Cancer stem cells, cancer cell plasticity and radiation therapy

Abstract

Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms.

Introduction

In 2010, the estimated medical costs of cancer care in the United States exceeded $124 billion (source: National Cancer Institute). Yet, despite the enormous spending for cancer care, many cancers are still fatal and 5-year survival rates have not significantly changed over the decades. This raises the question as to whether current radiation treatment approaches can be technically further fine-tuned to improve cancer cure rates, or if cancer therapy in general needs a paradigm shift to substantially improve future outcome.

Aside from surgery, other current standard cancer therapies, such as radiotherapy, chemotherapy, and most targeted therapies have been designed, developed and evaluated for their effectiveness based on bulk tumor responses. This approach for developing novel anti-cancer therapies continues to be widely applied despite our broad knowledge of the undisputable heterogeneity of human tumors. It has been known for over a century that tumors exhibit a remarkable phenotypical heterogeneity, which extends to their radiosensitivity, drug resistance and genetic alterations of the individual cells composing a tumor mass. Employing bulk tumor responses as the primary end point for determining the effectiveness of novel treatments is certainly a very practical approach. However, such an approach will only be successful in yielding cures if the response of the bulk tumor represents the response of the most resistant subpopulation of cells within the heterogeneous tumor and this might hold true for only some cancers like advanced melanoma.

In this review we hope to add to the ongoing discussions about clinically relevant tumor heterogeneity and its potential roots [1], [2]. We will focus on the effects of ionizing radiation on the heterogeneity of solid tumors in the context of competing models of tumor organization, the cancer stem cell hypothesis and the clonal evolution model.