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

Houck, Alexander L.; Seddighi, Sahba; Driver, Jane A.

doi:10.2174/1874609811666180223154436

Cited by 67 publications

(79 citation statements)

References 146 publications

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“…However, there are no available experimental data on the mechanism(s) leading to reduced LMTK2 level. Nonetheless, a recent theory suggesting that neurodegeneration is the cancer of neurons may serve as a potential explanation [39][40][41]. Because neurons are terminally differentiated cells it is possible that certain noxious stimuli which cause uncontrolled proliferation in other organs result in aberrant cell cycle re-entry with degenerative changes and apoptosis in nerve cells [42][43][44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

et al. 2020

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Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in different brain regions and neuropathological stages of AD is not clear. We performed chromogenic (CHR) LMTK2 and fluorescent phospho-tau/LMTK2 double-labelling (FDL) immunohistochemistry (IHC) on 10–10 postmortem middle frontal gyrus (MFG) and anterior hippocampus (aHPC) samples with early and late neuropathological Braak tau stages of AD. MFG in early stage was our ‘endogenous control’ region as it is not affected by NFTs. Semiquantitative CHR-IHC intensity scoring revealed significantly higher (p < 0.001) LMTK2 values in this group compared to NFT-affected regions. FDL-IHC demonstrated LMTK2 predominance in the endogenous control region, while phospho-tau overburden and decreased LMTK2 immunolabelling were detected in NFT-affected groups (aHPC in early and both regions in late stage). Spearman’s correlation coefficient showed strong negative correlation between phospho-tau/LMTK2 signals within each group. According to our results, LMTK2 expression is inversely proportionate to the extent of NFT pathology, and decreased LMTK2 level is not a general feature in AD brain, rather it is characteristic of the NFT-affected regions.

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Section: Discussionmentioning

confidence: 99%

Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

et al. 2020

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“…We need to mention that PARK6 (PINK1) may also have a protective and anti-tumor function and that both genes, Park2 and Park6 (PINK 1), possess not only anti-inflammatory but also tumor-suppressive characteristics. On the other side, PARK7 (DJ-1) has been described as an oncogene, and this condition appears to be mediated by the inhibitor function on the PTEN, as mentioned beforehand, a known tumor suppressor gene (Houck et al, 2018).…”

Section: Parkinson's Diseasementioning

confidence: 94%

“…Gene mutations, transcriptional, protein, and mitochondrial dysregulation in opposite directions play a substantial role in these disorders. In this sense, a tumor-suppressor gene with a transcriptional role, p53, is downregulated in several tumors and upregulated in PD, AD, and HD (Houck et al, 2018). Therefore, a link between cancer and neurodegeneration is plausible as they share several genes and biological pathways, including inappropriate activation and deregulation of the cell cycle, resulting in opposite endpoints.…”

Section: Introductionmentioning

confidence: 99%

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

Rojas

Cesarini

Etcheverry

et al. 2020

Journal of Integrative Neuroscience

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Several epidemiological studies support low cancer rates in patients with neurodegenerative disorders, including Parkinson's disease, Huntington's disease, and Alzheimer's disease. Different mechanisms were raised as possible causes, from mutated tumor suppressor genes (PARKIN, PINK1) to small interfering RNA based on the CAG trinucleotide repeat expansions located in introns or untranslated regions. However, as every rule has an exception, some tumors have an increased incidence in these neurodegenerative diseases such as breast and skin cancer (melanoma). This mini-review aims to establish the epidemiology between these neurodegenerative disorders and cancer to determine the possible mechanisms involved and therefore set eventual therapeutic applications. According to our findings, we conclude the presence of an inverse relationship among most cancers and the aforementioned neurodegenerative disorders. However, this concept needs to be considered cautiously considering specific genetic and extra-genetic linkage factors for particular tumors.

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“…This observation suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and implies that some shared variants modulate disease risk. Increasing evidence suggest that there are common pathophysiological features in both diseases, such as DNA damage, oxidative stress, mitochondrial dysfunction, metabolic dysregulation, and inflammation (Driver, 2014;Houck et al, 2018). Moreover, single nucleotide polymorphism (SNP)-trait genome-wide association studies (GWAS) have shown positive genetic correlations between AD and cancer (Feng et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease

et al. 2020

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Numerous clinical trials of drug candidates for Alzheimer's disease (AD) have failed, and computational drug repositioning approaches using omics data have been proposed as effective alternative approaches to the discovery of drug candidates. However, little multiomics data is available for AD, due to limited availability of brain tissues. Even if omics data exist, systematic drug repurposing study for AD has suffered from lack of big data, insufficient clinical information, and difficulty in data integration on account of sample heterogeneity derived from poor diagnosis or shortage of qualified post-mortem tissue. In this study, we developed a proteotranscriptomic-based computational drug repositioning method named Drug Repositioning Perturbation Score/Class (DRPS/C) based on inverse associations between disease-and drug-induced gene and protein perturbation patterns, incorporating pharmacogenomic knowledge. We constructed a Drug-induced Gene Perturbation Signature Database (DGPSD) comprised of 61,019 gene signatures perturbed by 1,520 drugs from the Connectivity Map (CMap) and the L1000 CMap. Drugs were classified into three DRPCs (High, Intermediate, and Low) according to DRPSs that were calculated using drug-and disease-induced gene perturbation signatures from DGPSD and The Cancer Genome Atlas (TCGA), respectively. The DRPS/C method was evaluated using the area under the ROC curve, with a prescribed drug list from TCGA as the gold standard. Glioblastoma had the highest AUC. To predict anti-AD drugs, DRPS were calculated using DGPSD and AD-induced gene/protein perturbation signatures generated from RNA-seq, microarray and proteomic datasets in the Synapse database, and the drugs were classified into DRPCs. We predicted 31 potential anti-AD drug candidates commonly belonged to high DRPCs of transcriptomic and proteomic signatures. Of these, four drugs classified into the nervous system group of Anatomical Therapeutic Chemical (ATC) system are voltage-gated sodium channel blockers (bupivacaine, topiramate) and monamine oxidase inhibitors (selegiline, iproniazid), and their mechanism of action was inferred from a potential anti-AD drug perspective. Our approach suggests a shortcut to discover new efficacy of drugs for AD.

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

Abstract: 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.

Cited by 67 publications

References 146 publications

Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease

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