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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.

Mutations leading to overexpression and activation of the oncogenes Myc and Ras are among the most frequent lesions known to occur in human and murine cancers. These genes are also the pioneering example for oncogene cooperation during tumorigenesis, whereby the anticancer effects of Myc deregulation (apoptosis) and oncogenic Ras (senescence) are antagonized and therefore canceled out by each other. Here I review the role of endogenous and overexpressed c-Myc in murine skin, focusing primarily on epidermal stem cells. In addition, recent data suggesting an essential role for the endogenous c-Myc-p21^CIP1 pathway in Ras-driven skin tumorigenesis are discussed.

The Wnt signal transduction pathway plays important roles during embryo development, regulating cell proliferation and survival of immature cells. However, its improper function can lead to harmful consequences for humans, such as aberrant cell proliferation and, therefore, cancer. Increasing evidence suggests that stem cells may be the source of mutant cells that cause cancers to develop and proliferate. Wnt signaling has been shown to promote self-renewal in both gut epithelial and hematopoietic stem cells (HSCs) and to trigger critical pathways in carcinogenesis. Although the function of stem cells in solid tumor development is unclear, the Wnt pathway's role in determining the fate and self-renewal potential of cancer stem cells suggests a critical role in carcinogenesis. The development of new inhibitors, such as antibodies or small molecules, to inhibit this pathway may be of great therapeutic utility against cancer.

Human glioblastomas appear to be established and expanded by cancer stem cells, which are endowed with tumour-initiating and perpetuating ability. We report that bone morphogenetic proteins (BMPs), amongst which BMP4 elicits the strongest effect, activate their cognate receptors (BMPRs) and trigger the Smad but not the MAP38 kinase signalling cascade in cells isolated from human glioblastomas (GBMs). This is followed by a reduction in proliferation and increased expression of differentiated neural markers, without affecting cell viability. The concomitant reduction in the clonogenic ability, both in the size of the CD133^+ side population and in the growth kinetics of GBM cells, indicates that BMP4 triggers a reduction in the in vitro cancer stem cell (CSC) pool. Accordingly, transient ex vivo exposure to BMP4 abolishes the capacity of transplanted GBM cells to establish intracerebral GBMs. Most important, in vivo delivery of BMP4 effectively blocks the tumour growth and associated mortality which occur in 100% of control mice in less than 12 weeks, following intracerebral grafting of human GBM cells. These findings show that the BMP-BMPR signalling system, which controls the activity of normal brain stem cells, may also act as a key inhibitory regulator of cancer-initiating, GBM stem-like cells and identifies BMP4 as a novel, non-cytotoxic therapeutic effector, which may be used to prevent growth and recurrence of GBMs in humans.

The cloning of mammals from adult donor cells has demonstrated that the oocyte can reprogram a differentiated nucleus into a pluripotent embryonic state. Reprogramming of committed cells into pluripotent cells can also be achieved by the explantation of germ line cells and by the fusion of differentiated cells with embryonic cells. The future challenge will be to stably convert a differentiated cell into embryonic stem (ES) cells by the transient expression of defined genes. Recent findings suggest that the exposure of adult cells to a few defined factors can indeed induce a pluripotent-like state resembling that of ES cells. This approach may allow for the generation of patient-specific stem cells in order to study and treat degenerative diseases without recourse to nuclear transfer.

Despite a wealth of experimental data, the precise mechanisms governing the maintenance and regeneration of the intestine remain relatively poorly elucidated. After physical or genetic injury, stem cells from the intestinal crypt are killed and the subsequent repopulation process recruits new stem cells from sources currently unknown. Understanding the genetic elements that determine stem cell fate and the basis by which repopulation occurs will greatly aid our understanding of both stem cell plasticity and the contribution made by the stem cell compartment to malignant disease. It would also provide a better platform to develop therapies to regenerate damaged intestinal epithelia as seen after radiation injuries or inflammatory bowel disease such as Crohn's disease. In this review we discuss some of the basic mechanisms that regulate intestinal stem cell viability and maintenance, and also summarise recent data from our laboratory on the requirement for the Wnt pathway in these processes.

