Photodynamic Therapy–Induced Angiogenic Signaling: Consequences and Solutions to Improve Therapeutic Response

Abstract

Photodynamic therapy (PDT) can be a highly effective treatment for diseases ranging from actinic keratosis to cancer. While use of this therapy shows great promise in preclinical and clinical studies, understanding the molecular consequences of PDT is critical to designing better treatment protocols. A number of publications have documented alteration in angiogenic factors and growth factor receptors following PDT, which could abrogate treatment effect by inducing angiogenesis and re-establishment of the tumor vasculature. In response to these findings, work over the past decade has examined the efficacy of combining PDT with molecular targeting drugs, such as anti-angiogenic compounds, in an effort to combat these PDT-induced molecular changes. These combinatorial approaches increase rates of apoptosis, impair pro-tumorigenic signaling, and enhance tumor response. This report will examine the current understanding of PDT-induced angiogenic signaling and address molecular-based approaches to abrogate this signaling or its consequences thereby enhancing PDT efficacy.

Tumor Microenvironment as a Determinant of Photodynamic Therapy Resistance

“…An antibody against murine VEGF highly suppressed the release of host VEGF and its addition to the treatment regimen resulted in a more durable treatment response (Fig. 3.6) [79]. These data emphasize the importance of the host cells that compose the tumor microenvironment in dictating the therapy-determining activation of molecular pathways.…”

“…In H460 human tumor xenografts, it was observed that treatment with BPD-PDT led to a nearly two-fold increase in human VEGF levels compared to untreated tumors [79]. Moderate increases in human VEGF have also been observed in the serum of mice bearing human bladder carcinoma cell xenografts following Hypericinmediated PDT [82].…”

“…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.…”

“…Second, PDT is known to activate signaling cascades that lead to the secretion of VEGF, potentially providing an additional source of this cytokine following light therapy. Notably, many of the aforementioned molecules, such as HIF-1α and EGFR, can induce pathways which ultimately culminate in the secretion of VEGF, which is important for long term tumor progression by promoting angiogenesis and cell survival/motility [66,79,[83][84][85].…”

Erlotinib Pretreatment Improves Photodynamic Therapy of Non–Small Cell Lung Carcinoma Xenografts via Multiple Mechanisms

“…Like other cancer therapies, PDT can induce increases in VEGF that contribute to tumor recurrence after treatment (16–18). Therefore, if erlotinib attenuates PDT-induced increases in VEGF, we might expect these decreases to contribute to the stronger vascular response in tumors pretreated with erlotinib.…”