Abstract
Recurrence and metastasis have been regarded as two of the greatest obstacles to cancer therapy. Cancer stem cells (CSCs) contribute to cancer development, with the distinctive features of recurrence and resistance to popular treatments such as drugs and chemotherapy. In addition, recent discoveries suggest that the epithelial mesenchymal transition (EMT) is an essential process in normal embryogenesis and tissue repair, as well as being a required step in cancer metastasis. Although there are many indications of the connections between metastasis and stem cells, these have often been studied separately or at most bi-laterally, not in an integrated way. In this study, we aimed to explore the global mechanisms and interrelationships among cancer, development, and metastasis, which are currently poorly understood. First, we constructed a core gene regulatory network containing specific genes and microRNAs of CSCs, EMT, and cancer. We uncovered seven distinct states emerging from the underlying landscape, denoted normal, premalignant, cancer, stem cell, CSC, lesion, and hyperplasia. Given the biological definition of each state, we also discuss the metastasis ability of each state. We show how and which types of cells can be transformed to a cancer state, and the connections among cancer, CSCs, and EMT. The barrier height and flux of the kinetic paths are explored to quantify how and which cells switch stochastically between the states. Our landscape model provides a quantitative approach to reveal the global mechanisms of cancer, development, and metastasis.
Highlights
Cell phenotypes change during the development of cellular differentiation (Wang et al, 2011; Xu et al, 2014)
MDM2 is an oncogene of cancer, P53 is a well-known tumor suppressor gene (Yu and Wang, 2016), ZEB is an epithelial mesenchymal transition (EMT) activator gene which suppresses the stemness-inhibition of a microRNA (Wellner et al, 2009), OCT4 is an essential gene which mediates phenotype self-renewal and stemness (Kumar et al, 2012), and mir-145 and mir-200 are two important microRNAs with vital roles in both Cancer stem cells (CSCs) and EMT regulation (Liu et al, 2015)
The regulation of OCT4−|mir-145−|MDM2 and MDM2−|P53−|OCT4 and ZEB−|mir-145−|MDM2 indicates that OCT4 effectively activates (!) MDM2, while MDM2 effectively activates (MDM2!) OCT4, and ZEB effectively activates (ZEB!) MDM2
Summary
Cell phenotypes change during the development of cellular differentiation (Wang et al, 2011; Xu et al, 2014). Differentiation starts from an oosperm, which develops into a complex biont system and continues into adulthood as stem cells (SCs) divide and generate differentiated daughter cells during tissue repair and cell regeneration (Sell, 2004). Induced pluripotent SCs (iPS) provide an opportunity for therapeutic use (Takahashi et al, 2007). Adult cells were reprogrammed into pluripotent SCs in 2006 (Takahashi and Yamanaka, 2006). This was a significant step in SC and regenerative biology, as the cell type switching could skip many intermediate steps. This lineage reprogramming technology may have profound implications for cancer biology
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