Interplay between receptor tyrosine kinases and hypoxia signaling in cancer.
Deregulated signaling via receptor tyrosine kinase (RTK) pathways is prevalent in numerous types of human cancers and is commonly correlated with worst prognosis, resistance to various treatment modalities and increased mortality. Likewise, hypoxic tumors are often manifested by aggressive mode of growth and progression following an adaptive genetic reprogramming with consequent transcriptional activation of genes encoding proteins, which support tumor survival under low oxygen-related conditions. Consequently, both the hypoxia-inducible factor (HIF) system, which is the major mediator of hypoxia-related signaling, and numerous RTK systems are considered critical molecular targets in current cancer therapy. It is now evident that there is an intricate molecular crosstalk between RTKs and hypoxia-related signaling in the sense that hypoxia can activate expression of particular RTKs and/or their corresponding ligands, while some RTK systems have been shown to trigger activation of the HIF machinery. Moreover, signaling regulation of some RTK systems under hypoxic conditions has also been documented to take place in a HIF-independent manner. With this review we aim at overviewing the most current observations on that topic and highlight the importance of the potential co-drugging the HIF system along with particular relevant RTKs for better tumor growth control.
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland.
Astrid A
AA
Glück
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland.
Daniel M
DM
Aebersold
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland.
Yitzhak
Y
Zimmer
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland. Electronic address: michaela.medova@dkf.unibe.ch.
Michaela
M
Medová
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D051793:Hypoxia-Inducible Factor 1; D020794:Receptor Protein-Tyrosine Kinases
Cancer; HIF system; Hypoxia; RTKs; VEGF