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

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.

Cancer and dementia: Two sides of the same coin?

“…Interestingly, these patients also show worse neuropsychological test performance and alterations on MRI scans compared to controls that cannot be explained by the distress accompanied by cancer diagnosis, suggesting that cancer itself may induce changes in the normal functioning of the brain. Preclinical support for this observation comes from studies showing that immunodeficient mice engrafted with patient tumour tissue show molecular changes in the brain similar to those seen in neurodegeneration and brain ageing …”

“…Preclinical support for this observation comes from studies showing that immunodeficient mice engrafted with patient tumour tissue show molecular changes in the brain similar to those seen in neurodegeneration and brain ageing. 39,40 Besides the role of cancer itself, cognitive problems in newly diagnosed cancer patients could also be explained by a shared pathology. For instance, genetic susceptibility, inflammation and oxidative stress are processes related to cancer and to cognitive decline.…”

Oxidative Stress and Cognitive Alterations Induced by Cancer Chemotherapy Drugs: A Scoping Review

“…Recently, studies have emerged suggesting that neurocognitive deficits that manifest before drug treatment may be associated with the presence of the tumor, a phenomenon recently termed 'tumor brain' [74]. To dissect the molecular mechanisms of tumor brain, the best experimental model is the TumorGraftTM obtained by grafting part of a patient's tumor into immunodeficient mice [75]. Increased oxidative lipid damage (elevated levels of 4-hydroxy-2-nonenal) is observed in the hippocampal tissues of mice bearing triplenegative (TNBC) or progesterone receptor-positive (PR + BC) xenografts.…”

An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study

“…In cancer patients undergoing chemotherapy, both cancer and its treatment have been speculated to trigger reprogramming of the genome, resulting in changes to gene expression and neuronal transmission 33 . A study using the TumorGraft mouse model found that global DNA methylation and DNMT1 levels decreased in the pre-frontal cortex of mice with triple-negative or progesterone-positive breast cancer TumorGrafts 36 . The A allele polymorphism may change DNMT1 activity to mitigate these adverse effects.…”