|Year : 2013 | Volume
| Issue : 7 | Page : 150-152
Cancer stem cells and tumor metastasis
Shaoqiang Sun1, Xue Shan Qiu2
1 Department of Clinical Medicine, China Medical University, Shenyang, China
2 Department of Pathology, China Medical University, Shenyang, China
|Date of Web Publication||30-Nov-2013|
Xue Shan Qiu
Department of Pathology, China Medical University, Shenyang
Source of Support: None, Conflict of Interest: None
Cancer stem cells (CSCs) are endowed with an inherent resistance to cytotoxic drugs, and are closely related to the migration, invasiveness, and anti-apoptotic ability of the cancer cells. Epithelial-mesenchymal transition (EMT) is a process where epithelial cells acquire the highly invasive and metastatic characteristics of mesenchymal cells, and has a close connection with CSCs. In this paper, the authors address the recent progress made in the relationship between the EMT status of CSCs and tumor metastasis and between the localization and chemotaxis of CSCs and the formation of the metastatic colonies, as well as the relation of CSCs with the therapeutic strategy for cancer treatment
Keywords: Cancer stem cells, tumor metastasis, epithelial-mesenchymal transition, review
|How to cite this article:|
Sun S, Qiu XS. Cancer stem cells and tumor metastasis. J Can Res Ther 2013;9, Suppl S2:150-2
| > Introduction|| |
Stem cells (SCs) have the ability to self-renew and generate diverse cells. In brief, after cell division, some cells keep the characteristics of SCs, while others commit to mature cells with limited life span. In vivo, SCs can not only compensate for normal apoptosis, but also repair damaged tissues to help maintain homeostasis. A study  has shown that active SCs mainly compensate for normal apoptosis and quiescent SCs repair damaged tissues. Moreover, it is assumed that SCs play a key role in the onset, development, invasion, and metastasis of tumors.
Cancer stem cells (CSCs) refer to a group of tumor cells that are able to self-renew and produce diverse cells.  Conceptually, the major difference between SCs and CSCs lies in the fact that SCs can regulate and keep the state of their microenvironment, but CSCs cannot. SCs regulate cell proliferation, differentiation, and apoptosis, which coordinate with each other. The generation of a new cell implies the apoptosis of another cell. The error at any stage may cause an imbalanced state and finally the formation of tumors.
| > Epithelial-Mesenchymal Transition Status of CSCs and Tumor Metastasis|| |
CSCs were originally detected in the malignant tumors of hematopoietic system,  and then were proved to exist in solid tumors such as tumors of the breast, colon, liver, etc. ,,, The tumorigenic ability of CSCs is stronger than that of tumor cells. The vaccination of a few CSCs in immunodeficient mice may cause tumors. CSCs are involved not only in the onset of tumors but also in the proliferation of tumors. A small amount of CSCs in tumors can induce the formation of the same tumor tissue with the primary tumor, which illustrates CSCs are able to generate diverse cells.
Mani et al.  have found that epithelial-mesenchymal transition (EMT) generates tumor cells with the properties of CSCs. Their study reveals a close relationship between CSCs and EMT. It implies that CSCs might promote the invasion and metastasis of tumors by acquiring some properties of the mesenchyma. When tumor cells interact with fibroblasts, granulocytes, macrophages, and other cells in niches, these cells may release the signal to induce EMT, resulting in increased invasion of tumor cells. 
EMT occurs in many malignant tumors. In certain microenvironment, some epithelial cells acquire the properties of mesenchymal cells and thus invade the adjacent tissues or spread to remote organs. EMT and mesenchymal-to-epithelial transition (MET) play a certain role in embryo development, tissue regeneration, and injury repair.  EMT is also crucial in invasion and metastasis of malignant tumors. It has been proved that EMT in patients with tumors indicates poor prognosis.  Brabletz et al.  have found that cells induced by EMT spread unevenly at the invasion front of colorectal cancers, and the expression of Wnt signal transduction pathway increases. In addition, they have found that in the extracellular matrix, single cells express nuclear β-catenin as well as salient mesenchymal characteristics such as the expression of vimentin and non-expression of E-cadherin. It is believed that EMT is irreversible during embryonic development; transitional mesenchymal cells can restore to their original epithelial state through MET. Similarly, the MET of CSCs may occur when the cells are induced by some factors during metastasis and lead to the formation of metastatic sites.
Patient with tumors might have a better prognosis if CSCs in circulation could be detected and target killed. In recent years, most researchers  use associated specific antigens and epithelial cell surface makers such as epithelial cell adhesion molecule (EpCAM) to detect CSCs in peripheral circulation, so some CSCs which do not express associated proteins are difficult to detect.
| > CSCs and Tumor Metastasis|| |
Localization and chemotaxis of CSCs
Hermann et al.  have found among CD133-positive pancreatic CSCs, some cells in circulation express C-X-C chemokine receptor type 4 (CXCR4) and these cells cause tumor metastasis. A study  shows CXCR4 is expressed at the surface of highly malignant and metastatic tumor cells. Hermann et al.  have also found CXCR4 receptor antagonists could reduce the circulating CSCs and tumor metastasis. Based on these results, it can be concluded that circulating CSCs play an important role in tumor metastasis. However, the specific metastatic mechanisms of different cancers are still unclear. Some people  think chemotaxis occurs between CSCs that can express CXCR4 and stromal cell-derived factor-1 (SDF-1). The concentration gradient of SDF-1 between the metastatic site and primary site induces the migration of CSCs. Because of chemotaxis, circulating CSCs migrate to certain organs or tissues and commit to the corresponding primary cancer. At present, no reliable evidence can prove that the circulating CSCs still retain the properties of SCs. 
