Recent advances in cancer stem cells
Introduction
In recent years, numerous cancers have been described as having a ‘cancer stem cell’ compartment. Alternative terminologies to cancer stem cells are cancer initiating cells [1, 2, 3•] and tumorigenic cancer cells [4]. Tumors recently described as having such populations of cells include cancers of the blood [1, 5••], breast [6••], brain [7•], pancreas [8], head and neck [9], and colon [2, 3•, 10•]. The purpose of this article is to bring attention to parallels between in vivo methods first used in hematopoietic stem cell research and recent publications in the solid tumor ‘cancer stem cell’ field. By doing so we hope to shed light onto why stem cell biologists view cancers from a ‘developmental paradigm’ and thus use certain nomenclatures such as the term ‘cancer stem cells.’ Viewing cancers from a developmental perspective has led to insights into tumor biology that otherwise would not be possible.
A ‘developmental paradigm’ of cancers emphasizes the hierarchy of cells present within a tumor [11]. This hierarchy by necessity implies cellular heterogeneity. Heterogeneity here does not refer to invasive endothelial cells, hematopoietic cells, or other non-cancer cells that infiltrate the tumor environment. Rather, it refers to differences in cancer cells within a single tumor. An example of one such difference is with surface antigen expression where cancer cells of a tumor do not all express the same antigens. More importantly, functional assays show that only a specific subset of cells within a tumor is able to propagate tumor growth in immunodeficient mice whereas other cells are unable to propagate tumor growth. It appears that cancer cells responsible for tumor propagation are able to self-renew as well as give rise to cells that cannot propagate tumor growth. Thus, the ‘cancer stem cell theory’ states that these tumor forming cells have two main properties that of self-renewal and differentiation [12, 13].
Section snippets
Normal hematopoietic stem cell markers and leukemia
Methods used in the isolation of ‘adult’ stem cell populations play a pivotal role in the definition of these cells. The best developed methods come from isolation of the hematopoietic stem cell (HSC) and the resultant hematopoietic lineage map [14]. Crucial methods for the in vivo study of hematopoiesis have been the ability to collect different hematopoietic cell populations by staining with various antibodies of interest in concert with sorting by magnetic bead and/or fluorescence activated
Solid tumor cancer studies
Utilizing concepts developed in the study of normal hematopoiesis and leukemic stem cells, solid tumors were also investigated. The first solid tumor to be studied utilizing methods described earlier was human breast cancer [6••]. Human breast tumor samples were analyzed for the expression of CD44 and CD24. As in AML, breast tumor cells were found to be heterogeneous in surface antigen expression. On the basis of the differences in surface antigen expression, human breast cancer cells were
Mouse modeling of mammary development and breast cancer
Insights to leukemogenesis were obtained through the study of normal mouse hematopoiesis and transgenic mouse leukemia models [24, 25, 26, 27, 28, 29, 30]. Recently, normal mouse breast stem and progenitor cells have been partially characterized. It has been known for some time that transplanting mouse breast tissue into recipient mice with surgically cleared mouse breast fat pads allows for regeneration of the lost fat pads [31, 32, 33]. Recently, it was shown that a single breast stem cell
Relevance of cancer stem cells to human disease
Possible implications of cancer stem cells to human disease are in the roles they play in tumor growth, metastasis, and relapse as all three are closely related to patient survival. It is not difficult to imagine a situation where a cancer stem cell escapes the primary tumor and imbeds itself at a distant site to initiate a metastatic tumor. Recent evidence suggests that leukemic stem cells are relatively resistant to standard cytotoxic treatments [43, 44], suggesting that these cells may lead
Conclusion
The theoretical advantage that isolation of cancer stem cells offers is the ability to study processes responsible for tumor propagation separately from the mechanisms present in the non-tumor forming cells. It remains to be seen whether known pathways already characterized in other stem cell systems have applicability to cancer stem cells. However, early evidence suggests that some pathways involved in normal stem cell self-renewal are important in cancer stem cells. An example of this is
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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