No abstract

The transforming growth factor-beta (TGF-beta) superfamily comprises nearly 30 growth and differentiation factors that include TGF-betas, activins, inhibins, and bone morphogenetic proteins (BMPs). Multiple members of the TGF-beta superfamily serve key roles in stem cell fate commitment. The various members of the family can exhibit disparate roles in regulating the biology of embryonic stem (ES) cells and tumor suppression. For example, TGF-beta inhibits proliferation of multipotent hematopoietic progenitors, promotes lineage commitment of neural precursors, and suppresses epithelial tumors. BMPs block neural differentiation of mouse and human ES cells, contribute to self-renewal of mouse ES cells, and also suppress tumorigenesis. ES cells and tumors may be exposed to multiple TGF-beta members, and it is likely that the combination of growth factors and cross-talk among the intracellular signaling pathways is what precisely defines stem cell fate commitment. This Connections Map Pathway in the Database of Cell Signaling integrates signaling not only from TGF-beta and BMP but also from the ligands nodal and activin, and describes the role of the signaling pathways activated by these ligands in mammalian development. Much of the evidence for the connections shown comes from studies on mouse and human ES cells or mouse knockouts. This pathway is important for understanding not only stem cell biology, but also the molecular effectors of TGF-beta and BMP signaling that may contribute to cancer suppression or progression and thus are potential targets for therapeutic intervention.

Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

Adult hepatic progenitor cells are activated during regeneration when hepatocytes and bile duct epithelium are damaged or unable to proliferate. On the basis of its role as a tumor suppressor and in the potential malignant transformation of stem cells in hepatocellular carcinoma, we investigated the role of key transforming growth factor beta (TGF-␤) signaling components, including the Smad3 adaptor protein ␤2-Spectrin (␤2SP), in liver regeneration. We demonstrate a streaming hepatocyte-specific dedifferentiation process in regenerating adult human liver less than 6 weeks following living donor transplantation. We then demonstrate a spatial and temporal expansion of TGF-␤ signaling components, especially L iver regeneration involves a complex sequence of signaling events to restore liver mass and function. Following two-thirds partial hepatectomy, 95% of differentiated hepatocytes exit G 0 and synchronously reenter the cell cycle. DNA synthesis begins within 24 hours and peaks 36-48 hours posthepatectomy in most mouse strains. 1 Restoration of liver mass is nearly complete by 5-7 days in rodents and by 3-4 months in humans. 2 When hepatocytes and bile duct epithelium are severely damaged or unable to proliferate, a population of hepatic progenitor cells is activated. These progenitors represent a heterogeneous spectrum of cells that express markers corresponding to both the hepatocytic and cholangiocytic lineages and serve as a source of cell replenishment and tissue repair as they differentiate into either cell type, thereby aiding in liver regeneration. 3,4 Hepatic progenitor cells have been described to reside and originate from several potential sources including the canals of Hering, intralobular bile ducts, periductal mononuclear cells, and peribiliary hepatocytes. 5 To date, progenitor