the PFC tissues of intact, triple negative breast cancer (TNBC) and positive breast cancer (PR+)BC TumorGraft mice (Fig. 1S)

Summary

Introduction

Breast cancer is one of the most commonly diagnosed cancers in the world, and it is the most common cause of cancer-related deaths in women. Many patients experience profound psychosocial effects that decrease their quality of life, including fatigue, cognitive dysfunction, and other signs of central nervous system (CNS) toxicity post-chemotherapy [1]. Chemotherapy-induced cognitive changes have become an increasing concern among cancer survivors. It has been found that chemotherapy-induced CNS side effects, or chemo brain, affect almost half of all breast cancer survivors and impacts the cognitive domains of attention, memory, psychomotor speed, and executive function. Current research shows that chemotherapy agents are more toxic to healthy brain cells than to cancer cells, and debilitating chemo brain manifestations affect patients for as long as five to ten years after treatment completion [3,4,5,6]

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