Abstract
Life starts with a zygote, which is formed by the fusion of a haploid sperm and egg. The formation of a blastomere by cleavage division (nuclear division without an increase in cell size) is the first step in embryogenesis, after the formation of the zygote. Blastomeres are responsible for reprogramming the parental genome as a new embryonic genome for generation of the pluripotent stem cells which then differentiate by Waddington’s epigenetic landscape to create a new life. Multiple authors over the past 150 years have proposed that tumors arises from development gone awry at a point within Waddington’s landscape. Recent discoveries showing that differentiated somatic cells can be reprogrammed into induced pluripotent stem cells, and that somatic cell nuclear transfer can be used to successfully clone animals, have fundamentally reshaped our understanding of tumor development and origin. Differentiated somatic cells are plastic and can be induced to dedifferentiate into pluripotent stem cells. Here, I review the evidence that suggests somatic cells may have a previously overlooked endogenous embryonic program that can be activated to dedifferentiate somatic cells into stem cells of various potencies for tumor initiation. Polyploid giant cancer cells (PGCCs) have long been observed in cancer and were thought originally to be nondividing. Contrary to this belief, recent findings show that stress-induced PGCCs divide by endoreplication, which may recapitulate the pattern of cleavage-like division in blastomeres and lead to dedifferentiation of somatic cells by a programmed process known as “the giant cell cycle”, which comprise four distinct but overlapping phases: initiation, self-renewal, termination and stability. Depending on the intensity and type of stress, different levels of dedifferentiation result in the formation of tumors of different grades of malignancy. Based on these results, I propose a unified dualistic model to demonstrate the origin of human tumors. The tenet of this model includes four points, as follows. 1. Tumors originate from a stem cell at a specific developmental hierarchy, which can be achieved by dualistic origin: dedifferentiation of the zygote formed by two haploid gametes (sexual reproduction) via the blastomere during normal development, or transformation from damaged or aged mature somatic cells via a blastomere-like embryonic program (asexual reproduction). 2. Initiation of the tumor begins with a stem cell that has uncoupled the differentiation from the proliferation program which results in stem cell maturation arrest. 3. The developmental hierarchy at which stem cells arrest determines the degree of malignancy: the more primitive the level at which stem cells arrest, the greater the likelihood of the tumor being malignant. 4. Environmental factors and intrinsic genetic or epigenetic alterations represent the risk factors or stressors that facilitate stem cell arrest and somatic cell dedifferentiation. However, they, per se, are not the driving force of tumorigenesis. Thus, the birth of a tumor can be viewed as a triad that originates from a stem cell via dedifferentiation through a blastomere or blastomere-like program, which then differentiates along Waddington’s landscape, and arrests at a developmental hierarchy. Blocking the PGCC-mediated dedifferentiation process and inducing their differentiation may represent a novel alternative approach to eliminate the tumor occurrence and therapeutic resistance.
Highlights
Tumors originate from a stem cell at a specific developmental hierarchy, which can be achieved by dualistic origin: dedifferentiation of the zygote formed by two haploid gametes via the blastomere during normal development, or transformation from damaged or aged mature somatic cells via a blastomere-like embryonic program
The birth of a tumor can be viewed as a triad that originates from a stem cell via dedifferentiation through a blastomere or blastomere-like program, which differentiates along Waddington’s landscape, and arrests at a developmental hierarchy
On the basis of the findings outlined above, we propose that the giant cell cycle represents a stress-induced endogenous mechanism for somatic cell dedifferentiation for generation of stem cells for tumor initiation
Summary
“Half a century of cancer research had generated an enormous body of observations about the behavior of the disease, but there were essentially no insights into how the disease begins and progresses to its life-threatening conclusions” [1]. In the past 50 years, cancer biologists have focused on a model in which cancer is viewed as arising from genetic and molecular alterations in somatic cells and tumors are interpreted as clusters of fast-replicating mutant cells that survive or die according to principles of via Darwinian evolution [2–4]. This simplified working model satisfies the desire, common in this era of molecular and genetic revolution, to find simple causes for complicated diseases. On the basis of this new knowledge, I propose a new, unified theory of human tumors, named the dualistic origin for human tumors This theory accounts for all tumors observed in oncopathology including embryonic/germ cell tumors, organ-derived tumors, and benign and malignant tumors. These terms will be used as described here to avoid any confusion that can arise from the use of tumor as a synonym for cancer, a practice observed in many articles in the oncology literature
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