CSCs and the formation of the metastatic colonies
In recent years, Pang et al.  have discovered that CD26 could be used as a CSC marker to predict the invasion and metastasis of colon cancer. Among 27 cases of colon cancer without hepatic metastasis, only 8 cases were CD26 positive. However, CD26-positive tumor cells were found in the primary and metastatic sites in all the patients with hepatic metastasis. The experiment on tumor formation in Nonobese Diabetic/Severe Combined Immunodeficiency (NOD/SCID) mice shows that the vaccination of CD26-positive and -negative cells causes the formation of tumor, but metastatic sites only form in mice vaccinated with CD26-positive cells and only CD26-positive circulation cancer cells can be detected in portal veins.
Al-Hajj et al.  vaccinated immunodeficient mice by limiting dilution analysis (LDA) and found that in breast cancer, the tumor cells which expressed CD44 and did not express CD24 or expressed CD24 to a lesser extent had the characteristics of SCs. It is reported that aldehyde dehydrogenase (ALDH) 1 can be used as a CSC marker for breast cancer to enrich CSCs.  ALDH can also be used as a marker for breast cancer to enrich CSCs. The vaccination experiment in NOD/SCID mice showed that compared with cells with ALDH (low expression) CD44 (high expression/−), cells with ALDH (high expression) CD44 (+) CD24 (−) or ALDH (high expression) CD44 (+) CD133 (+) have advanced malignant and metastatic ability.  Yet, the latest study  suggests the expression of ALDH1 in liver cancer is not related to liver cancer cells and might be an index of differentiation in liver cancer.
| > CSCs and the Therapeutic Strategy for Cancer Treatment|| |
CSCs have been found in many types of tumors, but their relationship with clinical treatment and prognosis still deserves further study. As mentioned above, SCs are composed of two types: Active and quiescent. Quiescent SCs are similar to dormant cancer cells. Stimulated by some external factors, dormant cancer cells, which are a small part of cancer cells in normal condition, may acquire energy and proliferate, leading to relapse and metastasis of tumors.  Cancer cells are thought to be dormant before relapse when the primary cancer reoccurs 5 years after the malignant tumor is removed. Breast cancer reoccurs even 10 years after the surgery.  Based on the evidence, a question might arise whether dormant cancer cells are quiescent CSCs that spread from the primary site before the surgery. If so, it is not difficult to understand that their resistance to cytotoxic drugs results from their properties of SCs. Therefore, it is significant for cancer treatment if quiescent SCs could be target killed or killed when they proliferate again after induction. It has been proved that quiescent SCs exist in cancers such as melanoma, leukemia, breast cancer, pancreatic cancer, and liver cancer. ,,,,
Quiescent CSCs are resistant to cytotoxic drugs because such drugs (e.g., drugs that induce DNA damage) can only affect proliferating cells. Besides, CSCs are resistant to radiotherapy or chemotherapy because of other mechanisms. There mechanisms are related to the fact that CSCs have the properties of SCs. For instance, the efflux mechanism of CSCs results in cancer resistance to several drugs, repair reaction after DNA damage or low concentration of reactive oxygen species (ROS). , Therefore, it is crucial to the treatment and prevention of tumor relapse that quiescent CSCs are killed, their resistance to radiotherapy or chemotherapy is damaged, or they are prevented from proliferation.
| > Problems and Prospects|| |
Direct evidence that CSCs cause tumor metastasis is still lacking. With more and more reports , on the relationship between CSCs and tumor metastasis, it becomes clear that not all the tumor cells are involved in tumor metastasis. It is possible that only a small part of tumor cells that have the characteristics of SCs and the ability to invade play an important role in tumor metastasis. There cells can escape from autoimmune system and resist external damage, so they can induce new metastatic sites in certain microenvironment.
In sum, various molecular mechanisms regulate the differentiation, self-renewal, proliferation, chemotaxis, and resistance to cytotoxic drugs of CSCs. The mechanisms and individualized therapies should be further explored so that the invasion, metastasis, and resistance to radiotherapy or chemotherapy of CSCs could be reduced and the prognosis after surgery might be improved. As for solid tumors, they can be confined to the primary sites if the relationship between CSCs and tumor invasion or metastasis is clarified, CSCs are killed, or CSCs are prevented from invading the blood vessels from tumor stroma, or from invading or moving at metastatic sites within the blood vessels or lymphatic vessels. If so, the tumor can be removed completely, thus increasing the survival rate and life quality of patients.
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