Limits...
Genome-wide profile of pleural mesothelioma versus parietal and visceral pleura: the emerging gene portrait of the mesothelioma phenotype.

Røe OD, Anderssen E, Helge E, Pettersen CH, Olsen KS, Sandeck H, Haaverstad R, Lundgren S, Larsson E - PLoS ONE (2009)

Bottom Line: It usually develops in the parietal pleura, from mesothelial lining or submesothelial cells, subsequently invading the visceral pleura.Circadian rhythm genes were expressed in favour of tumour growth.Similarly, in non-cancer parietal versus visceral pleura signal transduction, soluble transporter and adhesion genes were down-regulated.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, St Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway. olufdroe@yahoo.no

ABSTRACT

Background: Malignant pleural mesothelioma is considered an almost incurable tumour with increasing incidence worldwide. It usually develops in the parietal pleura, from mesothelial lining or submesothelial cells, subsequently invading the visceral pleura. Chromosomal and genomic aberrations of mesothelioma are diverse and heterogenous. Genome-wide profiling of mesothelioma versus parietal and visceral normal pleural tissue could thus reveal novel genes and pathways explaining its aggressive phenotype.

Methodology and principal findings: Well-characterised tissue from five mesothelioma patients and normal parietal and visceral pleural samples from six non-cancer patients were profiled by Affymetrix oligoarray of 38 500 genes. The lists of differentially expressed genes tested for overrepresentation in KEGG PATHWAYS (Kyoto Encyclopedia of Genes and Genomes) and GO (gene ontology) terms revealed large differences of expression between visceral and parietal pleura, and both tissues differed from mesothelioma. Cell growth and intrinsic resistance in tumour versus parietal pleura was reflected in highly overexpressed cell cycle, mitosis, replication, DNA repair and anti-apoptosis genes. Several genes of the "salvage pathway" that recycle nucleobases were overexpressed, among them TYMS, encoding thymidylate synthase, the main target of the antifolate drug pemetrexed that is active in mesothelioma. Circadian rhythm genes were expressed in favour of tumour growth. The local invasive, non-metastatic phenotype of mesothelioma, could partly be due to overexpression of the known metastasis suppressors NME1 and NME2. Down-regulation of several tumour suppressor genes could contribute to mesothelioma progression. Genes involved in cell communication were down-regulated, indicating that mesothelioma may shield itself from the immune system. Similarly, in non-cancer parietal versus visceral pleura signal transduction, soluble transporter and adhesion genes were down-regulated. This could represent a genetical platform of the parietal pleura propensity to develop mesothelioma.

Conclusions: Genome-wide microarray approach using complex human tissue samples revealed novel expression patterns, reflecting some important features of mesothelioma biology that should be further explored.

Show MeSH

Related in: MedlinePlus

Differentially overexpressed genes in tumour (red boxes) depicted in the Cell Cycle map from KEGG PATHWAYS (Kanehisa et al., 2008) (P<0.05).21 of 21 cell cycle genes were overexpressed in mesothelioma versus normal parietal pleura tissue. Potential targets for anti-tumour treatment described in the litterature are marked (see text). Abbreviations: CDK7 = cyclin-dependent kinase 7, CHEK1 = checkpoint homolog, E2F2 = E2F transcription factor 2, ORC6L = origin recognition complex, subunit 6 like, MCM2-3-4-6 = minichromosome maintenance complex component 2-3-4-6, PCNA = proliferating cell nuclear antigen, RB1 = retinoblastoma, BUB1 = budding uninhibited by benzimidazoles 1 homolog, BUB1B = BUB1 beta, CDC7 = cell division cycle 7 homolog, APC/C = CDC23, cell division cycle 23 homolog, anaphase-promoting complex subunit 8, CCNB1 = cyclin B1, CCNB2 = cyclin B2, ESPL1 = extra spindle pole bodies homolog 1, CDC2/CDK1 = cell division cycle 2, G1 to S and G2 to M, CDC6 = cell division cycle 6 homolog, CDC20 = cell division cycle 20 homolog, CDC25A = cell division cycle 25 homolog A.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2717215&req=5

