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TRAIL Induces Apoptosis in Human Colorectal Adenoma Cell Lines and Human Colorectal Adenomas

Authors' Affiliations: Departments of ¹ Gastroenterology and Hepatology, ² Medical Oncology, and ³ Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Requests for reprints: Jan H. Kleibeuker, Department of Gastroenterology and Hepatology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands. Phone: 31-50-361-3354; Fax: 31-50-361-9306; E-mail: j.h.kleibeuker{at}int.umcg.nl.

Purpose: Recombinant human (rh) tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a potential new anticancer drug which can induce apoptosis in colorectal cancer cell lines. The aim of this study was to investigate whether it is possible to induce apoptosis in human adenoma cell lines and human adenomas using rhTRAIL.

Experimental Design: Two human adenoma cell lines were exposed to 0.1 µg/mL of rhTRAIL for 5 hours. Apoptosis and caspase activation in cell lines were evaluated using immunocytochemistry, fluorimetric caspase assays, and Western blotting. Short-term explant cultures were established from freshly removed human adenomas (n = 38) and biopsies of normal colon epithelium (n = 15), and these were incubated for 5 hours in the presence or absence of 1 µg/mL of rhTRAIL. Apoptosis was determined in paraffin-embedded tissue using morphologic criteria and cleaved caspase-3 staining.

Results: In the adenoma cell lines, rhTRAIL induced up to 55% apoptosis. This coincided with caspase-8 and caspase-3 activation and could be inhibited by a pan-caspase inhibitor. rhTRAIL induced caspase-dependent apoptosis in adenomas with high-grade dysplasia (n = 21) compared with the paired untreated counterparts (apoptotic index, 34 ± 5% versus 17 ± 2%, mean ± SE; P = 0.002), but not in adenomas with low-grade dysplasia (n = 17) or in normal colon epithelium (n = 15).

Conclusions: Colorectal adenoma cell lines and adenomas with high-grade dysplasia are sensitive to rhTRAIL-induced apoptosis, whereas normal colon epithelium is not. This suggests the potential application of rhTRAIL in the treatment of adenomas with high-grade dysplasia.

Commentary

Selective TRAIL-Induced Apoptosis in Dysplastic Neoplasia of the Colon May Lead to New Neoadjuvant or Adjuvant Therapies

Niklas Finnberg and Wafik S. El-Deiry
Clin. Cancer Res. 2006 12: 4132-4136. [Full Text] [PDF]

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				N. Finnberg and W. S. El-Deiry Selective TRAIL-Induced Apoptosis in Dysplastic Neoplasia of the Colon May Lead to New Neoadjuvant or Adjuvant Therapies. Clin. Cancer Res., July 15, 2006; 12(14): 4132 - 4136. [Full Text] [PDF]