Abstract
BackgroundPhotodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined.Methodology/Principal FindingsHere we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth.ConclusionsOur results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious growth-stimulatory pathways.
Highlights
Photodynamic therapy (PDT) in oncology is based on the selective accumulation of a photosensitizer (PS) in cancer cells, followed by its activation by low-energy tissue-penetrating light
Our results indicate that PDT can support anti-tumor immune responses and is, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone
We selected two human prostate (PC-3, DU145) and two glioblastoma cell lines (U87, U373) as well as murine prostate carcinoma cell lines TRAMP-C1 and TRAMP-C2 which are derived from tumors of the transgenic mouse line ‘‘transgenic model of prostate cancer’’ (TRAMP) [19,20]
Summary
Photodynamic therapy (PDT) in oncology is based on the selective accumulation of a photosensitizer (PS) in cancer cells, followed by its activation by low-energy tissue-penetrating light. 5-Amino-levulinic acid (5-ALA) is a natural precursor for heme in mammalian cells. Cells metabolize 5-ALA to heme, producing protoporphyrin IX (PpIX) as an intermediate product in their mitochondria. Because conversion of PpIX to heme is a rate limiting step, PpIX accumulates in cancer cells as a result of preferential uptake and retention of 5-ALA. PhotofrinH, on the other hand, is an exogenous photosensitizer which accumulates in cancer cells but is located at various cellular membranes [3]. Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. The effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined
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