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1.
Int J Oncol ; 43(3): 831-8, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23857308

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 stem­cell 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 cell­induced 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 non­random 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.


Subject(s)
Neuroblastoma/therapy , Pluripotent Stem Cells/cytology , Teratoma/pathology , Tumor Microenvironment , Animals , Cell Line, Tumor , Humans , Mesoderm/cytology , Mice , Neuroblastoma/embryology , Neuroblastoma/pathology , Stem Cells/pathology , Transplantation, Heterologous , Tropism/genetics
2.
Br J Cancer ; 105(7): 1030-8, 2011 Sep 27.
Article in English | MEDLINE | ID: mdl-21863025

ABSTRACT

BACKGROUND: CRIPTO-1 (CR-1) is involved in the pathogenesis and progression of human carcinoma of different histological origin. In this study we addressed the expression and the functional role of CR-1 in cutaneous melanoma. METHODS: Expression of CR-1 protein in melanomas and melanoma cell lines was assessed by immunohistochemistry, western blotting and/or flow cytometry. Levels of mRNA were evaluated by real-time PCR. Invasion assays were performed in Matrigel-coated modified Boyden chambers. RESULTS: Expression of CR-1 protein and/or mRNA was found in 16 out of 37 primary human cutaneous melanomas and in 12 out of 21 melanoma cell lines. Recombinant CR-1 protein activated in melanoma cells c-Src and, at lesser extent, Smad signalling. In addition, CR-1 significantly increased the invasive ability of melanoma cells that was prevented by treatment with either the ALK4 inhibitor SB-431542 or the c-Src inhibitor saracatinib (AZD0530). Anti-CR-1 siRNAs produced a significant inhibition of the growth and the invasive ability of melanoma cells. Finally, a close correlation was found in melanoma cells between the levels of expression of CR-1 and the effects of saracatinib on cell growth. CONCLUSION: These data indicate that a significant fraction of cutaneous melanoma expresses CR-1 and that this growth factor is involved in the invasion and proliferation of melanoma cells.


Subject(s)
GPI-Linked Proteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Melanoma/metabolism , Melanoma/pathology , Neoplasm Proteins/metabolism , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Activin Receptors, Type I/antagonists & inhibitors , Activin Receptors, Type I/metabolism , Benzamides/pharmacology , Benzodioxoles/pharmacology , Blotting, Western , CSK Tyrosine-Protein Kinase , Cell Adhesion , Cell Movement , Cell Proliferation/drug effects , Dioxoles/pharmacology , Flow Cytometry , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/genetics , Humans , Immunoenzyme Techniques , Intercellular Signaling Peptides and Proteins/genetics , Melanoma/genetics , Neoplasm Invasiveness , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Quinazolines/pharmacology , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/genetics , Smad Proteins/metabolism , Tumor Cells, Cultured , src-Family Kinases
3.
J Cell Mol Med ; 10(1): 174-96, 2006.
Article in English | MEDLINE | ID: mdl-16563230

ABSTRACT

A dynamic, complex relationship exists between tumor cells and their microenvironment, which plays a pivotal role in cancer progression, yet remains poorly understood. Particularly perplexing is the finding that aggressive melanoma cells express genes associated with multiple cellular phenotypes, in addition to their ability to form vasculogenic-like networks in three-dimensional matrix--called vasculogenic mimicry, which is illustrative of tumor cell plasticity. This study addressed the unique epigenetic effect of the microenvironment of aggressive melanoma cells on the behavior of poorly aggressive melanoma cells exposed to it. The data show significant changes in the global gene expression of the cells exposed to 3-D matrices preconditioned by aggressive melanoma cells, including the acquisition of a vasculogenic cell phenotype, upregulation of ECM remodeling genes, and increased invasive ability--indicative of an epigenetic, microenvironment-induced reprogramming of poorly aggressive melanoma cells. However, this epigenetic effect was completely abrogated when a highly cross-linked collagen matrix was used, which could not be remodeled by the aggressive melanoma cells. These findings offer an unique perspective of the inductive properties associated with an aggressive melanoma microenvironment that might provide new insights into the epigenetic regulation of tumor cell plasticity and differentiation, as well as mechanisms that could be targeted for novel therapeutic strategies.


Subject(s)
Collagen Type I/pharmacology , Epigenesis, Genetic , Melanoma/genetics , Melanoma/pathology , Uveal Neoplasms/genetics , Cell Line, Tumor , Cell Movement , Cluster Analysis , Humans , Melanoma/blood supply , Neoplasm Invasiveness , Neovascularization, Pathologic , Oligonucleotide Array Sequence Analysis , Tissue Culture Techniques , Uveal Neoplasms/blood supply , Uveal Neoplasms/pathology
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