Physiological cellular reprogramming and cancer

Abstract

The traditional approaches to cancer research and therapy have been primarily focused in the aspect of aberrant, uncontrolled, proliferation. Although this is clearly a very important issue, however, the emphasis on this characteristic has led to a relative neglect of an essential aspect of cancer biology: the alteration of normal differentiation processes. The oncogenic alterations that arise in an otherwise healthy cell lead to a whole reprogramming of the normal cellular fate and open a new pathologic developmental program. In this way cancer, reprogramming and cellular plasticity are tightly intertwined, since only some cells posses the necessary plasticity so as to allow the tumoral reprogramming to take place, and only some oncogenes have, in the right cellular context, the required tumoral reprogramming capacity. Research in the field of induced pluripotency is shedding a new light on the molecular mechanisms of tumor initiation and differentiation. In this review we discuss the latest findings in the area of cellular reprogramming and their implications from the point of view of tumor biology.

Introduction

The specification of cellular fate during development and differentiation is a dynamic and evolving process that starts with stem and progenitor cells and ends with terminal differentiation into a given specialized cellular type. Along this way there can be many cellular intermediates, some of them long-lived, and some very transient. In all cases, the maintenance of cellular identity is determined to a certain degree by the signals from the environment and, more importantly, in an intrinsic manner, by specific transcription factors that, together with epigenetic chromatin modifications, establish a defined gene expression profile and specific gene regulatory networks (GRNs).

Although many evidences about cellular plasticity had being accumulating for decades [1], [2], [3], [4], the latest findings in the field of reprogramming are finally shaking our beliefs about the stability of cellular identity and showing how switching to a different phenotype can be a lot easier than previously expected, and can have actual physiological relevance outside of the laboratory. Cancer is a clear case of pathological reprogramming where, from a normal tissue, a whole new differentiation branch is opened with its own hierarchy and structure [5], [6]. So, beyond aberrant deregulation of proliferation, tumoral reprogramming is an essential part of the tumorigenesis process, and it is closely dependent on the cellular plasticity of the cancer-initiating cells. Here we define cellular plasticity as the ability of cells (stem or differentiated) to adopt the biological properties (gene expression profile, phenotype, etc.) of other differentiated types of cells (belonging to the same or different lineages). This broad acception includes the property of competence, defined as the ability of stem cells and progenitors to give rise to their different descendant lineages during normal development. With this wide definition we intend to reflect the fact that the mechanisms that are important for stem cell competence during normal development are also at the basis of the plasticity of more differentiated types of cells, both in pathological processes and in experimentally induced fate-changing processes. In this article we will discuss the essential role of cellular plasticity in the origin and maintenance of cancerous cells. To this aim, we will first comment on the latest findings about normal developmental and experimentally induced plasticity, to consider afterwards how these properties connect with what we know about cancer biology.