Linoleic-Acid-Induced Growth Suppression Induces Quiescent Cancer Cell Nests in Nude Mice

Abstract

We examined the effect of linoleic acid (LA) on tumor formation. Cell growth was suppressed by LA in a dose-dependent manner in MKN28 and Colo320 cells. Continuous treatment with LA provided growth arrest in both cells at 5–7 weeks after the treatment. LA-pretreated MKN28 and Colo320 cells showed higher tumorigenicity (9/10 and 10/10, respectively) than nontreated cells (2/10 and 3/10, respectively; p < 0.01) in nude mice. In contrast, LA-pretreated MKN28 and Colo320 cells showed more suppressed tumor growth than nontreated cells (p < 0.01). LA-pretreated MKN28 and Colo320 cells with LA administration after the inoculation did not form macroscopic tumors. Histological examination revealed small cancer cell aggregations, which showed no proliferative activity. In LA-treated MKN28 and Colo320 cells, protein production of Bcl-2 was increased, whereas Bak, EGFR and VEGF levels were decreased. These findings suggest that LA might induce quiescence and subsequent dormancy in cancer cells.

Fatty acids inhibit anticancer effects of 5-fluorouracil in mouse cancer cell lines

“…LA induces senescence in cultured CRC cells and dormancy in CRC cells inoculated into mice (11). Conversely, EA increases the proliferation of cells in spheres via the activation of epidermal growth factor receptor and the Wnt signaling pathway, and the upregulation of stem cell markers (16,17).…”

“…LA in combination with azoxymethane results in the upregulation of insulin-like growth factor-I/II receptors (5), Ras (6), cyclooxygenase-2 (7) and high mobility group box-1 (8), which act to accelerate colon carcinogenesis (6,7,9,10). Prolonged treatment with LA induces a quiescent state in CRC cells and the dormancy of subcutaneous tumors in mice, which is thought to be associated with low proliferation of cancer stem cells (CSCs) (11,12). …”

The Roles of Dietary PPARγ Ligands for Metastasis in Colorectal Cancer

“…On the contrary, in a long-term continuous treatment with adequate concentrations, LA induced reversible cell growth-arrest in cancer cells that escaped from apoptosis [62]. …”

Fatty Acids Induce Stemness in the Stromal Cells of a CT26 Mouse Tumor Model

“…The procarcinogenic effects of LA on colorectal cancer (CRC) are well known. These include induction of chronic inflammation by the production of prostaglandin E2 [9] or secretion of high-mobility group box-1 [10] . LA is also reported to inhibit peritoneal metastasis and in vitro transformation [11] .…”

“…LA is also reported to inhibit peritoneal metastasis and in vitro transformation [11] . Persistent treatment with LA induces dormancy of subcutaneous tumors in mice, which is thought to be associated with a low proliferation of cancer stem cells (CSC) [10,12] .…”