Dequalinium blocks macrophage-induced metastasis following local radiation

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)27537-27554
Number of pages18
JournalOncotarget
Volume6
Issue number29
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Colon cancer
  • Macrophages
  • Radiotherapy
  • Tumor microenvironment

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