Lung Cancer Malignant pleural mesothelioma: Genome-wide expression
Malignant pleural mesothelioma is an asbestos-related multi-resistant tumour with increasing incidence
worldwide. Well-characterized snap-frozen normal parietal, visceral pleura and mesothelioma samples
were analysed with Affymetrix Human Genome U133 Plus 2.0 GeneChip oligoarray of 38 500 genes.
We discovered a close relation between gene profile and resistance towards topoisomerase poisons,
alkylating agents, antitubulines, antifolates, platinum compounds and radiation therapy. Target genes
of chemo- (e.g. TOP2A, BIRC5/Survivin and proteasome) and radiotherapy (e.g. BRCA2, FANCA, FANCD2,
CCNB1 and RAD50) were significantly overexpressed. The Fanconi anemia/BRCA2 pathway, responsible
for homologous recombination DNA repair appears as a key pathway in both chemo- and radio-resistance
of mesothelioma. Leukocyte trans-endothelial migration gene down-regulation could partly explain resistance
against immunological therapies. Gene expression features found in other resistant cancer types
related to DNA repair and replication are shared by mesothelioma and could represent general features
of tumour resistance. Targeted suppression of some of those key genes and pathways combined with
chemotherapy or radiation could improve the outcome of mesothelioma therapy. We propose CHEK1,
RAD21, FANCD2 and RAN as new co-targets for mesothelioma treatment. The pro-angiogenic AGGF1
mRNA and protein was highly overexpressed in all tumours and may serve as a target for anti-angiogenic
treatment. Overexpression of NQO1 may render mesothelioma sensitive to the novel compound betaLapachone.
© 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Median survival of malignant mesothelioma is currently 12
months [1], an aggressive tumour derived from cells of the
pleura, peritoneum or tunica vaginalis testis, where pleural location
accounts for about 70% of the cases [2]. Epithelial subtype
is an important positive prognostic factor in contrast to the sarcomatous
and mixed subtypes. It is among the most chemo- and
radio-resistant malignant tumours [3] and no curative treatment
is available, but occasionally good responders and long-term survivors
are seen. Pemetrexed, a multi-folate inhibitor combined with
cisplatin is the only treatment that has shown increased median
survival in a Phase III study, from 9.3 to 12.1 months [4]. Studies
unraveling the biology of mesothelioma and identifying novel
molecular targets for treatment are thus urgently warranted. We
∗ Corresponding author. Tel.: +47 73900650.
E-mail address: oluf.roe@stolav.no (O.D. Røe).
recently did genome-wide expression analysis of human pleural
mesothelioma versus normal parietal pleura samples that portraits
the aggressive and resistant biology of mesothelioma (Røe et al., in
preparation). Here we focus on genes and pathways with signifi-
cant differential expression from the same material, that could be
related to the drug and irradiation resistance of pleural mesothelioma
and propose some future targets.
2. Materials and methods
2.1. Mesothelioma and control patients
Patients diagnosed between 2003 and 2005 were included after
obtaining informed written consent. Diagnostic biopsies and material
for gene expression were taken from adjacent locations with
needles by Computer Tomography and/or ultrasound guidance.
Diagnostic samples were formalin-fixed and paraffin-embedded.
Material for gene expression analysis was snap-frozen in liquid
nitrogen within two minutes. Biopsies of morphologically normal
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