Overexpression of the small transmembrane and glycosylated protein SMAGP supports metastasis formation of a rat pancreatic adenocarcinoma line

Small cell transmembrane and glycosylated protein (SMAGP) was recently identified in the metastasizing rat pancreatic adenocarcinoma line BSp73ASML. SMAGP, an evolutionary conserved transmembrane protein, is expressed on lateral epithelial cell membranes. SMAGP expression was restricted to or was upregulated in several metastasizing as compared to nonmetastasizing human and rat tumor lines. In contrast to nontransformed tissue, SMAGP was mainly expressed in the cytoplasm, as has already been described for high-grade human colorectal Cancer. This raised the question on the impact of SMAGP on tumor progression. To answer the question, metastasis formation was evaluated in the nonmetastasizing rat pancreatic adenocarcinoma subline BSp73AS (AS), which was stably transfected with SMAGP cDNA (AS-SMAGP). Cytoplasmic SMAGP expression promoted cell agglomeration, but inhibited tumor cell proliferation, adhesion to and migration toward vitronectin and matrigel invasion, which was accompanied by a failure of actin reorganization. AS-SMAGP clones strongly promoted metastasis formation by dislodgment of normal tissue; 82% of rats developed lymph node metastasis as compared to 22% of rats receiving AS or mock-cDNA-transfected AS cells. The incidence of lung metastasis was increased from 6% in AS to 98% in AS-SMAGP tumor-bearing rats. Thus, SMAGP strongly promotes tumor progression. This likely is due to redistribution from the plasma membrane into the cytoplasm. SMAGP redistribution does not only facilitate tumor cell detachment from neighboring cells and the extracellular matrix, but obviously contributes actively by a not yet defined mechanism to tumor cell agglomeration and capillary plugging.