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

Abstract

Transforming growth factor-6 (TGF-p) receptors constitute a family of transmembrane proteins that bind TGF-P ligands. In this study we assessed the growth responsiveness to TGF-P I in

The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer

“…These low levels of endogenous Smad7 may explain the lack of correlation between Smad7 mRNA levels in these cells and responsiveness to TGFb1 (Baldwin et al, 1996). These observations suggest that resistance to TGF-b-mediated growth inhibition in these cells was not Smad7-dependent.…”

“…Second, decreased expression of either TbRI or TbRII has been implicated as a mechanism for TGF-b resistance in human tumors. TbRI underexpression occurs in prostate, colon, and pancreatic cancer cell lines, and in chronic lymphocytic leukemia cells (Baldwin et al, 1996;DeCoteau et al, 1997;Kim et al, 1996;Wang et al, 1996), whereas TbRII levels are low in gastric cancer cells and in TGF-bresistant T-cell lymphoma cells (Kadin et al, 1994;Park et al, 1994). Third, inactivating mutations in components of the TGF-b signaling pathway, such as Smad2 or Smad4 lead to a TGF-b-resistant state Eppert et al, 1996;Riggins et al, 1996;.…”

“…This cell line was chosen because it is growth inhibited by TGF-b and expresses a normal Smad4 gene (Baldwin et al, 1996;Baldwin and Korc, 1993;. Accordingly, COLO-357 cells were stably transfected with a fulllength Smad7 construct.…”

“…Blots were hybridized with a 32 P labeled Smad7 cDNA probe and exposed at 7808C to Kodak Biomax MS ®lms. A 190 bp 7S cDNA probe, and a 150 bp b-actin cDNA probe were used to con®rm equivalent loading of total RNA and poly(A) + RNA, respectively (Baldwin et al, 1996;Korc et al, 1992).…”

“…As many as 50% of these cancers also harbor Smad4 mutations that render the cancer cells resistant to TGF-b-mediated growth suppression Schutte et al, 1996;Grau et al, 1997). In addition, these cancers often express low levels of TbRI, which may also contribute to the loss of responsiveness to TGF-b1 (Baldwin et al, 1996;Wagner et al, 1998). Recently, we reported that Smad6 expression is increased in pancreatic cancer (Klee et al, 1999).…”