New Prognostic Signature for NSCLC
The Campbell Family Cancer Research Institute ♦ University of Toronto
Published in PNAS, April 7, 2011
It has long been known that the tumour microenvironment, or niche, plays a major role in the development of cancer, the progression of disease, and eventually metastasis. Non-small cell lung carcinoma (NSCLC), which accounts for 85% of lung-cancer related deaths, is highly prone to influence from fibroblasts in the stroma surrounding cancer cells. Researchers at The Campbell Family Cancer Research Institute have been investigating one of the leading causes of cancer cell invasion, a process known as desmoplasia. During desmoplasia several things occur that exacerbate disease conditions, one of which is the evolution of normal fibroblasts to what are known as carcinoma-associated fibroblasts (CAFs). It seems that CAFs are able to enhance the tumorigenicity of lung cancer cell lines, and have a degree of prognostic power in assessing outcome. Using 15 resected NSCLCs, Dr. Tsao and his team established 15 matched normal fibroblast and CAF cell lines and carried out microarray gene-expression analysis to identify differentially expressed genes. In doing so the lab group identified 46 genes that were either upregulated or downregulated between the two sets of cells. A subset of 11 genes from this group was able to form a prognostic gene expression signature that was subsequently validated in several NSCLC microarray datasets. It was found that these genes encode extracellular matrix proteins that are regulated by the TGF-β signaling pathway. Protein-protein interaction analyses suggested that the focal adhesion and MAPK signaling pathways are involved in the transition from the normal to carcinoma-associated fibroblast states.
Bioinformatics Approach Reveals Resistance-based Genes
Mount Sinai Hospital ♦ Translational Genomics Research Institute (TGen), Arizona
Published in PLoS ONE, April 4, 2011
Statins have traditionally been used to lower cholesterol but recent evidence suggests they may have a future in treating cancer. Cholesterol accumulates in cell membranes in structures known as lipid rafts, which can influence processes such as cell growth and survival. By augmenting the composition of these lipid rafts, statins may exert cytotoxic effects on cancer cells. Many cancer cell lines exhibit resistance to statins though, limiting their utility as cancer therapeutics. In this eloquent study researchers used a panel of cancer cell lines (NCI60) and publicly available genomic and pharmacological data, to identify genes that conferred resistance to two statins, simvastatin and lovastatin. Pharmacological data identified simvastatin and lovastatin resistant cell lines which were then analyzed by whole-genome single marker association tests to uncover genes that regulate resistance. Three genes (NRP1, COL13A1, and MRPS31) were linked to resistance to simvastatin while another six (EAF2, ANK2, AKAP7, STEAP2, LPIN2, PARVB) were linked to resistance in the case of lovastatin. To confirm their findings researchers carried out a functional validation with the gene EAF2. Silencing this gene with RNAi changed the response of the colon cancer cell line HCT-116 to both statins. This work really illustrates the power of today’s genomic and pharmacological databases, and how they can be leveraged to provide insight into treating cancer.