Human colorectal cancer is one of the best, if not the best, understood tumour diseases. These tumours develop stepwise via an adenoma-carcinoma sequence. The steps in this process can easily be discriminated with light microscopy. The breakthrough in understanding carcinogenesis was the finding that mutations in tumour suppressor genes and oncogenes accumulate in parallel with these steps. This accumulation is the cause for the malignant progression of colorectal cancers, leading to highly invasive and migrating tumour cells. This concept is known as the multistep carcinogenesis model and has become the paradigm of tumour progression in general. But this model does not explain the complex, heterogeneous histology of colorectal tumours or the good differentiation of metastases, which are expected to have lost their differentiation because of the accumulation of mutations. Here, we present the model of migrating tumour stem cells, which explains these contradictions in the context of the histology of colorectal tumours. Thus colorectal tumours consist of tumour stem cells, which have recently been defined as a small CD133-positive population of tumour cells. These cells trans-differentiate into epithelial cells, which represent the main mass of the colorectal tumours. Moreover, the tumour stem cells are the active component of migration and invasion, thus conferring the malignant phenotype. Taken together, mutations confer to the tumour cells the capability to live outside of their stem cell niche and intestinal compartment. In addition, the trans-differentiation potential of the tumour cell confers plasticity to the tumour and thus contributes to the heterogeneity of colorectal cancers.

Mounting evidence indicates that human cancers may originate from malignant transformation of stem cells. The most convincing proof is found in acute myeloid leukemia, where only a small subset of slowly dividing cells was able to induce transplantable acute myeloid leukemia. Normal hematopoietic stem cells (HSC) are characterized by their unlimited ability to self-renew, give rise to a multitude of cells that exhibit more differentiated features, and show slow division kinetics. Using human HSC and mesenchymal stromal cells (MSC) as models, we and others have demonstrated the vital role of the cellular niche in maintaining the self-renewing capacity, that is, “stemness” of HSC. Without direct contact with the cellular niche, HSC tend to differentiate and lose their stemness. Similar to their normal counterparts, leukemia stem cells divide slowly and maintain their self-renewal capacity through interaction with the niche. As a consequence, they are resistant to conventional chemotherapy strategies that target rapidly dividing cells. Thus it is of utmost importance to understand the interaction between cellular niche and normal HSC as well as between leukemia stem cells and the niche to provide a basis for more efficient treatment strategies.

Recent results have increased our understanding of normal stem cells and the signalling pathways which regulate them during the development of the mammary gland. Tumours in many tissues are now thought to develop from dysregulated stem cells and depend on activated stem cell self-renewal pathways such as Notch for their tumourigenic capacity. These cancer stem cells are recognised by specific cell surface proteins that they express and their capacity to grow tumours in vivo or spheres in vitro . We have described human breast DCIS mammospheres grown from cancer stem cells and demonstrated their dependence on the EGF and Notch receptor pathways. Stem cell self-renewal pathways such as these may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.

Prostate cancer is now a common disease in men over 50 years of age. Medical therapies for prostate cancer are based on discoveries from the mid-twentieth century, and in the long term are rarely curative. Most treatments are directed towards an androgen receptor-expressing, highly proliferative target cell, which does indeed form the vast majority of cells in a prostate tumour. However, by invoking the existence of a cancer stem cell which, like normal epithelial stem cells in the prostate, does not express androgen receptor and is relatively quiescent, the observed resistance to most medical therapies can be explained. The phenotype of the prostate cancer stem cells is that of a basal cell and cultures derived from cancers, but not benign tissues, express a range of prostate cancer-associated RNAs. Furthermore, stem cells purified on the basis of α_2β_1 high integrin and CD133 cell surface antigen expression, from an established culture of Gleason 4 (2+2) prostate cancer (P4E6), were able to form multiple intraprostatic tumours in nude mice when grafted orthotopically in a matrigel plug containing human prostatic stroma. The final tumours re-expressed androgen receptor and displayed a histology similar to that of a Gleason 4 cancer.