Journal
CANCER SCIENCE
Volume 100, Issue 5, Pages 844-851Publisher
WILEY
DOI: 10.1111/j.1349-7006.2009.01105.x
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [17014020]
- Japan Society for Promotion of Science
- Organization for Pharmaceutical Safety and Research
- Grants-in-Aid for Scientific Research [17014020] Funding Source: KAKEN
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Antiangiogenic therapy is a potent cancer treatment, however, the possibility of recurrence and resistance to this approach remains. Here we show that hypoxia and low-nutrition double-deprivation stress induces reversible tumor aggressiveness. In a stress-cycle-dependent manner, murine melanoma cells showed morphological changes, up-regulated phospho-Akt, and abnormal regulation of multiple genes including fibroblast growth factor-21, a metabolic regulator, resulting in increased cell proliferation in vitro, and increased tumorigenesis and invasive potential in vivo. In this system, altered cellular metabolism participates in the adaptation of tumor to the double-deprivation stress. Our results suggest the targeting of a minor population of cancer cells resistant to both hypoxia and low nutrition to be an effective new antitumor strategy in combination with antiangiogenic therapy. (Cancer Sci 2009; 100: 844-851).
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