**1. Introduction**

Stem cells possess two main attributes, namely, a self-renewal capacity and multipotency. Selfrenewal refers to the ability of a cell to replicate itself without differentiating or losing multipotency. Multipotency is the ability to differentiate into more than one cell lineage. Recent studies have revealed that there are several types of stem cells. For example, neural stem cells can differentiate into neurons, astrocytes, and oligodendrocytes, while hematopoietic stem cells can differentiate into all types of blood cells. Embryonic stem (ES) cells were originally established from the inner cell mass (ICM) of mouse blastocysts [1, 2]. As the ICM gives rise to the embryo, ES cells can differentiate into most cell types in the body and are therefore pluripotent. The successful establishment of human pluripotent cells, namely, human ES cells and human induced pluripotent (iPS) cells, opens up the possibility of using these cells in regenerative medicine [3-5]. However, several issues remain to be resolved. One such issue is unanticipated tumor formation by transplanted pluripotent cells, which seems to be associated with the self-renewal capacity of these cells.

The self-renewal of mouse ES cells [6, 7] can be maintained by the presence of leukemia inhibitory factor (LIF) in the culture medium. LIF binds to LIF receptor (LIFR) and induces formation of gp130/LIFR heterodimers, leading to activation of the downstream transcription factor signal transducer and activator of transcription (STAT)-3. The LIF/STAT3 pathway plays a critical role in ES cell self-renewal by upregulating several self-renewal genes [8]. The expression of a set of self-renewal genes is also regulated by networks of important transcrip‐ tion factors, including Oct3/4, Sox2, and Nanog [9].

Cancer is one of the most feared diseases throughout the world. Approximately 10 million people die from cancer every year and the number of cancer patients is increasing. This disease is characterized by loss of cellular growth control, which is induced by genome alterations, such as DNA sequence changes, copy number aberrations, chromosomal rearrangements, and

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

modifications in DNA methylation. Recent studies have provided evidence that tumor tissue contains a small subset of stem-like cells called cancer stem cells. Cancer stem cells have stem cell-like attributes, namely, self-renewal and differentiation, which enables them to produce tumors by self-renewing and giving rise to differentiated progeny. The concept of cancer stem cells first arose from studies of leukemia stem cells [10] and subsequently of solid tumors [11, 12]. Given that cancer stem cells play a prominent role in cancer cell growth, it may be reasonable to expect similarities between ES cells and cancer cells.

**2. ES cell self-renewal genes that are involved in cancer cell growth**

of Oct3/4 for the acquisition of pluripotency [19].

eal carcinoma patients [29].

Oct3/4 was originally isolated by three groups [14-16]. Since Oct1 and Oct2 had already been identified, two groups named this protein Oct3, while the other group named it Oct4. Therefore, I will use the term "Oct3/4" to describe this protein. Oct3/4 is a transcription factor belonging to the POU family and is encoded by the *pou5f1* gene. The Oct3/4 protein contains three domains, namely, the N-terminal, POU, and C-terminal domains. The Nand C-terminal domains are transactivation domains with redundant functions, while the POU domain is a bipartite DNA-binding domain consisting of the POU-specific domain and the POU homeodomain. In mouse development, deficiency of this transcription factor results in loss of the ICM [17]. In agreement with this, conditional knockout of this gene in ES cells results in their differentiation into trophectoderm cells [18], indicating that Oct3/4 is a central player in the self-renewal of ES cells. Furthermore, the recent finding that Oct3/4 is one of the four factors required for the production of iPS cells indicates the importance

Embryonic Stem Cells and Oncogenes http://dx.doi.org/10.5772/57614 43

Not only suppression, but also overexpression of Oct3/4 induces ES cell differentiation [18], suggesting that the activity of Oct3/4 needs to be sustained at the correct level to main‐ tain ES cell self-renewal. Oct3/4 expression in ES cells is positively and negatively regulat‐ ed by multiple factors. The upstream region of the *pou5f1* gene contains proximal and distal enhancers, which regulate stem cell-specific expression of Oct3/4 [20]. An orphan nuclear receptor Lrh1 (also known as Nr5a2) binds to the proximal enhancer to maintain Oct3/4 expression [21], whereas Oct3/4 and Sox2 associate with the distal enhancer to stimulate Oct3/4 expression [22]. Negative regulators of Oct3/4 expression include Gcnf, Coup-tfs, and Cdx2, whose expression are induced upon ES cell differentiation. In addition to regulation of Oct3/4 expression, the transcriptional activity of Oct3/4 protein is regulated by Oct3/4-binding proteins. For example, it is well-established that Sox2 is a co-factor of Oct3/4. β-catenin binds to Oct3/4 and functions as a co-activator that enhances the transcrip‐ tional activity of Oct3/4 [23]. The orphan nuclear receptor Dax1 also binds to Oct3/4, but

acts as a negative regulator by interfering with the binding of Oct3/4 to DNA [24].

In adult human tissues, expression of Oct3/4 is restricted to germline cells and is very low in other tissues. By contrast, Oct3/4 is expressed in several types of human cancers, including prostate, breast, oral, bladder, and seminoma [25], suggesting the importance of this transcription factor in cancer development. Moreover, Oct3/4 is highly expressed in cancer stem-like cells in breast cancer, lung cancer, and bone sarcoma [26-28]. In lung cancer, Oct3/4 maintains the properties of cancer stem-like cells [28]. In agreement with these findings, high expression of Oct3/4 significantly correlates with poor overall survival of nasopharyng‐

**2.1. Oct3/4**

Indeed, ES cells are similar to cancer cells in several respects. When injected into immunode‐ ficient mice, ES cells and cancer cells can produce benign and malignant tumors, respectively. Both cell types have a rapid cell cycle, which results in fast proliferation. Telomerase activity is very high in both cell types, which allows them to proliferate indefinitely. Both cell types contain a "side population of cells" with a high drug efflux capacity, which gives rise to their drug-resistance phenotype. In addition, several signal transduction pathways seem to be used in both ES cell self-renewal and cancer cell growth. For example, the STAT3 pathway, which plays a central role in ES cell self-renewal, is activated in several types of cancer cells. On the other hand, the Wnt/β-catenin pathway, whose activation is associated with tumorigenesis in many tissues, is involved in ES cell self-renewal. Moreover, poorly differentiated tumors preferentially overexpress genes that are normally enriched in ES cells [13].

The similarities between ES cells and cancer cells raise the possibility that certain molecules that are involved in ES cell self-renewal play important roles in cancer cell growth, while certain oncogenes play critical roles in ES cell self-renewal (Fig. 1). In this chapter, I will provide examples of such molecules and describe their roles in ES cell self-renewal and tumorigenesis.

**Figure 1.** Similarity between ES cells and cancer cells.
