Cancer Stem Cells in Solid Organ Malignancies: Mechanisms of Treatment Resistance and Strategies for Therapeutic Targeting

Abstract

It has been long recognized that tumors are composed of a heterogenous population of cells with various levels of cellular differentiation and morphologic features. Previous explanations for this phenomenon have centered around the concept of clonal evoluation, with the gradual acquisition of mutations leading to distinct tumor cell populations. While this model has validity, more recent evidence suggests that distinct tumor cell populations likely also arise from differentiation of cancer cells with stem-like properties. Termed the cancer stem cell (CSC) theory, this model posits that tumors are composed of a small population of cells possessing the characteristics of self-renewal and pluripotency, and thus the ability to initiate or support tumor growth, as well as their differentiated progeny which lose these abilities with increasing differentiation (Figure 1). Much in the way a normal organ is supported by endogenous stem cells, the CSC theory holds that similarly-functioning cells with stem-like abilities are the driving force behind tumor initiation, progression and metastatic spread. Since they were first identified in acute myelogenous leukemia (AML) (Lapidot et al., 1994), CSCs have been indentified in a wide variety and number of malignancies, including colorectal, head and neck, pancreatic, prostate, central nervous system (CNS), lung and breast cancer. The CSC theory has garnered a great deal of attention, in part, because it proposes a fundamental shift in the way we think about and treat cancer. Similarly to how normal tissue stem cells are resistant to traditional cytotoxic cancer therapies, CSCs have increasingly been demonstrated to be preferentially spared by such treatment. It is thought that standard chemotherapy and radiation targets the differentiated tumor cell bulk, leaving the resistance CSC behind, which can lead to recurrence even years later (Figure 2). Along with the identification and an increasing focus on characterization of CSCs has been the search for therapies that effectively target this resistant subpopulation. While the search is still in its infancy, a number of intriguing treatment strategies have been proposed. In many cases these strategies target known resistance mechanisms employed by CSCs.