Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

Tu, Shi Ming; Bilen, Mehmet Asım; Hess, Kenneth R.; Broaddus, Russell R.; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C.; Karam, Jose A.; Ward, John F.; Wood, Christopher G.; Rao, Priya; Tu, Zachary H.; General, Rosale; Chen, Adrienne H.; Nieto, Yago; Yeung, Sai Ching Jim; Lin, Sue Hwa; Logothetis, Christopher J.; Pisters, Louis L.

doi:10.1002/cncr.29996

Cited by 40 publications

(55 citation statements)

References 38 publications

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“…Recently, a study found high intratumoral heterogeneity in GCC tissues from about 615 patients [31]. There, patients suffering from a mixed yolk-sac-seminoma tumor had the poorest clinical outcome [31]. In our study, strong upregulation of AFP in the OCT3/4 negative TCam-2-ΔSOX2 subpopulation is indicative for development of a yolk-sac tumor.…”

Section: Discussionsupporting

confidence: 56%

“…This differentiation is highly similar to the in vitro differentiation into a mixed non-seminoma. Recently, a study found high intratumoral heterogeneity in GCC tissues from about 615 patients [31]. There, patients suffering from a mixed yolk-sac-seminoma tumor had the poorest clinical outcome [31].…”

Section: Discussionmentioning

confidence: 99%

“…So, upon contact with a somatic microenvironment, seminomas may develop into more aggressive yolk-sac-seminoma-like tumors that need different therapeutic strategies as classical seminomas. Tu et al propose that an integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of non-seminomatous GCCs [31]. Xenografting of TCam-2-ΔSOX2 cells provides a useful model to adress these issues regarding mixed yolk-sac-seminoma-like tumors.…”

Section: Discussionmentioning

confidence: 99%

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SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

et al. 2016

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Type II germ cell cancers (GCC) are divided into seminomas, which are highly similar to primordial germ cells and embryonal carcinomas (EC), often described as malignant counterparts to embryonic stem cells.Previously, we demonstrated that the development of GCCs is a highly plastic process and strongly influenced by the microenvironment. While orthotopic transplantation into the testis promotes seminomatous growth of the seminoma-like cell line TCam-2, ectopic xenotransplantation into the flank initiates reprogramming into an EC-like fate.During this reprogramming, BMP signaling is inhibited, leading to induction of NODAL signaling, upregulation of pluripotency factors and downregulation of seminoma markers, like SOX17. The pluripotency factor and EC-marker SOX2 is strongly induced.Here, we adressed the molecular role of SOX2 in this reprogramming. Using CRISPR/Cas9-mediated genome-editing, we established SOX2-deficient TCam-2 cells. Xenografting of SOX2-deficient cells into the flank of nude mice resulted in maintenance of a seminoma-like fate, indicated by the histology and expression of OCT3/4, SOX17, TFAP2C, PRDM1 and PRAME. In SOX2-deficient cells, BMP signaling is inhibited, but NODAL signaling is not activated. Thus, SOX2 appears to be downstream of BMP signaling but upstream of NODAL activation. So, SOX2 is an essential factor in acquiring an EC-like cell fate from seminomas.A small population of differentiated cells was identified resembling a mixed non-seminoma. Analyses of these cells revealed downregulation of the pluripotency and seminoma markers OCT3/4, SOX17, PRDM1 and TFAP2C. In contrast, the pioneer factor FOXA2 and its target genes were upregulated, suggesting that FOXA2 might play an important role in induction of non-seminomatous differentiation.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

et al. 2016

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“…Known immunohistochemistry markers tend to lack sensitivity. Correct identification of YST is however essential, since this component is an independent poor prognostic indicator [8,9]. In a series of 49 YSTs from 45 patients, we show that HNF1, a factor necessary for early visceral endoderm differentiation, represents a highly sensitive immunohistochemical diagnostic marker for YST.…”

Section: Discussionmentioning

confidence: 78%

Role of HNF1β in the differential diagnosis of yolk sac tumor from other germ cell tumors

Rougemont

Tille

2018

Human Pathology

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Identification of the yolk sac tumor (YST) component in germ cell tumors (GCT) may prove challenging, and highly sensitive and specific immunohistochemical markers are still lacking.Preliminary data from the literature suggest that HNF1 may represent a sensitive marker of YST. The specificity of HNF1 has not been addressed in GCT. A cohort of 49 YST specimens from 45 patients was designed, occurring either as pure tumors, or as a component of a mixed GCT. Immunohistochemistry was conducted on whole tumor sections using HNF1. SALL4, OCT4, CD30, CDX2, Cytokeratin 19, Glypican 3, and GATA3 were used for classification of the GCT components. Patients were mostly male (39/45), aged 14 months to 49 years, with primary testicular tumors (37/39), or primary mediastinal pure YSTs (2/39).All 6 primary tumors occurring in females (6/45) were pure ovarian YSTs; age range was 4 to 72 years. HNF1 nuclear reactivity was seen in the YST component in all 49 tumors, with a moderate to strong nuclear pattern of staining. Embryonal carcinoma (EC, 0/32) and seminoma (0/6) were negative. Choriocarcinoma (6/6) showed faint focal cytoplasmic reactivity to HNF1 but no nuclear staining. In teratomas, only enteric-type glands showed nuclear reactivity to HNF1 (11/16). Therefore, HNF1 sensitivity in YST component identification was 100% and specificity was 80%. Thus, in our experience, HNF1 is a sensitive and reliable marker of the YST component in GCT, and allows distinction of YST from intricately admixed EC, especially in the diffuse embryoma pattern. Abstract Word Count: 243

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“…This task was made possible and might be enhanced by focusing on a potentially lethal phenotype of NSGCT that contained yolk sac tumor in the primary tumor [3]. Importantly, refractory tumor and lethal NSGCT were not observed in any of our patients with pure E. However, viable germ cell tumor or somatic transformation was frequently detected in the residual tumor after chemotherapy in patients with refractory EYT (70% and 20%, respectively) or EYST (33% and 50%, respectively).…”

Section: Discussionmentioning

confidence: 99%

Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis

et al. 2016

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BackgroundNonseminomatous germ cell tumor of the testis (NSGCT) is largely curable. However, a small group of patients develop refractory disease. We investigated the hypothesis that intratumoral heterogeneity contributes to the emergence of chemoresistance and the development of refractory tumor subtypes.ResultsOur institution's records for January 2000 through December 2010 included 275 patients whose primary tumor showed pure embryonal carcinoma (pure E); mixed embryonal carcinoma, yolk sac tumor, and teratoma (EYT); or mixed embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST). Patients with EYST had the highest cancer-specific mortality rate (P = .001). They tended to undergo somatic transformation (P = .0007). Two of 5 patients with clinical stage I EYST who had developed recurrence during active surveillance died of their disease.Materials and MethodsIn this retrospective study, we evaluated consecutive patients who had been diagnosed with the three most common histological phenotypes of NSGCT. Chemoresistance was defined as the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor or the development of progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 patients to identify any actionable genetic mutations.ConclusionsOur data suggest that patients with EYST in their primary tumor may harbor a potentially refractory NSGCT phenotype and are at increased risk of dying from disease. Despite intratumoral heterogeneity, improved patient selection and personalized care of distinct tumor subtypes may optimize the clinical outcome of patients with NSGCT.

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Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

Cited by 40 publications

References 38 publications

SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

Role of HNF1β in the differential diagnosis of yolk sac tumor from other germ cell tumors

Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis

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