Niche for Normal and Cancer Stem Cells

Center for Developmental Biology, Chuoku Minatojimaminamimachi 2-3-3,

650-0047 Kobe, Japan email: [email protected] riken.jp

1 Introduction 2

2 The Melanocyte Stem Cell Serves as an Ideal Model to Understand Quiescence of Stem Cells 3

3 Definition of MSC 4

4 Isolation of MSCs En Masse 5

5 Evaluation of Gene Function by MC-Specific Gene Manipulation . 6

6 Induction of Quiescent MSCs Requires Multiple Steps 7

7 A Working Hypothesis for the Induction of Quiescent MSCs ... 8

8 Induction of Quiescent MSCs In Vitro: Future Direction 10

References 12

Abstract. An important issue in cancer therapy is the presence of a population that is resistant to anticancer treatment. This resistance has been partly ascribed to the presence of quiescent stem cells in a cancer population. However, how the quiescent state is induced in a proliferating cancer population is totally obscure. We think that our study on the stem cell system of pigment cells will provide some insight into the molecular basis for cancer stem cells, because the quiescent melanocyte stem cell would be the ideal model for understanding the process generating quiescent stem cells. In this article, we review our latest understanding of the quiescent stem cells of the melanocyte lineage by referring to some related topics of cancer stem cells.

1 Introduction

The main purpose of this symposium is to discuss cancer stem cells (Clarke et al. 2006). While the cancer stem cell is not the direct subject of our study, we agree that the cancer stem cell is a notion that may have the potential to radically change our strategy of cancer treatment. The underlying idea is to regard cancer as a hierarchical entity comprising cell populations of distinct characteristics. However, this recognition is not novel. Indeed, there may be no researchers who believe that cancer consists of a homogeneous population. In most cases, in fact, a simple histological examination is enough to discern the heterogeneity of cancer. However, the molecular mechanisms underlying the generation of hierarchical diversity in cancer cells and the functional significance of the diversity have been left largely uninvestigated until recently. For decades, cancer research was concerned with how genetic alterations that accumulate in the genome lead to uncontrolled growth of cells (Vogelstein and Kinzler 2004). This direction of study thus assumed that a particular cancer population is represented by the most malignant population that is expected to dominate the population, and the cells that can grow less are regarded as those disappearing over time. The notion of the cancer stem cell brought this simple competition rule into question by showing that even a slowly cycling population can be the most malignant population. Hence, treatment of cancer needs to take into consideration not only the mechanisms driving cancer cells to proliferate, but also those conferring stem cell features. In this respect, it is interesting that the cancer stem cell has been defined by two features. One is proliferative ability in secondary recipients (Bonnet and Dick 1997), and the other is resistance to anticancer treatment, or in other words, quiescence (Dean et al. 2005). The two features appear contradictory. This may be due either to coexistence of two types of stem cells in one cancer or to coexpression of two contradictory features in the same stem cells. Nonetheless, this question can only be answered by defining the molecular mechanisms underlying the formation of cancer stem cell populations.

Indeed, this question remains unresolved even in the study of normal stem cell systems. In this symposium, we review our study of normal stem cells with these questions about cancer stem cells in mind.

2 The Melanocyte Stem Cell Serves as an Ideal Model to Understand Quiescence of Stem Cells

Hair pigmentation is mediated by the melanocyte (MC) stem cell (SC) system residing in each individual hair follicle (HF). The melanocyte stem cell (MSC) system represents a regenerative type SC system that undergoes a regeneration cycle repeating quiescent and activated states. Concerning the MSC system, the regeneration cycle is regulated coordi-nately with that of follicular keratinocytes (hair cycle). We have shown previously that MSCs are distinguished from other compartments of MCs by a number of features (Fig. 1) (Nishimura et al. 2002). First, MSCs localize in the vicinity of the bulge region of the HF, whereas other compartments are located in the hair matrix at the lower part of the HF. Second, MSCs are quiescent until being reactivated when the new hair regeneration cycle is initiated. Third, MSCs are resistant to block of the c-kit signal, whereas the c-kit signal is essential for survival of other MC compartments. In fact, when an antagonistic mAb to c-kit is injected in neonatal mice, all mice become depigmented because of depletion of mature MCs. However, MSCs are resistant to this treatment and are able to completely replenish the MC system in the next hair regeneration cycle. Using these phenomenological features, we next attempted to distinguish MSCs in molecular term.

During the course of the characterization of MSCs, we were intrigued by the parallelism between the resistance of MSCs to antagonistic antic-kit mAb and the resistance of cancer SCs to therapy. The most striking example is the gastrointestinal stromal tumor (GIST) that is caused by gain-of-function mutations of the c-kit gene. Like melanocyte SCs, a small fraction of the GIST resists treatment with imatinib, which inhibits c-Kit function. While the imatinib treatment suppresses the growth of the GIST tumor, thereby bringing complete remission to the patient, the tumor recurs in all cases in which treatment is stopped. Moreover, even with continuous treatment, GIST eventually recurs because of the accumulation of additional mutations that render the tumor cells resistant to imatinib treatment (van der Zwan and DeMatteo 2005). Although it is not clear whether the imatinib-resistant fraction of GIST corresponds to the stem cells that we defined in the MC system, this result encourages us to think that investigation of the mechanisms un-

-Immature and undifferentiated.

-Resting state.

-Can give rise to the matrix melanocytes.

-Can reconstitute melanocyte system in the hair follicle after transplantation.

Fig. 1. Characteristics of the stem cell compartment of melanocyte in hair follicles. Melanocytes present in a special region of the upper part of hair follicles, which is designated the bulge region, were proven to be stem cells with a number of characteristics listed in the figure derlying the maintenance of MSCs in the bulge region would provide some clues for understanding the resistance of tumor SCs to treatment. Nonetheless, the most important issue in this respect is to define SCs in molecular term.

3 Definition of MSC

How to define SCs is the first issue for the investigation of any SC systems. In the MC system, the most reliable means to distinguish SCs from other compartments is by its localization. As shown in Fig. 1, MSCs localize in the upper area of HFs, whereas other compartments are in the lower part that is called the hair matrix. Using transgenic mice that are engineered to express GFP specifically in the MC lineage, we isolated individual MSCs that are defined as GFP+ cells in the upper

Hair matrix Bulge

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