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(Chest. 2003;123:966-967.)
© 2003 American College of Chest Physicians

New Diagnostic Tool for Tumor Angiogenesis

Ken-ichiro Inoue, MD; Yutaka Kawahito, MD, PhD; Hajime Sano, MD, PhD; Hirohisa Takano, MD, PhD and Toshikazu Yoshikawa, MD, PhD

Kyoto Prefectural University of Medicine Kyoto, Japan

Correspondence to: Ken-ichiro Inoue, MD, Department of Internal Medicine, Naka Central Hospital, 1733-1, Iida, Naka-cho, Naka-gun, 311-0134, Japan; e-mail: keni{at}kk.iij4u.or.jp

To the Editor:

In a recent issue of CHEST, Ohta and colleagues (May 2002)1 showed excellent results in which the expression of vascular endothelial growth factor (VEGF) protein in BAL fluid was higher in patients with lung cancer than in those with noncancerous diseases, suggesting that VEGF concentrations in the airways may reflect responsive tumor angiogenic status on the host side.

Following the accepted concept that the growth of solid tumors is dependent on their ability to elicit the development of new blood vessels into the tumor mass, there has been an increasing focus on targeting tumor vasculature. The angiogenic potential of the endothelial cell is carefully balanced between positive and negative regulation. Tumors have the potential to up-regulate or down-regulate these controls, producing an environment in which new blood formation occurs, thereby supporting tumor growth. Angiogenic factors include VEGF, fibroblast growth factor (FGF)-{alpha} and FGF-ß, endothelial growth factor, tumor necrosis factor-{alpha}, and integrins.2 On the other hand, angiostatic factors include angiostatin, endostatin, transforming growth factor-ß, tissue inhibitors of metalloproteinases, 2-methoxyestradiol, and squalamine.2 3 Indeed, antiangiogenic agents offer a potential for the treatment of cancers, but emerging data suggest that there may be limits to their use as monotherapy in patients with advanced malignancies. Therefore, the further accumulation of other markers of angiogenesis or other antiangiogenic molecules in malignant tumors, including lung cancers, are needed for future novel strategies.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, which include vitamin D3, retinoid, and thyroid hormone receptors.4 Among PPARs, PPAR-{gamma} has been well-recognized to correlate with inflammation and tumorigenesis. In fact, agonists of PPAR-{gamma} suppress experimental arthritis5 and proliferation of cancer cell lines.6 7 We examined6 8 the expression of PPAR-{gamma} in two different types of cancer tissues, lung cancer and renal cell carcinoma. Because PPAR-{gamma} is expressed in endothelial cells,9 we compared the immunoreactive expression of PPAR-{gamma} protein in endothelial cells as well as cancer cells between these cancer tissues and normal tissues on a scale of 0 to 4, according to the grading methodology previously described.10 As a result, the mean (± SD) immunohistologic scores of PPAR-{gamma} in the endothelial cells of normal lung tissues and normal kidney tissues were 0.8 ± 0.3 and 0.6 ± 0.4, respectively. However, the immunohistologic scores of endothelial cells in lung cancer tissues and renal cell carcinoma tissues were 1.8 ± 0.9 and 3.1 ± 1.1, respectively (unpublished data), indicating that the extent and intensity of immunoreactive PPAR-{gamma} in endothelial cells in these cancer tissues was significantly greater than that in the corresponding normal tissues.

In conclusion, we would like to recommend PPAR-{gamma} as an angiogenic factor, and its ligands as angiostatic factors in malignant tumors.

References

  1. Ohta, Y, Ohta, N, Tamura, M, et al (2002) Vascular endothelial growth factor expression in airways of patients with lung cancer: a possible diagnostic tool of responsive angiogenic status on the host side. Chest 121,1624-1627[Abstract/Free Full Text]
  2. Brock, CS, Lee, SM Anti-angiogenic strategies and vascular targeting in the treatment of lung cancer. Eur Respir J 2002;19,557-570[Abstract/Free Full Text]
  3. Herbst, RS, Hidalgo, M, Pierson, AS, et al Angiogenesis inhibitors in clinical development for lung cancer. Semin Oncol 2002;29(suppl),66-77[CrossRef][ISI][Medline]
  4. Issemann, I, Green, S Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990;347,645-650[CrossRef][Medline]
  5. Kawahito, Y, Kondo, M, Tsubouchi, Y, et al 15-deoxy-{Delta}12, 14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest 2000;106,189-197[ISI][Medline]
  6. Inoue, K, Kawahito, Y, Tsubouchi, Y, et al Expression of peroxisome proliferator-activated receptor{gamma} in renal cell carcinoma and growth inhibition by its agonists. Biochem Biophys Res Commun 2001;287,727-732[CrossRef][ISI][Medline]
  7. Tsubouchi, Y, Sano, H, Kawahito, Y, et al Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-{gamma} agonists through induction of apoptosis. Biochem Biophys Res Commun 2000;270,400-405[CrossRef][ISI][Medline]
  8. Inoue, K, Kawahito, Y, Tsubouchi, Y, et al Expression of peroxisome proliferator-activated receptor (PPAR)-{gamma} in human lung cancer. Anticancer Res 2001;21,2471-2476[ISI][Medline]
  9. Xin, X, Yang, S, Kowalski, J, et al Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 1999;274,91116-91121
  10. Sano, H, Hla, T, Maier, JAM, et al In vitro cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis. Clin Invest 1992;89,97-108




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