Date Published: July 29, 2017
Publisher: Impact Journals LLC
Author(s): Anna Kovalchuk, Yaroslav Ilnytskyy, Rocio Rodriguez-Juarez, Svitlana Shpyleva, Stepan Melnyk, Igor Pogribny, Amanda Katz, David Sidransky, Olga Kovalchuk, Bryan Kolb.
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.
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. According to the Canadian Cancer Society in 2015, breast cancer accounted for 26% of all new cancer cases in Canadian women. Most breast cancer patients undergo chemo-therapy treatments, and the development of new chemotherapy regimens resulted in significant improvement of patient outcomes and increased survival. Despite the undisputed benefits, chemotherapy causes an array of side effects, such as myelosuppression, nausea, vomiting, infections, and bleeding. Additionally, 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 . Thus, chemotherapy-induced cognitive changes have become an increasing concern among cancer survivors. Survivors have coined the terms chemo fog or chemo brain to explain their symptoms . While the initial reports of chemo brain go back to the 1970s and the mid-1980s, the problem started to gain attention only in the ‘90s. Since then, numerous longitudinal and cross-sectional studies have reported the existence of chemo brain and its severity. Among these, the vast majority of work was conducted in breast cancer cohorts. 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 [3–6].
CNS toxicity is one of the major quality-of-life issues that cancer survivors face. Nevertheless, there is a lot to learn about the mechanisms of chemo brain [1, 25]. Along with chemo brain, studies have emerged reporting notable cognitive changes and memory deficits prior to chemotherapy or other cancer treat-ments, the ‘tumor brain’ phenomenon [1, 4, 25].
Both chemo brain and tumor brain were first reported in breast cancer; hence, we focused on breast-cancer PDX models. In this study, we analyzed mice that carried PDXs of T4 TNBC and T4 PR+BC tumors. In the future, it would be important to analyze tumor brain as a function of breast tumor type, stage, and grade. Clinical evidence shows that chemo brain occurs in other malignancies, including hematological malignancies, sarcoma, colon, and other cancers [2, 82]. Tt would be prudent to analyze tumor brain in the PDX models of these other cancers. Some changes may be tumor-specific, but some may be common for all tumor brain manifestations.