Analysis of Incidence and Expression Levels of a Cancer-Specific CCK2 Receptor Splice Variant in Gastrointestinal and Lung Tumors
M Korner, B Waser, JC Reubi, LJ Miller. Mayo Clinic, Scottsdale, AZ; Institute of Pathology of the University of Berne, Berne, Switzerland
Background: The CCK2 receptor (CCK2R) is expressed in many gastrointestinal and lung tumors. Recently, it was described that in colorectal and pancreatic cancers a subset of CCK2R corresponded to a splice variant with intron 4 retention (CCK2R-i4). Unlike the wild-type receptor, the CCK2R-i4 showed constitutive activity associated with increased tumor growth in vitro. Given the potential functional and clinical importance of this spliceoform, the aim of this study was to quantitatively characterize its occurrence in a broad collection of gastrointestinal and lung tumors.
Design: Eighty-one tumor samples, including insulinomas, ileal carcinoids, gastrointestinal stromal tumors (GIST), gastric, colorectal, and pancreatic ductal adenocarcinomas, cholangiocellular and hepatocellular carcinomas, small cell lung cancers (SCLC), non-SCLC, and bronchopulmonary carcinoids, as well as 21 samples of corresponding normal tissues were assessed for transcript expression of total CCK2R, wild-type CCK2R and CCK2R-i4 with end-point and real-time RT-PCR, and for total CCK2R protein expression on the basis of receptor binding with in vitro receptor autoradiography.
Results: Wild-type CCK2R transcripts were present in the vast majority of investigated tumors and normal tissues, except for cholangiocellular carcinomas and normal lung. Conversely, the CCK2R-i4 mRNA expression was restricted to specific tumor types, namely insulinomas (incidence 100%), GIST (100%), pancreatic carcinomas (14%), SCLC (67%), and non-SCLC (8%), and was not found in any normal tissues tested. CCK2R-i4 transcript levels in individual tumors were very low, ranging from 0.02% of total CCK2R transcripts in GIST to 0.14% in non-SCLC. Total CCK2R transcript levels correlated fairly well with the amount of total CCK2R protein as quantified with autoradiography (correlation coefficient r2=0.658, p<0.001).
Conclusions: The CCK2R-i4 is a marker of specific gastrointestinal and lung tumors. With its high selectivity for and high incidence in clinically important tumors like SCLC and GIST, the CCK2R-i4 represents an attractive potential diagnostic or therapeutic target. The low CCK2R-i4 transcript levels in these tumors predict that only highly sensitive diagnostic tests like PCR could prove clinically useful.
Monday, March 9, 2009 1:00 PM
Poster Session II # 91, Monday Afternoon