Review

Authors: Christian Winter, Andreas Hiester

Germ cell cancers are the most common solid tumors among men between 15 and 40 years. Non-seminomatous germ cell tumors (NSGCTs) represent a unique and exclusive cohort of germ cell tumor patients. Non-seminoma can harbor different histologic components. The most commonly found histologies are embryonal cell cancer, teratoma, yolk sack tumor and choriocarcinoma, as well as teratocarcinoma and seminoma, in combination with non-seminomatous germ cell tumors histologic types. The clinical definition of stage I non-seminoma is the absence of metastatic lesions on imaging and normal tumor markers. The cure rate for clinical stage I NSGCT is 99% and this can be achieved by three therapeutic strategies: Active surveillance with treatment at the time of relapse, retroperitoneal lymph node dissection or adjuvant chemotherapy. The balancing of these various strategies should always be based on an individual risk profile of NGSCG patient depending on the lymphovascular invasion of the tumor.

PubMed: 33996471
DOI: 10.1016/j.ajur.2021.03.001

Authors: G R Martin

This report describes the establishment directly from normal preimplantation mouse embryos of a cell line that forms teratocarcinomas when injected into mice. The pluripotency of these embryonic stem cells was demonstrated conclusively by the observation that subclonal cultures, derived from isolated single cells, can differentiate into a wide variety of cell types. Such embryonic stem cells were isolated from inner cell masses of late blastocysts cultured in medium conditioned by an established teratocarcinoma stem cell line. This suggests that such conditioned medium might contain a growth factor that stimulates the proliferation or inhibits the differentiation of normal pluripotent embryonic cells, or both. This method of obtaining embryonic stem cells makes feasible the isolation of pluripotent cells lines from various types of noninbred embryo, including those carrying mutant genes. The availability of such cell lines should made possible new approaches to the study of early mammalian development.

Topics: Animals; Blastocyst; Cell Differentiation; Cell Line; Cells, Cultured; Culture Media; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Teratoma

PubMed: 6950406
DOI: 10.1073/pnas.78.12.7634

Review

Authors: Chunfang Liu, Asad Moten, Zhan Ma...

The completion-of-tumor hypothesis involved in the dynamic interplay between the initiating oncogenic event and progression is essential to better recognize the foundational framework of tumors. Here we review and extend the gametogenesis-related hypothesis of tumors, because high embryonic/germ cell traits are common in tumors. The century-old gametogenesis-related hypothesis of tumors postulated that tumors arise from displaced/activated trophoblasts, displaced (lost) germ cells, and the reprogramming/reactivation of gametogenic program in somatic cells. Early primordial germ cells (PGCs), embryonic stem (ES) cells, embryonic germ cells (EGCs), and pre-implantation embryos at the stage from two-cell stage to blastocysts originating from fertilization or parthenogenesis have the potential to develop teratomas/teratocarcinomas. In addition, the teratomas/teratocarcinomas/germ cells occur in gonads and extra-gonads. Undoubtedly, the findings provide strong support for the hypothesis. However, it was thought that these tumor types were an exception rather than verification. In fact, there are extensive similarities between somatic tumor types and embryonic/germ cell development, such as antigens, migration, invasion, and immune escape. It was documented that embryonic/germ cell genes play crucial roles in tumor behaviors, e.g. tumor initiation and metastasis. Of note, embryonic/germ cell-like tumor cells at different developmental stages including PGC and oocyte to the early embryo-like stage were identified in diverse tumor types by our group. These embryonic/germ cell-like cancer cells resemble the natural embryonic/germ cells in morphology, gene expression, the capability of teratoma formation, and the ability to undergo the process of oocyte maturation and parthenogenesis. These embryonic/germ cell-like cancer cells are derived from somatic cells and contribute to tumor formation, metastasis, and drug resistance, establishing asexual meiotic embryonic life cycle. p53 inhibits the reactivation of embryonic/germ cell state in somatic cells and oocyte-like cell maturation. Based on earlier and our recent studies, we propose a novel model to complete the gametogenesis-related hypothesis of tumors, which can be applied to certain somatic tumors. That is, tumors tend to establish a somatic asexual meiotic embryonic cycle through the activation of somatic female gametogenesis and parthenogenesis in somatic tumor cells during the tumor progression, thus passing on corresponding embryonic/germ cell traits leading to the malignant behaviors and enhancing the cells' independence. This concept may be instrumental to better understand the nature and evolution of tumors. We rationalize that targeting the key events of somatic pregnancy is likely a better therapeutic strategy for cancer treatment than directly targeting cell mitotic proliferation, especially for those tumors with p53 inactivation.

