Novel tumor marker REG4 detected in serum of patients with resectable pancreatic cancer and feasibility for antibody therapy targeting REG4

Abstract

Pancreatic ductal adenocarcinoma (PDAC) shows the worst mortality rate among common malignancies, with a 5-year survival rate of only 4%, and the majority of PDAC patients are diagnosed at an advanced stage in which no effective therapy is available at present. Although the proportion of curable cases is still not so high, surgical resection of early stage PDAC is the only way to cure the disease. Hence, establishment of a screening strategy to detect early stage PDAC by novel serological markers is required urgently, and development of novel molecular therapies for PDAC treatment is also eagerly expected. We here report overexpression of REG4, a new member of the regenerating islet-derived (REG) family, in PDAC cells on the basis of genome-wide cDNA microarray analysis as well as reverse transcription-polymerase chain reaction and immunohistochemical analysis. We also detected significant elevation of REG4 in the serum of some patients with early-stage PDAC using our enzymelinked immunosorbent assay system, indicating the possibility of REG4 as a new serological marker of PDAC. Furthermore, we found that knockdown of endogenous REG4 expression in PDAC cell lines with small interfering RNA caused a decrease in cell viability. Concordantly, addition of recombinant REG4 to the culture medium enhanced growth of a PDAC cell line in a dose-dependent manner. A monoclonal antibody against REG4 neutralized its growth-promoting effects and attenuated significantly the growth of PDAC cells. These findings indicate that REG4 is a promising tumor marker to screen early-stage PDAC, and also that neutralization of REG4 by the antibody may offer novel potential tools for the treatment of PDAC. (Cancer Sci 2006; 97: 1191-1197) P ancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the western world and shows the worst mortality among common malignancies, with a 5-year survival rate of only 4%.(1,2) In 2006, it is estimated that approximately 33 730 new cases of pancreatic cancer will be diagnosed in the USA, with 32 300 of these people expected to die of the disease. In Japan nearly 20 000 PDAC patients die each year. Because the majority of PDAC patients are diagnosed at an advanced stage, no effective therapy to cure the disease is available at present. Several approaches that combine surgery with chemotherapy, including 5-fluorouracil (5-FU) or gemcitabine, with or without radiation, may improve patients' quality of life, (1,2) but those treatments have a very limited effect on long-term survival of PDAC patients due to its extremely aggressive and chemoresistant nature.The very poor prognosis of PDAC arises from several reasons, including the difficulty of detecting PDAC at an early stage.(1,2) Despite improvements in diagnostic imaging techniques, such as endoscopic ultrasound and magnetic resonance cholangiopancreatography,(1,2) most patients do not undergo imaging procedures because they do not have any symptoms until late in the course of the disease. An accurate and easy serological tes...

Expression of MK-1 and RegIV and its clinicopathological significances in the benign and malignant lesions of gallbladder

“…The expression of RegIV has been found to be related to the carcinogenesis, clinical biological behaviors, and prognosis of the carcinomas studied. Most of the high RegIV cases have poorly differentiated, high clinical stage, prone to metastasis and strong invasion ability, which are all considered being bad indicators of cancer prognosis [6-11,16]. These results all support that RegIV may involve in cancer formation and affect its development and prognosis.…”

REG4 is associated with carcinogenesis in the ‘intestinal’ pathway of intraductal papillary mucinous neoplasms

“…Recently, REG4 has been reported as a novel serum marker in several malignancies. 16,17,30 Therefore, REG4 may be a promising marker to indicate the need for surgery for IPMN limited to the branch ducts.…”

“…REG4 is also expressed in gastrointestinal carcinoma. [14][15][16][17] REG4 is involved in the carcinogenesis of colon cancer and is associated with proliferative function. 15,18 REG4 is also detected in goblet cells of intestinal metaplasia of the stomach, which is associated with CDX2.…”

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

“…7 The Reg family of proteins have been reported to play a role in pancreatic, gastric, liver and intestinal growth or differentiation. 8 Upregulation of Reg IV has been reported in colorectal, prostate, gallbladder, salivary, gastric and pancreatic cancers [9][10][11][12][13][14][15][16][17][18][19] ; additionally, it is amplified in pancreatic cancer. 20 Reg IV has also been negatively associated with relapse-free survival in prostate cancer and metastasis in both prostate and colorectal cancer.…”

“…22 Functional studies with Reg IV have demonstrated an impact on cell growth in pancreatic and colorectal cell lines, and an antibody directed against Reg IV inhibited pancreatic cancer cell line growth. 16,23 In addition, in colon cancer models, Reg IV overexpression promoted invasion and migration, 24,25 which could be neutralized with an anti-Reg IV antibody. 26 The study of Reg IV on …”