The Microenvironment of Breast Cancer Stem Cells

Abstract

Ernst Haeckel first described the term “stem” as a concept for the evolution or organisms. For representation purpose he described the ancestor organism as a “stem” from which all the other organisms evolved. Arthur Pappenheim later adopted this concept in the context of cells, and he elegantly placed the “stem cell” in the centre in cartoon from which all the blood cells arise describing hematopoiesis (Ramalho-Santos and Willenbring, 2007). The concept was carried forward and the term “cancer stem cell” was first coined in 1980 (Carney et al., 1982) where the authors described the stem cell origin of lung cancer cells. The difficulty in isolation and the absence of specific markers of cancer stem cell stalled the research in this area. However a decade later Bonnet and Dick successfully isolated CSC in AML which then incited the development in the field of cancer stem cells (Bonnet and Dick, 1997). Their discovery was later supported by many groups, which also resulted in isolation of CSC from a variety of malignancies including solid tumors. Now a large body of evidence suggests that cancer comprises of different population of cells with various tumorogenic potentials. The tumor cells follow a hierarchy, where the subset capable of self-renewal, generate the tumor heterogeneity and are called cancer stem cells (CSC). Very low number of these cancer stem cells generates tumors in immunocompromised mice whereas large number of non-CSCs fails to generate tumors. CSCs have been characterized based on their ability to form colonies in soft agar and their ability to form spheres in serum free media. The generation of tumors in immunocompromised mice however remains the gold standard. Another characteristic of CSC is their ability to resist the action of common chemotherapeutic drugs which is attributed to higher expression of ABC transporters and their slow cycling nature. Further it has also been documented that these CSCs have activated signaling pathways as in the case of normal stem cells. Hence CSCs are distinct from other non-CSC in many respects. Cancer stem cells have been isolated based on membrane markers. One of the characteristics is their ability to efflux the Hoechst dye. However this ability to efflux the dye is also attributed to membrane ABC transporter ABCG2. ABCG5 has been used as a cancer stem cell marker as it pumps out the drug doxorubicin. ALDH1 has the ability to convert retinol to retinoic acid, which has diverse role in cell physiology, and this activity is used as a marker for CSC. CD 44, CD 133, EpCAM and CD 90 are also abundantly expressed in CSCs and are used to isolate or enrich CSC (Visvader and Lindeman, 2008). A number of groups have isolated CSC based on these markers however a robust marker for CSC still remains to be identified.