Tropism of the in situ growth from biopsies of childhood neuroectodermal tumors following transplantation into experimental teratoma

Abstract

Experimental teratoma induced from human pluripotent stem cells with normal karyotype can be described as a failed embryonic process and includes besides advanced organoid development also large elements of tissue with a prolonged occurrence of immature neural components. Such immature components, although benign, exhibit strong morphological resemblance with tumors of embryonic neuroectodermal origin. Here, we demonstrate that biopsy material from childhood tumors of neural embryonic origin transplanted to mature experimental teratoma can show an exclusive preference for matching tissue. Tumor specimens from five children with; Supratentorial primitive neuroectodermal tumor (sPNET); Pilocytic astrocytoma of the brainstem; Classic medulloblastoma; peripheral primitive neuroectodermal tumor (pPNET) or neuroblastoma (NB), respectively, were transplanted. Analysis of up to 120 sections of each tumor revealed an engraftment for three of the transplanted tumors: pPNET, sPNET, and NB, with a protruding growth from the latter two that were selected for detailed examination. The histology revealed a strict tropism with a non-random integration into what morphologically appeared as matched embryonic microenvironment recuperating the patient tumor histology. The findings suggest specific advantages over xenotransplantation and lead us to propose that transplantation to the human embryonic microenvironment in experimental teratoma can be a wellneeded complement for preclinical in vivo studies of childhood neuroectodermal tumors.The attrition rate in clinical trials of new drug candidates in the field of oncology is alarmingly high. 1,2 The background for this situation is multifactorial but the translation from preclinical efficacy in characterised in vitro cell lines and in vivo xenografts to successful clinical data is a recognized challenge. Existing animal models entail either the study of non-human cancer, or human cancer in a non-human environment, conditions that do not fully mimic the circumstances in the patient.Better capturing of the relevant in vivo neoplastic niche could be of benefit for improved predictive reliability. A means to avoid species incompatibility in engraftment studies was previously reported by the group of Tzukerman and Skorecki, who demonstrated that experimental teratoma derived from xenografts of human embryonic stem cells (hESC) could provide a human in vivo microenvironment supporting in vivo growth of human tumor cell lines of a variety of origins (ovarian, prostate, lung, glioblastoma, breast, colorectal cancer), 3,4 and also ascites ovarian cancer. 5 We have reported results with growth from a human malignant melanoma cell line injected to a well-characterized experimental teratoma model from the hESC line HS181. 6 Our study revealed a subpopulation of melanoma cells with a dedifferentiated phenotype, not detected in xenografts,

Doxorubicin-provoked increase of mitotic activity and concomitant drain of G0-pool in therapy-resistant BE(2)-C neuroblastoma

“…Pluripotent stem cell induced experimental teratoma (PSCT) was generated in NOD SCID gamma (NSG) mice from diploid bona fide hESC as described [ 23 , 24 , 26 ]. In brief; 8–12 weeks old NSG male mice received an injection of 10 5 HS181 cells (46XX) under the testicular capsule (one side) [ 27 ].…”

“…The model represents increasingly chaotic embryonic processes, comprising compartmentalised tissues or organoid-like development including stages immediately preceding the positioning of adrenal sympatical progenitors in embryonic mesenchyme [ 22 ]. This led us to test the PSCT milieu for in vivo support of tumours of embryonic origin, establishing the NB-PSCT model ([ 23 , 24 ] and reviewed in [ 25 ]). The embryonic nature of the model makes the approach especially applicable for so-called ‘embryonic childhood cancers’ originating early in life.…”

Tumor Specific Recruitment and Reprogramming of Mesenchymal Stem Cells in Tumorigenesis

“…This model provides an in vivo platform which has the ease of standard xenograft models, with the advantage that the tumor microenvironment is comprised of a wide variety of nontransformed differentiated tissues of human origin . In particularly, the advantages of this model were proven for investigating in vivo growth of childhood neuroblastoma by the developmental match between the tumor and the microenvironment where exclusive integration of neuroblastoma cells into the embryonic loose mesecnhymal stroma and close recapitulation of neuroblastoma native presentation in patients can be observed .…”

Neuroblastoma patient‐derived orthotopic xenografts retain metastatic patterns and geno‐ and phenotypes of patient tumours

“…By implantation of intact patient tumour explants, including human tumour stroma, in vitro induced modifications are bypassed. PDXs have been established by subcutaneous implantation of patient‐derived tumour explants from paediatric cancers, including neuroblastoma and by implantation of neuroblastoma samples into human pluripotent stem cell‐derived experimental teratomas . By subcutaneous and/or orthotopic implantation of diverse adult tumours (reviewed in Tentler et al …”

“…PDXs have been established by subcutaneous implantation of patient-derived tumour explants from paediatric cancers, including neuroblastoma 13 and by implantation of neuroblastoma samples into human pluripotent stem cellderived experimental teratomas. 14 By subcutaneous and/or orthotopic implantation of diverse adult tumours (reviewed in Tentler et al 10 ), PDX-based tumour models have been increasingly utilised for preclinical drug screening. For this purpose and for mechanistic studies of metastasis and treatment resistance, it would be important to establish orthotopic PDX models of neuroblastoma to faithfully resemble the clinical features of the disease.…”