Tumor Angiogenesis and the Cancer Stem Cell Model

Abstract

In recent years, research and interest in the area of cancer stem cells has grown tremendously. An increasing number of studies are finding that many different cancers contain a subpopulation of tumor cells that display several defining characteristics of adult tissue stem cells, including multipotent differentiation potential, long-term self-renewal capacity, and the expression of various molecular markers of stemness. Most importantly, these stem-like cancer cells also appear to possess the strongest tumorinitiating potential of all the cells in the tumor, a finding that has led to the development of the cancer stem cell model for tumor progression. This model suggests that tumors are organized in a developmental hierarchy (similar to a healthy tissue), with longterm tumor progression being driven by a self-renewing tumor stem cell at the top of the hierarchy. As this new model for tumor progression takes shape, researchers are beginning to investigate how cancer stem cells fit into various other aspects of cancer biology. In this regard, several recent studies are uncovering an intriguing relationship between tumor angiogenesis and cancer stem cells. This chapter reviews recent data suggesting that cancer stem cells may play an important role in promoting tumor angiogenesis, and that tumor vasculature may in turn have a role in supporting and maintaining cancer stem cells. Related work suggesting that antiangiogenic therapy may be used as a strategy to eliminate the critical CSC population is also discussed. The Cancer Stem Cell Hypothesis: a New Model for Tumor Progression More than a decade ago, pioneering studies by John Dick and colleagues identified a subpopulation of leukemic cells with stem-like properties in patients with acute myelogenous leukemia [1, 2]. These leukemic stem cells (LSCs) were found exclusively in the CD34+CD38− leukemic cell fraction, a surface immunophenotype also found on hematopoietic stem cells [3]. Only the CD34+CD38− cells were able to transplant disease into immune deficient mice. The resulting disease displayed a phenotypic heterogeneity resembling that of the original human donor, and CD34+CD38− cells isolated from primary engrafted mice and serially transplanted into secondary recipient mice produced disease with comparable efficiency, indicating that LSCs are capable of differentiation and selfrenewal, two key properties of stem cells. These findings provided some of the first significant evidence supporting the ‘cancer stem cell’ model for tumor progression [4]. This model posits that a tumor is organized as a hierarchy—a distorted mirror image of its normal tissue counterpart. At the top of the hierarchy is a cancer stem cell (CSC), a self-renewing cancer cell that expresses surface markers of primitive cells and possesses differentiation potential and limitless proliferative potential. The CSC can divide asymmetrically, maintaining its proliferative potential through self-renewal, or giving rise to a transit amplifying daughter cell that can divide rapidly for a limited period of time, differentiating (aberrantly) and giving rise to the bulk of cells in the tumor mass, which are non-CSCs. Since only the CSC population can divide repeatedly without loss of proliferative potential, it is the CSC population that is responsible for tumor initiation and driving tumor progression in the long term. Several years after the initial discovery of the leukemic stem cell, similar studies in breast cancer by Clarke and colleagues revealed that experimental tumor initiating capacity resides largely in a minority subpopulation of self-renewing breast tumor cells with primitive surface immunophenotype and differentiation potential [5], demonstrating for the first time that the CSC model may also be applicable to solid tumors. In the years since these early groundbreaking studies, interest in the CSC model has grown tremendously, and CSCs have now been implicated and characterized to varying degrees in many different cancers, including brain [6–12], prostate [13–15], melanoma [16], colon [17, 18], lung [19], ovarian [20, 21], gastric [22], pancreatic [23], retinoblastoma [24], bone sarcoma [25], hepatocellular carcinoma [26–28], head and neck squamous cell carcinoma [29,30], multiple myeloma [31], and chronic myelogenous leukemia [32–34]. While more extensive work will be required to determine how 249 1 Deparment of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 2 Department of Medical Biophysics, University of Toronto, Toronto,