pone-0006554-g007: Differentially overexpressed genes in tumour (red boxes) depicted in the Cell Cycle map from KEGG PATHWAYS (Kanehisa et al., 2008) (P<0.05).21 of 21 cell cycle genes were overexpressed in mesothelioma versus normal parietal pleura tissue. Potential targets for anti-tumour treatment described in the litterature are marked (see text). Abbreviations: CDK7 = cyclin-dependent kinase 7, CHEK1 = checkpoint homolog, E2F2 = E2F transcription factor 2, ORC6L = origin recognition complex, subunit 6 like, MCM2-3-4-6 = minichromosome maintenance complex component 2-3-4-6, PCNA = proliferating cell nuclear antigen, RB1 = retinoblastoma, BUB1 = budding uninhibited by benzimidazoles 1 homolog, BUB1B = BUB1 beta, CDC7 = cell division cycle 7 homolog, APC/C = CDC23, cell division cycle 23 homolog, anaphase-promoting complex subunit 8, CCNB1 = cyclin B1, CCNB2 = cyclin B2, ESPL1 = extra spindle pole bodies homolog 1, CDC2/CDK1 = cell division cycle 2, G1 to S and G2 to M, CDC6 = cell division cycle 6 homolog, CDC20 = cell division cycle 20 homolog, CDC25A = cell division cycle 25 homolog A.

Mentions: It is known that cell cycle deregulation is a general feature of malignancy. Overexpression of the cell cycle, replication and M-phase genes reflect the importance of this also in mesothelioma (Fig. 6 and 7, Table 5). Genes driving all the phases of the cell cycle were significantly overexpressed (Fig. 6). No cyclins or cyclin dependent kinases (CDKs) that drive the cell cycle were down-regulated. Several of these genes are related to oncogenesis and/or have been proposed as anti-cancer targets for other tumours (Fig. 7) and some will be discussed here.


Genome-wide profile of pleural mesothelioma versus parietal and visceral pleura: the emerging gene portrait of the mesothelioma phenotype.

Røe OD, Anderssen E, Helge E, Pettersen CH, Olsen KS, Sandeck H, Haaverstad R, Lundgren S, Larsson E - PLoS ONE (2009)

Differentially overexpressed genes in tumour (red boxes) depicted in the Cell Cycle map from KEGG PATHWAYS (Kanehisa et al., 2008) (P<0.05).21 of 21 cell cycle genes were overexpressed in mesothelioma versus normal parietal pleura tissue. Potential targets for anti-tumour treatment described in the litterature are marked (see text). Abbreviations: CDK7 = cyclin-dependent kinase 7, CHEK1 = checkpoint homolog, E2F2 = E2F transcription factor 2, ORC6L = origin recognition complex, subunit 6 like, MCM2-3-4-6 = minichromosome maintenance complex component 2-3-4-6, PCNA = proliferating cell nuclear antigen, RB1 = retinoblastoma, BUB1 = budding uninhibited by benzimidazoles 1 homolog, BUB1B = BUB1 beta, CDC7 = cell division cycle 7 homolog, APC/C = CDC23, cell division cycle 23 homolog, anaphase-promoting complex subunit 8, CCNB1 = cyclin B1, CCNB2 = cyclin B2, ESPL1 = extra spindle pole bodies homolog 1, CDC2/CDK1 = cell division cycle 2, G1 to S and G2 to M, CDC6 = cell division cycle 6 homolog, CDC20 = cell division cycle 20 homolog, CDC25A = cell division cycle 25 homolog A.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2717215&req=5

