Role of Akt Isoforms Controlling Cancer Stem Cell Survival, Phenotype and Self-Renewal.

Sergio Rivas,Carla Gómez-Oro,Francisco Wandosell,Inés Antón

doi:10.3390/biomedicines6010029

Abstract

The cancer stem cell (CSC) hypothesis suggests that tumours are maintained by a subpopulation of cells with stem cell properties. Although the existence of CSCs was initially described in human leukaemia, less evidence exists for CSCs in solid tumours. Recently, a CD133+ cell subpopulation was isolated from human brain tumours exhibiting stem cell properties in vitro as well as the capacity to initiate tumours in vivo. In the present work, we try to summarize the data showing that some elements of the Phosphoinositide 3-kinase Class I (PI3K)/ Thymoma viral oncogene protein kinase (Akt) pathway, such the activity of PI3K Class I or Akt2, are necessary to maintain the CSC-like phenotype as well as survival of CSCs (also denoted as tumour-initiating cells (TICs)). Our data and other laboratory data permit a working hypothesis in which each Akt isoform plays an important and specific role in CSC/TIC growth, self-renewal, maintaining survival, and epithelial-mesenchymal transition (EMT) phenotype, not only in breast cancer, but also in glioma. We suggest that a more complete understanding is needed of the possible roles of isoforms in human tumours (iso-signalling determination). Thus, a comprehensive analysis of how hierarchical signalling is assembled during oncogenesis, how cancer landmarks are interconnected to favour CSC and tumour growth, and how some protein isoforms play a specific role in CSCs to ensure that survival and proliferation must be done in order to propose/generate new therapeutic approaches (alone or in combination with existing ones) to use against cancer.

Highlights

Glioblastoma (GBM) is the most common and aggressive subtype of the malignant gliomas, which is characterized by intense proliferation, invasion, and intratumour heterogeneity
The heterogeneity and capacity for interconversion among phenotypes make tumours more adaptable in different physiological and tissue environments, and in the resistance to therapy. It has been reported in a variety of tumour types that some cells with cancer stem cell (CSC) properties are more resistant to chemotherapeutic treatments or radiotherapy [25,33,34], which may help to explain the recurrence of many tumour types
We demonstrated that the Phosphoinositide 3-kinase Class I (PI3K)-Akt pathway includes elements that are essential to maintain the CSC-like phenotype, survival, and epithelial-mesenchymal transition (EMT) characteristics in breast cancer cells and gliomas [70,71]

Summary

Introduction

Glioblastoma (GBM) is the most common and aggressive subtype of the malignant gliomas, which is characterized by intense proliferation, invasion, and intratumour heterogeneity. This hypothesis suggests that the oncogenic capacity and biological plasticity of a tumouris that is maintained by a minor fraction of cells with stem-like properties, denoted as CSCs or tumor-initiating cells (TICs) In some cases, these are detectable by the high level expression of markers, such as hyaluronic acid receptor (CD44), prominin-1 (CD133), Nestin, or SRY (sex-determining region Y)-box 2 (Sox2), are expressed, among others. It has been proposed that oncogene-induced dedifferentiation of mature cells in the brain to a stem/progenitor-like state leads to heterogeneous glioma tumours (for review see [9]) When considering all these data, the initiation of oncogenesis perhaps is not a question of “unique cell type”, but might be a combination of mutations that first generate this stem-like phenotype with a subsequent accumulation of mutation that boost the oncogenic progression. It has been reported in a variety of tumour types that some cells with CSC properties are more resistant to chemotherapeutic treatments or radiotherapy [25,33,34], which may help to explain the recurrence of many tumour types

The “Long Road” to Oncogenesis

Akt in Cancer

Conclusions