Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

Castro‐Gamero, Angel Mauricio; Borges, Kleiton Silva; Lira, Régia Caroline Peixoto; Andrade, Augusto Faria; Fedatto, Paola Fernanda; Cruzeiro, Gustavo Alencastro Veiga; Bonfim-Silva, Ricardo; Fontes, Aparecida Maria; Valera, Elvis Terci; Bobola, Michael S.; Scrideli, Carlos Alberto; Tone, Luíz Gonzaga

doi:10.1007/s10616-012-9529-z

Cited by 9 publications

(6 citation statements)

References 66 publications

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“…Although all three MB cell lines showed high levels of LDHA expression, the UW402 MB cell line was chosen for examination in more detail as it is known to have isochromosome 17q, which is typical of Group 3 and Group 4 MBs, the most metastatic MBs that carry the poorest prognosis [ 31 ]. DAOY cells have been molecularly subgrouped as Shh MB [ 32 ] and Res256 cells have not been subgrouped, to our knowledge.…”

Section: Resultsmentioning

confidence: 99%

Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

Valvona

Fillmore²

2018

Brain Sciences

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Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4), which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA) is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis. Studies indicate MBs have a glycolytic phenotype; however, LDHA has not yet been explored as a therapeutic target for medulloblastoma. LDHA expression was examined in medulloblastoma subgroups and cell lines. The effects of LDHA inhibition by oxamate or LDHA siRNA on medulloblastoma cell line metabolism, migration and proliferation were examined. LDHA was significantly overexpressed in Group 3 and Wnt MBs compared to non-neoplastic cerebellum. Furthermore, we found that oxamate significantly attenuated glycolysis, proliferation and motility in medulloblastoma cell lines, but LDHA siRNA did not. We established that aerobic glycolysis is a potential therapeutic target for medulloblastoma, but broader LDH inhibition (LDHA, B, and C) may be more appropriate than LDHA inhibition alone.

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Section: Resultsmentioning

confidence: 99%

Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

Valvona

Fillmore²

2018

Brain Sciences

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“…1 we show the results of hierarchical clustering of 39 HOx genes with tumor cell lines which are not characterized (UW473 and UW402 cell lines) and primary cell cultures from the cerebellum (CP4, CP5 and CP6), and also 39 HOX genes with tumor cell lines which are characterized as being from the SHH subgroup (ON-S76 and DAOY cell lines) ( Fig. 1A and B) (35,46,47).…”

Section: Resultsmentioning

confidence: 99%

“…Four independent medulloblastoma cell lines (UW402, UW473, DAOY and ONS-76) were used in this study. UW402 and UW473 cell lines, have been previously characterized regarding chromosomal heterogeneity, instability profiles, cell morphology, cell population doubling time, colony-forming efficiency as well as chemo-sensitivity heterogeneity (35). Both DAOY and ONS-76 cell lines are long-established MB cell lines (36)(37)(38).…”

Section: Methodsmentioning

confidence: 99%

Functional analysis of HOXA10 and HOXB4 in human medulloblastoma cell lines

Bonfim-Silva

Melo

Thomé

et al. 2017

International Journal of Oncology

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Medulloblastoma (MB) is a malignant childhood brain tumor which at molecular level is classified into at least four major subtypes: WNT, SHH, group C and group D differing in response to treatment. Previous studies have associated changes in expression levels and activation of certain HOX genes with MB development. In the present study, we investigate the role of HOX genes in two attributes acquired by tumor cells: migration and proliferation potential, as well as, in vivo tumorigenic potential. We analyzed UW402, UW473, DAOY and ONS-76 human pediatric MB cell lines and cerebellum primary cultures. Two-color microarray-based gene expression analysis was used to identify differentially expressed HOX genes. Among the various HOX genes significantly overexpressed in DAOY and ONS-76 cell lines compared to UW402 and UW473 cell lines, HOXA10 and HOXB4 were selected for further analysis. The expression levels of these HOX genes were validated by real-time PCR. A mouse model was used to study the effect of the HOXA10 and HOXB4 genes on the in vivo tumorigenic potential and the in vitro proliferative and migration potential of MB cell lines. Our results show that the inhibition of HOXA10 in DAOY cell line led to increased in vitro cell migration while in vitro cell proliferation or in vivo tumorigenic potential were unaffected. We also observed that induced expression of HOXB4 in the UW473 cell line significantly reduced in vitro cell proliferation and migration capability of UW473 cells with no effect on the in vivo tumorigenicity. This suggests that HOXA10 plays a role in migration events and the HOXB4 gene is involved in proliferation and migration processes of medulloblastoma cells, however, it appears that these genes are not essential for the tumorigenic process of these cells.

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“…Furthermore, the formation of unique genomes in cancer is incredibly common; there is proclivity for chromosomal change during every cell division when the genome is highly unstable. The tradition of ignoring the non-specific changes in the cancer research field is the reason that these stochastic chromosomal aberrations have only recently been reconsidered as drivers of tumorigenesis and tumor growth (Castro-Gamero et al, 2013;Heng et al, 2004;Heng et al, 2006a;Heng et al, 2006b;Heng et al, 2006c;Heng et al, 2010a;Klein et al, 2010;McCormack et al, 2013;Podlaha et al, 2012;Valind and Gisselsson, 2014). The crucial realizations that have led to this reconsideration are: chromosome alterations change genome-defined systems; the high level of NCCAs is essential for cancer evolution (Heng et al, 2006a;Heng et al, 2013a); and massive and seemingly stochastic chromosomal alterations seem to be the only shared findings among many cancer types.…”

Section: Genome Theory Emphasizes the Ultimate Importance Of Chromosomentioning

confidence: 99%

Insights on processes of evolutionary tumor growth

Horne¹,

Wexler²,

Stevens³

et al. 2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Application of traditional somatic evolutionary theory can offer an appropriate context for studying tumor growth at the molecular level. However, high degrees of heterogeneity (especially genome-level heterogeneity) within tumors coupled with a lack of common driver mutations have posed a challenge to the generally accepted stepwise concept of cancer evolution, where clonal expansion is the key. In order to account for multiple levels of heterogeneity and better understand tumor growth and progression, a new, holistic conceptual framework must be applied in cancer research. Herein, we discuss one such framework, the genome theory of cancer evolution, with respect to tumor growth. This includes detailing the ultimate importance of chromosome aberrations in cancer, the somatic cell evolutionary pattern, and single-cell/population growth dynamics. Under this new framework, tumor growth is a highly dynamic process where emergent outlier subpopulations can greatly influence the pattern of progression and the direction of evolution. Further, genome level changes have a greater impact on cancer evolution than individual gene mutations in most cancer types, as karyotype alteration often results in altered system inheritance which defines the network structure and even can change the meaning of individual genes (representing 'parts inheritance' by changing the gene context. Based on this analysis, we call for a focus shift back on cytogenetic and cytogenomic alterations (especially on non-clonal chromosomal aberrations) in monitoring population growth, identifying the emergence of new subpopulations and studying patterns of evolutionary dynamics. This new insight has implications in understanding cancer evolution in general as well as searching for new diagnostic and treatment strategies.

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Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

Cited by 9 publications

References 66 publications

Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

Functional analysis of HOXA10 and HOXB4 in human medulloblastoma cell lines

Insights on processes of evolutionary tumor growth

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