Generation and characterization of novel local and metastatic human neuroblastoma variants.
Neuroblastoma (NB) is the most commonly occurring solid tumor in children. The disease usually arises in the adrenal medulla, and it is characterized by a remarkable heterogeneity in its progression. Most NB patients with an advanced disease have massive bone marrow infiltration at diagnosis. Lung metastasis represents a widely disseminated stage and is typically considered to be a terminal event. Much like other malignancies, NB progression is a complex, multistep process. The expression, function, and significance of the various factors involved in NB progression must be studied in relevant in vivo and in vitro models. Currently, models consisting of metastatic and nonmetastatic cell variants of the same genetic background exist for several types of cancer; however, none exists for NB. In the present study, we describe the generation of a NB metastasis model. SH-SY5Y and MHH-NB-11 NB cells were inoculated orthotopically into the adrenal glands of athymic nude mice. Neuroblastoma cells metastasizing to the lungs were isolated from mice bearing adrenal tumors. Lung metastatic variants were generated by repeated cycles of in vivo passage. Characterization of these variants included cellular morphology and immunophenotyping in vitro, aggressiveness in vivo, and various biologic parameters in vitro. The NB metastatic variant in each model displayed unique properties, and both metastatic variants demonstrated a metastatic phenotype in vivo. These reproducible models of human NB metastasis will serve as an unlimited source of transcriptomic and proteomic material. Such models can facilitate future studies on NB metastasis and the identification of novel NB biomarkers and targets for therapy.
Nevo
Ido
I
Department of Cell Research and Immunology, George S Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.
Sagi-Assif
Orit
O
Edry Botzer
Liat
L
Amar
Dana
D
Maman
Shelly
S
Kariv
Naam
N
Leider-Trejo
Leonor E
LE
Savelyeva
Larissa
L
Schwab
Manfred
M
Yron
Ilana
I
Witz
Isaac P
IP
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007621:Karyotyping; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D003676:Deferoxamine