-
Cancer Research Jan 2023Epithelial ovarian cancer is a highly heterogeneous and malignant female cancer with an overall low survival rate. Mutations in p53 are prevalent in the major ovarian...
UNLABELLED
Epithelial ovarian cancer is a highly heterogeneous and malignant female cancer with an overall low survival rate. Mutations in p53 are prevalent in the major ovarian cancer histotype, high-grade serous ovarian carcinoma (HGSOC), while p53 mutations are much less frequent in other ovarian cancer subtypes, particularly in ovarian clear cell carcinoma (OCCC). Advanced stage OCCC with wild-type (WT) p53 has a worse prognosis and increased drug resistance, metastasis, and recurrence than HGSOC. The mechanisms responsible for driving the aggressiveness of WT p53-expressing ovarian cancer remain poorly understood. Here, we found that upregulation of MEX3A, a dual-function protein containing a RING finger domain and an RNA-binding domain, was critical for tumorigenesis in WT p53-expressing ovarian cancer. MEX3A overexpression enhanced the growth and clonogenicity of OCCC cell lines. In contrast, depletion of MEX3A in OCCC cells, as well as ovarian teratocarcinoma cells, reduced cell survival and proliferative ability. MEX3A depletion also inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase p53 protein stability. MEX3A-mediated p53 protein degradation was crucial to suppress ferroptosis and enhance tumorigenesis. Consistently, p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in ovarian cancer cells expressing WT p53.
SIGNIFICANCE
Degradation of p53 mediated by MEX3A drives ovarian cancer growth by circumventing p53 tumor suppressive functions, suggesting targeting MEX3A as a potential strategy for treating of ovarian cancer expressing WT p53.
Topics: Female; Humans; Adenocarcinoma, Clear Cell; Carcinogenesis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Transformation, Neoplastic; Ferroptosis; Ovarian Neoplasms; Phosphoproteins; RNA-Binding Proteins; Tumor Suppressor Protein p53
PubMed: 36354374
DOI: 10.1158/0008-5472.CAN-22-1159 -
Asian Journal of Urology Apr 2021Germ 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... (Review)
Review
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 -
Vaccines Mar 2023The footprint of human endogenous retroviruses (HERV), specifically HERV-K, has been found in malignancies, such as melanoma, teratocarcinoma, osteosarcoma, breast... (Review)
Review
The footprint of human endogenous retroviruses (HERV), specifically HERV-K, has been found in malignancies, such as melanoma, teratocarcinoma, osteosarcoma, breast cancer, lymphoma, and ovary and prostate cancers. HERV-K is characterized as the most biologically active HERV due to possession of open reading frames (ORF) for all Gag, Pol, and Env genes, which enables it to be more infective and obstructive towards specific cell lines and other exogenous viruses, respectively. Some factors might contribute to carcinogenicity and at least one of them has been recognized in various tumors, including overexpression/methylation of long interspersed nuclear element 1 (LINE-1), HERV-K Gag, and Env genes themselves plus their transcripts and protein products, and HERV-K reverse transcriptase (RT). Therapies effective for HERV-K-associated tumors mostly target invasive autoimmune responses or growth of tumors through suppression of HERV-K Gag or Env protein and RT. To design new therapeutic options, more studies are needed to better understand whether HERV-K and its products (Gag/Env transcripts and HERV-K proteins/RT) are the initiators of tumor formation or just the disorder's developers. Accordingly, this review aims to present evidence that highlights the association between HERV-K and tumorigenicity and introduces some of the available or potential therapies against HERV-K-induced tumors.
PubMed: 37112663
DOI: 10.3390/vaccines11040751 -
Journal For Immunotherapy of Cancer Aug 2022One of the main difficulties of adoptive cell therapies with chimeric antigen receptor (CAR)-T cells in solid tumors is the identification of specific target antigens....
BACKGROUND
One of the main difficulties of adoptive cell therapies with chimeric antigen receptor (CAR)-T cells in solid tumors is the identification of specific target antigens. The tumor microenvironment can present suitable antigens for CAR design, even though they are not expressed by the tumor cells. We have generated a CAR specific for the splice variant extra domain A (EDA) of fibronectin, which is highly expressed in the tumor stroma of many types of tumors but not in healthy tissues.
METHODS
EDA expression was explored in RNA-seq data from different human tumor types and by immunohistochemistry in paraffin-embedded tumor biopsies. Murine and human anti-EDA CAR-T cells were prepared using recombinant retro/lentiviruses, respectively. The functionality of EDA CAR-T cells was measured in vitro in response to antigen stimulation. The antitumor activity of EDA CAR-T cells was measured in vivo in C57BL/6 mice challenged with PM299L-EDA hepatocarcinoma cell line, in 129Sv mice-bearing F9 teratocarcinoma and in NSG mice injected with the human hepatocarcinoma cell line PLC.
RESULTS
EDA CAR-T cells recognized and killed EDA-expressing tumor cell lines in vitro and rejected EDA-expressing tumors in immunocompetent mice. Notably, EDA CAR-T cells showed an antitumor effect in mice injected with EDA-negative tumor cells lines when the tumor stroma or the basement membrane of tumor endothelial cells express EDA. Thus, EDA CAR-T administration delayed tumor growth in immunocompetent 129Sv mice challenged with teratocarcinoma cell line F9. EDA CAR-T treatment exerted an antiangiogenic effect and significantly reduced gene signatures associated with epithelial-mesenchymal transition, collagen synthesis, extracellular matrix organization as well as IL-6-STAT5 and KRAS pathways. Importantly, the human version of EDA CAR, that includes the human 41BB and CD3ζ endodomains, exerted strong antitumor activity in NSG mice challenged with the human hepatocarcinoma cell line PLC, which expresses EDA in the tumor stroma and the endothelial vasculature. EDA CAR-T cells exhibited a tropism for EDA-expressing tumor tissue and no toxicity was observed in tumor bearing or in healthy mice.
