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Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids.

L'Espérance S, Bachvarova M, Tetu B, Mes-Masson AM, Bachvarov D - BMC Genomics (2008)

Bottom Line: However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment.Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids.Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Laval University, Québec (Québec), Canada. syles@hotmail.com

ABSTRACT

Background: Chemotherapy (CT) resistance in ovarian cancer (OC) is broad and encompasses diverse unrelated drugs, suggesting more than one mechanism of resistance. To better understand the molecular mechanisms controlling the immediate response of OC cells to CT exposure, we have performed gene expression profiling in spheroid cultures derived from six OC cell lines (OVCAR3, SKOV3, TOV-112, TOV-21, OV-90 and TOV-155), following treatment with 10,0 microM cisplatin, 2,5 microM paclitaxel or 5,0 microM topotecan for 72 hours.

Results: Exposure of OC spheroids to these CT drugs resulted in differential expression of genes associated with cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling. Genes, functionally involved in DNA repair, DNA replication and cell cycle arrest were mostly overexpressed, while genes implicated in metabolism (especially lipid metabolism), signal transduction, immune and inflammatory response, transport, transcription regulation and protein biosynthesis, were commonly suppressed following all treatments. Cisplatin and topotecan treatments triggered similar alterations in gene and pathway expression patterns, while paclitaxel action was mainly associated with induction of genes and pathways linked to cellular assembly and organization (including numerous tubulin genes), cell death and protein synthesis. The microarray data were further confirmed by pathway and network analyses.

Conclusion: Most alterations in gene expression were directly related to mechanisms of the cytotoxics actions in OC spheroids. However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment. Similarly, overexpression of different tubulin genes upon exposure to paclitaxel could represent an early compensatory effect to this drug action. Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids. Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

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Network analysis of dynamic gene expression in OC spheroids based on the 1.5-fold common gene expression list obtained following paclitaxel treatment. The three top-scoring networks were merged and are displayed graphically as nodes (genes/gene products) and edges (the biological relationships between the nodes). Figure legends are as described in Fig. 2.
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Figure 6: Network analysis of dynamic gene expression in OC spheroids based on the 1.5-fold common gene expression list obtained following paclitaxel treatment. The three top-scoring networks were merged and are displayed graphically as nodes (genes/gene products) and edges (the biological relationships between the nodes). Figure legends are as described in Fig. 2.

Mentions: We found 126 genes to be up-regulated and 139 genes to be down-regulated at least 1.5 fold in paclitaxel-treated OC spheroids [see Additional file 7]. Table 6 shows list of selected functional groups of these genes. Thus, up-regulated genes upon paclitaxel exposure are implicated in apoptosis, cell adhesion and cytoskeleton structure (including a number of tubulin genes), while down-regulated functional groups comprised genes linked to cell growth and proliferation, immune response and transcription regulation. Comparatively high number of genes with similar function displayed proportional up- and down-regulation upon paclitaxel treatment, and more specifically, genes related to cell cycle control, metabolism, protein biosynthesis and modification, signal transduction and transport. Network analysis identified up-regulated functional pathways linked to cellular assembly and organization, cell death and protein synthesis, while down-regulated pathways included cellular growth and proliferation, control of gene expression, and protein trafficking. Pathways, associated with cell cycle, metabolism, transport and cell signaling displayed comparative altered expression in both directions (Figure 4B). Eleven significant networks were identified following paclitaxel exposure [see Additional file 8], and the five top-scoring pathways were mostly associated with cancer, cell death, drug metabolism, gene expression, molecular transport and inflammatory disease (Table 3D). A common network obtained upon merging the three top-scoring networks identified the pro-apoptotic BCL2-associated X protein (BAX) node and several tubulin genes, that were up-regulated upon paclitaxel treatment, as well as a number of differentially expressed genes linked with the p53 and the tumor necrosis factor (TNF) pathways (Figure 6).


Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids.

