Cancer stem cells (CSCs) are rare, immortal cells within a tumor that display the characteristics of stemness. Stemness means that a cell has the ability to perpetuate its lineage, give rise to differentiated cells, as well as to interact with its environment to maintain a balance between quiescence, proliferation, and regeneration. CSCs can self-renew by dividing, and they can also give rise to the many cell types that constitute the tumor. They are able to form tumors, sustain cancer progression, interact with their environment in search for key survival factors, and persist after therapy. CSCs have been found in various types of human tumors and might be attractive targets for cancer treatment (Nature.com).
Cancer Stem Cells vs. Cancer Cells
Malignant solid tumors are composed of heterogeneous populations of cells with varying levels of malignity. Also, different types of cells exist among the circulating cancerous cells of a leukemia. Whereas CSCs can reproduce themselves and sustain the cancer, other cancer cells can cause problems, but they cannot initiate tumors. This difference is crucial when evaluating anti-cancer therapies. If radiation or chemotherapy shrink tumors, but do not kill CSCs, the tumor will grow back (Papaccio et al., 2017).
Stochastic vs. Cancer Stem Cell Model
The CSC theory is one of the most controversial topics in current biomedical research. The hierarchical stem cell model puts CSCs at the top of the hierarchically organized tumor because of their tumorigenic ability, but the stochastic model proposes that all tumor cells can undergo mutations and become tumorigenic (Wang et al., 2014).
Cultivation and Characterization
- Cancer Stem Cell Culture
Currently, the greatest obstacle in CSC research is the isolation and purification of sufficient numbers of functional, homogenous CSC populations. The lack of a primary model system means that research is forced to rely on indirect readouts generated by alternative model systems and tests. The PromoCell 3D Tumorsphere Medium XF has been designed to allow an extended serial 3D tumorsphere culture, exploiting the biologic features of CSCs, such as anoikis resistance and self-renewal. This culture system is also applicable for in vitro models of metastasis (Lee et al., 2016).
- Cancer Stem Cell-Based Assays
The gold standard functional in vivo assay for CSCs is the serial transplantation into orthotopic sites of immunocompromised mice. However, this is labor-intensive, and the results can be difficult to interpret. Established in vitro methods include assays for serial colony-forming units (CFU) in semi-solid media and label-retention, as well as testing for the formation of serially passageable tumorspheres in a 3D suspension culture (Rycaj and Tang, 2015).
- Cancer Stem Cell Markers
Various approaches have been undertaken to characterize CSCs based on marker detection. These include staining of intra- and extracellular molecules, as well as measuring the activity of certain cellular enzymes, or small molecule transporters. However, research is hindered by the heterogeneity of CSCs in different cancers, as well as a lack of specificity, consistency and correlation of established markers with functional CSC features, such as tumorigenesis (Pan et al., 2015).
Role of cancer stem cells
- Cancer Stem Cells in Solid Tumors
Solid cancers are organized hierarchically, with a small number of CSCs driving tumor growth, repopulation after therapy and metastasis (Vlashi and Pajonik, 2015). CSCs were first identified in breast cancer and melanoma. Today, CSCs have been found in a number of solid tumors, where they play a pivotal role for tumor progression (Dawood et al., 2014).
- Cancer Stem Cells in Hematological Malignancies
Cancer stem cells have been found in leukemias as well, where they also have the ability of renewing themselves, which means they are responsible for long-term disease maintenance. Researchers postulate that patient outcome is linked closely to the properties of CSCs and that curing the disease depends on eradication of CSCs (Thomas and Majeti, 2017).
Persistence and Tumor Therapy
- Drug Resistance in Cancer Stem Cells
Many researchers believe relapse is caused by quiescent CSCs that are able to evade current therapeutic regimens by using protective mechanisms mediated by their stem cell properties. A landmark study (Chen et al., 2012) showed that a restricted population of CSCs can promote tumor re-growth after chemotherapy.
- Cancer Stem Cell Therapy
CSCs play a major role in the therapy of cancer, and their elimination could lead to permanent remission or even cure. New anticancer strategies, including immunotherapeutic approaches, need to be tested for their efficacy against CSCs (Gammaitoni et al., 2014). One major obstacle is selectively targeting CSCs without harming healthy tissue stem cells.