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

Our plain-English summary of Vascular-targeted low dose photodynamic therapy stabilizes tumor vessels by modulating pericyte contractility, by S. Cavin, T. Riedel, P. Rosskopfova, et al (Lasers in Surgery and Medicine, 2019).

The study

• Authors: S. Cavin, T. Riedel, P. Rosskopfova, M. Gonzalez, G. Baldini, M. Zellweger, G. Wagnières, P.J. Dyson, H.B. Ris, T. Krueger, J.Y. Perentes
• Journal: Lasers in Surgery and Medicine
• Published: 2019;51(6):550-561
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

© 2019 Wiley Periodicals, Inc.

In plain English

This laboratory and animal study from Switzerland examined how vascular-targeted low-dose photodynamic therapy (L-PDT) acts on tumor vessels in malignant pleural mesothelioma. L-PDT is a treatment in which a light-sensitive drug (Visudyne) is activated by laser light. The authors first treated co-cultures of human brain pericytes (cells that wrap around small blood vessels) and endothelial cells (the cells lining vessels). L-PDT caused stress fibers to form and made pericytes contract, but did not change endothelial cell contraction. Blocking an enzyme called ROCK prevented a contraction-related protein change (myosin light chain phosphorylation) and stopped pericyte contraction. The authors then grew two human mesothelioma tumor types (H-Meso-1 and MSTO211H) in nude mice. In treated tumors, pericytes covered the vessels more closely. Fluid pressure inside the tumors dropped, while pressure in the surrounding normal tissue did not change. Uptake of a large tracer molecule rose 2-fold in H-Meso-1 tumors and 1.5-fold in MSTO211H tumors. Vessel density and diameter did not change. The authors concluded that L-PDT could stabilize tumor vessels and improve transport. They cautioned that brain-derived pericytes were used, and noted that the tumor measurements were made within an hour of treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (cell culture) experiments followed by animal experiments in mice carrying human mesothelioma tumors
• Who was studied: In the cell experiments: human brain vascular pericytes (HBVP) and an endothelial cell line (EC-RF24). In the animal experiments: 6- to 7-week-old female Swiss nude mice carrying tumors grown from two human malignant pleural mesothelioma cell lines, H-Meso-1 and MSTO211H. Groups were about 5 to 7 mice each. The work was done in Lausanne, Switzerland.
• Exposure: The exposure studied was a treatment, not asbestos. In mice, L-PDT used the photosensitizer Visudyne (liposomal BPD-MA) given intravenously, followed 10 minutes later by 690 nm laser light at 50 mW/cm2 and a light dose of 10 J/cm2. In cell cultures, the light dose was 0.15 J/cm2.
• Main results:
  • In the cell co-cultures, L-PDT induced stress fiber formation in pericytes. It caused only minor cytoskeletal changes in endothelial cells.
  • Pericytes contracted collagen gels significantly more after L-PDT than controls. Endothelial cells showed no difference between control and L-PDT groups.
  • In pericytes, pretreatment with the ROCK inhibitor Y-27632 prevented myosin light chain phosphorylation. It also abolished the pericytes' ability to contract collagen gels after L-PDT.
  • In both mouse tumor models, L-PDT significantly increased myosin light chain phosphorylation in pericytes but not in endothelial cells.
  • In both tumor types, overlap between pericytes and endothelial cells (co-localization of the two stains) increased significantly in L-PDT-treated tumors compared with controls.
  • In both tumor types, L-PDT caused a significant and sustained drop in tumor interstitial fluid pressure compared with controls. Pressure in the surrounding normal tissues did not change. The article gives figures of 4.59 plus or minus 3.18 mmHg (H-Meso tumors) and 4.19 plus or minus 3.62 mmHg (MSTO211H tumors) at 60 minutes after L-PDT. Damaged symbols in the scanned text make it unclear whether these are the pressure values or the size of the drop.
  • Tumor vessel density and diameter were comparable between control and L-PDT-treated tumors in both tumor types over 60 minutes.
  • Tumor blood flow was not significantly affected in MSTO-211H tumors within the first hour. In H-Meso tumors, it decreased briefly right after treatment (120.5 AU after versus 166.3 AU before L-PDT) and fully recovered within 20 minutes.
  • L-PDT increased uptake of the tracer molecule (2000 KDa FITC-dextran) 2-fold in H-Meso-1 tumors (P = 0.005) and 1.5-fold in MSTO211H tumors (P = 0.02) compared with controls. The tracer did not accumulate in surrounding normal tissue.
• The authors' conclusion: The authors concluded that L-PDT has the potential to stabilize the tumor vascular bed, which improves vascular transport. They also stated that the mechanism they describe may help translate and optimize this approach in patients.
• Limitations the authors state:
  • The cell-culture findings should be interpreted with caution because the pericytes used came from the central nervous system (brain), not from tumors.
  • The authors noted that their experiments and assessments were performed within an hour of L-PDT. For this reason, changes in cell junctions that could develop over longer periods were not examined. (The methods also mention collagen-gel pictures of cultured cells taken at 24 hours.)
  • Further work is needed to determine how L-PDT is linked to RhoA activation.
  • Further studies are needed to determine how long the window of improved vascular distribution lasts.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, Interstitial.

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