Identification of a survival-independent metastasis-enhancing role of hypoxia-inducible factor-1alpha with a hypoxia-tolerant tumor cell line.
During tumor progression, malignant cells must repeatedly survive microenvironmental stress. Hypoxia-inducible factor-1 (HIF-1) signaling has emerged as one major pathway allowing cellular adaptation to stress. Recent findings led to the hypothesis that HIF-1alpha may enhance the metastatic potential of tumor cells by a survival-independent mechanism. So far it has not been shown that HIF-1alpha also directly regulates invasive processes during metastasis in addition to conferring a survival advantage to metastasizing tumor cells. In a hypoxia-tolerant tumor cell line (L-CI.5s), which did not rely on HIF-1 signaling for viability in vitro and in vivo, knockdown of Hif-1alpha reduced invasiveness of the tumor cells in vitro as well as extravasation and secondary infiltration in vivo. Liver metastases associated induction of proinvasive receptor tyrosine kinase Met phosphorylation as well as gelatinolytic activity were Hif-1alpha-dependent. Indeed, promoter activity of the matrix metalloproteinase-9 (mmp-9) was shown to be Hif-1alpha-dependent. This study uncovers a new survival-independent biological function of HIF-1alpha contributing to the efficacy of metastases formation.
Schelter
Florian
F
Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, München, Germany.
Gerg
Michael
M
Halbgewachs
Birgit
B
Schaten
Susanne
S
Görlach
Agnes
A
Schrötzlmair
Florian
F
Krüger
Achim
A
D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008113:Liver Neoplasms / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020794:Receptor Protein-Tyrosine Kinases; D020780:Matrix Metalloproteinase 9