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Extragonadal germ cell tumors (EGCT) are a rare entity, most of them being located in the mediastinum and retroperitoneum. Information on these tumors is scarce, requiring carrying out large population-based studies to better understand these diseases. We aimed to determine the clinical features and prognosis of patients with EGCT of the mediastinum and retroperitoneum.Demographic and clinicopathological features of patients diagnosed with EGCT of the mediastinum and retroperitoneum from 1975 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database.A total of 1674 patients were included, 1297 (77.5%) of mediastinal origin and 377 (22.5%) of retroperitoneum. Nonseminomatous tumors (56.3%) were slightly more frequent than seminomas (43.7%) with similar distribution between mediastinum and retroperitoneum. After a median follow-up of 137 months, the median overall survival was 263 months (95% CI, 220-296) whereas the median cause-specific survival (CSS) has still not been reached. The 10-year overall survival and CSS were 57.4% (95% CI, 55-59.7) and 63% (95% CI, 60.6-65.2) respectively. Multivariate analysis showed that older age, mediastinal location, nonseminomatous histology, and distant disease at diagnosis were independent prognostic factors correlated with a worse prognosis. Patients with mediastinal choriocarcinoma and embryonal carcinoma have the worst prognosis, both with a median CSS of only 12 months.Despite a decreasing incidence observed in recent decades, EGCT continues to represent a challenge for oncologists. The prognosis of choriocarcinoma and embryonal carcinoma of the mediastinum remains poor and treatment strategies need to be improved urgently.

Objective To systematically evaluate evidence on prognostic factors for tumor recurrence in clinical stage I nonseminoma patients other than lymphovascular invasion (LVI). Methods We performed a systematic literature search in the biomedical databases Medline (via Ovid) and Cochrane Central Register of Controlled Trials (search period January 2010 to February 2021) for full text publications in English and German language, reporting on retro- or prospectively assessed prognostic factors for tumor recurrence in patients with stage I nonseminomatous germ cell tumors. Results Our literature search yielded eleven studies reporting on 20 potential prognostic factors. Results are based on cohort studies of mostly moderate to low quality. Five out of eight studies found a significant association of embryonal carcinoma (EC) in the primary tumor with relapse. Among the different risk definitions of embryonal carcinoma (presence, predominance, pure), presence of EC alone seems to be sufficient for prognostification. Interesting results were found for rete testis invasion, predominant yolk sac tumor, T-stage and history of cryptorchidism, but the sparse data situation does not justify their clinical use. Conclusions No additional factors that meet the prognostic value of LVI, especially when determined by immunohistochemistry, could be identified through our systematic search. The presence of EC might serve as a second, subordinate prognostic factor for clinical use as the data situation is less abundant than the one of LVI. Further efforts are necessary to optimize the use of these two prognostic factors and to evaluate and validate further potential factors with promising preliminary data.

The pluripotent transcription factor NANOG is essential for maintaining embryonic stem cells and driving tumorigenesis. We previously showed that PKC activity is involved in the regulation of NANOG expression. To explore the possible involvement of microRNAs in regulating the expression of key pluripotency factors, we performed a genome-wide analysis of microRNA expression in the embryonal carcinoma cell line NT2/D1 in the presence of the PKC activator, PMA. We found that MIR630 was significantly upregulated in PMA-treated cells. Experimentally, we showed that transfection of MIR630 mimic into embryonal carcinoma cell lines directly targeted the 3′UTR of OCT4, SOX2, and NANOG and markedly suppressed their expression. RNAhybrid and RNA22 algorithms were used to predict miRNA target sites in the NANOG 3′UTR, four possible target sites of MIR630 were identified. To examine the functional interaction between MIR630 and NANOG mRNA, the predicted MIR630 target sites in the NANOG 3′UTR were deleted and the activity of the reporters were compared. After targeted mutation of the predicted MIR630 target sites, the MIR630 mimic inhibited NANOG significantly less than the wild-type reporters. It is worth noting that mutation of a single putative binding site in the 3′UTR of NANOG did not completely abolish MIR630-mediated suppression, suggesting that MIR630 in the NANOG 3′UTR may have multiple binding sites and act together to maximally repress NANOG expression. Interestingly, MIR630 mimics significantly downregulated NANOG gene transcription. Exogenous expression of OCT4, SOX2, and NANOG lacking the 3′UTR almost completely rescued the reduced transcriptional activity of MIR630. MIR630 mediated the expression of differentiation markers in NT2/D1 cells, suggesting that MIR630 leads to the differentiation of NT2/D1 cell. Our findings show that MIR630 represses NANOG through transcriptional and post-transcriptional regulation, suggesting a direct link between core pluripotency factors and MIR630.

Melanoma-associated antigen A2 (MAGE-A2) is a member of the cancer-testis antigen family differentially overexpressed in a variety of malignancies and is associated with tumor development. However, clinical significance and prognostic value of MAGE-A2 in different histological subtypes of testicular germ cell tumors (TGCTs) have not been explored. Here, we aimed to investigate the clinical significance and prognostic impact of MAGE-A2 expression in TGCTs compared to benign tumors as well as adjacent normal tissues and then between seminomas and non-seminomas groups using immunohistochemistry on tissue microarrays. The results indicated a statistically significant difference between overexpression of MAGE-A2 and histological subtypes of TGCTs. A statistically significant association was found between a high level of nuclear expression of MAGE-A2 protein and advanced pT stage (P = 0.022), vascular invasion (P = 0.037), as well as involvement of rete testis (P = 0.022) in embryonal carcinomas. Increased nuclear expression of MAGE-A2 was observed to be associated with more aggressive behaviors and tumor progression rather than cytoplasmic expression in these cases. Further, high level nuclear expression of MAGE-A2 had shorter disease-specific survival (DSS) or progression-free survival (PFS) compared to patients with moderate and low expression of MAGE-A2, however, without a statistically significant association. Our results confirm that increased nuclear expression of MAGE-A2 has a clinical significance in embryonal carcinomas and is associated with progression of disease. Moreover, MAGE-A2 may act as a potential predictive biomarker for the prognosis in embryonal carcinomas if follow-up period becomes longer. Further investigations for the biological function of MAGE-A2 are required in future studies.

