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Tumor Biology

Loss of Adipocyte-type Fatty Acid Binding Protein and Other Protein Biomarkers Is Associated with Progression of Human Bladder Transitional Cell Carcinomas

Julio E. Celis, Morten Østergaard, Bodil Basse, Ariana Celis, Jette B. Lauridsen, Gitte P. Ratz, Inger Andersen, Bente Hein, Hans Wolf, Torben F. Ørntoft and Hanne Holm Rasmussen
Julio E. Celis
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Morten Østergaard
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Bodil Basse
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Ariana Celis
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Jette B. Lauridsen
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Gitte P. Ratz
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Inger Andersen
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Bente Hein
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Hans Wolf
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Torben F. Ørntoft
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Hanne Holm Rasmussen
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DOI:  Published October 1996
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Abstract

Multifocal recurrent papillary tumors provide a unique model system to study the molecular mechanisms underlying the steps involved in transitional cell carcinoma progression and offer a valuable source of material to search for biomarkers that may form the basis for diagnosis, prognosis, and treatment. We have examined the protein expression profiles of normal bladder urothelium and of 63 transitional cell carcinomas of various histopathological grades and T stages using high-resolution, two-dimensional gel electrophoresis, microsequencing, mass spectrometry, and a two-dimensional gel protein database approach for polypeptide identification (http://biobase.dk/cgi-bin/celis). In general, the results revealed a striking similarity between the overall qualitative expression patterns of papillary tumors of all grades, as well as of papillary and solid tumors of grade III. With few exceptions, tumors of grades I–III expressed, albeit at different levels, all of the keratins (7, 8, 13, 17, 18, 19, and 20) found in the normal urothelium. Grade IV tumors lacked or expressed reduced levels of keratin 13 but most resembled low-grade tumors. One invasive grade IV tumor, however, expressed a fibroblast-like protein phenotype. Four proteins that were expressed by normal urothelium and were lost at various stages of progression were identified as glutathione S-transferase µ, prostaglandin dehydrogenase (PGDH), a fatty acid binding protein with homology to the adipocyte isoform (A-FABP), and keratin 13. The percentage of tumors expressing A-FABP was very high in low-grade lesions but decreased drastically (P = 0.0006) in grade III and IV neoplasms. In addition, low-grade tumors contained more A-FABP than their high-grade counterparts. The stage of the disease was also statistically (P = 0.0269) related to the presence or absence of A-FABP in grade III tumors. Similar analysis of glutathione S-transferase µ and PGDH showed a statistically significant decrease of these proteins in high-grade (grades III and IV) tumors (P = 0.0026 and P = 0.0044, respectively). Only PGDH showed a suggestive correlation (P = 0.0775) with the stage of the disease in grade III tumors. Keratin 13 showed a drastic decrease in grade IV tumors. In addition to identifying biomarkers that may have prognostic value, our studies have suggested that A-FABP is an important component of the pathway(s) leading to bladder cancer development.

Footnotes

  • ↵1 This work was supported by grants from the Danish Cancer Society, the Biotechnology Program, the European Union, the Aarhus University Research Fund, Novo Nordisk and the Medical Association for the Advancement of Medical Sciences. M. Ø. and H. H. R. were supported by fellowships from the Danish Cancer Society.

  • ↵2 To whom requests for reprints should be addressed.

  • Received March 4, 1996.
  • Accepted August 15, 1996.
  • ©1996 American Association for Cancer Research.
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October 1996
Volume 56, Issue 20
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Loss of Adipocyte-type Fatty Acid Binding Protein and Other Protein Biomarkers Is Associated with Progression of Human Bladder Transitional Cell Carcinomas
Julio E. Celis, Morten Østergaard, Bodil Basse, Ariana Celis, Jette B. Lauridsen, Gitte P. Ratz, Inger Andersen, Bente Hein, Hans Wolf, Torben F. Ørntoft and Hanne Holm Rasmussen
Cancer Res October 15 1996 (56) (20) 4782-4790;

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Loss of Adipocyte-type Fatty Acid Binding Protein and Other Protein Biomarkers Is Associated with Progression of Human Bladder Transitional Cell Carcinomas
Julio E. Celis, Morten Østergaard, Bodil Basse, Ariana Celis, Jette B. Lauridsen, Gitte P. Ratz, Inger Andersen, Bente Hein, Hans Wolf, Torben F. Ørntoft and Hanne Holm Rasmussen
Cancer Res October 15 1996 (56) (20) 4782-4790;
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