Abstract
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 < 0.02), and lower plasma levels of Spp1 with reduced numbers of MDSCs in jejunum and in lung (p < 0.03). We conclude that Tg6F alters levels of specific oxidized lipids and 25-OHC to modulate Notch pathways and Spp1, which alter small intestine immune cells, leading to similar changes in lung that reduce tumor burden.
Highlights
Of apolipoprotein A-I (apoA-I) were effective in inhibiting tumor development in a mouse model of ovarian cancer
We report on two mouse models of metastatic lung cancer, i) BALB/c mice injected intravenously with colon cancer cells that metastasize to the lungs; and ii) C57BL/6J mice injected with Lewis lung cancer cells that metastasize to the lungs
Oral administration of Tg6F resulted in an increase in patrolling monocytes in the lamina propria of the villi of the small intestine, and in the lung, that was similar in magnitude
Summary
Of apoA-I were effective in inhibiting tumor development in a mouse model of ovarian cancer. Peptides mimicking the proteins associated with HDL were shown to inhibit tumor development in both induced and spontaneous mouse models of colon cancer[6]. Feeding Tg6F resulted in a decrease in myeloid derived suppressor cells (MDSCs) in the lamina propria of the small intestine and in the lung, that was similar in magnitude. Recent studies have shown that the Notch pathway promotes patrolling monocytes[16] whereas Spp[1] facilitates MDSC formation[17,18] These studies suggest that oral administration of an apoA-I mimetic peptide alters specific oxidized lipids, which alter cytokines and immune cells in the lamina propria of the small intestine resulting in favorable immunomodulation of cancers in tissues distant from the intestine
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