**3.3. Brief history of cancer stem cells (CSCs)**

History of cancer stem cells dates back to the nineteenth century. A hypothesis of cancer stem cells (CSCs) that have similar properties to stem cells (SCs) was first described by Rudolf Virchow and Julius Conheim in 1855 [23]. Virchow suggested that cancers arise from the activation of dormant cells present in mature tissue, which are remainders of embryonic cells (perhaps similar to cells now known as stem cells) [23]. Virchow believed that cancer is caused by severe irritation in the tissues, and his theory came to be known as chronic irritation theory. However, Conheim had suspected that the remaining embryonic cells from which cancers form during organogenesis were "lost."

In 1997, Bonnet and Dick described a subpopulation of cells with the presence of a specific surface marker CD34 (CD34+ ) and the absence of a CD38 marker (CD38<sup>−</sup> ) in patients with acute myeloid leukemia capable of inducing a cancerous disease after transplanting those cells to mice with an altered immunological system—leukemic-initiating cells [24, 25].

CSCs have already been identified in breast, lung, ovarian, prostate, gastric, colorectal cancer, and brain tumors [26].

It is estimated that in these malignancies, CSCs constitute <5% of all tumor cells [26].
