Semaphorin 3A Overcomes Cancer Hypoxia and Metastatic Dissemination Induced by Antiangiogenic Treatment in Mice

J Clin Invest. 2012 May;122(5):1832-48. doi: 10.1172/JCI58976. Epub 2012 Apr 9.

Abstract

Cancer development, progression, and metastasis are highly dependent on angiogenesis. The use of antiangiogenic drugs has been proposed as a novel strategy to interfere with tumor growth, but cancer cells respond by developing strategies to escape these treatments. In particular, animal models show that antiangiogenic drugs currently used in clinical settings reduce tumor tissue oxygenation and trigger molecular events that foster cancer resistance to therapy. Here, we show that semaphorin 3A (Sema3A) expression overcomes the proinvasive and prometastatic resistance observed upon angiogenesis reduction by the small-molecule tyrosine inhibitor sunitinib in both pancreatic neuroendocrine tumors (PNETs) in RIP-Tag2 mice and cervical carcinomas in HPV16/E2 mice. By improving cancer tissue oxygenation and extending the normalization window, Sema3A counteracted sunitinib-induced activation of HIF-1α, Met tyrosine kinase receptor, epithelial-mesenchymal transition (EMT), and other hypoxia-dependent signaling pathways. Sema3A also reduced tumor hypoxia and halted cancer dissemination induced by DC101, a specific inhibitor of the VEGF pathway. As a result, reexpressing Sema3A in cancer cells converts metastatic PNETs and cervical carcinomas into benign lesions. We therefore suggest that this strategy could be developed to safely harnesses the therapeutic potential of the antiangiogenic treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Cell Hypoxia / drug effects
  • Combined Modality Therapy
  • Drug Resistance, Neoplasm
  • Epithelial-Mesenchymal Transition
  • Female
  • Genetic Therapy
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Liver Neoplasms / secondary*
  • Lymphatic Metastasis
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neovascularization, Physiologic
  • Neuroendocrine Tumors / blood supply
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology*
  • Neuroendocrine Tumors / therapy
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / therapy
  • Pericytes / pathology
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Semaphorin-3A / biosynthesis
  • Semaphorin-3A / genetics*
  • Sunitinib
  • Tumor Burden
  • Uterine Cervical Neoplasms / blood supply
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / therapy
  • Uterine Cervical Neoplasms / virology

Substances

  • Angiogenesis Inhibitors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indoles
  • NF-kappa B
  • Pyrroles
  • Recombinant Proteins
  • Semaphorin-3A
  • Proto-Oncogene Proteins c-met
  • Sunitinib