Dequalinium blocks macrophage-induced metastasis following local radiation.
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.
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Michael
M
Timaner
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Rotem
R
Bril
Department of Radio-Oncology, Rambam Health Care Campus, Haifa, Israel.
Orit
O
Kaidar-Person
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Chen
C
Rachman-Tzemah
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Dror
D
Alishekevitz
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Ruslana
R
Kotsofruk
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Valeria
V
Miller
Department of Radio-Oncology, Rambam Health Care Campus, Haifa, Israel.
Alexander
A
Nevelsky
Department of Radio-Oncology, Rambam Health Care Campus, Haifa, Israel.
Shahar
S
Daniel
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Ziv
Z
Raviv
Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, NY, USA.
Susan A
SA
Rotenberg
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Yuval
Y
Shaked
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000737:chemistry; D003868:Dequalinium / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; C554602:DECA-14; D003868:Dequalinium
colon cancer; macrophages; radiotherapy; tumor microenvironment