Topics: Female; Gametogenesis; Germ Cells; Humans; Pregnancy; Teratocarcinoma; Teratoma; Tumor Suppressor Protein p53

PubMed: 33940178
DOI: 10.1016/j.semcancer.2021.04.018

Authors: J Devkota, S White

Precise localization, detection, and recognition of minor changes in testicular lesions are important because teratocarcinoma is notorious for manifesting as secondaries at the time the primary site is obvious to the clinician. In the past, questionable enlargement of the testis due to significant pathology required numerous radiographic invasive special procedures to provide a correct diagnosis. Due to the advent of the sophisticated digital ultrasound imager with high frequency quarter wave transducer, it is possible to detect minor changes in the tissue character of the testis, thus enabling the physician to tackle primary neoplasms prior to distant spread.In our case we were able to detect the abnormality in the testis, but unfortunately a large secondary abnormal mass was present. Even at that stage we were able to map out the extent of the lesion which was beneficial to the surgeon and the patient. Ultrasound studies were utilized in serial follow-up studies.

Topics: Adult; Humans; Male; Teratoma; Testicular Neoplasms; Ultrasonography

PubMed: 7401191
DOI: No ID Found

Review

Authors: Olga Gordeeva

The transforming growth factor-β (TGFβ) family factors induce pleiotropic effects and are involved in the regulation of most normal and pathological cellular processes. The activity of different branches of the TGFβ family signaling pathways and their interplay with other signaling pathways govern the fine regulation of the self-renewal, differentiation onset and specialization of pluripotent stem cells in various cell derivatives. TGFβ family signaling pathways play a pivotal role in balancing basic cellular processes in pluripotent stem cells and their derivatives, although disturbances in their genome integrity induce the rearrangements of signaling pathways and lead to functional impairments and malignant transformation into cancer stem cells. Therefore, the identification of critical nodes and targets in the regulatory cascades of TGFβ family factors and other signaling pathways, and analysis of the rearrangements of the signal regulatory network during stem cell state transitions and interconversions, are key issues for understanding the fundamental mechanisms of both stem cell biology and cancer initiation and progression, as well as for clinical applications. This review summarizes recent advances in our understanding of TGFβ family functions in naїve and primed pluripotent stem cells and discusses how these pathways are involved in perturbations in the signaling network of malignant teratocarcinoma stem cells with impaired differentiation potential.

Topics: Animals; Cell Differentiation; Cell Self Renewal; Humans; Male; Neoplastic Stem Cells; Pluripotent Stem Cells; Signal Transduction; Teratocarcinoma; Testicular Neoplasms; Transforming Growth Factor beta

PubMed: 31771212
DOI: 10.3390/cells8121500

Review

Authors: Jolene Ooi, Pentao Liu

Pluripotency is depicted by a self-renewing state that can competently differentiate to form the three germ layers. Different stages of early murine development can be captured on a petri dish, delineating a spectrum of pluripotent states, ranging from embryonic stem cells, embryonic germ cells to epiblast stem cells. Anomalous cell populations displaying signs of pluripotency have also been uncovered, from the isolation of embryonic carcinoma cells to the derivation of induced pluripotent stem cells. Gaining insight into the molecular circuitry within these cell types enlightens us about the significance and contribution of each stage, hence deepening our understanding of vertebrate development. In this review, we aim to describe experimental milestones that led to the understanding of embryonic development and the conception of pluripotency. We also discuss attempts at exploring the realm of pluripotency with the identification of pluripotent stem cells within mouse teratocarcinomas and embryos, and the generation of pluripotent cells through nuclear reprogramming. In conclusion, we illustrate pluripotent cells derived from other organisms, including human derivatives, and describe current paradigms in the comprehension of human pluripotency.

PubMed: 25408870
DOI: 10.1186/2045-9769-1-7

Review

Authors: Gregory M Kelly, Mohamed I Gatie

Just over ten years have passed since the seminal Takahashi-Yamanaka paper, and while most attention nowadays is on induced, embryonic, and cancer stem cells, much of the pioneering work arose from studies with embryonal carcinoma cells (ECCs) derived from teratocarcinomas. This original work was broad in scope, but eventually led the way for us to focus on the components involved in the gene regulation of stemness and differentiation. As the name implies, ECCs are malignant in nature, yet maintain the ability to differentiate into the 3 germ layers and extraembryonic tissues, as well as behave normally when reintroduced into a healthy blastocyst. Retinoic acid signaling has been thoroughly interrogated in ECCs, especially in the F9 and P19 murine cell models, and while we have touched on this aspect, this review purposely highlights how some key transcription factors regulate pluripotency and cell stemness prior to this signaling. Another major focus is on the epigenetic regulation of ECCs and stem cells, and, towards that end, this review closes on what we see as a new frontier in combating aging and human disease, namely, how cellular metabolism shapes the epigenetic landscape and hence the pluripotency of all stem cells.