pone-0006554-g007: Differentially overexpressed genes in tumour (red boxes) depicted in the Cell Cycle map from KEGG PATHWAYS (Kanehisa et al., 2008) (P<0.05).21 of 21 cell cycle genes were overexpressed in mesothelioma versus normal parietal pleura tissue. Potential targets for anti-tumour treatment described in the litterature are marked (see text). Abbreviations: CDK7 = cyclin-dependent kinase 7, CHEK1 = checkpoint homolog, E2F2 = E2F transcription factor 2, ORC6L = origin recognition complex, subunit 6 like, MCM2-3-4-6 = minichromosome maintenance complex component 2-3-4-6, PCNA = proliferating cell nuclear antigen, RB1 = retinoblastoma, BUB1 = budding uninhibited by benzimidazoles 1 homolog, BUB1B = BUB1 beta, CDC7 = cell division cycle 7 homolog, APC/C = CDC23, cell division cycle 23 homolog, anaphase-promoting complex subunit 8, CCNB1 = cyclin B1, CCNB2 = cyclin B2, ESPL1 = extra spindle pole bodies homolog 1, CDC2/CDK1 = cell division cycle 2, G1 to S and G2 to M, CDC6 = cell division cycle 6 homolog, CDC20 = cell division cycle 20 homolog, CDC25A = cell division cycle 25 homolog A.
Mentions: It is known that cell cycle deregulation is a general feature of malignancy. Overexpression of the cell cycle, replication and M-phase genes reflect the importance of this also in mesothelioma (Fig. 6 and 7, Table 5). Genes driving all the phases of the cell cycle were significantly overexpressed (Fig. 6). No cyclins or cyclin dependent kinases (CDKs) that drive the cell cycle were down-regulated. Several of these genes are related to oncogenesis and/or have been proposed as anti-cancer targets for other tumours (Fig. 7) and some will be discussed here.

Bottom Line: It usually develops in the parietal pleura, from mesothelial lining or submesothelial cells, subsequently invading the visceral pleura.Circadian rhythm genes were expressed in favour of tumour growth.Similarly, in non-cancer parietal versus visceral pleura signal transduction, soluble transporter and adhesion genes were down-regulated.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, St Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway. olufdroe@yahoo.no

ABSTRACT

Background: Malignant pleural mesothelioma is considered an almost incurable tumour with increasing incidence worldwide. It usually develops in the parietal pleura, from mesothelial lining or submesothelial cells, subsequently invading the visceral pleura. Chromosomal and genomic aberrations of mesothelioma are diverse and heterogenous. Genome-wide profiling of mesothelioma versus parietal and visceral normal pleural tissue could thus reveal novel genes and pathways explaining its aggressive phenotype.

Methodology and principal findings: Well-characterised tissue from five mesothelioma patients and normal parietal and visceral pleural samples from six non-cancer patients were profiled by Affymetrix oligoarray of 38 500 genes. The lists of differentially expressed genes tested for overrepresentation in KEGG PATHWAYS (Kyoto Encyclopedia of Genes and Genomes) and GO (gene ontology) terms revealed large differences of expression between visceral and parietal pleura, and both tissues differed from mesothelioma. Cell growth and intrinsic resistance in tumour versus parietal pleura was reflected in highly overexpressed cell cycle, mitosis, replication, DNA repair and anti-apoptosis genes. Several genes of the "salvage pathway" that recycle nucleobases were overexpressed, among them TYMS, encoding thymidylate synthase, the main target of the antifolate drug pemetrexed that is active in mesothelioma. Circadian rhythm genes were expressed in favour of tumour growth. The local invasive, non-metastatic phenotype of mesothelioma, could partly be due to overexpression of the known metastasis suppressors NME1 and NME2. Down-regulation of several tumour suppressor genes could contribute to mesothelioma progression. Genes involved in cell communication were down-regulated, indicating that mesothelioma may shield itself from the immune system. Similarly, in non-cancer parietal versus visceral pleura signal transduction, soluble transporter and adhesion genes were down-regulated. This could represent a genetical platform of the parietal pleura propensity to develop mesothelioma.

Conclusions: Genome-wide microarray approach using complex human tissue samples revealed novel expression patterns, reflecting some important features of mesothelioma biology that should be further explored.

Show MeSH
Related in: MedlinePlus