This study aimed to determine the disease characteristics and prognosis of patients with primary mediastinal nonseminomas (PMNS) in a Surveillance, Epidemiology, and End Results (SEER) analysis.Demographic, treatment, and survival outcome data of cases with PMNS from 1975 to 2016 were retrieved. Cases with unknown variables mentioned in the analysis were excluded. Relative statistical methods were applied to analyze clinical characteristics and prognosis.A total of 587 PMNS patients met the selection criteria, 526 of whom were men. The mean age of patients was 28 (1-85) y. A total of 511 PMNS patients had validated subtypes, including 172 mixed germ cell tumors, 117 yolk sac tumors, 111 malignant teratomas, 70 choriocarcinomas, and 41 embryonal carcinomas. Patients with yolk sac tumors had the highest 3-y cancer-specific survival (CSS) rate (66.9%), while those with choriocarcinoma and embryonal carcinoma showed the worst prognosis. Surgery + chemotherapy (46.2%) was the most common and effective treatment for each subtype of PMNS. Multivariate Cox proportional hazards analysis identified embryonal carcinoma, malignant teratoma, choriocarcinoma, tumor size15 cm, nodal metastasis, and distant stage as risk factors. In contrast, surgery-based care and younger age were protective factors. Propensity score matching analysis revealed significant improvement in the 5-y CSS rate from 35.8% to 60.3% with surgery (P0.001). However, radiotherapy (P = 0.436) and chemotherapy (P = 0.978) showed no survival benefits.10 percent of the PMNS patients were female. Choriocarcinomas and embryonal carcinomas had the worst prognosis. Surgery was demonstrated to be the only way to prolong survival time. Chemotherapy and radiotherapy had minimal effects on prognosis.

The epithelium-specific ETS transcription factor-1 (ESE-1) plays multiple roles in pathogenesis and normal development of epithelial tissues. NANOG, a key mediator of stem cell self-renewal and pluripotency, is also expressed in various cancers and pluripotent cells. In this study, we investigated how ESE-1 influences NANOG expression and NANOG-induced proliferation in human germ cell-derived embryonic carcinoma NCCIT cells. Endogenous ESE-1 expression in NCCIT cells significantly increased during differentiation, whereas NANOG expression decreased. In addition, NANOG expression was downregulated by exogenous overexpression of ESE-1, and increased by shRNA-mediated knockdown of ESE-1. NANOG transcriptional activity was reduced by dose-dependent ESE-1 overexpression and a putative ESE-1 binding site (EBS) was mapped within conserved region 2. Site-directed mutagenesis of the putative EBS abrogated the repressive effect of ESE-1 on NANOG promoter activity. ESE-1 directly interacted with the putative EBS to regulate transcriptional activity of NANOG. Furthermore, NANOG-induced proliferation and colony formation of NCCIT cells were inhibited by ESE-1 overexpression and stimulated by ESE-1 shRNA-mediated knockdown. Altogether, our results suggest that ESE-1 exerts an anti-proliferative effect on NCCIT cells by acting as a novel transcriptional repressor of NANOG.

OBJECTIVE: To describe the clinical and ultrasound characteristics of three types of rare malignant ovarian germ cell tumor: embryonal carcinoma, non-gestational choriocarcinoma and malignant mixed germ cell tumor. METHODS: This was a retrospective multicenter study. From the International Ovarian Tumor Analysis (IOTA) database, we identified patients with a histological diagnosis of ovarian embryonal carcinoma, non-gestational choriocarcinoma or malignant mixed germ cell tumor, who had undergone preoperative ultrasound examination by an experienced ultrasound examiner between 2000 and 2020. Additional patients with the same histology were identified from the databases of the departments of gynecological oncology in the participating centers. All tumors were described using IOTA terminology. Three examiners reviewed all available ultrasound images and described them using pattern recognition. RESULTS: One patient with embryonal carcinoma, five patients with non-gestational ovarian choriocarcinoma and seven patients with ovarian malignant mixed germ cell tumor (six primary tumors and one recurrence) were identified. Seven patients were included in the IOTA studies and six patients were examined outside of the IOTA studies. The median age at diagnosis was 26 (range, 14-77) years. Beta-human chorionic gonadotropin levels were highest in non-gestational choriocarcinomas and alpha-fetoprotein levels were highest in malignant mixed germ cell tumors. Most tumors were International Federation of Gynecology and Obstetrics (FIGO) Stage I (9/12 (75.0%)). All tumors were unilateral, and the median largest diameter was 129 (range, 38-216) mm. Of the tumors, 11/13 (84.6%) were solid and 2/13 (15.4%) were multilocular-solid; 9/13 (69.2%) manifested abundant vascularization on color Doppler examination. Using pattern recognition, the typical ultrasound appearance was a large solid tumor with inhomogeneous echogenicity of the solid tissue and often dispersed cysts which, in most cases, were small and irregular. Some tumors had smooth contours while others had irregular contours. CONCLUSIONS: A unilateral, large solid tumor with inhomogeneous echogenicity of the solid tissue and with dispersed small cystic areas in a young woman should raise the suspicion of a rare malignant germ cell tumor. This suspicion can guide the clinician to test tumor markers specific for malignant germ cell tumors. © 2020 International Society of Ultrasound in Obstetrics and Gynecology. ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:57 issue:6 pages:987-994 ispartof: location:England status: published

