SMAD4/DPC4 and Pancreatic Cancer Survival

Pancreatic cancer is the fourth leading cause of cancer deaths in both men and women in the United States, accounting for 30,000 deaths annually. It is a deadly disease with a 5-year survival of only 3–5% (1). The diagnosis of pancreatic adenocarcinoma is devastating to patients and their families, because the diagnosis is usually made at a late stage of disease that is not amenable to cancer curative surgery, and is little affected by chemotherapy, radiation therapy, or immunotherapy. Patients have a median survival of only 4–8 months after diagnosis (1). A small number of pancreatic cancer patients are diagnosed when the disease is limited to the pancreas and periampullary region. Surgery (pancreaticoduodenectomy) provides the only potentially curative intervention for the disease with a 5-year survival of 15–20% (1). SMAD4, also termed DPC4, was originally isolated from human chromosome 18q21.1 as a tumor suppressor gene for pancreatic cancer (2). Approximately 55% of pancreatic cancers bear deletions or mutations in SMAD4/DPC4 ( 30% homozygous deletion and 22%-25% mutation with LOH; Ref. 2). In this issue, Tascilar et al. (3) report that among patients undergoing surgical resection of their pancreatic adenocarcinoma, survival of patients whose tumors expressed SMAD4 protein was significantly longer (unadjusted median survival, 19.2 months) as compared with 14.7 months without SMAD4 protein expression (P 0.03; Ref. 3). This SMAD4 survival benefit persisted after adjustment for prognostic factors including tumor size, margin status, lymph node status, pathological stage, blood loss, and use of adjuvant chemoradiotherapy (3). For a disease with such a poor prognosis, the median survival advantage of 5 months with SMAD4 expression is clinically significant. Pancreatic cancer is primarily a genetic disease. Inactivation of several tumor suppressor genes, such as p16, SMAD4, and p53, coupled with activation of the K-ras oncogene, are common events in pancreatic cancer (4). Mutation frequencies for p16, p53, and K-ras are approximately 80, 70, and 90%, respectively (4). Several molecular markers have been investigated previously for their prognostic significance, including p53 status (5), K-ras mutation (5), expression of bcl-2 (6), bax (6), and TGF1 (7). Only the DNA index has been shown consistently to provide prognostic information independent of standard pathological prognostic indicators (8). SMAD4 is a member of the SMAD family and plays a pivotal role in mediating members of the TGFsuperfamily signal transduction and gene regulation events (9, 10). The major members of the TGFfamily include TGFs, activins, and BMPs (9, 10). The TGFfamily members exert a wide variety of biological activities. For example, TGFcan regulate the proliferation, differentiation, motility, and death of cells. TGFcan also enhance extracellular matrix formation, promote angiogenesis, and inhibit immune function. Because of their multifunctional nature, TGFand related factors can elicit different effects in a cell context-dependent manner (9, 10). TGFsignals through two types of transmembrane serine/ threonine kinase receptors (9, 10). It binds and brings together the type I and type II receptors (TGFBR1 and TGFBR2). In the resulting complex, the constitutively active TGFtype II receptor phosphorylates the type I receptor, which then plays a major role in transducing the signal to downstream components to affect gene expression. Other members of the TGFfamily also signal through two types of transmembrane serine/threonine kinase receptors (9, 10). The activin type IB receptor (ACVR1B) and the TGFtype I receptor (TGFBR1) share 90% homology in their kinase domains, which may explain the finding that TGFand activin share some common biological activities, including growth-inhibitory effects. SMAD proteins can transduce the TGFsignal from the cell surface to the nucleus (9, 10). On the basis of structural and functional characteristics, the nine members of the SMAD family can be divided into distinct groups. One group includes those pathway-specific SMADs that are phosphorylated by receptor kinases (also called receptor-regulated SMADs). For example, SMAD1 and its close homologues SMAD5 and SMAD8 mediate BMP responses and can be directly phosphorylated by BMP receptor kinases (9, 10). SMAD2 and SMAD3 mediate TGFand activin responses and can be directly phosphorylated by the highly homologous TGFand activin receptor kinases (9, 10). Phosphorylated receptor-regulated SMADs then form heteromeric complexes with the common partner SMAD4 (co-SMAD; Ref. 11). These heteromeric complexes then move to the nucleus, where SMAD4 contributes to DNA binding and is critical for transcriptional activation (12). SMAD4 is the only member of the SMAD family that can participate in TGF, activin, and Received 11/7/01; accepted 11/9/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Center for Advanced Biotechnology and Medicine, Rutgers University, 679 Hoes Lane, Piscataway, NJ 08854. Phone: (732) 235-5372; Fax: (732) 2354850; E-mail: [email protected]. 2 The abbreviations used are: DPC4, deleted in pancreatic carcinoma, locus 4; LOH, loss of heterozygosity; TGF, transforming growth factor ; BMP, bone morphorgenetic protein; CDK, cyclin-dependent kinase; APC, adenomatous polyposis coli; VEGF, vascular endothelial growth factor; TSP, thrombospondin. 3853 Vol. 7, 3853–3856, December 2001 Clinical Cancer Research