It is well known that cancer and dementia are devastating diseases that have affected thousands across the globe as well as drastically altered the world of medical research. Recent studies reveal a possible relationship between the two ailments, indicating hope of using one to combat the other. In a recent issue of the journal, Alzheimer Disease & Associated Disorders, Mary Ganguli discusses the various advancements and observations that have been made on the subject. Although the relationship between cancer and dementia is complicated, associations appear more distinct when narrowed to a particular type of cancer and a specific neurodegenerative disorder. Several mechanisms for the relationship are currently being explored, including effects of environmental exposure such as smoking, chronic inflammation and the immune system, as well as common risk factors such as aging. Furthermore, various cancer treatments have shown neurotoxic effects, while others yield reduction of neurodegeneration in animals.  The ultimate goal of this research is to develop potential treatment and prevention strategies for both afflictions.

Cancer and dementia can be described as being on opposite ends of a spectrum.  On one end of the spectrum is abnormal cell growth, the cancer end, while on the other end is abnormal cell death, neurodegeneration.  The spectrum description illustrates the common factor of cell cycle control, central to both disorders.  In general, those who suffer from a neurodegenerative disorder have reduced risk of developing most cancers, while those with cancer generally have a reduced risk of developing a neurodegenerative disorder.  The reason for this correlation remains in question; however, various observational studies have strengthened the validity of this relationship.

Majority of information about the relationship thus far is from observational studies that relate cancer to specific neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s Disease (PD). Investigation into the relationship between overall cancer and AD has demonstrated an inverse association, meaning that for individuals with AD there seems to be a reduced risk of cancer and vice versa.  The inverse relationship was established through a case-control study performed by the Alzheimer Disease Research Center cohort at Washington University in St Louis. Furthermore, the inverse association was more prevalent when smoking-related cancers of the oral cavity, pharynx, larynx, esophagus, etc. were observed. Various other studies have yielded similar results, such as the multisite Alzheimer Disease Neuroimaging Initiative, which demonstrated that those with a history of cancer showed lower risk of developing Alzheimer’s disease.

Despite the appearance of a mechanistic correlation between the two diseases, other explanations must also be considered. For example, survival bias could play a role in that developing cancer reduces the chances of an individual living long enough to develop Alzheimer’s disease. Furthermore, underreporting and under-ascertainment of individuals with AD may contribute to the appearance of a relationship; health care professionals may choose not to screen dementia patients for cancer.

Regardless of the significance of these alternative explanations, the role of bias was largely overcome with the Framingham Heart Study, in which survivors of smoking-related cancers showed a reduced risk of developing AD.  In this study, 1278 participants with and without a history of cancer and free of a dementia baseline were examined, all aged 65 or older. The experiment’s results strongly suggest that overall cancer survivors had a lower risk of AD, and the risk was lower for smoking related cancers when compared with non-smoking related cancers. The Framingham Heart Study distinctly suggests an inverse association between cancer and neurodegeneration beyond the influence of bias.  The decrease in risk for smoking related cancer survivors could be due to the fact that although smoking is a known risk for cancer, acute smoking has shown protective effects against neurodegeneration.

While the relationship between cancer and AD appears one sided, the relationship between cancer and Parkinson’s disease is mixed in that both direct and inverse associations have been observed. However, despite the appearance of a mixed relationship, observations are more consistent when cancer type is considered. The Danish National Hospital Register performed a study that showed that individuals with Parkinson’s disease had a lower standardized incidence ratio (SIR) for overall cancer, smoking-related cancer, and smoking-unrelated cancers. However, the individuals had higher SIR for malignant melanoma and non-melanoma skin cancer, as well as female breast cancer.

In order to mechanistically explain these relationships researchers are investigating possible immune mechanisms.  Immunosenescence, the deterioration of the innate and adaptive immune system over time, has been linked to the association between cancer and aging. On the other hand, the prompting of the innate immune system has been linked to neurodegeneration.  The opposing roles of the immune system is a possible means to explain the mechanism responsible for the relationship between cancer and dementia; it also relates to the spectrum description of cancer and dementia in terms of cell cycle control. The immune system plays a role in both inhibiting and promoting tumor growth in the form of cancer immunoediting, a process that is enhanced in certain neurodevelopmental and neurodegenerative disorders.

Another possible mechanism for the relationship between cancer and dementia is alterations in genetic pathways, mainly of genes involved in cell cycle control. Regulation of the PIN1 gene could contribute to both diseases in that it is overexpressed in certain cancers but is also necessary for tau phosphorylation, meaning decreased expression could lead to Alzheimer’s disease. Associations between cancer and neurodegeneration could also be due to confounding treatment effects.  Patients undergoing chemotherapy for cancer treatment have shown cognitive impairment, in that it can decrease grey matter in the brain. Other cancer treatments such as taxanes have shown neuroprotective effects and have been proposed as potential therapeutic agents for Alzheimer’s disease due to its microtubule stabilizing effect. A new topic of investigation is the role of functional microRNA that are expressed differently in cancer and neurodegenerative diseases, and show inversely associated pathways.

Thus far, majority of the findings are from observational studies, however, the findings and their consistency warrant further mechanistic investigation of genetic factors and the immune system. Studies using genetic screening, as well as population-based studies, could provide more conclusive results in hopes of developing treatment strategies and prevention methods for both conditions.


REFERENCES

1 Ganguli, Mary. (2015).  Cancer and Dementia: It’s Complicated. Alzheimer Disease & Associated 1Disorders, 29(1), 177-82.

Other information gathered from:

2 Driver JA, Beiser A, Au R, et al. Inverse association between cancer and Alzheimer’s disease: results from the Framingham Study.  BMJ. 2012; 322;e1442. 3 Plun-Favreau H, Lewis PA, Hardy J, et al.  Cancer and neurodegeneration: between the devil and the deep blue sea.  PLoS Genet.  2010;6e1001257. 4 Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease.  Nat Rev Immunol.  2014;14:463-477. 5 McDonald BC, Conroy SK, Ahles TA, et al.  Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study.  Breast Cancer Res Treatment.  2010; 123: 819-828 6 Brunden KR, Yao Y, Potuzak JS, et al.  The characterization of microtubule-stabilizing drugs possible therapeutic agents for Alzheimer’s disease and related tauopathies.  Pharmacol Res. 2011; 63: 341-351

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