Germ cell tumors (GCTs) are the most common type of cancer in Germany in young men between 15 and 44 years of age. The routinely performed diagnostic procedures are essential for the patient's treatment, but can be difficult due to heterogenous histologies. Additionally, the molecular mechanisms of the development of the special forms growing teratoma syndrome (GTS) and testicular tumors with malignant somatic transformation (MST) as well as of therapy resistance are not fully understood.Updated understanding of the molecular processes underlying GCT development and their special forms as well as recommendations for new and useful biomarkers.The development of GCTs is a dynamic process largely influenced by the microenvironment. Seminomas (SEs) in particular seem to posses a higher cellular plasticity than previously assumed, allowing SEs to be reprogrammed into an embryonal carcinoma (EC) or differentiate into extra-embryonal tissues (yolk sac tumors [YSTs], trophoblastic differentiation). Novel serological (mi371a-3p) and pathological (FOXA2) biomarkers are well suited to early detect GCTs and YSTs, respectively. For more aggressive tumors and special cases (GTS, MST), there are still no reliable diagnostics or specific/tailored therapies available.The ability of SEs to transit into EC or YSTs should be considered during therapy. Future research should focus on deciphering the special forms GTS and MST as well as the early recognition of YSTs, since their development seems to be an escape mechanism to chemotherapy.HINTERGRUND: Keimzelltumoren (KZT) sind deutschlandweit die häufigste Krebserkrankung bei jungen Männern (15–44 Jahren). Die differenzielle Routinediagnostik ist essenziell für die Behandlung, ist aber aufgrund der komplexen Histologie herausfordernd. Auch das molekulare Verständnis über die Entstehung der Sonderformen Growing-Teratoma-Syndrom (GTS) und Hodentumoren mit maligner somatischer Transformation (MST) sowie der Therapieresistenzen ist begrenzt.Aktualisierte Betrachtung der molekularen Mechanismen der KZT-Entwicklung und deren Sonderformen sowie die Vorstellung relevanter neuer Biomarker.Die KZT-Entwicklung ist ein dynamischer Prozess, der maßgeblich durch das Mikromilieu mitbestimmt wird. Dabei scheinen besonders die Seminome (SE) plastischer als bisher angenommen und könnten in der Lage sein, in embryonale Karzinome (EK) reprogrammiert zu werden oder in extraembryonale Tumoren (Dottersacktumor [DST], trophoblastäre Differenzierung) zu differenzieren. Neuartige serologische (mi371a-3p) und pathologische (FOXA2) Biomarker eignen sich sehr gut, um KZT bzw. DST frühzeitig zu erkennen. Für besonders aggressive Tumoren und Sonderfälle GTS und Hodentumoren mit MST stehen immer noch keine präzisen Marker oder spezifische Therapiemöglichkeiten zur Verfügung.Die Fähigkeit von SE zur Transition in ein EK bzw. DST sollte bei Therapieentscheidungen bedacht werden. Besonderer Fokus sollte zukünftig auf der Erforschung der Sonderformen GTS und Hodentumoren mit MST und der Früherkennung von DST liegen, deren Entwicklung einen Therapiefluchtmechanismus darstellen könnte.

In recent years, several studies investigated the complex process called "reprogramming" of seminoma (S) cells. The accepted pathogenetic model is a complex network including SOX2, SOX17, OCT3/4 and PRAME, which modulates the epigenetic transcription of numerous downstream genes and drives a divergent gene expression profile resulting in the transition from pure S (P-S) to S component (S-C) of mixed germ cell tumors of the testis (M-GCTT), and finally to embryonal carcinoma (EC). Herein, we tested a large cohort of GCTT with SOX2 and PRAME to evaluate their expression in the evolutionary steps of GCTT and verify if the modulation in the expression of these two molecules could be relevant for the fate of GCTT.We tested 43, 19 and 17 consecutive and retrospectively enrolled cases of GCTT, germ cell neoplasia in situ (GCNIS) and uninvolved background testes (UBT), respectively. SOX2 and PRAME expressions have been evaluated with H-score and compared by adopting the appropriate statistic tests (Student's t-test and Mann-Whitney U test).We found that SOX2 was more expressed by nonseminomatous-GCTT (NS-GCTT) (p 0.001) and EC (p 0.001) rather than S; by contrast, PRAME showed an opposite expression profile being expressed by S but not by NS-GCTT (p 0.001) and EC (p 0.001). S-C showed different expressions of SOX2 and PRAME compared to both P-S (p = 0.002 and0.001, respectively) and EC (p 0.001 and 0.042, respectively), with intermediate values between these latter two categories. GCNIS and UBT showed no expression of SOX2 (scattered positive Leydig cells) but high H-score levels of PRAME.SOX2 and PRAME are differentially expressed and specularly modulated during the "reprogramming" of S cells [P-S (high levels of PRAME, no expression/low levels of SOX2) → S-C (intermediate levels of PRAME, intermediate levels of SOX2) → EC (no expression/low levels of PRAME, high levels of SOX2)], therefore supporting a complex pathogenetic model where the interactions between these two molecules are crucial in determining the fate of GCTT.

One hundred malignant mixed germ cell tumors of the ovary that occurred in patients 3 to 55 years (mean: 20 y) of age are described. The clinical presentation was usually that of any highly malignant tumor of the ovary (abdominal pain and distension), but rarely (3 cases) endocrine manifestations were present. The tumors were usually unilateral (96%), ranged from 4 to 38 cm (mean: 16 cm), and were uniformly solid or, more often, solid and cystic; occasionally the typical appearance of dysgerminoma could be appreciated. The most common tumor type was yolk sac tumor (91%), followed by dysgerminoma (61%), immature teratoma (58%), embryonal carcinoma (38%), and choriocarcinoma (11%). A variety of admixtures were encountered; dysgerminoma and yolk sac tumor was the most common combination (25% of the tumors) with the 2 components often being sharply demarcated. Immature teratoma and yolk sac tumor was the next most common pairing (20%) followed by yolk sac tumor and embryonal carcinoma, with or without immature teratoma (16%). Tumors with a choriocarcinoma component had the most varied combinations of tumor types. Embryoid bodies were seen in 21% of the tumors, most often as fragmented forms arranged in a nodular manner with yolk sac tumor and/or embryonal carcinoma; uncommonly they occurred singly or in clusters. Numerous confluent well-formed embryoid bodies (polyembryoma) were prominent in 2 tumors. Three tumors had a focal diffuse embryoma pattern. The specific tumor types showed the known diverse spectrum of microscopic appearances, but the frequent haphazard arrangement of 2 or more subtypes often resulted in complex morphology. Overgrowth of another neoplastic component, most often primitive neuroectodermal tumor, occurred in 10% of the tumors further complicating the histologic picture. This is the largest series of ovarian malignant mixed germ cell tumors reported and details their characteristics including associations of their subtypes and the frequent apparent role of embryoid bodies in giving rise to yolk sac tumor and embryonal carcinoma components.

