Abstract
The relationships between cancer and stemness have a long history that is traced here. From the mid-19th century when the first theory on the embryonic origin of cancer was formulated to works on embryonal carcinoma cells in the mid-20th century, many steps have been crossed leading to the current cancer stem cell theory postulating that tumor growth is supported by a small fraction of the tumoral cells that have stem-like properties. However, in the last fifteen years, many works regularly encourage us to revise the concept of cancer stem cell. This article mentions key results that lead to a new perspective where cancer stem cells are primarily seen as cells exhibiting increased epigenetic plasticity and increased gene expression variability. This perspective suggests new therapeutical interventions consisting in stabilizing gene expression to control cancer cell proliferation and prevent stochastic gene expression variations that could lead to therapeutic resistance.
Highlights
It is interesting to note that Hugo Ribbert (1855-1920), professor of pathology in Bonn, formulated a modified version of Cohnheim’s theory considering that sequestration of undifferentiated cells could take place during development, and during the life of the individual because such cells could be generated if a lack of “tissue tension” appears
These ideas had a great influence because tumor cells have been considered during the following decades as welldifferentiated cells that have become dedifferentiated. This was the opposite of Cohnheim’s conception. It was only in the 1960s and 1970s that new works on teratocarcinomas renewed in a different modern context the question of the role of stem cells in the genesis of cancers
It is logically that, based on teratomas, on the more aggressive tumor type teratocarcinomas, and on the very aggressive cancer embryonal carcinoma consisting only in poorly differentiated embryonal carcinoma (EC) cells, efforts were made to characterize the potential role of undifferentiated cells in tumorigenesis [4, 5]
Summary
The last point is essential because, contrary to the initial hypothesis that these tumors develop from poorly differentiated germ cells, it showed that highly undifferentiated cells of the early embryo, and not just primordial germ cells, are capable of generating teratomas Stevens referred to this type of cell as a “pluripotent embryonic stem cell” (the origin of the term embryonic stem (ES) cell [1]), a term that was long interchangeable with that of EC cells [1, 2]. The production of the first lines of human ES cells arrived in 1998 thanks to two groups that independently isolated them from aborted embryos [25] or embryos fertilized in vitro [26] These works may seem late when considering the availability of markers necessary for the identification of human ES and EC cells, and of ES cell isolation techniques that have been established for a long time for mice and are comparable for human cells. This delay can be explained by difficulties in obtaining human embryos allowing this isolation and especially by the reluctance of many researchers on works that cause problems of legal nature, and political and moral dilemmas
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