Stress-Inducible Gene Atf3 Dictates a Dichotomous Macrophage Activity in Chemotherapy-Enhanced Lung Colonization

• Published in: International journal of molecular sciences 2021-07, Vol.22 (14), p.7356
• Main Authors: Middleton, Justin D, Fehlman, Jared, Sivakumar, Subhakeertana, Stover, Daniel G, Hai, Tsonwin
• Format: Article
• Language: English
• Subjects: Activating transcription factor 3; Activating Transcription Factor 3 - physiology; Animal models; Animals; Antimicrobial Cationic Peptides - biosynthesis; Antimicrobial Cationic Peptides - genetics; Atf3; Breast cancer; breast cancer metastasis; Cancer therapies; Cell death; Cell Line, Tumor; Cell proliferation; Chemotherapy; Colonization; Cyclophosphamide; Cyclophosphamide - pharmacology; Cyclophosphamide - toxicity; Cytotoxicity; Extravasation; Gene Expression Regulation, Neoplastic - drug effects; Genes, Reporter; Genotype; Humans; Lung cancer; lung colonization; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Lungs; Macrophage Activation; macrophage dichotomy; Macrophages; Macrophages - physiology; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Metastasis; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; Neoadjuvant Therapy - adverse effects; Neoplasm Metastasis - genetics; Neoplasm Metastasis - physiopathology; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neoplasm Transplantation - methods; Neoplastic Stem Cells - pathology; Phenotypes; stress response; Stress, Physiological - genetics; Transendothelial and Transepithelial Migration; Tumor Microenvironment; Tumor-Associated Macrophages - drug effects; Tumor-Associated Macrophages - physiology; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22147356

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on , a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization-despite the initial increase in cell retention. In summary, the status of dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not KO lung.