Heterogeneity maintenance in glioblastoma: a social network

Abstract

Glioblastoma multiforme (GBM), the most common intracranial tumor in adults, is characterized by extensive heterogeneity at the cellular and molecular levels. This insidious feature arises inevitably in almost all cancers and has great significance for the general outcome of the malignancy, because it confounds our understanding of the disease and also intrinsically contributes to the tumor's aggressiveness and poses an obstacle to the design of effective therapies. The classic view that heterogeneity arises as the result of a tumor's "genetic chaos" and the more contemporary cancer stem cell (CSC) hypothesis tend to identify a single cell population as the therapeutic target: the prevailing clone over time in the first case and the CSC in the latter. However, there is growing evidence that the different tumor cell populations may not be simple bystanders. Rather, they can establish a complex network of interactions between each other and with the tumor microenvironment that eventually strengthens tumor growth and increases chances to escape therapy. These differing but complementary ideas about the origin and maintenance of tumor heterogeneity and its importance in GBM are reviewed here.

Figure 1. Heterogeneity origins and maintenance

According to clonal evolution (A), heterogeneity is caused by the acquisition of mutations and expansion. Upon a selective pressure, such as drug treatment, more adapted clones survive and, through consequent mutations, give rise again to a heterogeneous population. The CSC model (B) postulates that only CSCs are able to divide indefinitely, giving rise to cells that will differentiate heterogeneously. CSCs can also acquire mutations and generate a heterogeneous CSC population. CSCs are considered to be drug resistant, such that surviving cells serve as a reservoir for tumor relapse. Whether heterogeneity arises by clonal evolution, CSCs or CSCs undergoing clonal evolution, its maintenance requires interactions between CSCs/tumor cells and their microenvironment and between different CSCs/tumor cell clones (C). Those interactions can drive an increase in tumor growth, drug resistance, immune suppression, angiogenesis, invasion, or even CSC renewal. (D) ΔEGFR cells secreted factors, such as IL-6 and LIF, which through a paracrine mechanism activate wtEGFR cells, resulting in a significant tumor growth enhancement as compared to a wtEGFR homogeneous tumor.