The Distant Molecular Effects on the Brain by Cancer Treatment

Abstract

Cancer survivors experience cancer-related cognitive impairment (CRCI) secondary to treatment. Chemotherapy and radiation therapy independently contribute to cognitive dysfunction; however, the underlying mechanisms leading to dysfunction remain unclear. We characterized brain gene expression changes in a mouse model of CRCI to identify the mechanistic underpinnings. Eleven-to-twelve-week-old SKH1 mice were treated with doxorubicin (DOX), hindlimb radiation (RT), concurrent hindlimb radiation and doxorubicin (DOX-RT), or no treatment (control). Sixteen days following treatment, gene expression was measured from murine brains using the NanoString nCounter® glial profiling panel. Gene expression was normalized and compared between groups. No two groups shared the same expression pattern, and only Gnb1 and Srpr were upregulated in multiple treatment groups. Brains from DOX-treated mice had upregulated Atf2, Atp5b, Gnb1, Rad23b, and Srpr and downregulated Sirt5 expression compared to control brains. Brains from RT-treated mice demonstrated increased Abcg2 and Fgf2 and decreased C1qa and C1qb expression compared to control brains. Brains from DOX-RT-treated mice had upregulated Adar, E2f3, Erlec1, Gnb1, Srpr, Vim, and Pdgfra expression and downregulated Rock2 and Inpp5f expression compared to control brains. The gene expression changes demonstrated here highlight roles for neuronal transmission and oxidative stress in the pathogenesis of doxorubicin-related CRCI and inflammation in RT-related CRCI.

Cancer related cognitive impairment: a downside of cancer treatment

“…Within the chemotherapy space, rodent studies have evaluated the effects of intravenous or intraperitoneal administration of alkylating agents (CYP, temozolomide, thiotepa), platinums (cisplatin, oxaliplatin, carboplatin), antimetabolites (MTX, 5-FU, cytosine arabinoside, cytarabine), anthracycline (DOX, epirubicin), antimicrotubule agents (vincristine, paclitaxel, DTX), cytosine arabinoside (cytarabine) and topoisomerase I inhibitor (topotecan) ( 5 , 23 , 26 , 87 , 99 ). Rodent studies investigating the mechanisms of ECRT induced CRCI, include ECRT models of non-CNS cancer treatment ( 5 , 7 , 12 , 102 ). In this model, ECRT is represented by a single dose of ECRT to an extracranial region, such as the skin of the hindlimb, in tumor-free or tumor-bearing animals ( 5 , 7 , 12 , 102 ).…”

“…Rodent studies investigating the mechanisms of ECRT induced CRCI, include ECRT models of non-CNS cancer treatment ( 5 , 7 , 12 , 102 ). In this model, ECRT is represented by a single dose of ECRT to an extracranial region, such as the skin of the hindlimb, in tumor-free or tumor-bearing animals ( 5 , 7 , 12 , 102 ).…”

“…Cancer survivors affected by CRCI report visual and verbal memory impairment, learning and attention impairment, and difficulty processing new information and multitasking ( 6 – 8 ). CRCI decreases cancer survivors’ quality of life by negatively impacting their daily tasks and personal relationships, negatively impacting work performance and, decreasing their ability to return to work ( 9 – 12 ). This review will cover the proposed mechanisms for CRCI in cancer patients and the animal models being used to determine potential therapeutic targets.…”

Longitudinal Neuropathological Consequences of Extracranial Radiation Therapy in Mice

“…There is a limited understanding as to the clinical cognitive impact of ECRT and the mechanism(s) that link CRCI and radiation prescribed to anatomic sites distant from the brain. We previously characterized an SKH1 mouse model of ECRT-induced CRCI, and this model allows us to investigate the crucial mechanisms by which ECRT triggers neuroinflammatory pathology [ 3 , 20 ]. Because breast cancer survivors are over-represented in populations with ECRT-induced CRCI, acute dermatitis is the most common radiation-induced acute adverse event in breast cancer patients, and our prior work demonstrating the occurrence of CRCI following radiation in SKH1 mice, our studies utilize this strain to examine the effects of ECRT on the central nervous system over time [ 1 , 2 , 3 , 7 , 16 , 21 ].…”