Species-Specific <i>In vivo</i> Engraftment of the Human BL Melanoma Cell Line Results in an Invasive Dedifferentiated Phenotype Not Present in Xenografts

Cedervall, Jessica; Jamil, Seema; Prasmickaite, Lina; Eskandarpour, Malihe; Hansson, Johan; Mælandsmo, Gunhild Mari; Ringborg, Ulrik; Gulyás, Miklós; Zhen, He Suo; Kanter, Lena; Ährlund‐Richter, Lars

doi:10.1158/0008-5472.can-08-3746

Cited by 6 publications

(9 citation statements)

References 41 publications

(58 reference statements)

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“…PSCT were allowed to progress for 45 days before injected with NB tumor cells. The variations of germ layer formation in separate HS181 PSCT formed under the present conditions have been described previously in more detail and were in all cases minor (9,15).…”

Section: Cell Linessupporting

confidence: 74%

“…The stem cell induced teratoma environment has earlier been suggested as an experimental platform for studying human tumor cell lines of a variety of origins (ovarian, prostate, lung, glioblastoma, breast, colorectal cancer) (12)(13)(14). Similarly, we studied growth from a malignant melanoma cell line in human experimental teratoma and identified a de-differentiated tumor phenotype not present in xenografts from the same cell line (15), possibly indicating an adaptation of the tumor cells to the embryonic microenvironment.…”

Section: Introductionmentioning

confidence: 74%

“…Dysregulated expression has however been detected in several malignancies and expression of Nodal has been linked with invasiveness and metastasis; as reported for melanoma, glioma, and cancers of breast endometrium and prostate (25)(26)(27)(28). In a previous study using a melanoma cell line we detected Nodal positive tumor cells invading surrounding mesenchymal stroma in the PSCT model (15). We therefore wanted to know whether expression of Nodal could be similarly identified for NB.…”

Section: Discussionmentioning

confidence: 94%

“…Presence of NB tumor cells was verified using genetic identification as described previously (15). Human Y-and X-chromosomes was detected using mixed probes (CEP XY; Vysis Inc, Downers Grove, IL, USA) against the human X-and Y-chromosomes, thus positively separating human from mouse cells in xenografts, as well as separating IMR-32 cells (XX) from PSCT cells (XY), as previously described (15). For the identification of Kelly and SK-N-BE(2), both lacking stable Y-chromosome centromeres, the identification of their genetic MYCN amplification was performed using the probes LSI N-MYC, 2p24 (Vysis Inc).…”

Section: Injection Of Nb Cells Cells From the Indicated Cell Lines (mentioning

confidence: 99%

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Neuroblastoma cells injected into experimental mature teratoma reveal a tropism for embryonic loose mesenchyme

Jamil

Cedervall

Hultman

et al. 2013

International Journal of Oncology

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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...

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Section: Cell Linessupporting

confidence: 74%

Section: Introductionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 94%

Section: Injection Of Nb Cells Cells From the Indicated Cell Lines (mentioning

confidence: 99%

See 2 more Smart Citations

Neuroblastoma cells injected into experimental mature teratoma reveal a tropism for embryonic loose mesenchyme

Jamil

Cedervall

Hultman

et al. 2013

International Journal of Oncology

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“…For the identification of human cells, Fluorescent In Situ Hybridization (FISH) was performed using a mixed probe against the human X-chromosome (red) and Y- chromosome (green) (CEP XY; Vysis Inc, IL, USA), as previously described [37].…”

Section: Methodsmentioning

confidence: 99%

Characterization of Stem-Like Cells in Mucoepidermoid Tracheal Paediatric Tumor

et al. 2014

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Stem cells contribute to regeneration of tissues and organs. Cells with stem cell-like properties have been identified in tumors from a variety of origins, but to our knowledge there are yet no reports on tumor-related stem cells in the human upper respiratory tract. In the present study, we show that a tracheal mucoepidermoid tumor biopsy obtained from a 6 year-old patient contained a subpopulation of cells with morphology, clonogenicity and surface markers that overlapped with bone marrow mesenchymal stromal cells (BM-MSCs). These cells, designated as MEi (mesenchymal stem cell-like mucoepidermoid tumor) cells, could be differentiated towards mesenchymal lineages both with and without induction, and formed spheroids in vitro. The MEi cells shared several multipotent characteristics with BM-MSCs. However, they displayed differences to BM-MSCs in growth kinectics and gene expression profiles relating to cancer pathways and tube development. Despite this, the MEi cells did not possess in vivo tumor-initiating capacity, as proven by the absence of growth in situ after localized injection in immunocompromised mice. Our results provide an initial characterization of benign tracheal cancer-derived niche cells. We believe that this report could be of importance to further understand tracheal cancer initiation and progression as well as therapeutic development.

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

Jamil

Hultman

Cedervall

et al. 2013

Intl Journal of Cancer

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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,

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Species-Specific In vivo Engraftment of the Human BL Melanoma Cell Line Results in an Invasive Dedifferentiated Phenotype Not Present in Xenografts

Cited by 6 publications

References 41 publications

Neuroblastoma cells injected into experimental mature teratoma reveal a tropism for embryonic loose mesenchyme

Neuroblastoma cells injected into experimental mature teratoma reveal a tropism for embryonic loose mesenchyme

Characterization of Stem-Like Cells in Mucoepidermoid Tracheal Paediatric Tumor

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

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