Amyloids and brain cancer: molecular linkages and crossovers

Abstract

Amyloids are high-order proteinaceous formations deposited in both intra- and extracellular spaces. These aggregates have tendencies to deregulate cellular physiology in multiple ways; for example, altered metabolism, mitochondrial dysfunctions, immune modulation, etc. When amyloids are formed in brain tissues, the endpoint often is death of neurons. However, interesting but least understood is a close connection of amyloids with another set of conditions in which brain cells proliferate at an extraordinary rate and form tumor inside brain. Glioblastoma is one such condition. Increasing number of evidence indicate a possible link between amyloid formation and depositions in brain tumors. Several proteins associated with cell cycle regulation and apoptotic pathways themselves have shown to possess high tendencies to form amyloids. Tumor suppressor protein p53 is one prominent example that mutate, oligomerize and form amyloids leading to loss- or gain-of-functions and cause increased cell proliferation and malignancies. In this review article, we present available examples, genetic links and common pathways that indicate that possibly the two distantly placed pathways: amyloid formation and developing cancers in the brain have similarities and are mechanistically intertwined together.

Keywords: Cancer; aging; amyloid; glioma; neurodegeneration; proteostasis.

Figure 1. Common links and distinctive features of the two broad classes of diseases: neurodegeneration and brain cancer

The two classes of diseases are primarily represented by rapid neuronal loss and unlimited cell proliferation, respectively. There are multiple common pathways affecting systemic changes in these diseases. However, several distinctive features also delineate these diseases and show distinctive characteristics.

Figure 2. Common link between brain tumors and amyloid formation

Primary cerebral amyloidoma is a tumor-like formation that presents both features simultaneously: neoplasia and neurodegeneration although number of cells remain consistent. Another important link between the two conditions is p53 aggregates. Formation of these aggregates leads to loss- or gain-of-functions that lead to poor DNA binding, altered cell cycle progression, apoptotic changes and many others. Several reports indicate p53 aggregates may develop amyloid or prion-like depositions as well, which a common feature of most, if not all, neurodegenerative diseases.

Figure 3. Key genetic mutations in brain tumors

Cancers are always an outcome of multiple gene mutations. Some mutations are common for different cancers and some are specific to cancer types. Common genetic mutations in all kinds of brain tumors are summarized in this figure. Each of these gene mutations alters different cellular pathways, which leads to tumorigenesis. The figure was created with Biorender.com.

Figure 4. Genetic and immunomodulatory factors among cancers and degenerative diseases in the brain

Microglia cell activation is a common factor in both, tumor microenvironment and amyloids nanoenvironment. These cells, through a highly regulated but complex mechanisms, initiate a number of systemwide changes that may impact, alter or worsen the conditions. Several genes have been identified in the past affecting these diseases independently as well as in concerted manner. One common gene, that has been studied in great detail in conditions of brain tumors is TREM2. In recent years, it has been projected as a potential AD gene and has been tested for its potential roles in affecting amyloid formation pathways.