The embryonic rest hypothesis of cancer development – an old XIX century theory revisited

In the middle of XIX century, two German pathologists Rudolf Virchow and Julius Cohnheim proposed the intriguing hypothesis that cancer may develop from cell remnants that remain in the developing organs following embryo- genesis. This hypothesis is known as the embryonic rest hypothesis of cancer development and was popular among pathologist in the 19th and 20th centuries and later on somehow abandoned. In fact the morphology of most primitive tumors often mimics developmentally early tissues, and such tumors may express markers that are characteristic for epiblast and/or germ line cells. This observation could reflect the phenomenon of dedifferentiation of somatic cells in which cancer develops to moreprimitivestateorincontrastapossibilitythatcanceroriginatesinprimitivestemcellscloselyrelatedtotheepiblast/germline. The identification of primitive epiblast/germline-derived so called very small embryonic/epiblast-like stem cells (VSELs) in adult organs raised the possibility that these cells may give rise to some malignancies. In addition VSELs may also support tumor growthbyprovidingstromaandareinvolvedinneovasculogenesis.Inthisreview,wewillpresentahypothesizethatVSELscould be a missing link that supports the rest- or germline-origin hypothesis of cancer development; however, further experimental evidence is needed to support this intriguing concept.