Cancer has been primarily considered to be a consequence of disorders in the tumor cells themselves, resulting in unrestrained cell growth and invasion. Mounting evidence in the past few years indicated that cancers might be the result of complex disorders in the interaction between the corresponding cell type with its microenvironment. Disorders in the microenvironment are viewed as a major cause for the breakdown of tissue homeostasis and tumor development. Cancer can therefore be considered as a ''disorganized tissue,'' with the cancer stem cells at the top of the hierarchy of fairly heterogeneous tumor tissues. This concept, first demonstrated in human acute myeloid leukemia, has attracted much attention among basic and clinical researchers.
Cancer stem cells are perceived, in analogy to normal stem cells, as the real culprit in tumor development, progression, and relapse. Several studies have implicated that cancer stem cells are responsible for metastasis and for tumor recurrence after initial tumor control by chemotherapy. Similarly to their normal counterparts, cancer stem cells are resistant to conventional treatment because of their slow proliferation rate. They have preserved the ability to self-renew and to generate large populations of more differentiated and heterogeneous descendants. In contrast to the strictly regulated hierarchical organization in normal tissue homeostasis, genetic instability and phenotypic plasticity allow cancer cells to dynamically enter and exit from stem-cell states. Despite all the controversies concerning their identification, the concept of cancer stem cells has provided a better understanding of intra-tumoral heterogeneity, tumor dormancy, and their propensity to develop resistance and recurrence.
Thus far, cancer stem cells, or tumor-initiating cells, have been defined by certain surface markers, and by their ability to engraft and form tumors when a relative low number of cells are implanted into immune-deficient mouse models. Some studies have reported putative cancer stem cells in established cancer cell lines in vitro. The significance and biologic relevance of such results obtained in long-term cultured cell populations with inherent genetic and phenotypic instability have, however, been severely challenged.
The first evidence for the existence of cancer stem cells was derived from hematological malignancies. Based on cellsurface marker expressions characteristic for normal hematopoietic stem cells, the same constellation has been applied to enrich leukemia-initiating cells. A small subset of such slowly dividing cells derived from patients with acute myeloid leukemia was able to induce leukemia in xenotransplant models, which are still considered to be the ultimate proof for the concept of leukemia stem cells. Major problems have been encountered in attempting to translate this knowledge into the clinic, though, as the prospective identification of leukemia stem cells, their efficient separation, and the definition of their biologic properties still constitute major challenges.