factors through interactions with ROS (reactive oxygen species). Tumor cells undergoing an EMT may be precursors for metastatic cancer cells, or even metastatic CSCs. In the invasive edge of pancreatic carcinoma, a subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells was defined. These cells exhibited significantly stronger migratory activity than their counterpart CD133+CXCR4− cells, but both showed similar tumor development capacity. Moreover, inhibition of the CXCR4 receptor reduced metastatic potential without altering tumorigenic capacity. Two-phase expression pattern In breast cancer CD44+CD24−/low cells are detectable in metastatic pleural effusions. By contrast, an increased number of CD24+ cells have been identified in distant metastases in breast cancer patients. It is possible that CD44+CD24−/low cells initially metastasize and in the new site change their phenotype and undergo limited differentiation. The two-phase expression pattern hypothesis proposes two forms of cancer stem cells - stationary (SCS) and mobile (MCS). SCS are embedded in tissue and persist in differentiated areas throughout tumor progression. MCS are located at the tumor-host interface. These cells are apparently derived from SCS through the acquisition of transient EMT (Figure 7). Implications CSCs have implications for cancer therapy, including for disease identification, selective drug targets, prevention of metastasis and intervention strategies. Treatment CSCs are inherently more resistant to chemotherapeutic agents. There are 5 main factors that contribute to this: 1. Their niche protects them from coming into contact with large concentrations of anti-cancer drugs. 2. They express various transmembrane proteins, such as MDR1 and BCRP, that pump drugs out of the cytoplasm. 3. They divide slowly, like adult stem cells tend to do, and are thus not killed by chemotherapeutic agents that target rapidly replicating cells via damaging DNA or inhibiting mitosis. 4. They upregulate DNA damage repair proteins. 5. They are characterized by an overactivation of anti-apoptotic signaling pathways. After chemotherapy treatment, surviving CSCs are able to repopulate the tumor and cause a relapse. Additional treatment targeted at removing CSCs in addition to cancerous somatic cells must be used to prevent this. Targeting Selectively targeting CSCs may allow treatment of aggressive, non-resectable tumors, as well as prevent metastasis and relapse. The hypothesis suggests that upon CSC elimination, cancer could regress due to differentiation and/or cell death. The fraction of tumor cells that are CSCs and therefore need to be eliminated is unclear. Studies looked for specific markers and for proteomic and genomic tumor signatures that