A microarray study of altered gene expression in colorectal cancer cells after treatment with immunomodulatory drugs: differences in action in vivo and in vitro.
Thalidomide and lenalidomide are FDA approved for the treatment of multiple myeloma, and along with pomalidomide are being investigated in a variety of other cancers. Although these agents display immunomodulatory, anti-angiogenic and anti-apoptotic effects, little is known about the primary mode of therapeutic action in patients with cancer. This paper describes a microarray study of the in vitro and in vivo effects of these drugs, and contrasts the difference in gene profiles achieved in the two models. In the current study, Agilent whole mouse genome oligonucleotide microarrays (44 K) were used to examine alterations in gene expression of colorectal cancer cells after treatment. Venn analysis revealed a divergence of gene signature for pomalidomide and lenalidomide, which although similar in vitro, different in vivo. Several clusters of genes involved in various cellular processes such as immune response, cell signalling and cell adhesion were altered by treatment, and common to the three drugs. Notably, the expressions of linked genes within the Notch/Wnt signalling pathway, including kremen2 and dtx4, highlighted a possible novel mechanistic pathway for these drugs. This study also showed that gene signatures were not greatly divergent in the models, and recapitulated the complex nature of these drugs. Overall, these microarray studies highlighted the diversity of this class of drug, which have effects ranging from cell signalling to translation initiation.
Liu
Wai M
WM
Department of Oncology, Division of Cellular and Molecular Medicine, St George's University of London, 2nd Floor, Jenner Wing, London, SW17 0RE, UK. w.liu@sgul.ac.uk
Laux
Holger
H
Henry
Jake Y
JY
Bolton
Thomas B
TB
Dalgleish
Angus G
AG
Galustian
Christine
C
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D052138:Genes, Neoplasm / Q000235:genetics; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D000077269:Lenalidomide; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011786:Quality Control; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D015415:Biomarkers; D007155:Immunologic Factors; D013792:Thalidomide; C467566:pomalidomide; D000077269:Lenalidomide