Cancer Res Treat.  2005 Jun;37(3):171-176.

Co-Expression of Cox-2, C-Met and beta-catenin in Cells Forming Invasive front of Gallbladder Cancer

  • 1Department of Pathology, Chonbuk National University, Medical School and Center for Healthcare Technology Development, Jeonju, Korea.
  • 2Department of Forensic Pathology, Chonbuk National University, Medical School and Center for Healthcare Technology Development, Jeonju, Korea.
  • 3Department of Medicine, Veterans Administration Medical Center, Long Beach, California and the University of California, Irvine, California, USA.


Gallbladder cancer is a malignancy with poor prognosis, predominantly resulting from invasion and metastasis. Our previous studies have demonstrated that prostaglandin E2 (PGE2), generated by cyclooxygenase 2 (Cox-2), transactivates epidermal growth factor receptor (EGFR), c-Met and beta-catenin; thus, enhancing colon cancer cell growth and invasiveness in vitro. To determine whether these findings are applicable to clinical conditions, we examined the expression and cellular localization/co-localization of Cox-2, c-Met, beta-catenin, EGFR and c-erbB2 in gallbladder cancer. MATERIALS AND METHODS: Thirty-five specimens of invasive gallbladder cancer, 8 in situ carcinoma and 7 adenoma specimens were immunostained with specific antibodies against Cox-2, c-Met, beta-catenin, EGFR and c-erbB2. The cellular distribution, localization and co- localization were examined, and the signal intensities quantified in: a) the central area of gallbladder cancer and b) cancer cells forming the invasive front. RESULTS: Cox-2, c-Met, beta-catenin, c-erbB2 and EGFR were over-expressed in 80, 74, 71, 62 and 11% of invasive gallbladder cancers, respectively. beta-catenin was expressed in 80% of non-malignant specimens, exclusively in the cell membrane, while the cancer specimens showed cytoplasmic and/or nuclear staining. Significantly higher Cox-2, c-Met and beta-catenin expressions were present in cancer cells of the invasive front than in the tumor central areas (p<0.001), and these expressions were significantly (p=0.01) associated with the invasion depth. Co- expressions of Cox-2, c-Met, beta-catenin and c-erbB2 were present in 42% of the specimens in cancer cells forming the invasive front. CONCLUSION: The overexpressions, and often co-localizations, of Cox-2, c-Met and beta-catenin in cancer cells forming the invasive front indicate their local interactions and important roles in invasion.


Gallbladder neoplasms; Immunohistochemistry; Cyclooxygenase 2; Proto-Oncogene Protein c-met; Beta catenin

MeSH Terms

beta Catenin*
Cell Membrane
Colonic Neoplasms
Cyclooxygenase 2
Gallbladder Neoplasms*
Neoplasm Metastasis
Receptor, Epidermal Growth Factor
Cyclooxygenase 2
Receptor, Epidermal Growth Factor
beta Catenin


  • Fig. 1 Representative immunostaining for EGFR, c-erbB2, Cox-2, c-Met and β-catenin in gallbladder cancer. A-B) Cancer cells showed selective membrane staining for EGFR (A, ×200, scale bar 100 µm) and c-erbB2 (B, ×400, scale bar 100 µm). Note the absence of immunoreactivity in normal mucosal cells. Immunohistochemistry for c-Met (C, ×400, scale bar 100 µm) and Cox-2 (D, ×400, scale bar 100 µm) displayed cytoplasmic and membrane positivity. E-G) β-catenin staining showed normal mucosal cells, with membrane staining (E, ×200, scale bar 100 µm), cytoplasmic immunoreactivity in cancer cells (F, ×100, scale bar 100 µm), and nuclear localization in cancer cells at the invasive front (G, ×400, scale bar 100 µm).

  • Fig. 2 Comparison of the signal intensities in cancer cells between the central area and invasive front. A-B) β-catenin (A, ×100, scale bar 100µm) (B, ×100, scale bar 100µm), C-D) Cox-2 (C, ×40, scale bar 1 mm) (D, ×100, scale bar 100µm) and E-F) c-Met (E, ×40, scale bar 1 mm) (F, ×100, scale bar 100µm). Note the increased immunoreactivities of Cox-2, c-Met and β-catenin in cancer cells forming the invasive front (arrows) compared to those of cells in the central area.


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