Tumors induce complex DNA damage in distant proliferative tissues in vivo

摘要

That tumors cause changes in surrounding tissues is well docu-mented, but whether they also affect distant tissues is uncertain. Such knowledge may be important in understanding the relation-ship between cancer and overall patient health. To address this question, we examined tissues distant to sites of implanted tumors for genomic damage using cohorts of C57BL/6 and BALB/c mice with early-stage subcutaneous syngeneic grafts, specifically, 616 mela-noma, MO5076 sarcoma, and COLON26 carcinoma. Here we report that levels of two serious types of DNA damage, double-strand breaks (DSBs) measured by γ-H2AX focus formation and oxidatively induced non-DSB clustered DNA lesions (OCDLs), were elevated in tissues distant from the tumor site in tumor-bearing mice compared with their age- and sex-matched controls. Most affected were crypts in the gastrointestinal tract organs and skin, both highly proliferative tissues. Further investigation revealed that, compared with controls, tumor-bearing mice contained elevated amounts of activated macro-phages in the distant gastrointestinal tissues, as well as elevated serum levels of several cytokines. One of these cytokines, CCL27 MCP-1, has been linked to several inflammation-related conditions and macrophage recruitment and strikingly, CCL2-deficient mice lacked increased levels of DSBs and OCDLs in tissues distant from implanted tumors. Thus, this study is unique in being a direct dem-onstration that the presence of a tumor may induce a chronic inflam-matory response in vivo, leading to increased systemic levels of DNA damage. Importantly, these findings suggest that tumors may have more profound effects on their hosts than heretofore expected.