At the Crossroads Between Neurodegeneration and Cancer: A Review of Overlapping Biology and Its Implications

Abstract

Background: A growing body of epidemiologic evidence suggests that neurodegenerative diseases occur less frequently in cancer survivors, and vice versa. While unusual, this inverse comorbidity is biologically plausible and could be explained, in part, by the evolutionary tradeoffs made by neurons and cycling cells to optimize the performance of their very different functions. The two cell types utilize the same proteins and pathways in different, and sometimes opposite, ways. However, cancer and neurodegeneration also share many pathophysiological features.

Objective: In this review, we compare three overlapping aspects of neurodegeneration and cancer.

Method: First, we contrast the priorities and tradeoffs of dividing cells and neurons and how these manifest in disease. Second, we consider the hallmarks of biological aging that underlie both neurodegeneration and cancer. Finally, we utilize information from genetic databases to outline specific genes and pathways common to both diseases.

Conclusion: We argue that a detailed understanding of the biologic and genetic relationships between cancer and neurodegeneration can guide future efforts in designing disease-modifying therapeutic interventions. Lastly, strategies that target aging may prevent or delay both conditions.

Keywords: Aging; carcinogenesis; dividing cells; hallmarks; neurodegeneration; neurons; trade-offs..

Fig. (1).

Two patterns of association between cancer and neurodegeneration, as depicted in the figure as “proliferation,” and “apoptosis,” respectively. The horizontal axis denotes specific genes, proteins, and pathways that are inversely regulated in cancer and neurodegeneration. The vertical axis shows age-associated pathophysiologic features that are directly associated with both families of diseases.

Fig. (2).

The differential priorities of dividing cells and neurons. Dividing cells prioritize DNA integrity, frequent self-replacement, and bioenergetic self-sufficiency but need to die on time to avoid cancer. The mission of neurons requires longevity and maintenance of networked connections. Their complexity, dependence, and high performance come at the cost of vulnerability to cell death.

Fig. (3).

Overlap between hallmarks of aging and cancer and neurodegeneration. The nine hallmarks of aging are shared by carcinogenesis and neurodegeneration [31].

Fig. (4).

NetAge gene categorization of AD and cancer. In both cancer and AD, the majority of classified genetic contributors are associated with signaling activities. Compared to cancer, in AD, a disproportionate number of genes involved in general metabolism (18.46% vs. 5.28%), protein metabolism (12.82% vs. 6.44%), and transport (9.74% vs. 2.50%) are mutated. Compared to AD, in cancer, a disproportionate number of genes involved in nucleotide metabolism (22.67% vs. 12.31%) are affected.

Fig. (5).

Overlap between genes associated with AD and cancer. Of the 456 genes associated with AD and the 3006 genes associated with cancer, 286 overlap between the two diseases.

Fig. (6).

Functions of the overlapping genes between AD and cancer. It is evident that genes regulating innate immunity, cell growth, and detoxification are most commonly implicated in both diseases.