Treating the Intestine with Oral ApoA-I Mimetic Tg6F Reduces Tumor Burden in Mouse Models of Metastatic Lung Cancer

• Published in: Scientific reports 2018-06, Vol.8 (1), p.9032-12, Article 9032
• Main Authors: Chattopadhyay, Arnab, Yang, Xinying, Mukherjee, Pallavi, Sulaiman, Dawoud, Fogelman, Hannah R., Grijalva, Victor, Dubinett, Steven, Wasler, Tonya C., Paul, Manash K., Salehi-Rad, Ramin, Mack, Julia J., Iruela-Arispe, M. Luisa, Navab, Mohamad, Fogelman, Alan M., Reddy, Srinivasa T.
• Format: Article
• Language: English
• Subjects: 14; 14/19; 38/39; 631/67/1059/153; 631/67/70; 64; 64/60; 82; 82/51; 82/80; Animal models; Animals; Apolipoprotein A; Apolipoprotein A-I; Apolipoprotein A-I - chemistry; Apolipoprotein A-I - metabolism; Cancer; Cell Line, Tumor; Colon cancer; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Immunoreactivity; Jejunum; Jejunum - drug effects; Jejunum - metabolism; Jejunum - pathology; Lipids; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Metastases; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes; multidisciplinary; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Notch1 protein; Notch2 protein; Osteopontin; Peptides; Peptides - pharmacology; Phospholipids; Plasma levels; Receptors, Notch - genetics; Rodents; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signal Transduction - genetics; Small intestine; Suppressor cells; Tomatoes; Tumor Burden - drug effects; Tumor Burden - genetics; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-26755-0

Having demonstrated that apolipoprotein A-I (apoA-I) mimetic peptides ameliorate cancer in mouse models, we sought to determine the mechanism for the anti-tumorigenic function of these peptides. CT-26 cells (colon cancer cells that implant and grow into tumors in the lungs) were injected into wild-type BALB/c mice. The day after injection, mice were either continued on chow or switched to chow containing 0.06% of a concentrate of transgenic tomatoes expressing the apoA-I mimetic peptide 6F (Tg6F). After four weeks, the number of lung tumors was significantly lower in Tg6F-fed mice. Gene expression array analyses of jejunum and lung identified Notch pathway genes significantly upregulated, whereas osteopontin (Spp1) was significantly downregulated by Tg6F in both jejunum and lung. In jejunum, Tg6F increased protein levels for Notch1, Notch2, Dll1, and Dll4. In lung, Tg6F increased protein levels for Notch1 and Dll4 and decreased Spp1. Tg6F reduced oxidized phospholipid levels (E06 immunoreactivity) and reduced 25-hydroxycholesterol (25-OHC) levels, which are known to inhibit Notch1 and induce Spp1, respectively. Notch pathway promotes anti-tumorigenic patrolling monocytes, while Spp1 facilitates pro-tumorigenic myeloid derived suppressor cells (MDSCs) formation. Tg6F-fed mice had higher numbers of patrolling monocytes in jejunum and in lung (p