Limits...
Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine.

Castellsagué J, Gel B, Fernández-Rodríguez J, Llatjós R, Blanco I, Benavente Y, Pérez-Sidelnikova D, García-Del Muro J, Viñals JM, Vidal A, Valdés-Mas R, Terribas E, López-Doriga A, Pujana MA, Capellá G, Puente XS, Serra E, Villanueva A, Lázaro C - EMBO Mol Med (2015)

Bottom Line: These aggressive malignancies confer poor survival, with no effective therapy available.Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines.Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth.

View Article: PubMed Central - PubMed

Affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

No MeSH data available.


Related in: MedlinePlus

SNP array analysis of cell line S462 and its orthotopic xenograft tumorsOrthotopic xenograft MPNSTs derived from cell line S462 showed a number of differences in genomic alterations when compared to the S462 cell line itself. The outermost layer shows the full set of canonical human chromosomes. The next layers, from outside to inside, show the BAF of the S462 cell line (A), and its derived xenograft at passages 1 (B) and 4 (C). Copy number variations are represented by a colored line under each BAF (gray: 2n, red: > 2n (chromosomal gain); green: < 2n (chromosomal loss). LOH events are shown in blue. Pink highlights mark the differences between cell line and xenografts compatible with a selection process, while orange highlights mark the regions consistent with structural genomic changes due to engraftment process and passaging.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492820&req=5

fig08: SNP array analysis of cell line S462 and its orthotopic xenograft tumorsOrthotopic xenograft MPNSTs derived from cell line S462 showed a number of differences in genomic alterations when compared to the S462 cell line itself. The outermost layer shows the full set of canonical human chromosomes. The next layers, from outside to inside, show the BAF of the S462 cell line (A), and its derived xenograft at passages 1 (B) and 4 (C). Copy number variations are represented by a colored line under each BAF (gray: 2n, red: > 2n (chromosomal gain); green: < 2n (chromosomal loss). LOH events are shown in blue. Pink highlights mark the differences between cell line and xenografts compatible with a selection process, while orange highlights mark the regions consistent with structural genomic changes due to engraftment process and passaging.

Mentions: In addition to the orthoxenograft models generated from primary MPNSTs, we also developed an orthoxenograft model from an established MPNST cell line (S462), following similar experimental procedures used for the other models. Histological characterization of the generated orthoxenograft showed that it retained the immunocytochemical marker characteristics of the original cell line, as well as reproducing the histological patterns of the NF1-associated orthoxenografts (Table2 and Supplementary Fig S1). At the molecular level, the number of point mutations and the expression pattern indicated a high degree of similarity between the cell line and the derived orthoxenografts (Figs5 and 6). However, at the structural genomic levels, the number of differences between the S462 cell line and the orthoxenografts at passages 1 and 4 was greater than observed in the MPNST-derived models (Fig8 and Supplementary Fig S4). These differences were classified in two groups. The first group contained genomic changes identical to those identified in models generated from primary tumors, that is, differences between orthoxenograft passages 1 and 4, consistent with structural genomic changes due to the successive engraftments (highlighted in yellow in Fig8). The percentage of genome affected by these changes was low and similar to that observed in the other models. The second group of differences corresponded to progressive changes along passages that were consistent with a selection process. We had previously observed a high diversity in the chromosomal content of S462 cells in culture by cytogenetic karyotyping (data not shown), and these progressive changes from primary tumor to passage 1 and passage 4 pointed to a clonal selection process, reducing the heterogeneity of the original cell culture (highlighted in magenta in Fig8).


Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine.

Castellsagué J, Gel B, Fernández-Rodríguez J, Llatjós R, Blanco I, Benavente Y, Pérez-Sidelnikova D, García-Del Muro J, Viñals JM, Vidal A, Valdés-Mas R, Terribas E, López-Doriga A, Pujana MA, Capellá G, Puente XS, Serra E, Villanueva A, Lázaro C - EMBO Mol Med (2015)

SNP array analysis of cell line S462 and its orthotopic xenograft tumorsOrthotopic xenograft MPNSTs derived from cell line S462 showed a number of differences in genomic alterations when compared to the S462 cell line itself. The outermost layer shows the full set of canonical human chromosomes. The next layers, from outside to inside, show the BAF of the S462 cell line (A), and its derived xenograft at passages 1 (B) and 4 (C). Copy number variations are represented by a colored line under each BAF (gray: 2n, red: > 2n (chromosomal gain); green: < 2n (chromosomal loss). LOH events are shown in blue. Pink highlights mark the differences between cell line and xenografts compatible with a selection process, while orange highlights mark the regions consistent with structural genomic changes due to engraftment process and passaging.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492820&req=5

fig08: SNP array analysis of cell line S462 and its orthotopic xenograft tumorsOrthotopic xenograft MPNSTs derived from cell line S462 showed a number of differences in genomic alterations when compared to the S462 cell line itself. The outermost layer shows the full set of canonical human chromosomes. The next layers, from outside to inside, show the BAF of the S462 cell line (A), and its derived xenograft at passages 1 (B) and 4 (C). Copy number variations are represented by a colored line under each BAF (gray: 2n, red: > 2n (chromosomal gain); green: < 2n (chromosomal loss). LOH events are shown in blue. Pink highlights mark the differences between cell line and xenografts compatible with a selection process, while orange highlights mark the regions consistent with structural genomic changes due to engraftment process and passaging.
Mentions: In addition to the orthoxenograft models generated from primary MPNSTs, we also developed an orthoxenograft model from an established MPNST cell line (S462), following similar experimental procedures used for the other models. Histological characterization of the generated orthoxenograft showed that it retained the immunocytochemical marker characteristics of the original cell line, as well as reproducing the histological patterns of the NF1-associated orthoxenografts (Table2 and Supplementary Fig S1). At the molecular level, the number of point mutations and the expression pattern indicated a high degree of similarity between the cell line and the derived orthoxenografts (Figs5 and 6). However, at the structural genomic levels, the number of differences between the S462 cell line and the orthoxenografts at passages 1 and 4 was greater than observed in the MPNST-derived models (Fig8 and Supplementary Fig S4). These differences were classified in two groups. The first group contained genomic changes identical to those identified in models generated from primary tumors, that is, differences between orthoxenograft passages 1 and 4, consistent with structural genomic changes due to the successive engraftments (highlighted in yellow in Fig8). The percentage of genome affected by these changes was low and similar to that observed in the other models. The second group of differences corresponded to progressive changes along passages that were consistent with a selection process. We had previously observed a high diversity in the chromosomal content of S462 cells in culture by cytogenetic karyotyping (data not shown), and these progressive changes from primary tumor to passage 1 and passage 4 pointed to a clonal selection process, reducing the heterogeneity of the original cell culture (highlighted in magenta in Fig8).

Bottom Line: These aggressive malignancies confer poor survival, with no effective therapy available.Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines.Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth.

View Article: PubMed Central - PubMed

Affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

No MeSH data available.


Related in: MedlinePlus