Cancer stem cells: A promising concept and therapeutic challenge

Cancer has been primarily considered to be a consequence ofdisorders in the tumor cells themselves, resulting in unre-strained cell growth and invasion. Mounting evidence in thepast few years indicated that cancers might be the result ofcomplex disorders in the interaction between the correspond-ing cell type with its microenvironment. Disorders in themicroenvironment are viewed as a major cause for the break-down of tissue homeostasis and tumor development. Cancercan therefore be considered as a ‘‘disorganized tissue,’’ withthe cancer stem cells at the top of the hierarchy of fairly het-erogeneous tumor tissues. This concept, first demonstrated inhuman acute myeloid leukemia, has attracted much attentionamong basic and clinical researchers.

Cancer stem cells are perceived, in analogy to normal stemcells, as the real culprit in tumor development, progression, andrelapse. Several studies have implicated that cancer stem cells areresponsible for metastasis and for tumor recurrence after initialtumor control by chemotherapy. Similarly to their normal coun-terparts, cancer stem cells are resistant to conventional treatmentbecause of their slow proliferation rate. They have preserved theability to self-renew and to generate large populations of moredifferentiated and heterogeneous descendants. In contrast to thestrictly regulated hierarchical organization in normal tissuehomeostasis, genetic instability and phenotypic plasticity allowcancer cells to dynamically enter and exit from stem-cell states.Despite all the controversies concerning their identification, theconcept of cancer stem cells has provided a better understandingof intra-tumoral heterogeneity, tumor dormancy, and their pro-pensity to develop resistance and recurrence.

Thus far, cancer stem cells, or tumor-initiating cells, havebeen defined by certain surface markers, and by their abilityto engraft and form tumors when a relative low number ofcells are implanted into immune-deficient mouse models.Some studies have reported putative cancer stem cells inestablished cancer cell lines in vitro. The significance and bio-logic relevance of such results obtained in long-term culturedcell populations with inherent genetic and phenotypic insta-bility have, however, been severely challenged.

The first evidence for the existence of cancer stem cellswas derived from hematological malignancies. Based on cell-surface marker expressions characteristic for normal hemato-poietic stem cells, the same constellation has been applied toenrich leukemia-initiating cells. A small subset of such slowlydividing cells derived from patients with acute myeloid leuke-mia was able to induce leukemia in xenotransplant models,which are still considered to be the ultimate proof for theconcept of leukemia stem cells. Major problems have beenencountered in attempting to translate this knowledge intothe clinic, though, as the prospective identification of leuke-mia stem cells, their efficient separation, and the definition oftheir biologic properties still constitute major challenges.

Moreover, the leukemia stem cells have recently been shownto be fairly heterogeneous. The clinical relevance of leukemiastem cell research, the role of cancer stem cells in develop-ment of refractoriness, and novel strategies to overcome thisresistance is reviewed by Buss and Ho, pp. 2328.

Putative cancer stem cells have been identified in severalother solid tumors based on the expression of some typicalstem cell surface markers and their growth potential follow-ing isolation. Conceptually and in analogy to normal tissues,the number of cancer stem cells should be small within agiven tumor cell population. Genetic modifications and inter-actions with the tumor microenvironment may affect thenumber of cancer stem cells that have accumulated. So far nomarkers, single or combined, could be defined unequivocallyto specifically identify cancer stem cells in solid tumors andto localize them within their particular microenvironment.

Recognition of cancer stem cells is further complicated byrecent observations demonstrating phenotypic plasticity incancer cell populations both in culture and in tumors bywhich differentiated tumor cells may acquire stem cell traitsand thus increase the stem cell pool. Characteristics of cancerstem cells and their phenotypic plasticity with, for example,acquisition of mesenchymal properties by epithelial cells, theso-called epithelial-mesenchymal transition (EMT), as well asthe potential role of such transitions in cancer stem cellbehavior are reviewed by Scheel and Weinberg, pp. 2310.

The niche is the environment in which stem cells resideand is responsible for maintaining the self-renewal capacityand an undifferentiated state, as exemplified by the bone mar-row for hematopoietic stem cells. Identification of the mecha-nisms and signaling processes between tumor and stromal cellswithin the niche has been complicated by the fact that stemcells represent such a rare population and are difficult to iden-tify in vivo. As the transcription factors Oct4, Nanog, andSox2 are essential regulators for maintaining stemness of em-bryonic stem cells, it has been suggested that they might alsoplay a role in maintenance of cancer stem cells.

As reviewed in detail by Cabarcas, Mathews and Farrer,pp. 2315, evidence is emerging that the factors responsiblefor maintaining the cancer stem cell also utilize the samecell-signaling pathways traditionally used to maintain proc-esses such as inflammation, EMT, hypoxia, and angiogenesis.

Finally, Sun and Wang, pp. 2337, reported in an originalpaper that c-Met could serve as a novel marker for headneck squamous cell carcinoma cells (HNSCC) recoveredfrom heterotransplants of fresh tumor specimens, and thatthe c-Metþ HNSCC population had cancer stem cell capaci-ties and were highly chemoresistant and metastatic.

We are very grateful to all the authors for their excellentcontributions.

Anthony Ho and Norbert Fusenig

Editorial

Int. J. Cancer: 129, 2309 (2011) VC 2011 UICC

International Journal of Cancer

IJC