Hypoxia, Metastasis, and Antiangiogenic Therapies

Part of the Cancer Drug Discovery and Development book series (CDD&D)


It is well known that aberrant microenvironmental conditions in solid tumors negatively impact their response to conventional anticancer therapies. Indeed the presence of hypoxia in the primary tumor has been identified as a prognostic indicator of treatment outcome in a number of clinical settings. Hypoxic conditions can arise at the limits of oxygen diffusion from blood vessels (diffusion or chronic hypoxia) or as a consequence of vascular collapse (perfusion or acute hypoxia). Both types of hypoxia upregulate key signaling pathways associated with metastasis and related tumor cell behavior and function; and although the impact of acute and chronic oxygen deprivation on these pathways may differ markedly, the effect of such exposures is to significantly enhance the metastatic phenotype. In lieu of the critical role of metastasis in treatment failures, there has been significant interest in developing molecular targeting strategies that impair signaling pathways associated with tumor cell dissemination. Many of these targeted tumor cell associated functions are enhanced by hypoxia, including invasion and angiogenesis. Agents targeting angiogenesis are of interest because they could interfere with the progression of established microtumor deposits to macroscopic size by interfering with blood vessel development but they also raise the caveat that the use of such agents might induce hypoxia in the primary tumor which could conceivably enhance the dissemination of tumor cells. This chapter discusses the impact of oxygen deficiencies on the maintenance of stem-like characteristics of tumor initiating cells, the potential interplay between genomic markers and hypoxia/HIFs, and the effect of hypoxia on signaling pathway critical to the metastatic process, including VEGF, c-Src, and the HGF/c-Met axis. It further explores how the interference with signaling molecules may have significant therapeutic potential in the development of novel therapeutic intervention approaches for the treatment of cancer metastasis.


Tumor-initiating cells (TIC) Angiogenesis inhibitors HIF-1 VEGF SOX2 c-Src c-Met Acute and chronic hypoxia 


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Dietmar W. Siemann
    • 1
  • Yao Dai
    • 1
  • Michael R. Horsman
    • 2
  1. 1.Department of Radiation OncologyUniversity of Florida Shands Cancer CenterGainesvilleUSA
  2. 2.Department of Experimental Clinical OncologyAarhus University HospitalAarhus CDenmark

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