Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 285

is a ubiquitous aldehyde dehydrogenase family of enzymes, which catalyzes the oxidation of aromatic aldehydes to carboxyl acids. For instance, it has a role in conversion of retinol to retinoic acid, which is essential for survival.

The first solid malignancy from which CSCs were identified was breast cancer and these CSCs are the most intensely studied. Breast cancer stem cells have been enriched in CD44+CD24–/low, SP, ALDH+ subpopulations. However, recent evidence indicates that breast CSCs are very diverse. There is also evidence that CSC marker expression in breast cancer cells are heterogeneous and that there exist many subsets of breast CSC. Both CD44+CD24– and CD44+CD24+ cell populations are tumor-initiating cells; however, CSCs are most highly enriched using the marker profile CD44+CD49fhiCD133/2hi.

CSCs have been reported in many brain tumors. Stem-like tumor cells have been identified using cell surface markers including CD133, SSEA-1 (stage-specific embryonic antigen-1), EGFR, and CD44. However, there is uncertainty about the use of CD133 for identification of brain tumor stem–like cells because tumorigenic cells are found in both CD133+ and CD133– cells in some gliomas, and some CD133+ brain tumor cells may not possess tumor-initiating capacity. CSCs have also been reported in human colon cancer.

Metastasis is the major cause of tumor lethality in patients, but not every cell in the tumor has the ability to metastasize. This potential depends on factors that determine growth, ability to form new blood vessels, invasion of surrounding structures, and other processes of tumor cells. In many epithelial tumors, the epithelial-mesenchymal transition (EMT) is considered a crucial event in the metastatic process. EMT and the reverse transition from mesenchymal to an epithelial phenotype (MET) are involved in embryonic development, which involves disruption of epithelial cell homeostasis and the acquisition of a migratory mesenchymal phenotype. The EMT appears to be controlled by pathways such as WNT and transforming growth factor β (TGF-β) pathway. The important feature of EMT is the loss of membrane E-cadherin in adherent junctions, where β-catenin may play a significant role. Translocation of β-catenin from adherent junctions to the nucleus may lead to a loss of E-cadherin, and subsequently to EMT. There is evidence that nuclear β-catenin can transcriptionally activate EMT-associated target genes, such as the E-cadherin gene repressor SLUG (also known as SNAI2).

Recent data has supported the concept that tumor cells undergoing an EMT could be precursors for metastatic cancer cells, or even metastatic cancer stem cells. In the invasive edge of pancreatic carcinoma, a subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells has been defined. These cells exhibit significantly stronger migratory activity than their counterpart CD133+CXCR4– cells, but both cell subsets show similar tumor development capacity. Moreover, inhibition of the CXCR4 receptor led to reduced metastatic potential without altering tumorigenic capacity.

On the other hand, in breast cancer, CD44+CD24– cells are detectable in metastatic pleural effusions. By contrast, an increased number of CD24+ cells have been identified in distant spread in patients with breast cancer. Although there are only few data on mechanisms mediating spread in breast cancer, it is possible that CD44+CD24– cells initially metastasize and in the new site change their phenotype and undergo limited differentiation. These findings led to a new dynamic two-phase expression pattern concept based on the existence of two forms of cancer stem cells: stationary cancer stem cells (SCS) and mobile cancer stem cells (MCS). SCS are embedded in tissue and persist in differentiated areas throughout all tumor progression. The term MCS describes cells that are located at the tumor–host interface. There is evidence that these cells are derived from SCS through the acquisition of transient EMT.

Multiple CSCs have been reported in prostate, lung, and many other organs, including liver, pancreas, kidney, and ovary. In prostate cancer, the tumor-initiating cells have been identified in CD44+ cell subset as CD44+α2β1+, TRA-1–60+CD151+CD166+, or ALDH+ cell populations. Markers for lung cancer stem cells have been reported, including CD133+, ALDH+, CD44+, and oncofetal protein 5T4+.

The existence of cancer stem cells has several implications in terms of future cancer treatment and therapies. These include disease identification, selective drug targets, prevention of metastasis, and development of new intervention strategies.

Normal somatic stem cells are naturally resistant to chemotherapeutic agents. They produce various pumps, such as multidrug-resistant (MDR) pump, that pump out drugs and DNA repair proteins. They also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). Cancer stem cells that develop from normal stem cells may also produce these proteins, which could increase their resistance toward chemotherapeutic agents. The surviving CSCs then repopulate the tumor, causing a relapse. By selectively targeting CSCs, it would be possible to treat patients with aggressive, nonresectable tumors, as well as preventing patients from metastasizing and relapsing. The hypothesis suggests that upon cancer stem cells’ elimination, cancer could regress due to differentiation and/or cell death.

A number of studies have investigated the possibility of identifying specific markers that may distinguish cancer stem cells from the bulk of the tumor (as well as from normal stem cells). Proteomic and genomic signatures of tumors are also being investigated. In 2009, scientists identified one compound, salinomycin, that selectively reduces the proportion of breast cancer stem cells in mice by more than 100-fold relative to Paclitaxel, a commonly used chemotherapeutic agent.

The cell surface receptor interleukin-3 receptor-alpha (CD123) was shown to be overexpressed on CD34+CD38– leukemic stem cells (LSCs) in acute myelogenous leukemia (AML), but not on normal CD34+CD38– bone marrow cells. Jin et al. then demonstrated that treating AML-engrafted NOD/SCID mice with a CD123-specific monoclonal antibody impaired LSCs homing to the bone marrow and reduced overall AML cell repopulation, including the proportion of LSCs in secondary mouse recipients.