The aims of the present study were to investigate the expression of the classic estrogen receptors ESR1 and ESR2, the splicing variant ESR1-36 and GPER in human testicular embryonal carcinoma NT2/D1 cells, and the effects of the activation of the ESR1 and ESR2 on cell proliferation. Immunostaining of ESR1, ESR2, and GPER were predominantly found in the nuclei, and less abundant in the cytoplasm. ESR1-36 isoform was predominantly expressed in the perinuclear region and cytoplasm, and some weakly immunostained in the nuclei. In nonstimulated NT2/D1 cells (control), proteins of the cell cycle CCND1, CCND2, CCNE1 and CDKN1B are present. Activation of ESR1 and ESR2 increases, respectively, CCND2 and CCNE1 expression, but not CCND1. Activation of ESR2 also mediates upregulation of the cell cycle inhibitor CDKN1B. This protein co-immunoprecipitated with CCND2. Also, E2 induces an increase in the number and viability of the NT2/D1 cells. These effects are blocked by simultaneous pretreatment with ESR1-and ESR2-selective antagonists, confirming that both estrogen receptors regulate NT2/D1 cell proliferation. In addition, E2 increases SRC phosphorylation, and SRC mediates cell proliferation. Our study provides novel insights into the signatures and molecular mechanisms of estrogen receptor in NT2/D1 cells.

Hepatocyte Nuclear Factor 1 beta (HNF1β) is a transcription factor which plays an important role during early organogenesis, especially of the pancreato-biliary and urogenital tract. Furthermore, HNF1β is an established marker in the differential diagnosis of ovarian cancer and shows a distinct nuclear expression in the clear cell carcinoma subtype. Recently, it has been described in yolk sac tumor, which represents a common component in many non-seminomatous germ cell tumors. Due to its broad histologic diversity, the diagnosis may be challenging and additional tools are very helpful in the workup of germ cell tumors. Immunohistochemistry was used to study HNF1β expression in a tissue microarray (TMA) of 601 testicular germ cell tumors including seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, germ cell neoplasia in situ (GCNIS), and normal tissue. The expression pattern was compared to glypican 3 (GPC3) and α-fetoprotein (AFP), two markers currently in use for the detection of yolk sac tumor. HNF1β showed a distinct nuclear staining in comparison to the cytoplasmic pattern of GPC3 and AFP. The sensitivity and specificity of HNF1β were 85.4% and 96.5%, of GPC3 83.3% and 90.7%, of AFP 62.5% and 97.7%. We conclude that HNF1β allows a reliable distinction of yolk sac tumor from other germ cell tumor components. Therefore, we propose HNF1β as a novel and robust marker in the immunohistochemical workup of testicular germ cell tumors.

Mixed germ cell tumours occur rarely in veterinary species. This report describes a case of metastatic mixed germ cell tumour in a female Eurasian harvest mouse (Micromys minutus). The tumour was extensive in one ovary and the uterus, and was characterized by two distinct tumour cell populations with features typical of embryonal carcinoma (EC) and choriocarcinoma (CC). Metastases of CC to the lungs and liver were observed. The exact origin of the CC was unclear, but the possibility of a non-gestational CC is favoured, given the context of a mixed germ cell tumour and lack of p53 expression. EC diagnosis was confirmed by immunohistochemical labelling of CD30 and lack of immunoreactivity for c-Kit. In addition, membranous β-catenin expression was present in the EC component, indicating an inactive Wnt/β-catenin pathway, which is required for the maintenance of pluripotency.

Curcumin, the yellow pigment derived from turmeric rhizomes, exhibits antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. We have previously reported in a study that curcumin could induce differentiation in embryonal carcinoma cell (EC). EC cells are the primary constituents of teratocarcinoma tumors, and hence differentiating them to a non-proliferative cell type may be useful in anticancer therapies. Here, we conducted a detailed study using various molecular approaches to characterize this differentiation at the cellular and molecular levels. The cells were treated with 20 µM curcumin, which was the optimal concentration to produce the highest amount of differentiated cells. Changes in protein and RNA expression, membrane dynamics, and migration of these cells after treatment with curcumin were then studied in a time-dependent manner. The differentiated cells were morphologically distinct from the precursor cells, and gene expression profiles were altered in curcumin-treated cells. Curcumin promoted cell motility and cell adhesion. Curcumin also induced changes in membrane fluidity and the lateral mobility of lipids in the plasma membrane. The findings of this study suggest that curcumin might have therapeutic potential in differentiation therapy for the treatment of teratocarcinomas or germ cell tumors (GCTs) such as testicular and ovarian GCTs.

Testicular tumors account for 1-2% of all tumors in men, with 95% of these being germ cell tumors. Paraneoplastic limbic encephalitis is a rare sequela of testicular tumors associated with anti-Ma2 and KLH11 antibodies. The most effective treatment for paraneoplastic limbic encephalitis is treatment of the primary malignancy. We report a 41-year-old male that presented to the emergency department with episodic alteration of consciousness and memory disturbances. Negative neurologic evaluation and imaging led to concern for a paraneoplastic process from a distant malignancy. CT imaging revealed an enlarged, necrotic para-aortic lymph node and subsequent ultrasound demonstrated a right-sided testicular mass. Right radical orchiectomy was performed. Microscopically, the mass consisted of mixed respiratory epithelium, gastrointestinal glands, and squamous epithelium with keratinization consistent with a post-pubertal testicular teratoma with associated in situ germ cell neoplasia. Resection of the para-aortic mass revealed large anaplastic cells with epithelioid features, nuclear pleomorphism and frequent mitoses. Immunostaining was positive for Pan-Keratin and OCT4, consistent with poorly differentiated embryonal carcinoma. Resection of the primary and metastatic disease, as well as treatment with corticosteroids, resulted in resolution of the encephalitis. This presentation of severe neurological disturbances in the setting of a metastatic mixed non-seminomatous germ cell tumor represents a rare presentation of paraneoplastic limbic encephalitis.

To elucidate the molecular pathogenesis of pediatric germ cell tumors (GCTs), we performed DNA methylation array analysis, whole transcriptome sequencing, targeted capture sequencing, and single-nucleotide polymorphism array analysis using 51 GCT samples (25 female, 26 male), including 6 germinomas, 2 embryonal carcinomas, 4 immature teratomas, 3 mature teratomas, 30 yolk sac tumors, and 6 mixed germ cell tumors. Among the 51 samples, 11 were from infants, 23 were from young children, and 17 were from those aged ≥10 years. Sixteen of the 51 samples developed in the extragonadal regions. Germinomas showed upregulation of pluripotent genes and global hypomethylation. Pluripotent genes were also highly expressed in embryonal carcinomas. These genes may play essential roles in embryonal carcinomas given that their binding sites are hypomethylated. Yolk sac tumors exhibited overexpression of endodermal genes, such as GATA6 and FOXA2, the binding sites of which were hypomethylated. Interestingly, infant yolk sac tumors had different DNA methylation patterns from those observed in older children. Teratomas had higher expression of ectodermal genes, suggesting a tridermal nature. Based on our results, we suggest that KIT, TNFRSF8, and ERBB4 may be suitable targets for the treatment of germinoma, embryonal carcinomas, and yolk sac tumors, respectively., Yasuo Kubota et al. report a multi-omic analysis of pediatric germ cell tumors from 51 patients ranging in age from 2 months to 19 years. They identify unique methylation, expression, and mutational patterns for each of the main subtypes and propose potential target genes for treatments against the three main subtypes.

