Induction of Prosurvival Molecules During Treatment: Rethinking Therapy Options for Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) not only causes direct cytotoxicity to malignant cells within a tumor but also appears to have both direct and indirect effects on nonmalignant components of the tumor microenvironment. A host of preclinical studies have been performed to document how PDT modulates the tumor microenvironment. This article explores the role of cellular components such as the hypoxia-inducible factor 1α, vascular endothelial growth factor, cyclooxygenase-2, matrix metalloproteinases, the antiapoptotic protein survivin, and 17-AAG (an inhibitor of heat shock proteins), with the hope that combined modality regimens targeting these processes may improve PDT tumor responsiveness.

Low dose photodynamic-therapy induce immune escape of tumor cells in a HIF-1α dependent manner through PI3K/Akt pathway

“…It is assumed that PDT can affect the tumor microenvironment by the dysregulation of cytoprotective molecules [5]. This dysregulation leads to a malignant phenotype characterized by an enhanced angiogenesis, cell proliferation, and cell invasion, thus promoting tumor progression or recurrence [6]. Therefore, specific attention to microenvironment should be paid, focusing on these cytoprotective molecules that may be involved in the tumor recurrence and therapyresistance, to obtain an improvement of the clinical outcomes of PDT.…”

“…The cytoprotective molecules involved in PDT-induced tumor recurrence and therapy-resistance, include hypoxia-inducible factor 1α (HIF-1α), cyclooxygenase-2 (COX2), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), the anti-apoptotic protein survivin, and heat shock proteins (HSPs) [6]. Among them, HIF-1α plays an important role participating in the regulation of the immune responses in the tumor microenvironment [7,8].…”

Tumor Microenvironment as a Determinant of Photodynamic Therapy Resistance

“…3.5) [65][66][67]. These signaling changes may counteract the therapeutic benefit of treatment, and even make a tumor more aggressive, thus, it is necessary to consider the impact of PDT on the molecular microenvironment.…”

“…It is important to note that MMPs are not typically expressed by tumor cells, but rather macrophages and the stromal cells of the matrix [65]. PDT is known to impact the expression of the proenzyme forms of several MMPs, including MMP-1, MMP-2, MMP-3, and MMP-9, as well as proteins which stimulate or impair their activity [65,67,97]. For example, Photofrin-PDT is reported to induce the expression of MMP-9 and the extracellular matrix metalloproteinase inducer (EMMPRIN), which activates MMP-9.…”

“…Several reports have highlighted "resistance" to PDT as a result of treatmentinduced changes to tumor and endothelial cell biology [68,69]. The most common molecules known to impair PDT response due to alteration in their expression or signaling following light treatment include the epidermal growth factor receptor (EGFR) [70][71][72], ERKs [73,74], signal transducer and activator of transcription 3 (STAT3) [70], cyclooxygenase 2 (COX-2) [75,76], heat shock proteins (Hsp) [67,68,77], matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) [78][79][80]. These proteins contribute to tumor progression through processes that include the induction of survival signaling, cell growth and proliferation, promotion of cell motility and metastasis, inflammation, angiogenesis, and prevention of apoptosis.…”