Vascular‐targeted low dose photodynamic therapy stabilizes tumor vessels by modulating pericyte contractility

Abstract

Vascular‐targeted low‐dose photodynamic therapy (L‐PDT) was shown to improve chemotherapy distribution in malignant pleural tumors such as malignant pleural mesothelioma (MPM). However, the mechanisms triggered by L‐PDT on the tumor vasculature are still debated. In pericyte and endothelial cell co‐cultures, we show that pericytes exhibit enhanced sensitivity towards L‐PDT compared to endothelial cells, displaying actin stress fibers and cellular contraction via Rho/ROCK kinase signaling myosin light chain and focal adhesion kinase phosphorylation (MLC‐P, FAK‐P). We then confirm, in two separate MPM models, in mice the phosphorylation of the MLC in pericytes specifically following L‐PDT. Furthermore, while L‐PDT does not affect tumor vascular density or diameter, we show that it enhances tumor vascular pericyte coverage, leads to a drop in tumor interstitial fluid pressure and enhances the transport of FITC‐dextran throughout tumors. In conclusion, L‐PDT has the potential to stabilize the tumor vascular bed which improves vascular transport. The mechanism described in the present study may help translate and optimize this approach in patients. Lasers Surg. Med. 51:550–561, 2019. © 2019 Wiley Periodicals, Inc.

Vascular Shutdown by Photodynamic Therapy Using Talaporfin Sodium

“…Additionally, a significant increase in the phosphorylation of MLC (a Rho-kinase downstream effector) was detected at 5, 15, and 30 min post TS-PDT administration ( Figure 4 ). Several studies have demonstrated the importance of the RhoA/ROCK pathway in pericyte contractility and activation [ 24 , 40 ]. Y27632, a synthetic pyridine derivative that inhibits ROCK by competing with ATP for the active site of the kinase, was able to impair the TS-PDT-induced phosphorylation of MLC ( Figure 5 a,b).…”

“…The vascular shutdown effect is commonly known to be photosensitizer dependent [ 19 ]. The selective vascular effects of TS have been demonstrated in preclinical studies [ 20 , 21 , 22 , 23 , 24 ]. Compared with porfimer-based PDT, TS-PDT resulted in a more significant vascular shutdown effect and consequently greater tumor necrosis resulting from ischemia [ 25 ].…”

Characterization of Laser‐Resistant Port Wine Stain Blood Vessels Using In Vivo Reflectance Confocal Microscopy

“…Other non-invasive imaging systems that have been used or currently under development for evaluation of dermal vasculatures include laser Doppler flowmeter, laser Doppler imaging, dermoscopy, cross-polarized diffuse reflection color imaging system, and optical coherence tomography [39][40][41][42][43][44][45][46][47][48]. The main feature of RCM is that it can directly reveal the dermal structure in a simple and fast way, which makes it be a promising bedside tool for prognostic evaluation.…”

Photodynamic Therapy and the Biophysics of the Tumor Microenvironment

“…Additionally, when liposomal doxorubicin was administered following L‐PDT treatment, the drug penetrated significantly deeper into the tumor tissue compared to the control. Recently, Cavin et al explored the mechanism through which L‐PDT alters vasculature to modulate IFP. Using a pericyte and endothelial cell coculture, they found that PDT alters the function of pericytes, strengthening their association with endothelial cells.…”