CONCLUSIONS
These results suggest that targeting the tumor-specific fibronectin splice variant EDA with CAR-T cells is feasible and offers a therapeutic option that is applicable to different types of cancer.
Topics: Animals; Endothelial Cells; Fibronectins; Humans; Mice; Mice, Inbred C57BL; Receptors, Chimeric Antigen; T-Lymphocytes; Teratocarcinoma; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 35918123
DOI: 10.1136/jitc-2021-004479 -
Seminars in Cancer Biology Jun 2022The completion-of-tumor hypothesis involved in the dynamic interplay between the initiating oncogenic event and progression is essential to better recognize the... (Review)
Review
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 -
The American Journal of Pathology Sep 2021The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular... (Review)
Review
The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome (NS), a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular, and nervous systems. Consistent with the abnormalities seen in NS, a host of new studies have implicated R-Ras proteins in physiological and pathologic changes in cellular morphology, adhesion, and migration in the cardiovascular, immune, and nervous systems. These changes include regulating the migration and homing of mature and immature immune cells, vascular stabilization, clotting, and axonal and dendritic outgrowth during nervous system development. Dysregulated R-Ras signaling has also been linked to the pathogenesis of cardiovascular disease, intellectual disabilities, and human cancers. This review discusses the structure and regulation of R-Ras proteins and our current understanding of the signaling pathways that they regulate. It explores the phenotype of NS patients and their implications for the R-Ras subfamily functions. Next, it covers recent discoveries regarding physiological and pathologic R-Ras functions in key organ systems. Finally, it discusses how R-Ras signaling is dysregulated in cancers and mechanisms by which this may promote neoplasia.
Topics: Animals; Cell Movement; Humans; Noonan Syndrome; Signal Transduction; ras Proteins
PubMed: 34111428
DOI: 10.1016/j.ajpath.2021.05.008 -
Cells Nov 2019The transforming growth factor-β (TGFβ) family factors induce pleiotropic effects and are involved in the regulation of most normal and pathological cellular... (Review)
Review
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 -
Nature Communications Mar 2023Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different...
Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. Human embryonic stem cells (hESCs) with appropriate in vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically, TPCs harboring BRAF or NRAS mutations generate papillary or follicular TC, respectively, whereas addition of TP53 generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs.
Topics: Humans; Receptors, Kisspeptin-1; Iodine Radioisotopes; Tissue Inhibitor of Metalloproteinase-1; Thyroid Neoplasms; Embryonic Stem Cells; Proto-Oncogene Proteins B-raf; Mutation
PubMed: 36906579
DOI: 10.1038/s41467-023-36922-1 -
Biomedical and Environmental Sciences :... Sep 2023Circular RNAs (circRNAs) participate in several important pathological processes and have been used in the diagnosis and treatment of various diseases. This study aimed...
OBJECTIVE
Circular RNAs (circRNAs) participate in several important pathological processes and have been used in the diagnosis and treatment of various diseases. This study aimed to investigate the role of circRNAs in neural tube defects (NTDs).
METHOD
We characterized circRNA-associated competitive endogenous RNA (ceRNA) networks in brain tissue of low folate -induced NTDs mouse at embryonic day 13.5 by high-throughput sequencing. The expression levels of Circzfp644, miR-20-5p and were detected by RT-PCR. and Circzfp644 functions were determined by miRNA-mimics and inhibitors in mouse teratocarcinoma cells (F9 cells), and luciferase gene reporter assay was assessed in the F9 cells. In addition, the expression levels of Circzfp644, miR-20-5p and were determined by Nanostring in human NTDs tissues.
RESULTS
We detected 57 circRNA transcripts, 16 miRNAs, and 148 mRNAs that were significantly dysregulated in NTDs brain tissues compared with their expression levels in control (normal) tissues. Circzfp644 shared miRNA response elements with the growth arrest specific 7 ( ) gene and competitively bound with miR-20-5p to increase the expression of . Downregulation of Circzfp644 and and upregulation of miR-20-5p were found in human NTD tissue.
CONCLUSION
This study provides new perspectives on the role of circRNAs in nervous system development and the pathogenesis of NTDs.
Topics: Humans; Animals; Mice; RNA, Circular; MicroRNAs; Down-Regulation; Neural Tube Defects; Folic Acid
PubMed: 37803896
DOI: 10.3967/bes2023.071 -
Stem Cells Translational Medicine Aug 2022Human pluripotent stem cells (hPSCs) are currently evaluated for clinical applications due to their proliferation and differentiation capacities, raising the need to...
Human pluripotent stem cells (hPSCs) are currently evaluated for clinical applications due to their proliferation and differentiation capacities, raising the need to both assess and enhance, the safety of hPSC-based treatments. Distinct molecular features contribute to the tumorigenicity of hPSCs, manifested in the formation of teratoma tumors upon transplantation in vivo. Prolonged in vitro culturing of hPSCs can enhance selection for specific genetic aberrations, either at the chromosome or gene level. Some of these aberrations are tightly linked to human tumor pathology and increase the tumorigenic aggressiveness of the abnormal cells. In this perspective, we describe major tumor-associated risk factors entailed in hPSC-based therapy, and present precautionary and safety measures relevant for the development and application of such therapies.
Topics: Carcinogenesis; Cell Differentiation; Humans; Pluripotent Stem Cells; Teratoma
PubMed: 35679163
DOI: 10.1093/stcltm/szac039