Abstract
A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor–depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.
Highlights
The microenvironment within a solid tumor can be highly heterogeneous [1]
Survival of cell lines under chronic hypoxia To investigate the effect of prolonged hypoxia on cancer cells in vitro, we examined several pancreatic cancer and colorectal cancer cell lines cultured in 1% oxygen for more than a week to represent the chronic condition, as opposed to the shorter frame of a day or so for the acute condition (Figure S1)
Knockdown of hypoxia-inducible factor-1a (HIF-1a) had little effect on AKT/ mTOR complex 1 (mTORC1) signaling and somewhat increased pS6 levels (Figure S6D), but overexpression of AKT had no effect on induction of HIF-1a (Figure 3B). These results indicated that HIF-1a and AKT independently regulated the dormant status in chronic hypoxia
Summary
Because of incomplete blood vessel networks and the imbalance between proliferation and angiogenesis, the microenvironment in some parts of a solid tumor can be hypoxic and poorly supplied with nutrients [2,3]. Depending on their microenvironment, cancer cells can show quite different characteristics of cell activity including proliferation, oncogenic pathway activation, and metabolism [4]. Tumor cells in a hypoxic region distant from blood vessels show decreased proliferation [5] and resistance to chemo- or radiotherapy [6,7]. In contrast to the responses of cancer cells to acute hypoxia, how cancer cells respond to the important but different condition of chronic hypoxia [11] remains elusive
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