Literature data about pancreatic resections for metastases are limited to small series, so that the role of surgery in this setting remains unclear. We herein report our experience from a tertiary care center, analyzing the outcomes of patients who underwent pancreatic resections for metastases and discussing the role of surgical resection in their management.From January 1999 to January 2019, 26 patients underwent pancreatic resections for metastases from renal cell carcinoma (RCC-group) or other primitive tumors (non-RCC-group). Details regarding pre-, intra-, post-operative course, and follow-up, prospectively collected in a database of pancreatic resection, were retrospectively analyzed and compared.RCC-group was composed of 21 patients, non-RCC-group of 5 patients. RCC-group presented a longer disease-free interval: 96.4 vs. 5.4 months (p 0.001). In 9/21 patients (42.9%) of RCC-group the surgical resection of other organs or vascular structures was performed, while in non-RCC-group pancreatic resection alone was performed in all cases, p = 0.070. No local recurrence was reported in all cases. The systemic recurrence rate was 42.9% (9/21 patients) in RCC-group and 80% (4/5 patients) in non-RCC-group, p = 0.135. RCC-group presented a longer DFS and OS: 107.5 vs. 25.2 months (p = 0.002), and 109.1 vs. 36.2 months (p = 0.016), respectively.Radical pancreatic resection may confer a survival benefit for RCC metastases, while for other primitive tumors it should be applied more selectively. For RCC pancreatic metastases, an aggressive surgical approach, even in patient with locally advanced tumors, or associated extra-pancreatic localizations, or recurrent metastases should be taken in consideration.

The pluripotent mouse embryonal carcinoma cell line P19 is widely used as a model for research on all-trans-retinoid acid (RA)-induced neuronal differentiation; however, the signaling pathways involved in this process remain unclear. This study aimed to reveal the molecular mechanism underlying the RA-induced neuronal differentiation of P19 cells. Real-time quantitative polymerase chain reaction and Western blot analysis were used to determine the expression of neuronal-specific markers, whereas flow cytometry was used to analyze cell cycle and cell apoptosis. The expression profiles of messenger RNAs (mRNAs) in RA-induced neuronal differentiation of P19 cells were analyzed using high-throughput sequencing, and the functions of differentially expressed mRNAs (DEMs) were determined by bioinformatics analysis. RA induced an increase in both class III β-tubulin (TUBB3) and neurofilament medium (NEFM) mRNA expression, indicating that RA successfully induces neuronal differentiation of P19 cells. Cell apoptosis was not affected; however, cell proliferation decreased. We found 4117 DEMs, which were enriched in the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, Wnt signaling pathway, and cell cycle. Particularly, a few DEMs could be identified in the PI3K/Akt signaling pathway networks, such as PI3K, Akt, glycogen synthase kinase-3β (GSK3β), cyclin-dependent kinase 4 (CDK4), P21, and Bax. RA significantly increased the protein expression of PI3K, Akt, phosphorylated Akt, GSK3β, phosphorylated GSK3β, CDK4, and P21, but it reduced Bax protein expression. The Akt inhibitor affected the increase of TUBB3 and NEFM mRNA expression in RA-induced P19 cells. The molecular mechanism underlying the RA-induced neuronal differentiation of P19 cells is potentially involved in the PI3K/Akt/GSK3β signaling pathway. The decreased cell proliferation ability of neuronally differentiated P19 cells could be associated with the expression of cell cycle proteins.

Objective: To systematically review the literature on the prognostic value of lymphovascular invasion (LVI) and embryonal carcinoma (EC) for occult metastatic disease in clinical stage I nonseminomatous germ cell tumour (CS I NSGCT). Materials and methods: The PubMed, Embase (OVID) and SCOPUS databases were searched up to March 2019. Studies reporting on the association between LVI and/or EC and occult metastatic disease were considered for inclusion. The quality and risk of bias were evaluated by the Quality in Prognosis Studies tool. Results: We screened 5287 abstracts and 207 full-text articles. We included 35 studies in the narrative synthesis and 24 studies in a meta-analysis. LVI showed the strongest effect. Pooled rates of occult metastasis were 47.5% and 16.9% for LVI-positive and LVI-negative patients, respectively (odds ratio [OR] 4.33, 95% confidence interval [CI] 3.55–5.30; P 50% and 20.0% for EC 50% have similar ORs for occult metastasis. This shows that the assessment of EC presence is sufficient for the classification of EC.

Coccidioidomycosis (CM) is a fungal infection endemic to the southwestern United States with a wide range of clinical presentations depending on the infected organ systems. Most infections are asymptomatic. Coccidioidomycosis causes a primary pulmonary infection and when symptoms occur, they most often resemble community-acquired pneumonia. One percent of cases disseminate, typically via hematogenous or lymphatic spread. It is in these cases that more severe symptoms may present and potentially overlap with those characteristics of other systemic illnesses. This is a case of CM disseminated to lymph nodes in a 24-year-old man with concomitant metastatic embryonal carcinoma. It is difficult to identify the primary etiology for many components of this patient’s presentation, including diffuse lymphadenopathy and multiple pulmonary nodules. Furthermore, the relationship between these 2 concurrent disease processes is not entirely clear. Factors that may contribute include the well-known phenomenon of locus minoris resistentiae (LMR) or potentially a shared immune failure between infectious organisms and malignant cells.