L'Espérance S, Bachvarova M, Tetu B, Mes-Masson AM, Bachvarov D - BMC Genomics (2008)

Network analysis of dynamic gene expression in OC spheroids based on the 1.5-fold common gene expression list obtained following paclitaxel treatment. The three top-scoring networks were merged and are displayed graphically as nodes (genes/gene products) and edges (the biological relationships between the nodes). Figure legends are as described in Fig. 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2279123&req=5

Figure 6: Network analysis of dynamic gene expression in OC spheroids based on the 1.5-fold common gene expression list obtained following paclitaxel treatment. The three top-scoring networks were merged and are displayed graphically as nodes (genes/gene products) and edges (the biological relationships between the nodes). Figure legends are as described in Fig. 2.
Mentions: We found 126 genes to be up-regulated and 139 genes to be down-regulated at least 1.5 fold in paclitaxel-treated OC spheroids [see Additional file 7]. Table 6 shows list of selected functional groups of these genes. Thus, up-regulated genes upon paclitaxel exposure are implicated in apoptosis, cell adhesion and cytoskeleton structure (including a number of tubulin genes), while down-regulated functional groups comprised genes linked to cell growth and proliferation, immune response and transcription regulation. Comparatively high number of genes with similar function displayed proportional up- and down-regulation upon paclitaxel treatment, and more specifically, genes related to cell cycle control, metabolism, protein biosynthesis and modification, signal transduction and transport. Network analysis identified up-regulated functional pathways linked to cellular assembly and organization, cell death and protein synthesis, while down-regulated pathways included cellular growth and proliferation, control of gene expression, and protein trafficking. Pathways, associated with cell cycle, metabolism, transport and cell signaling displayed comparative altered expression in both directions (Figure 4B). Eleven significant networks were identified following paclitaxel exposure [see Additional file 8], and the five top-scoring pathways were mostly associated with cancer, cell death, drug metabolism, gene expression, molecular transport and inflammatory disease (Table 3D). A common network obtained upon merging the three top-scoring networks identified the pro-apoptotic BCL2-associated X protein (BAX) node and several tubulin genes, that were up-regulated upon paclitaxel treatment, as well as a number of differentially expressed genes linked with the p53 and the tumor necrosis factor (TNF) pathways (Figure 6).

Bottom Line: However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment.Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids.Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Laval University, Québec (Québec), Canada. syles@hotmail.com

ABSTRACT

Background: Chemotherapy (CT) resistance in ovarian cancer (OC) is broad and encompasses diverse unrelated drugs, suggesting more than one mechanism of resistance. To better understand the molecular mechanisms controlling the immediate response of OC cells to CT exposure, we have performed gene expression profiling in spheroid cultures derived from six OC cell lines (OVCAR3, SKOV3, TOV-112, TOV-21, OV-90 and TOV-155), following treatment with 10,0 microM cisplatin, 2,5 microM paclitaxel or 5,0 microM topotecan for 72 hours.

Results: Exposure of OC spheroids to these CT drugs resulted in differential expression of genes associated with cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling. Genes, functionally involved in DNA repair, DNA replication and cell cycle arrest were mostly overexpressed, while genes implicated in metabolism (especially lipid metabolism), signal transduction, immune and inflammatory response, transport, transcription regulation and protein biosynthesis, were commonly suppressed following all treatments. Cisplatin and topotecan treatments triggered similar alterations in gene and pathway expression patterns, while paclitaxel action was mainly associated with induction of genes and pathways linked to cellular assembly and organization (including numerous tubulin genes), cell death and protein synthesis. The microarray data were further confirmed by pathway and network analyses.

Conclusion: Most alterations in gene expression were directly related to mechanisms of the cytotoxics actions in OC spheroids. However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment. Similarly, overexpression of different tubulin genes upon exposure to paclitaxel could represent an early compensatory effect to this drug action. Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids. Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

Show MeSH
Related in: MedlinePlus