期刊
MOLECULAR THERAPY
卷 29, 期 5, 页码 1772-1781出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2020.12.026
关键词
-
资金
- Department of Defense Breast Cancer Research Program [W81XWH-16-1-0512, W81XWH-161-0513]
- National Cancer Institute Advanced Immunobiology Training Program for Surgeons [T32AI141342-01]
- National Cancer Institute Translation Research in Surgical Oncology [T32CA093245-12]
The study demonstrates that PAMAM-G3 can scavenge NA DAMPs and mitigate their proinflammatory effects, reducing lung metastasis. Treatment with PAMAM-G3 decreases cell-free DNA levels and lung metastasis, associated with reduction in inflammatory immune cell subsets and proinflammatory cytokine levels in the tumor and the periphery. The findings support the potential inclusion of NAS therapy in breast cancer patients undergoing standard-of-care surgery.
Tumor cells release nucleic acid-containing proinflammatory complexes, termed nucleic acid-containing damage-associated molecular patterns (NA DAMPs), passively upon death and actively during stress. NA DAMPs activate pattern recognition receptors on cells in the tumor microenvironment leading to prolonged and intensified inflammation that potentiates metastasis. No strategy exists to control endogenous or therapy-induced inflammation in cancer patients. We discovered that the generation 3.0 polyamidoamine dendrimer (PAMAM-G3) scavenges NA DAMPs and mitigates their proinflammatory effects. In this study, we tested if the nucleic acid scavenger (NAS) PAMAM-G3 reduces lung metastasis in murine models of breast cancer. Our data indicate that PAMAM-G3 treatment decreases cell-free DNA levels and reduces lung metastasis in the experimental intravenous tumor-injection model and the postsurgical tumor-resection model of 4T1 breast cancer. Reduction in lung metastasis is associated with reduction in inflammatory immune cell subsets and proinflammatory cytokine levels in the tumor and the periphery. This study is the first example of NAS-mediated inhibition of metastasis to the lung. The study results provide a strong rationale for inclusion of NAS therapy in women with breast cancer undergoing standard-of-care surgery.
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