Extracellular HSP90: An Emerging Target for Cancer Therapy

Cancer is a genetic disease which progresses from benign to malignant stages through the steady acquisition of genomic mutations in key cell-regulatory genes, namely oncogenes, tumor-suppressors, and stability genes. In many ways cancer is considered as a disease of de-regulated signal transduction. Oncogenic mutations frequently lead to overexpression and/or constitutive activation of signal transduction components, allowing cancer cells to override the controlling mechanisms of signalling networks and acquire the cancer-associated traits known as the six hallmarks of cancer. The molecular chaperone HSP90 is viewed as a key player in the subversion of normal cells toward transformation, since many of its client proteins are linked to signalling pathways, commonly de-regulated during tumorigenesis. Consequently, over the past years HSP90 has emerged as a promising and exciting target for the development of cancer chemotherapeutics and already several HSP90 inhibitors are under clinical evaluation. Recently, a pool of HSP90 was identified at the cell surface, where it was shown to be involved in signalling pathways leading to cell motility and invasion. Independent studies suggest that surface HSP90 could be a promising target for the development of effective anti-metastatic strategies. Thus a need for the development of novel cell-impermeable HSP90 inhibitors is emerging.