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Microsatellite instability and a defective Heat Shock protein are linked in Colorectal Cancer

A review of the recent Nature paper: 

Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis.

Dorard C, de Thonel A, Collura A, Marisa L, Svrcek M, Lagrange A, ..., Parc Y, Tiret E, Fléjou JF, Gaub MP, Garrido C, Duval A  Nat Med. 2011 Oct; 17(10):1283-9

Microsatellite instability (MSI) is a well-known feature of a subset of colorectal cancer (CRC) that harbors a defective DNA mismatch system. MSI CRC is characterised by an improved prognosis and may not benefit from adjuvant fluorouracil (5FU) therapy in particular stages. Interestingly, this paper provides a possible MSI-related mechanism with possible implications for treatment and stratification.

The authors found that MSI CRCs can be associated to an aberrant splicing of the heat shock protein HSP111, producing an aberrant isoform, namely HSP110DeltaE9. The overexpression of this isoform in CRC cells affects the function of the naïve protein and increases the sensitivity to 5FU. So, if those cells are more sensitive to 5FU, why clinical trials show that MSI may not respond to this drug? The authors say that subjects with MSI-HSP110DeltaE9 (high) represent only a small fraction of the total MSI CRC cases and clinical heterogeneity is present in this group with respect to 5FU response. Interestingly, this aberrant molecule could be considered a natural inhibitor of HSP110, which has been found overexpressed in CRC and other tumors and associated with poor prognosis and metastases.