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Cancer and neurodegenerative disease (a group of disorders that involve progressive degeneration of the central nervous system) are two very serious and distinct ailments. The basis of their development is distinctly different, with hallmarks of cancer centering around abnormally prolonging cell life and hallmarks of neurodegenerative disease centering around triggering premature cell death. But surprisingly, there are multiple potential links between these two conditions.
Epidemiological studies have seen inverse comorbidities between some neurodegenerative diseases and some cancers. For example, in many cancer survivors, especially survivors of smoking-related cancers (like lung and colorectal cancer), Alzheimer’s (AD) and Parkinson’s (PD) diseases were found to be less frequently occuring, suggesting a decreased risk for these diseases following cancer. However, this inverse correlation is not a simple, guaranteed occurrence. It does not apply to all cancer types, as most notably demonstrated by the finding that PD patients are more likely to develop melanoma (a type of skin cancer), and vice versa. Chemotherapy may also affect this relationship. For instance, some studies have found that chemotherapy may lower the risk of AD, while other studies have shown that chemotherapy alters brain connectivity and causes significant cognitive impairment in breast cancer patients.
Even though epidemiological data are inconsistent, these two sets of disorders are still found to be biologically connected. More specifically, some important genes, pathways, and molecules that are dysregulated in cancer are dysregulated in neurodegenerative disease as well.
Take for instance, p53, a well-known tumor suppressor gene. Expression of this gene is found to be downregulated in a majority of cancers but upregulated in AD, PD, and Huntington’s disease. Another example is a family of proteins called cyclins, which help regulate the various stages of the cell cycle. Dysregulated cyclins or their regulators are tightly linked to cancer initiation and neurodegenerative disease. For example, cyclin D1, which modulates entry from the quiescent (or dormant) phase to the first cell growth phase of the cell cycle, is overexpressed in most cancers, and this overexpression has also found to be important in the progression of neurodegeneration. (Seo and Park)
The link between neurodegeneration and cancer is more readily apparent upon investigating the communication between neurons and cancer cells in the brain. Studies have shown that malignant brain tumor glioma cells secrete excessive amounts of an amino acid called glutamate, which causes the environment that immediately surrounds the tumor to become toxic to any nearby neuron (Seo and Park). These neurons are then damaged or even killed, creating room for the tumor to grow further. Additionally, glutamate can also serve as a chemical messenger to send signals to other cells. When released by active neuronal cells, past research showed that receptors on breast cancer cells that had metastasized to the brain received this glutamate signal, which, in turn, promotes breast-to-brain cancer metastasis. (Seo and Park)
Further biological overlap between cancer and neurodegeneration involves some of the key hallmarks of physiological aging. Three of these hallmarks are telomere shortening, cellular senescence, and genome instability (where a high frequency of mutations occur within a genome).
Telomeres are repetitive nucleotide sequences at the ends of chromosomes that serve as protective caps. In normally aging body cells, after each cell division, telomeres get shorter and shorter until they reach a critical length that signals the cell to stop dividing. When telomeres are critically short, chromosomes are left unprotected, which can lead to genome instability. Genome instability can then possibly give rise to mutations related to the development of both cancer and central nervous system disorders. Telomere shortening, in and of itself, also plays a role in the development of AD via oxidative stress and inflammation (Houck et al.).
Cellular senescence (a condition where the cell can no longer proliferate) promotes neurodegeneration but may protect against cancer. For example, senescent non-neuronal cells in the central nervous system display progressive weakness and altered cell functionality. Meanwhile, senescent oncogenic cells cannot proliferate, preventing further tumor progression. (Houck et al.) One thing to note, however, is that this senescence in oncogenic cells can be reversed by the inactivation of p53 and another tumor suppressor protein, p16. More specifically, when p16 expression is absent, then p53 inactivation would allow previously senescent cells to re-enter the cell cycle and proliferate despite short telomeres. The p53 protein can be inactivated by viral oncoproteins that are able to inactivate p53 or by short synthetic DNA or RNA that are able to alter protein expression. (Beauséjour et al.)
Due to all of these connections between cancer and neurodegenerative disease, drugs that usually treat one ailment are currently being tested for their potential ability to treat the other. For example, medicines for decreasing cancer-related inflammation are being actively tested for use as neuroprotective agents. (Houck et al.)
As we’ve seen, some molecular and cellular features of overlap between the two ailments are inversely associated, while other features are shared, which may explain the mixed results from past epidemiological studies. Further research into the mechanisms behind these features and the underlying reasons behind their development will aid in the development of prognostic markers and targeted therapy treatments for both cancer and neurodegeneration.
Edited by Kate Secombe
Houck, Alexander L et al. “At the Crossroads Between Neurodegeneration and Cancer: A Review of Overlapping Biology and Its Implications.” Current aging science vol. 11,2 (2018): 77-89. doi:10.2174/1874609811666180223154436
Seo, J., Park, M. Molecular crosstalk between cancer and neurodegenerative diseases. Cell. Mol. Life Sci. vol. 77 (2020): 2659–2680. https://doi.org/10.1007/s00018-019-03428-3
Beauséjour, Christian M et al. “Reversal of human cellular senescence: roles of the p53 and p16 pathways.” The EMBO journal vol. 22,16 (2003): 4212-22. doi:10.1093/emboj/cdg417