The "life code": A theory that unifies the human life cycle and the origin of human tumors.

Abstract

Tumors arise from the transformation of normal stem cells or mature somatic cells. Intriguingly, two types of tumors have been observed by pathologists for centuries: well-differentiated tumors and undifferentiated tumors. Well-differentiated tumors are architecturally similar to the tissues from which they originate, whereas undifferentiated tumors exhibit high nuclear atypia and do not resemble their tissue of origin. The relationship between these two tumor types and the human life cycle has not been clear. Here I propose a unifying theory that explains the processes of transformation of both tumor types with our life cycle. Human life starts with fertilization of an egg by a sperm to form a zygote. The zygote undergoes successive rounds of cleavage division to form blastomeres within the zona pellucida, with progressive decreases in cell size, and the cleaved blastomeres then compact to form a 32-cell or a "64n" morula [n = 1 full set of chromosomes]. Thus early embryogenesis can be interpreted as a progressive increase in ploidy, and if the zona pellucida is considered a cell membrane and cleavage is interpreted as endomitosis, then the 32-cell morula can be considered a multinucleated giant cell (or 64n syncytium). The decrease in cell size is accompanied by an increase in the nuclear-to-cytoplasmic (N/C) ratio, which then selectively activates a combined set of embryonic transcription factors that dedifferentiate the parental genome to a zygotic genome. This process is associated with a morphologic transition from a morula to a blastocyst and formation of an inner cell mass that gives rise to a new embryonic life. If the subsequent differentiation proceeds to complete maturation, then a normal life results. However, if differentiation is blocked at any point along the continuum of primordial germ cell to embryonic maturation to fetal organ maturation, a well-differentiated tumor will develop. Depending on the level of developmental hierarchy at which the stem cell differentiation is blocked, the resulting tumor can range from highly malignant to benign. Undifferentiated tumors are derived from mature somatic cells through dedifferentiation via a recently described reprogramming mechanism named the giant cell life cycle or the giant cell cycle. This mechanism can initiate "somatic embryogenesis" via an increase in ploidy ranging from 4n to 64n or more, similar to that in normal embryogenesis. This dedifferentiation mechanism is initiated through an endocycle and is followed by endomitosis, which leads to the formation of mononucleated or multinucleated polyploid giant cancer cells (PGCCs), that is, cancer stem-like cells that mimic the blastomere-stage embryo. The giant cell life cycle leads to progressive increases in the N/C ratio and awakens the suppressed embryonic reprogram, resulting in mature somatic transformation into undifferentiated tumors. Thus, the increase in ploidy explains not only normal embryogenesis for well-differentiated tumors but also "somatic embryogenesis" for undifferentiated tumors. I refer to this ploidy increase as the 'life code". The concept of the "life code" may provide a simple theoretical framework to guide our immense efforts to understand cancer and fight this disease.