Testicular germ cell tumors (GCTs) are stratified into seminomas and nonseminomas. Seminomas share many histological and molecular features with primordial germ cells, whereas the nonseminoma stem cell population—embryonal carcinoma (EC)—is pluripotent and thus able to differentiate into cells of all three germ layers (teratomas). Furthermore, ECs are capable of differentiating into extra‐embryonic lineages (yolk sac tumors, choriocarcinomas). In this study, we deciphered the molecular and (epi)genetic mechanisms regulating expression of CD24, a highly glycosylated signaling molecule upregulated in many cancers. CD24 is overexpressed in ECs compared with other GCT entities and can be associated with an undifferentiated pluripotent cell fate. We demonstrate that CD24 can be transactivated by the pluripotency factor SOX2, which binds in proximity to the CD24 promoter. In GCTs, CD24 expression is controlled by epigenetic mechanisms, that is, histone acetylation, since CD24 can be induced by the application histone deacetylase inhibitors. Vice versa, CD24 expression is downregulated upon inhibition of histone methyltransferases, E3 ubiquitin ligases, or bromodomain (BRD) proteins. Additionally, three‐dimensional (3D) co‐cultivation of EC cells with microenvironmental cells, such as fibroblasts, and endothelial or immune cells, reduced CD24 expression, suggesting that crosstalk with the somatic microenvironment influences CD24 expression. In a CRISPR/Cas9 deficiency model, we demonstrate that CD24 fulfills a bivalent role in differentiation via regulation of homeobox, and phospho‐ and glycoproteins; that is, it is involved in suppressing the germ cell/spermatogenesis program and mesodermal/endodermal differentiation, while poising the cells for ectodermal differentiation. Finally, blocking CD24 by a monoclonal antibody enhanced sensitivity toward cisplatin in EC cells, including cisplatin‐resistant subclones, highlighting CD24 as a putative target in combination with cisplatin.

Purpose: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. Materials and Methods: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. Results: The elevated prechemotherapy tumor markers were alpha-fetoprotein in 48% of cases, beta-human chorionic gonadotropin in 14%, and alpha-fetoprotein and beta-human chorionic gonadotropin in 38%. Median alpha-fetoprotein and beta-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. Conclusions: Stage IS testicular cancer is more commonly associated with elevated alpha-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

Background and importance Primary tumors of the brachial plexus are rare. Most are benign and characterized as Schwannoma and neurofibroma, whereas malignant peripheral nerve sheath tumors are less common. Here, we report a rare case of primary embryonal carcinoma in the brachial plexus. Clinical presentation A 17-yr-old male presented with a 3-mo history of a mass growing in the left supraclavicular region over the middle part of the clavicle. Magnetic resonance imaging revealed a well-defined mass (diameter 2.5 cm) straddling the brachial plexus. After surgical resection, and the mass was histologically confirmed to be an embryonal carcinoma. Conclusion Primary embryonal carcinoma in the brachial plexus has not been reported previously. This case highlights the importance of considering the possibility that some primary brachial plexus tumors may be malignant and should be treated promptly.

PURPOSE Active surveillance (AS) for testicular nonseminomatous germ cell tumors (NSGCT) is widely used. Although there is no consensus for optimal treatment at relapse on surveillance, globally patients typically receive chemotherapy. We describe treatment of relapses in our non–risk-adapted NSGCT AS cohort and highlight selective use of primary retroperitoneal lymph node dissection (RPLND). METHODS From December 1980 to December 2015, 580 patients with clinical stage I NSGCT were treated with AS, and 162 subsequently relapsed. First-line treatment was based on relapse site and extent. Logistic regression was used to explore factors associated with need for multimodal therapy on AS relapse. RESULTS Median time to relapse was 7.4 months. The majority of relapses were confined to the retroperitoneum (66%). After relapse, first-line treatment was chemotherapy for 95 (58.6%) and RPLND for 62 (38.3%), and five patients (3.1%) underwent other therapy. In 103 (65.6%), only one modality of treatment was required: chemotherapy only in 58 of 95 (61%) and RPLND only in 45 of 62 (73%). Factors associated with multimodal relapse therapy were larger node size (odds ratio, 2.68; P = .045) in patients undergoing chemotherapy and elevated tumor markers (odds ratio, 6.05; P = .008) in patients undergoing RPLND. When RPLND was performed with normal markers, 82% required no further treatment. Second relapse occurred in 30 of 162 patients (18.5%). With median follow-up of 7.6 years, there were five deaths (3.1% of AS relapses, but 0.8% of whole AS cohort) from NSGCT or treatment complications. CONCLUSION The retroperitoneum is the most common site of relapse in clinical stage I NSGCT on AS. Most are cured by single-modality treatment. RPLND should be considered for relapsed patients, especially those with disease limited to the retroperitoneum and normal markers, as an option to avoid chemotherapy.

Testicular germ cell tumors (TGCTs) are generally rare but represent the most common solid tumors in young men. They are classified broadly into seminoma, which resemble primordial germ cells (PGCs), and non-seminoma, which are either undifferentiated (embryonic carcinoma) or differentiated (teratoma, yolk sac tumor, choriocarcinomas) patterning. A widespread role for microRNAs (miRNAs), in diverse molecular processes driving initiation and progression of various types of TGCTs has been recently studied. We discuss the involvement of different miRNAs in the development and progression of different types of TGCTs. Moreover, we highlight the aberrant expression of miRNAs in TGCTs and several targets, which may define miRNAs as oncomiRs or tumor suppressors. A better understanding of miRNA biology may ultimately yield further insight into the molecular mechanisms of tumorigenesis and new therapeutic strategies against TGCTs.

Oct4 is an important mammalian POU family transcription factor expressed by early human embryonic stem cells (hESCs). The precise level of Oct4 governs the pluripotency and fate determination of hESCs. Several post-translational modifications (PTMs) of Oct4 including phosphorylation, ubiquitination, and SUMOylation have been reported to regulate its critical functions in hESCs. Ubiquitination and deubiquitination of Oct4 should be well balanced to maintain the pluripotency of hESCs. The protein turnover of Oct4 is regulated by several E3 ligases through ubiquitin-mediated degradation. However, reversal of ubiquitination by deubiquitinating enzymes (DUBs) has not been reported for Oct4. In this study, we generated a ubiquitin-specific protease 3 (USP3) gene knockout using the CRISPR/Cas9 system and demonstrated that USP3 acts as a protein stabilizer of Oct4 by deubiquitinating Oct4. USP3 interacts with endogenous Oct4 and co-localizes in the nucleus of hESCs. The depletion of USP3 leads to a decrease in Oct4 protein level and loss of pluripotent morphology in hESCs. Thus, our results show that USP3 plays an important role in controlling optimum protein level of Oct4 to retain pluripotency of hESCs.

