Editorial [Hot Topic: Cancer and Stem Cells (Guest Editor: Eiichi Tahara)]

Recent advances in stem cell biology have highlighted the “cancer stem cell hypothesis”. This hypothesis constitutes two important related concepts. The first is that cancers arise from the mutational transformation of normal stem cells or restricted progenitors/differentiated cells that acquire self-renewal potential. The second is that cancers contain a small subset with stem cell like properties that are responsible for the growth, progression, and invasion of cancer [1-3]. The AACR Cancer Stem Cells Workshop in 2006 reported that the consensus definition of cancer stem cells is those cells within a tumor that have the capacity to self-renew and to bring about the heterogeneous lineages of cancer cells, and that such a definition needs experimentally conclusive evidence to recapitulate the generation of a continuously growing tumor [4]. The existence of cancer stem cells was first proven in the context of acute myelogenous leukemia [5,6] and subsequently verified in brain and breast tumors, using cell surface markers specific for the normal stem cells of the same organ [7,8]. The tumorigenicity and the “stemness” of these cells have been confirmed by performing in vitro clonogenicity and in vivo tumorigenicity. Recently, the identification of cancer stem cells has also been reported in prostate, ovary, pancreas and nasopharynx cancers [9-12]. The stem cell niche, a specialized microenvironment in which stem cells reside, plays an essential role in the self-renewal and maintenance of stem cells and also organizes interaction between stem cells and their niche thorough several signaling pathways, at least in the hematopoietic, intestinal, and hair follicle systems [13]. It is possible that cancer stem cells may also signal to their niche to allow it to induce proliferation and progression of a tumor [4]. Currently, a body of evidence indicates that bone marrow-derived stem cells can engraft and differentiate into nonhematopoietic cells of ectodermal, mesodermal, and endodermal tissues other than hematopoeitic tissues. These stem cells also contribute to cancer stroma in mouse models [3]. Moreover, gastric cancer originating from bone marrow derived cells has also been reported in a murine model [14]. However, University of Florida News reported that ”bone marrow stem cells mimic cancer but do not initiate it“ in human cancers [15] Several signaling pathways that confer the self-renewal of stem cells, contribute to proliferation of cancer cells. The WNT, sonic hedgehog (SHH), Notch, PTEN and the BMI1 pathways have all been shown to promote the self-renewal of normal stem cells as well as proliferation of cancer cells in the same tissues [1,13]. In addition to these positive signals, transforming growth factor-beta (TGF-beta) and TGF-beta-related proteins, such as bone morphogenetic protein (BMP) act as key regulators of stem cell renewal and differentiation [16]. BMP signaling mediated by BMP receptor BMPR1a directly inhibits stem cell proliferation in the niches of intestine and skin and indirectly regulates hematopoietic stem cells through control of its niches [13,16]. Mutations in the BMPR1a and Smad4 induce juvenile intestinal polyposis and Cowden disease, respectively [17]. The interplay between BMP negative signal and the Wnt positive signal regulates the homeostatic balance of stem cell self-renewal and ongoing regeneration. If this balance is disrupted by loss of BMP signaling or abnormal activation of Wnt signaling, unusual proliferation of stem cells occurs, leading to tumorigenesis [18]. Telomeres and telomerase are also implicated in stem cell biology and cancer. Telomerase expression is restricted to germ cells, stem/progenitor cells of the adult normal tissues and the vast majority of cancer cells. Recent data on loss-of-function and gain-of-function mouse models for telomerase indicate that the effects of telomerase length and telomerase activity on different stem cell compartments (hematopoietic stem cells, epidermal stem cells and neural stem cells) are cell autonomous and that these effects are intrinsic to the stem cells and do not depend on physiological niche micro-environments [19]. The fact that telomerase is specifically expressed in highly proliferative stem/progenitor compartments as well as in cancer cells suggests that telomerase may be regarded as a stem cell factor [19]. The concept of cancer stem cells also has implications for the development of targeted therapies for cancer. Normal stem cells, including haematopoietic stem cells, characteristically express drug-resistance proteins, such as the MDR1 and APC transporters [1]. Just as normal stem cells are resistant to the induction of apoptosis by cytotoxic agents and radiation therapy, cancer stem cells display increased resistance to these agents compared with more differentiated cancer cells, and thus they remain in patients after cancer therapy.