Abstract
Ambient temperature can regulate the immune response and affect tumor growth. Although thermoneutral caging reduces tumor growth via immune activation, little attention has been paid to the tumorigenic effect of low temperature. In the present study, tumor growth was higher at low ambient temperature (4 °C for 8 h/d) than at the standard housing temperature (22 °C) in allograft models. Low temperature-stimulated tumor growth in mice was reduced by monocyte depletion using clodronate liposomes. Proliferation was considerably greater in cancer cells treated with 33 °C-cultured RAW264.7 cell-conditioned media (33CM) than in cells treated with 37 °C-cultured RAW264.7 cell-conditioned media (37CM). Additionally, glutamine levels were markedly higher in 33CM-treated cells than in 37CM-treated cells. We further confirmed that the addition of glutamine into 37CM enhanced its effects on cancer cell proliferation and glutamine uptake inhibition ameliorated the accelerated proliferation induced by 33CM. Consistently, the inhibition of glutamine uptake in the allograft model exposed to low temperature, effectively reduced tumor volume and weight. Collectively, these data suggest that the secretion and utilization of glutamine by macrophages and cancer cells, respectively, are key regulators of low temperature-enhanced cancer progression in the tumor microenvironment.
Highlights
Ambient physical factors, such as temperature and humidity, induce biological events from the cellular to the organismal level [1]
We found that tumors originating from Lewis lung carcinoma (LLC) cells
To determine whether the enhanced tumor growth originating from LLC cells isolated from control mice (Figure 1B‒D)
Summary
Ambient physical factors, such as temperature and humidity, induce biological events from the cellular to the organismal level [1]. The formation, growth, and metastasis of tumors are markedly decreased in immunocompetent mice housed at thermoneutral temperatures (30–31 ◦ C) compared with those in standard housing temperatures (22–23 ◦ C) These effects occur via an increase in the number of Cd8+ T cells and a decrease in the number of myeloid-derived suppressor cells and regulatory T cells [7]. The co-injection of Lewis lung carcinoma (LLC) cells with adipocytes activated by hypothermic stress promotes allograft cancer cell growth in athymic mice [8]. These studies demonstrated that cells in the tumor microenvironment are important for the accelerated tumor growth induced by low ambient temperature. IL-4 and/or IL-10 alternatively activate macrophages and polarize them into tumor-associated macrophages, resulting in tumor promotion/progression
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