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Review
. 2020 Mar 4;11(10):2887-2920.
doi: 10.7150/jca.41324. eCollection 2020.

Evidence for Immortality and Autonomy in Animal Cancer Models Is Often Not Provided, Which Causes Confusion on Key Issues of Cancer Biology

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Free PMC article
Review

Evidence for Immortality and Autonomy in Animal Cancer Models Is Often Not Provided, Which Causes Confusion on Key Issues of Cancer Biology

Xixi Dou et al. J Cancer. .
Free PMC article

Abstract

Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase roughly 250 years ago, establishing morphological traits of tumors for pathologic diagnosis, and setting immortality and autonomy as indispensable criteria for neoplasms. A century ago, medical doctors, biologists and chemists started to enhance "experimental cancer research" by establishing many animal models of chemical-induced carcinogenesis for studies of cellular mechanisms. In this second phase, the two-hit theory and stepwise carcinogenesis of "initiation-promotion" or "initiation-promotion-progression" were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. The last 40 years are the third incarnation, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many lesions had already been collected from animals for analyses of molecular mechanisms of "cancer" before the lesions became autonomous. We herein review the monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in most animal models. It is imperative to resume many forerunners' work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.

Keywords: Transgenic; autonomy; cancer; cancer stem cells; carcinogenesis; immortality; senescence..

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The Solt-Farber's “resistant hepatocyte” model of liver carcinogenesis in the rat. A toxic dose of diethylnitrosamine (DEN) will 1) cause liver necrosis and 2) create initiated hepatocytes. Two weeks later, when the liver has recovered from the necrosis, the rat will be given a low dose of 2-acetylaminofluorene (AAF) for two weeks, function of which is to inhibit proliferation, so-called mitoinhibition, of hepatocytes, but the initiated cells are resistant to this inhibition. In the middle of AAF treatment, hepatectomy will be performed to remove two-thirds of the liver, which provides a strong impetus for regeneration. Because normal hepatocytes are mitoinhibited, all regeneration pressure is imposed onto the initiated cells, driving them to proliferate robustly and form nodules. The image at the left shows these nodules visualized by immunohistochemical staining of the P form of glutathione S transferase, a marker for the nodular cells, in the three remaining lobes of the liver four weeks post cessation of AAF treatment ,. These nodules will regress afterwards but some new focal cells, which can proliferate spontaneously and are coined by Farber as “phenotype 4”, will later develop from some of the nodules ,. One or several of these phenotype-4 lesions will eventually progress to overt cancers.
Figure 2
Figure 2
Illustration of a speculative difference at the time point for the establishment of immortality and autonomy between the tumorigenesis in most animal models and that in most human situations. In humans, immortality (Immort.) and autonomy (Auto.) may occur at a very early time point, thus establishing small lesions as genuinely benign or malignant neoplasms. In contrast, tumorigenesis in most animal models is a stepwise procedure of initiation, promotion and, in some cases, progression as well. Initiated cells are still mortal and thus are not neoplastic. Immortality and autonomy in animal models occur at late promotion or at the progression.
Figure 3
Figure 3
Illustration of our three-hit hypothesis. Coupling the traditional two-hit principle with the initiation-promotion theory leads us to a supposition that the first genetic hit establishes initiated cells that are still mortal and non-autonomous, whereas the second hit creates immortality and autonomy, thus establishing neoplastic cells, either benign or malignant. Since formation of benign neoplasms also requires two genetic hits, we extrapolate that, in some animal models and probably also in many human situations, establishment of malignant morphologies and behaviors requires a third hit on the relevant gene(s).
Figure 4
Figure 4
Reversion of pluripotent cells between normal and cancers. Embryonic (e) or induced (i) pluripotent stem (PS) cells introduced into the blastocyst in the uterus can develop to live animals (a). However, if the cells are transplanted to extrauterine sites of adult animals, they will likely develop to teratomas or teratocarcinomas (b). If teratocarcinoma cells are inoculated into the blastocyst, they will be incorporated into the developing embryo, and the tissues of the animal developed from the embryo will be chimeric, i.e. containing cells from both the embryo and the cancer (c). Moreover, if inoculation of the nuclei isolated from the Kucké renal cancer cells of the frog origin into enucleated frog eggs, the eggs can hatch out live tadpoles with all tissues normal (d).
Figure 5
Figure 5
Depiction of the “coercion hypothesis”. Our manipulation, say as a transfected cDNA (the large black triangle in the cytoplasm of Cell A) or as a transgene or a gene-knockout on the chromosome 17 (black dot in Cell A), coerces the primary cell into incessantly replicating and manifesting transformed morphology or behavior, such as colony formation in agar. The relentless proliferation will eventually lead to spontaneous occurrence of the epigenetic (red dots on the DNA of chromosomes 8 and 22 in Cell B) or genetic (black dots on the DNA of chromosomes 8 and 22 in Cell C) alterations that establish immortality and autonomy, making the cell truly neoplastic in behavior. Continuous proliferation will also cause spontaneous occurrence of the epigenetic (small red triangles on the DNA of chromosomes 8 and 22 in Cell B) or genetic (small black triangles on the DNA of chromosomes 8 and 22 in Cell C) alterations that establish neoplastic morphology. This is to say that immortality and autonomy as “the behavior aspect” of neoplastic property, as well as “the morphology aspect” of neoplastic property, may sometimes be controlled separately by different sets of epigenetic or genetic alterations, i.e. different sets of “hits”. Moreover, the cell authentically transformed via epigenetic mechanisms (Cell B) may initially be reversible back to the normal, but later it will likely develop such genetic alterations that make the cell lose the reversibility and progress into the state of Cell C. If our manipulation is made in a controllable manner and is withdrawn early, the primary cell (Cell A) will no longer manifest the transformed morphology and behavior and will undergo senescent death (if the cell is in a culture dish) or both senescent death and apoptosis (if the cell is in a live animal). However, the truly transformed cells (Cells B and C) may retain their neoplastic properties sustained by the epigenetic or genetic alterations, unless some extrinsic factors (such as a chemical) cause the cells to circumvent or override the epigenetic or genetic alterations and make the cells reverse back to the normal state with or without retaining the alterations. In other words, neoplastic morphology and behavior incurred by our manipulation, an extrinsic factor, are inauthentic, but those caused intrinsic epigenetic or genetic alteration(s) are authentic.

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