Background Testicular cancer constitutes 1.0% of male cancer and typically carries a good prognosis. As far as we are aware, the role for hydrogen sulfide in testicular cancer and the level of hydrogen sulfide-synthesizing enzyme have never been addressed. Here we examined cystathionine gamma-lyase (CSE) expression in several germ-cell testicular tumors. Materials and methods Tissue microarrays were employed to examine CSE expression in 32 benign testicular samples, 88 testicular seminomas, 34 embryonal carcinomas, 4 mature teratomas, and 16 yolk sac tumors, and CSE expression was compared to that seen in benign testicular tissue. Results Compared to benign testicular tissue, CSE expression was increased in all three types of testicular neoplasm but not in mature teratomas. Highest CSE expression was identified in embryonal carcinomas, which often show a relatively aggressive clinical course. Conclusion For the first time, we show that CSE is increased in several common testicular germ-cell tumor types.

To evaluate the perioperative and oncological outcomes after post-chemotherapy robot-assisted retroperitoneal lymph node dissection (PC-RARPLND).We retrospectively reported the perioperative and oncological outcomes of all the patients with testicular cancer who underwent PC-RARPLND at three tertiary teaching centers. Descriptive statistical measures were used to report demographic, clinical, intraoperative, postoperative and oncological outcomes.There were 43 consecutive patients who underwent PC-RARPLND at the participating institutions. Mean patient age was 29.2 years (± 8.2), BMI was 26.6 kg/mPC-RAPLND is safe and technically reproducible. It provides improved morbidity and less convalescence.

The pharmacological effects of BST204&mdash, a fermented ginseng extract&mdash, on several types of cancers have been reported. However, the effects of ginseng products or single ginsenosides against cancer stem cells are still poorly understood. In this study, we identified the anti-tumorigenic and anti-invasive activities of BST204 through the suppression of the cancer stem cell marker, CD133. The treatment of embryonic carcinoma cells with BST204 induced the expression of the tumor suppressor protein, p53, which decreased the expression of cell cycle regulatory proteins and downregulated the expression of CD133 and several stemness transcription factors. These changes resulted in both the inhibition of tumor cell proliferation and tumorigenesis. The knockdown of CD133 suggests that it has a role in tumorigenesis, but not in cancer cell proliferation or cell cycle arrest. Treatment with BST204 resulted in the reduced expression of the mesenchymal marker, N-cadherin, and the increased expression of the epithelial marker, E-cadherin, leading to the suppression of tumor cell migration and invasion. The knockdown of CD133 also exhibited an anti-invasive effect, indicating the role of CD133 in tumor invasion. The single ginsenosides Rg3 and Rh2&mdash, major components of BST204&mdash, exhibited limited effects against cancer stem cells compared to BST204, suggesting possible synergism among several ginsenoside compounds.

A recent study suggested a role of CHEK2 loss-of-function germ-line pathogenic variants in the predisposition to testicular cancer (TC) (AlDubayan et al. JAMA Oncol 5:514-522, 2019). We attempted to validate this finding relying on the high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2 + 1G A [c.444 + 1G A]) were detected in 7/280 (2.5%) TC patients vs. 3/424 (0.7%) healthy men and 6/1007 (0.6%) healthy women [OR 4.0 (95% CI 1.5-11), p = 0.009 for pooled control groups]. Somatic CHEK2 loss-of-heterozygosity (LOH) was detected in 4 out of 6 tumors available for analysis; strikingly all these instances of LOH involved inactivation of the wild-type allele. The CHEK2 c.470T C (p.Ile157Thr) variant was detected in 21/280 (7.5%) affected vs. 22/424 (5.2%) non-affected men [OR 1.5 (95% CI 0.8-2.7), p = 0.3]. Somatic CHEK2 LOH was revealed only in 6 out of 21 tumors obtained from CHEK2 c.470T C (p.Ile157Thr) carriers, with the C-allele lost in two cases and T-allele deleted in four tumors. The results of comparison of allele frequencies in TC patients versus population controls coupled with the data on CHEK2 LOH status in tumor tissues support the association of CHEK2 pathogenic variants with TC risk.

