## 1 Introduction  
Colorectal cancer (CRC) is the third-most common type of cancer, and the second leading cause for cancer-related mortality worldwide [1]. About 20% of patients already suffer from metastatic lesions at the time of diagnosis, whereas 60% of the patients with no metastatic disease progress to develop metastasis within five years [2], with the liver and lung being the most frequent distant organs involved [1]. Surgery is the first-line treatment option, and it is provided to selected patients with respectable metastases and operable primary tumors. Inoperable tumors, residual lesions, or disease that has already spread to distant organs may require drug-based tumor therapy, frequently including VEGF inhibitors,such as bevacizumabab [3]. However, in some clinical cases, treatment fails to eliminate chemotherapy-resistant quiescent tumor cells [4], and therapy (including chemotherapy, radiotherapy, targeted therapy, and/or immunotherapy) may sometimes promote escape from dormancy and the generation of metastatic lesions in remote organs [5; 6]. Therefore, a better understanding of the mechanisms that regulate the entrance and exit from dormancy is needed, in the hope of identifying new opportunities for a future therapeutic approach. Metastatic cells can spread even in early tumor stages [7]. To allow epithelial cells to migrate to remote organs, they must first activate the epithelial-to-mesenchymal transition (EMT) program, which increases their invasive capabilities and motility. Cells that undergo EMT can detach from their neighboring cells, intravascular through the basement membrane into an adjacent blood or lymphatic vessel, extravasate, and colonize a remote organ [8]. Only a very small fraction of these circulating tumor cells (CTCs), will survive this journey. Those cells that end up lodging and colonizing the metastatic organ will become disseminating tumor cells (DTCs) that may remain dormant for months or years [9]. To overcome the quiescence-mediating signals in the remote organ [10], and to generate a metastatic lesion, the cell must re-acquire its epithelial properties through the activation of the mesenchymal-to-epithelial transition (MET) program, which enables proliferation, generation of macro-metastases, and cancer recurrence [11]. Thus, metastatic cells exhibit plasticity (epithelial-mesenchymal plasticity--EMP), and cells that co-express both epithelial and mesenchymal properties in varying degrees (known as E/M hybrids) are considered to have the greatest metastatic and aggressive potential [12; 13; 14]. EMT markers, such as reduced E-cadherin expression and increased vimentin expression, as well as increased EMT transcription factors (EMT-TFs), such as Snail/ SNAI1, Slug/ SNAI2, Zeb1, or Twist1, were shown to drive the EMT program, repress the epithelial markers, and induce a more mesenchymal phenotype associated with dormancy [15]. The DTCs that have successfully lodged in a distant organ, and do not immediately die by apoptosis nor continue to proliferate, receive signals from their new microenvironment that activate a dormancy program [16]. Two non-mutually-exclusive mechanisms have been proposed for tumor dormancy. Cellular dormancy results when DTCs enter the G0 phase in their cellular cycle and their proliferation is arrested. This state is accompanied by an increased resistance to drugs that preferentially target proliferating cells. Tumor mass dormancy describes a balance between cells that proliferate and cells that die by apoptosis, so that the small cluster of DTCs or micro-metastasis remains in a stable size and does not generate a detectable macro-metastatic lesion. This can be the result of a lack of sufficient blood supply (angiogenic dormancy) or pressure exerted by the immune response [12; 17]. Cellular and tumor-mass dormancies are influenced by interactions with the surrounding tissue and stroma cells in the metastatic niche, through signals mediated by soluble factors or transmembrane proteins.