Attenuated ALK5 receptor expression in human pancreatic cancer: correlation with resistance to growth inhibition.

Abstract

Transforming growth factor-beta (TGF-beta) receptors constitute a family of transmembrane proteins that bind TGF-beta ligands. In this study we assessed the growth responsiveness to TGF-beta 1 in pancreatic cancer cell lines and characterized the levels of expression of TGF-beta receptors in these cell lines and in human pancreatic cancer tissues. COLO 357 cells were most sensitive to the growth inhibitory actions of TGF-beta 1, PANC-1 cells exhibited moderate sensitivity, Hs766T cells exhibited slight sensitivity and MIA PaCa-2 and T3M4 cells were resistant to TGF-beta 1. Only COLO 357 cells expressed high levels of ALK5, the major type I TGF-beta receptor (T beta RI). Hs766T and PANC-1 cells expressed high levels of SKR1, another T beta RI subtype. Only MIA PaCa-2 cells did not exhibit the type II TGF-beta receptor (T beta-RII) transcript, whereas type III TGF-beta receptor (T beta-RIII) mRNA levels were elevated in this cell line and in HS766T cells. All the cell lines expressed TGF-beta 1, but TGF-beta 2 and TGF-beta 3 mRNA levels were variable. ALK5 and SKR1 mRNA levels were 6.8- and 9-fold greater in the pancreatic tumors in comparison with the corresponding levels in the normal pancreas. However, in the cancer cells, ALK5 immunoreactivity was faint, whereas T beta RII immunoreactivity was focal and intense. Conversely, in ductal cells adjacent to cancer cells ALK5 immunoreactivity was strong, whereas T beta RII immunoreactivity was weak. Since ALK5 heterodimerization with T beta RII is crucial for TGF-beta-mediated signaling, our findings suggest that low levels of ALK5 in pancreatic cancer cells within a tumor may protect against growth inhibition.