5.09] The molecular basis of tumor cell escape from protoporphyrin IX-based photodynamic therapy

Abstract

Objective Photodynamic therapy (PDT) uses a combination of a photosensitizing drug and light to cause selective damage to solid tumors. For early or localized disease, PDT can be a curative therapy with many advantages over available alternatives. For more advanced or disseminated disease curative therapy is usually not possible with current technologies of light application, however it can improve quality of life and lengthen survival. More recently there is increasing evidence that PDT can also induce systemic anti-tumor immunity, indicating that PDT could become a rational therapeutic option, even if not all tumor cells are primarily eliminated by PDT. One prerequisite to minimize tumor relapse in these settings is to elucidate how tumor cells can cope with the PDT-induced damage. Material and methods Here we have characterized the rescue response of human prostate cancer and glioblastoma cells exposed in vitro to sub-lethal PDT after 5-aminolevulinic acid-induced protoporphyrin IX sensitization at the transcriptome level using Affymetrix U133 2.0 oligonucleotide microarrays. Cells were irradiated with laser light at a wavelength of 635 nm adjusted to an irradiance of 100 mW/cm 2 with fluences varying between 0.5 and 3 J/cm 2 . Results The early response was characterized by the up-regulation of early response genes like FOS, JUN, EGR1, ATF3, DUSP, heat-shock protein genes as well as histone and metallothionein genes, therefore resembling the early response of tumor cells to high-dose PDT but without signs of irreversible cell damage. Twenty-four hours after PDT the cells still expressed high level of early response genes but 241 additional probe sets/genes were significantly up-regulated (5 x ) compared to those that were not up-regulated (⩽2 x ) 4 h after PDT. The most prominently up-regulated genes belong to gene families encoding the aldo-keto reductases, fibroblast growth factors and Hsp40-related proteins. In terms of a possible anti-tumor immune response it is noteworthy that also a multitude of chemokines and interleukins were up-regulated by the tumor cells upon PDT. Most of them are involved in granulocyte attraction and activation and some are also important for angiogenesis. Conclusion In conclusion, the global molecular characterization of the rescue response to PDT of tumor cells indicated that PDT rather favors an anti-tumor immune response than tumor immune escape reactions. Therefore combining PDT and immunotherapy seem to be an attractive direction for the establishment of novel multimodal tumor therapies.