Glioblastoma multiforme: a look inside its heterogeneous nature

Abstract

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

Figure 1

Models for the origin of intra-tumor heterogeneity. (a) Clonal evolution: tumor cells divide and acquire mutations, upon a selective pressure the most fit clone (s) will survive and cause tumor relapse; (b) CSC model: CSCs divide asymmetrically and generate CSCs and more differentiated tumor cells that can acquire mutations. Upon treatment, resistant CSCs will survive and cause tumor relapse; (c) Heterogeneity can be generated by cell plasticity in response to microenvironment cues that mainly through epigenetic mechanisms generate cells with different tumorigenic properties as in example tumor initiation capacity or drug resistance; (d) Branched tree model: Mutations shared by all tumor cells proceed from the founder clone which is depicted as the trunk of the tree. The branches are composed by tumor cells that acquire mutations present only in a subset of the tumor cells.