Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts.

Abstract

A definitive test for developmental totipotency of mouse malignant teratocarcinoma cells was conducted by cloning singly injected cells in genetically marked blastocysts. Totipotency was conclusively shown in an adult mosaic female whose tumor-strain cells had made substantial contributions to all of the wide range of its somatic tissues analyzed; the clonally propagated cell lineage had therefore differentiated in numerous normal directions. The test cells were from "cores" of embryoid bodies of a euploid, chromosomally male (X/Y), ascites tumor grown only in vivo by transplantation for 8 years. The capacity of cells from the same source to differentiate, in a phenotypic male, into reproductively functional sperms, has been shown in our previous experiments [(1975) Proc. Nat. Acad. Sci. USA 72, 3585-3589]. Cells from this transplant line therefore provide material suitable for projected somatic and germ-line genetic analyses of mammalian differentiation based on "cycling" of mutation-carrying tumor cells through developing embryos. In some animals obtained from single-cell injections tumor-derived cells were sporadically distributed in developmentally unrelated tissues. These cases can be accounted for by delayed and haphazard cellular integration, and by a marked degree of sustained cellular developmental flexibility in early mammalian development, irrespective of certain classical "germ-layer" designations. All mosaic mice obtained have thus far been free of teratomas. In one case, the injected stem cell contributed only to the pancreas and gave rise to a malignancy resembling pancreatic adenocarcinoma. The high modal frequency of euploidy in these individually tested cells thus tends to indicate that a near-normal chromosome complement is sufficient for total restoration of orderly gene expression in a normal embryonic environment; it may also be necessary for teratoma stem-cell proliferation to be terminated there.

Differential expression of Protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples

“…Whereas normal stroma can postpone or prevent tumorigenesis, abnormal stromal components can promote tumor development. 28 It has been demonstrated for example, that PAR1 (as also PAR2) is expressed in the stromal microenvironment of malignant tumors whereas it is absent in both benign tumors and normal epithelium. 29 Reactive stromal myofibroblasts, local mast cells, macrophages, endothelium and vascular smooth muscle cells of the tumor microenvironment express PAR1 and likely to express FAK.…”

Participation of Adult Mouse Bone Marrow Cells in Reconstitution of Skin

“…Even teratocarcinoma cells were found to contribute to the formation of some normal tissues when injected into blastocysts. 20 Another aspect to note in the formation of tissues from progenitor/stem cells in vivo is that adult organs are often self-sufficient, ie, they can compensate cell loss without any supply of cells from other organs. Thus, significant repopulation of exogenous hepatocyte progenitor cells in the liver was observed only when the liver was severely damaged.…”

Stem cell pluripotency and transcription factor Oct4

“…By injecting embryonic carcinoma (EC) cells derived from the central portions of mouse embryoid bodies into blastocysts, Mintz and colleagues demonstrated that EC cells can contribute to the development of most of the tissues and cell lineages in the newly formed mosaics [2], [3]. These observations led them to conclude that these EC cells remain multipotent, despite being passaged in vivo as an ascites tumor for 8 years [2], [3]. Culture conditions were subsequently established that allowed the isolation of pluripotent embryonic stem (ES) cells from mouse embryos [4].…”