Platelet-activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy

I A Da Silva-Jr,A P Lepique,R Chammas,S Jancar

doi:10.1038/oncsis.2016.90

Abstract

A major drawback of radiotherapy is the accelerated growth of the surviving tumor cells. Radiotherapy generates a variety of lipids that bind to the receptor for platelet-activating factor, expressed by cells in the tumor microenvironment. In the present study, using the TC-1 tumor cell line, we found that irradiation induced a twofold increase in receptor expression and generated agonists of receptor. Irradiated cells induced a 20-fold increase in live TC-1 proliferation in vitro. Furthermore, subcutaneous co-injection of irradiated TC-1 cells with TC-1 expressing luciferase (TC-1 fluc+) markedly increased TC-1 fluc+ proliferation in a receptor-dependent way. Moreover we used a human carcinoma cell line not expressing the PAF receptor (KBM) and the same cell transfected with the receptor gene (KBP). Following co-injection of live KBP cells with irradiated KBM in RAG mice, the tumor growth was significantly increased compared with tumor formed following co-injection of live KBM with irradiated KBM. This tumor cell repopulation correlated with increased infiltration of tumor-promoting macrophages (CD206+). We propose that receptor represents a possible target for improving the efficacy of radiotherapy through inhibition of tumor repopulation.

Highlights

Radiotherapy is an effective way to control cancer locally, a major drawback of this treatment is the accelerated growth of surviving cells
Irradiation increases the expression of the platelet-activating factor (PAF) receptor in TC-1 carcinoma cells and generates PAF receptor agonists
The murine carcinoma cell line TC-1 was analyzed for the expression of the PAF receptor by flow cytometry analysis

Summary

Introduction

Radiotherapy is an effective way to control cancer locally, a major drawback of this treatment is the accelerated growth of surviving cells. This compensatory proliferation is an evolutionarily conserved process involved in tissue regeneration in lower animals, and is thought to occur with tumor cells treated with cytotoxic radiotherapy, as previously discussed.[1] The alkyl- acyl-glycerophosphocholine (GPC), platelet-activating factor (PAF), binds to the PAF receptor. Injection of apoptotic cells with a sub-tumorigenic dose of melanoma cells was found to promote tumor growth, and this was reversed by blocking PAF receptor signaling.[9] The generation of anti-inflammatory macrophages and PAF receptor agonists in the tumor microenvironment may represent possible mechanisms underlying radiotherapy failure. We examined the effect of gamma radiation on the proliferation of PAF receptor-expressing tumor cells, and tumor cell repopulation

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Results

Conclusion