Biomedical Engineering Reference
In-Depth Information
2.1.1 Transplantability
In 1952, Harry Green pointed out that embryonic and cancer tissues, but not
normal or hyperplastic tissues, will grow in immune-privileged sites in ''alien''
animals (Green, 1952). Transplantable tumor cells, the so-called tumor-initiat-
ing cells, were found, through dilution studies, to comprise from 1 in 30 to 1 in
1,000 of the cells in solid cancers (Reinhard et al., 1952a; Hewitt, 1952). For
example, to achieve a success rate of 50% in transplantation requires the
injection of 300 adenocarcinoma cells (Reinhard et al., 1952b).
2.1.2 Growth In Vitro
The frequency of tumor-initiating cells was later found to be of the same order
of magnitude as the frequency of cells that survive and grow in soft agar. In
1955, Puck and Marcus developed the soft agar culture method (Puck and
Marcus, 1955). Using this approach, Salmon (1952) found that 1 in 1,000 to 1
in 100,000 cells would form colonies (called ''tumor colony-forming units'').
This range of proportions of tumor colony-forming units is similar to the
proportions found more recently for leukemic tumor-initiating cells (Suther-
land et al., 1996; Bonnet and Dick, 1997; Lapidot et al., 1994). The rediscovery
of the properties of tumor growth in vitro and tumor initiation after transplan-
tation has served as a stimulus for the present resurgence in interest in cancer
stem cells.
2.1.3 Resistance to Therapy
The ability of a small population of tumor cells to resist radiation therapy was
studied using a library of transplantable HCCs in rats developed by the late
Harold Morris at Howard University (Morris and Meranze, 1974). Character-
ization of the cellular composition and biological behavior of Morris hepato-
mas in the 1960 s revealed that these cancers contained cells with stem cell-like
characteristics including the ability to be cultured in vitro (Morris andMeranze,
1974). Transplantation of the Morris hepatomas revealed heterogeneity in
growth properties. Some of the Morris hepatomas could be transplanted by
means of just a few cells, which then grew very quickly, whereas others could
only be transplanted by means of large numbers of cells and grew very slowly
(Morris and Meranze, 1974; Looney et al., 1971).These findings demonstrated
the first property of cancer stem cells noted above, i.e., transplantability.
Finally, extensive studies on the response to irradiation treatment, by William
Looney's group (Kovacs et al., 1977), demonstrated that after high-dose radia-
tion, the tumors were able to regrow, indicating the presence of a therapy-
resistant cancer stem cell. More recently, as an example of resistance to therapy,
highly tumorigenic subpopulations of cancer-initiating cells derived from
human glioblastomas were found to resist radiation because of their increased
protection against DNA damage (Rich, 2007), thus supporting the idea