Introduction: Embryonal carcinomas are the rarest, and usually present when they are already associated with other components of germ cells. They have clinical and radiological features similar to yolk sac tumors. Case report: Patient G.A.S.L, male, 30 years old, former smoker and alcoholic. Initially, the patient reported pain in the left hemithorax in February 2018 with extension of the symptoms to the region of the thoracic and lumbar spine. A tomography of the total abdomen and chest was performed, with result suggestive of mediastinal tumor, pulmonary nodules, tissue material with soft tissue density in the posterior mediastinum and numerous retroperitoneal lymph node enlargement, which evolved with paraplegia of the lower limbs by nerve compression and hypoesthesia. It was conducted a biopsy of a mediastinal tumor posterior to the left with result of malignant epithelial neoplasia and diagnosis of extragonadal embryonic carcinoma very little differentiated. The patient presented pulmonary metastasis confirming that these tumors frequently infiltrate into the adjacent organs. Cisplatinbased chemotherapy is the standard treatment, leading to improved survival in patients with this type of tumor. After chemotherapy, the tumor volume decreased, but the patient continued with paraplegia of lower limbs due to nerve compression. Conclusion: This study reports the case of a young patient with a rare germ cell tumor and pulmonary metastasis who evolved clinically stable after specific chemotherapy treatment. Because there is still scarce literature on the subject, this study brings new evidences and findings. Introducción: Los carcinomas embrionarios son los más raros y generalmente se presentan cuando ya están asociados con otros componentes de células germinativas. Se presentan características clínicas y radiológicas similares a los tumores de saco vitelino. Relato del caso: Paciente G.A.S.L, sexo masculino, 30 años, ex tabaquista y etilista. Se inició con cuadro de dolores en el hemitórax izquierdo en febrero de 2018 con extensión de los síntomas para la región de la columna torácica y lumbar. Se realizó una tomografía de abdomen total y tórax, con resultado sugestivo de tumor de mediastino, nódulos pulmonares, material tisular con densidad de partes blandas en el mediastino posterior y numerosas linfonodomegalias retroperitoneales, evolucionó con paraplejia de miembros inferiores por compresión nerviosa y con hipoestesia. Se realizó biopsia de tumor de mediastino posterior a la izquierda con resultado de neoplasia maligna epitelial y diagnóstico de carcinoma embrionario extra gonodal poco diferenciado. El paciente presentó metástasis pulmonar confirmando que estos tumores frecuentemente se infiltran en los órganos adyacentes. La quimioterapia basada en cisplatino es el tratamiento estándar, llevando a la mejora de la supervivencia en pacientes con este tipo de tumor. Después de la quimioterapia hubo la disminución del volumen tumoral, sin embargo, siguió con la paraplejia de miembros inferiores debido a la compresión nerviosa. Conclusión: Este estudio informa el caso de un paciente joven con un tumor raro de células germinales y metástasis pulmonar que evolucionó clínicamente estable después de un tratamiento de quimioterapia específico. Debido a que todavía hay poca literatura sobre el tema, este estudio aporta nuevas pruebas y hallazgos. Introdução: Os carcinomas embrionários são os mais raros e, geralmente, se apresentam quando já estão associados com outros componentes de células germinativas. Possuem características clínicas e radiológicas similares aos tumores de saco vitelino. Relato do caso: Paciente G.A.S.L, sexo masculino, 30 anos, ex-tabagista e etilista. Iniciou com quadro de dores no hemitórax esquerdo em fevereiro de 2018 com extensão dos sintomas para a região da coluna torácica e lombar. Realizou tomografia de abdômen total e tórax, com resultado sugestivo de tumor de mediastino, nódulos pulmonares, material tecidual com densidade de partes moles no mediastino posterior e numerosas linfonodomegalias retroperitoneais, evoluiu com paraplegia de membros inferiores por compressão nervosa e com hipoestesia. Realizou biópsia de tumor de mediastino posterior à esquerda com resultado de neoplasia maligna epitelial e diagnóstico de carcinoma embrionário extragonodal pouco diferenciado. O paciente apresentou metástase pulmonar, confirmando que esses tumores frequentemente se infiltram nos órgãos adjacentes. A quimioterapia baseada em cisplatina é o tratamento padrão, levando à melhora da sobrevida em pacientes com esse tipo de tumor. Após a quimioterapia, houve diminuição do volume tumoral, porém, seguiu com a paraplegia de membros inferiores em razão da compressão nervosa. Conclusão: Este estudo relata o caso de um paciente jovem, com tumor raro de células germinativas e metástase pulmonar, que evoluiu clinicamente estável após tratamento específico com quimioterápicos. Por ainda haver uma escassa literatura acerca do tema, este estudo traz novas evidências e achados. &nbsp

B3GALT5 is involved in the synthesis of embryonic stem (ES) cell marker glycan, stage-specific embryonic antigen-3 (SSEA3). This gene has three native promoters and an integrated retroviral long terminal repeat (LTR) promoter. We found that B3GALT5-LTR is expressed at high levels in human ES cells. B3GALT5-LTR is also involved in the synthesis of the cancer-associated glycan, sialyl Lewis a. Sialyl Lewis a is expressed in ES cells and its expression decreases upon differentiation. Retinoic acid induced differentiation of ES cells, decreased the short form of NFYA (NFYAs), increased phosphorylation of STAT3, and decreased B3GALT5-LTR expression. NFYAs activated, and constitutively-active STAT3 (STAT3C) repressed B3GALT5-LTR promoter. The NFYAs and STAT3C effects were eliminated when their binding sites were deleted. Retinoic acid decreased the binding of NFYA to B3GALT5-LTR promoter and increased phospho-STAT3 binding. Lamin A repressed NFYAs and SSEA3 expression. SSEA3 repression mediated by a SIRT1 inhibitor was reversed by a STAT3 inhibitor. Repression of SSEA3 and sialyl Lewis a synthesis mediated by retinoic acid was partially reversed by lamin A short interfering RNA (siRNA) and a STAT3 inhibitor. In conclusion, B3GALT5-LTR is regulated by lamin A-NFYA and SIRT1-STAT3 signaling that regulates SSEA3 and sialyl Lewis a synthesis in ES cells, and sialyl Lewis a is also a ES cell marker.

Cancer cells with a less differentiated stem-like phenotype are more resistant to therapeutic manipulations than their differentiated counterparts, and are considered as one of the main causes of cancer persistence and relapse. As such, induction of differentiation in cancer stem-like cells (CSLCs) has emerged as an alternative strategy to enhance the efficacy of anticancer therapies. CSLCs are metabolically distinct from differentiated cells, and any aberration from the intrinsic metabolic state can induce differentiation of CSLCs. Therefore, metabolism-related molecular targets, with a capacity to promote differentiation within CSLCs, are of therapeutic importance. Here, we demonstrate that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme catalyzing the synthesis of amino acid serine, is important for maintaining the poorly differentiated, stem-like state of CSLCs. Our data shows that PHGDH deficiency impairs the tumorsphere formation capacity in embryonal carcinoma stem-like cells (ECSLCs), breast cancer stem-like cells (BCSLCs) and patient-derived brain tumor-initiating cells (BTICs), which is accompanied by the reduced expression of characteristic stemness-promoting factors, such as Oct4, Nanog, Sox-2, and Bmi-1. Mechanistically, PHGDH deficiency in ECSLCs promotes differentiation to various lineages via degradation of Oct4 and by increasing the stability of differentiation marker β3-tubulin. Furthermore, PHGDH inhibition promotes p-mTOR independent but Beclin-1-dependent autophagy, independent of apoptosis. When studied in combination, the inhibition of both PHGDH and p-mTOR in ECSLCs causes further augmentation of autophagy, and additionally promotes apoptosis, demonstrating the clinical applicability of PHGDH-based manipulations in cancer therapies. Recapitulating these in vitro findings in CSLC models, the intratumoral PHGDH expression in patient-derived tumors is positively correlated with the mRNA levels of stemness factors, especially Oct4, and cancer patients co-expressing high levels of PHGDH and Oct4 display significantly lower survival than those with low PHGDH/Oct4 co-expression. Altogether, this study identifies a clinically-relevant role for PHGDH in the regulation of stemness-differentiation axis within CSLCs.