Dequalinium blocks macrophage-induced metastasis following local radiation

Michael Timaner,Susan A Rotenberg,Chen Rachman-Tzemah,Dror Alishekevitz,Ruslana Kotsofruk,Orit Kaidar-Person,Ziv Raviv,Shahar Daniel,Rotem Bril,Yuval Shaked,Valeria Miller,Alexander Nevelsky

doi:10.18632/oncotarget.4826

Abstract

A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis.

Highlights

Ionizing radiation is a major treatment strategy for a variety of cancers, such as brain, rectal, cervix and breast cancers among others
We found that the exposure of ‘naïve’ mice to local radiation enhances the metastatic phenotype of tumors, an effect partially mediated by macrophages which home to radiotherapy-treated tumors
We examined the mobilization of different types of angiogenesis-promoting bone marrow derived cells (BMDCs) to peripheral blood in naïve mice that were exposed to escalating dosages of radiation

Summary

Introduction

Ionizing radiation is a major treatment strategy for a variety of cancers, such as brain, rectal, cervix and breast cancers among others. Recent studies by Brown and colleagues demonstrated that recurrence following radiotherapy of brain tumors is associated with the recruitment of bone marrow derived cells (BMDCs) to the irradiated tumor site, and that such cells contribute to angiogenesis and tumor resistance [6, 7]. They showed that HIF-1 induction in the irradiated tumors promotes BMDC influx, and that therapeutic blockade of BMDC trafficking prevents or delays tumor recurrence [6]

Methods

Results

Conclusion