Abstract. Embryonic neural tumors are responsible for a disproportionate number of cancer deaths in children. Although dramatic improvements in survival for pediatric malignancy has been achieved in previous years advancements seem to be slowing down. For the development of new enhanced therapy and an increased understanding of the disease, pre-clinical models better capturing the neoplastic niche are essential. Tumors of early childhood present in this respect a particular challenge. Here, we explore how components of the embryonic process in stem-cell induced mature teratoma can function as an experimental in vivo microenvironment instigating the growth of injected childhood neuroblastoma (NB) cell lines. Three human NB cell lines, IMR-32, Kelly and SK-N-BE(2), were injected into mature pluripotent stem cell-induced teratoma (PSCT) and compared to xenografts of the same cell lines. Proliferative NB cells from all lines were readily detected in both models with a typical histology of a poorly differentiated NB tumor with a variable amount of fibrovascular stroma. Uniquely in the PSCT microenvironment, NB cells were found integrated in a non-random fashion. Neuroblastoma cells were never observed in areas with well-differentiated somatic tissue i.e. bone, muscle, gut or areas of other easily identifiable tissue types. Instead, the three cell lines all showed initial growth exclusively occurring in the embryonic loose mesenchymal stroma, resulting in a histology recapitulating NB native presentation in vivo. Whether this reflects the 'open' nature of loose mesenchyme more easily giving space to new cells compared to other more dense tissues, the rigidity of matrix providing physical cues modulating NB characteristics, or if embryonic loose mesenchyme may supply developmental cues that attracted or promoted the integration of NB, remains to be tested. We tentatively hypothesize that mature PSCT provide an embryonic niche well suited for in vivo studies on NB. IntroductionKey knowledge is still missing for the successful cure of aggressive neuroblastoma (NB), representing one of the most deadly pediatric malignancies (1-4). Neuroblastoma is a small round cell tumor of childhood and is considered to arise from dedifferentiation of primordial neural crest cells that populate the sympathetic trunks and the adrenal medulla (reviewed in ref. 5). During this process, an aberrant response to microenvironment cues may play an important role in modulating the tumor phenotype, and hence also lead to the variable clinical presentations of NB in patients. The clinical presentation spans from a benign type with the ability to spontaneously regress to a variant with a high rate of recurrence, metastatic spread and a high frequency of therapy-resistance. Current consensus supports the importance of a strong interplay with the surrounding tissue promoting tumor growth and spread (6). Thus, pre-clinical studies of childhood NB would for increased relevance benefit from in vivo models better matching the embryonic neoplastic niche i...
For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell-derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo.
Xenografting is widely used for assessing in vivo pluripotency of human stem cell populations. Here, we report on early to late events in the development of mature experimental teratoma from a well-characterized human embryonic stem cell (HESC) line, HS181. The results show an embryonic process, increasingly chaotic. Active proliferation of the stem cell derived cellular progeny was detected already at day 5, and characterized by the appearance of multiple sites of engraftment, with structures of single or pseudostratified columnar epithelium surrounding small cavities. The striking histological resemblance to developing embryonic ectoderm, and the formation of epiblast-like structures was supported by the expression of the markers OCT4, NANOG, SSEA-4 and KLF4, but a lack of REX1. The early neural marker NESTIN was uniformly expressed, while markers linked to gastrulation, such as BMP-4, NODAL or BRACHYURY were not detected. Thus, observations on day 5 indicated differentiation comparable to the most early transient cell populations in human post implantation development. Confirming and expanding on previous findings from HS181 xenografts, these early events were followed by an increasingly chaotic development, incorporated in the formation of a benign teratoma with complex embryonic components. In the mature HS181 teratomas not all types of organs/tissues were detected, indicating a restricted differentiation, and a lack of adequate spatial developmental cues during the further teratoma formation. Uniquely, a kinetic alignment of rare complex structures was made to human embryos at diagnosed gestation stages, showing minor kinetic deviations between HS181 teratoma and the human counterpart.
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,
Background Systemic lupus erythematosus (SLE) and systemic vasculitis are autoimmune diseases. SLE is of an unknown cause that occurs primarily in women and can involve many organs. Systemic vasculitis is characterized by inflammatory destruction of the blood vessels and tissue necrosis, there are several types of vasculitis classified by size of the affected blood vessels. Mycophenolate mofetil (MMF) is an immunosuppressive drug that is commonly used within the transplantation area, but also for autoimmune systemic diseases such as SLE and systemic vasculitis. Objectives The aim of this study was to investigate the outcome of MMF in patients with SLE and systemic vasculitis. Methods This study included patients with SLE or systemic vasculitis with ongoing or previous MMF treatment at Karolinska University Hospital, Stockholm, Sweden. Data on specific information regarding disease and treatment was obtained through medical record review. Results Out of a total of 648 patients with SLE and 455 with systemic vasculitis; 135 patients (21%) with SLE and 43 patients (9%) with vasculitis had ongoing or previous MMF treatment. The most common organ manifestation at baseline was renal involvement (50%) among SLE patients. Median MMF dose was 2g/day and glucocorticoids (GC) doses were significantly reduced during MMF treatment from 21.7 mg/day to 8.3 mg/day after 12 months. By physician assessment, 79% of the patients were good or moderate responders to MMF treatment after 12 months. The most common adverse events leading to discontinuation were side effects in the gastrointestinal tract (40%) and general side effects (30%). A “survival-on-drug” Kaplan-Meier curve showed that 40% of the patients remained on long-term MMF treatment. Conclusions MMF was used in 16% of all patients with SLE and systemic vasculitis. The treatment appeared to be effective with a reasonable survival-on-drug as well as a GC sparing effect for many patients with SLE or systemic vasculitis. Disclosure of Interest C. Lourdudoss: None Declared, S. Jamil: None Declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, Consultant for: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB
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