Human embryonic stem cells (HESCs) are the in vitro descendants of the pluripotent inner cell mass (ICM) of human blastocyst stage embryos. HESCs can be kept undifferentiated in culture or be differentiated to tissues representing all three germ layers, both in vivo and in vitro. These properties make HESC-based therapy remarkably appealing for the treatment of various disorders. Upon transplantation in vivo, undifferentiated HESCs rapidly generate the formation of large tumors called teratomas. These are benign masses of haphazardly differentiated tissues. Teratomas also appear spontaneously in humans and in mice. When they also encompass a core of malignant undifferentiated cells, these tumors are defined as teratocarcinomas. These malignant undifferentiated cells are termed embryonic carcinoma (EC), and are the malignant counterparts of embryonic stem cells. Here we review the history of experimental teratomas and teratocarcinomas, from spontaneous teratocarcinomas in mice to induced teratomas by HESC transplantation. We then discuss cellular and molecular aspects of the tumorigenicity of HESCs. We also describe the utilization of HESC-induced teratomas for the modeling of early human embryogenesis and for modeling developmental diseases. The problem of HESC-induced teratomas may also impede or prevent future HESC-based therapies. We thus conclude with a survey of approaches to evade HESC-induced tumor formation.

The tumorigenicity of human embryonic stem cells.

The p27Kip1 gene codes for a cyclin-dependent kinase inhibitor implicated in G1 arrest by transforming growth factor beta, cell-cell contact, agents that elevate cyclic AMP, and the growth-inhibitory drug rapamycin. p27 binds to and inhibits complexes formed by cyclin E-cdk2, cyclin A-cdk2, and cyclin D-cdk4. The involvement of p27 in the negative regulation of cell proliferation suggests that it may also function as a tumor suppressor gene. Using a combination of somatic cell hybrid panels and fluorescence in situ hybridization p27Kip1 has been mapped to the short arm of chromosome 12 at the 12p12-12p13.1 boundary, reported to harbor deletions and rearrangements in leukemia and mesotheliomas. In order to assess potential p27Kip1 gene alterations, we have screened a total of 147 human primary solid tumors and found no detectable cancer-specific mutations. These results argue that the often observed loss of antimitogenic transforming growth factor beta responsiveness in human cancer cells is not due to structural defects in p27Kip1.

https://cancerres.aacrjournals.org/content/canres/55/6/1211.full.pdf

p27Kip1: Chromosomal Mapping to 12p12–12p13.1 and Absence of Mutations in Human Tumors

Pathogenesis of adult testicular germ-cell tumors - a cytogenetic model

The aim of this review is to provide insight into the molecular mechanisms by which transforming growth factor-beta (TGF-beta) modulates cell cycle progression in different cell types. Particular attention is focused on the differences between these mechanisms in cells of epithelial origin and in mesenchymally derived cells. This is important because many transformed epithelial cells lose responsiveness to the growth-inhibitory effects of TGF-beta, thus generating a more fibroblast-like phenotype. Loss of negative growth control, including a lack of response to growth-inhibitory factors, is a common feature of many tumor cells. G1 phase cyclin-dependent kinases (cdks) and their inhibitors (ckis) are central to the pathways that regulate commitment to cellular division in response to positive as well as negative growth effectors. Many checkpoints are deregulated in oncogenesis, and this is often due to alterations in cyclin-cdk complexes. The loss of R-point regulation, in particular, can allow cell growth and division to proceed autonomously of external signals. This may occur due to either the aberrant expression of positive regulators, such as the cyclins and cdks, or the loss of negative regulators, such as the ckis. Beginning with a survey of the role of the cdks in the mammalian cell cycle, the review examines how cdk activity is modulated by cyclin binding, phosphorylation, and ckis, including the Ink4 proteins and the closely related inhibitors p21Cip1 and p27Kip1. Particular attention is paid to the role of p27Kip1 and p21Cip1 in the mechanisms of TGF-beta-induced suppression or stimulation of the cell cycle and how these mechanisms contrast between epithelial cells and cells of mesenchymal origin. Other aspects of TGF-beta signal transduction are discussed, including its effects on cyclin and cdk expression in various cell types, and the downstream targets of cdks and their modulation by TGF-beta and other growth factors are also discussed. These include proteins of the retinoblastoma family, and the related modulation of the transcriptional activity of the E2F family members. Finally, the role of cell cycle regulatory proteins in oncogenesis is review in view of the findings described here.

Cyclin-dependent kinase regulation during G1 phase and cell cycle regulation by TGF-beta.

Human embryonic stem cells (HESCs) and induced pluripotent stem cells (HiPSCs) offer an immense potential as a source of cells for regenerative medicine. However, the ability of undifferentiated HESCs and HiPSCs to produce tumors in vivo presents a major obstacle for the translation of this potential into clinical reality. Therefore, characterizing the nature of HESC- and HiPSC-derived tumors, especially their malignant potential, is extremely important in order to evaluate the risk involved in their clinical use. Here we review recent observations on the tumorigenicity of human pluripotent stem cells. We argue that diploid, early passage, HESCs produce benign teratomas without undergoing genetic modifications. Conversely, HESCs that acquired genetic or epigenetic changes upon adaptation to in vitro culture can produce malignant teratocarcinomas. We discuss the molecular mechanisms of HESC tumorigenicity and suggest approaches to prevent tumor formation from these cells. We also discuss the differences in the tumorigenicity between mouse embryonic stem cells (MESCs) and HESCs, and suggest methodologies that may help to identify cellular markers for culture adapted HESCs.

The tumorigenicity of diploid and aneuploid human pluripotent stem cells.

i(12p) in a malignant ovarian tumor

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i(12p) in a malignant ovarian tumor