PubMed: 28373885
DOI: 10.1155/2017/3684178

Review

Authors: Arnold J Levine, Shelley L Berger

Epigenetic programs regulate the development and maintenance of organisms over a lifetime. These programs are carried out through chemical modifications of DNA and proteins such as histones and transcription factors. These epigenetic modifications are less stable than genetic alterations and even reversible under a variety of circumstances, such as developmental changes, regeneration of tissues, cell divisions, aging, and pathological conditions observed in many cancers. The p53 protein not only enforces the stability of the genome by the prevention of genetic alterations in cells but also plays a role in regulating the epigenetic changes that can occur in cells. The full-length p53 protein is largely inactive in stem cells but, when activated, helps to commit these cells to developmental lineages through a series of epigenetic changes. Just as p53 impacts epigenetic change, the enzyme activities that carry out epigenetic protein modifications act on the p53 protein and its splice variants in stem and progenitor cells to silence or activate its transcriptional activities. Thus, there is a great deal of cross-talk between the p53 protein and epigenetic programs. This review collects the diverse experimental evidence that leads to these conclusions. This in turn permits new ideas and directions for the treatment of cancers, reactivating developmental pathways for tissue regeneration and responses to the impact of aging.

Topics: Animals; Cellular Reprogramming; Epigenesis, Genetic; Humans; Neoplasms; Regeneration; Stem Cells; Teratocarcinoma; Tumor Suppressor Protein p53

PubMed: 28765161
DOI: 10.1101/gad.298984.117

Review

Authors: Alex Vassilev, Melvin L DePamphilis

Cancers can be categorized into two groups: those whose frequency increases with age, and those resulting from errors during mammalian development. The first group is linked to DNA replication through the accumulation of genetic mutations that occur during proliferation of developmentally acquired stem cells that give rise to and maintain tissues and organs. These mutations, which result from DNA replication errors as well as environmental insults, fall into two categories; cancer driver mutations that initiate carcinogenesis and genome destabilizing mutations that promote aneuploidy through excess genome duplication and chromatid missegregation. Increased genome instability results in accelerated clonal evolution leading to the appearance of more aggressive clones with increased drug resistance. The second group of cancers, termed germ cell neoplasia, results from the mislocation of pluripotent stem cells during early development. During normal development, pluripotent stem cells that originate in early embryos give rise to all of the cell lineages in the embryo and adult, but when they mislocate to ectopic sites, they produce tumors. Remarkably, pluripotent stem cells, like many cancer cells, depend on the Geminin protein to prevent excess DNA replication from triggering DNA damage-dependent apoptosis. This link between the control of DNA replication during early development and germ cell neoplasia reveals Geminin as a potential chemotherapeutic target in the eradication of cancer progenitor cells.

PubMed: 28125050
DOI: 10.3390/genes8020045

Review

Authors: Ian Chambers, Austin Smith

Pluripotent stem cells derived from preimplantation embryos, primordial germ cells or teratocarcinomas are currently unique in undergoing prolonged symmetrical self-renewal in culture. For mouse embryonic stem (ES) cells, self-renewal is dependent on signals from the cytokine leukaemia inhibitory factor (LIF) and from either serum or bone morphogenetic proteins (BMPs). In addition to the extrinsic regulation of gene expression, intrinsic transcriptional determinants are also required for maintenance of the undifferentiated state. These include Oct4, a member of the POU family of homeodomain proteins and a second recently identified homeodomain protein, Nanog. When overexpressed, Nanog allows ES cells to self-renew in the absence of the otherwise obligatory LIF and BMP signals. Although Nanog can act independent of the LIF signal, a contribution of both pathways provides maximal self-renewal efficiency. Nanog function also requires Oct4. Here, we review recent progress in ES cell self-renewal, relate this to the biology of teratocarcinomas and offer testable hypotheses to expose the mechanics of ES cell self-renewal.

Topics: Animals; Base Sequence; Cell Differentiation; Cell Division; Cell Line, Tumor; Clone Cells; Cytokines; DNA-Binding Proteins; Embryo, Mammalian; Embryonal Carcinoma Stem Cells; Growth Substances; Homeodomain Proteins; Humans; Kidney Neoplasms; Male; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Molecular Sequence Data; Nanog Homeobox Protein; Neoplastic Stem Cells; Pluripotent Stem Cells; Receptors, Cytokine; Receptors, Growth Factor; Stem Cells; Teratocarcinoma; Testicular Neoplasms; Transcription Factors

PubMed: 15378075
DOI: 10.1038/sj.onc.1207930