Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer

Abstract

TGFβ signaling Smads (Smad2, 3, and 4) were suspected tumor suppressors soon after their discovery. Nearly two decades of research confirmed this role and revealed other divergent and cancer-specific functions including paradoxical tumor promotion effects. Although Smad4 is the most potent tumor suppressor, its functions are highly context-specific as exemplified by pancreatic cancer and head-and-neck cancer: in pancreatic cancer, Smad4 loss cannot initiate tumor formation but promotes metastases while in head-and-neck cancer Smad4 loss promotes cancer progression but also initiates tumor formation, likely through effects on genomic instability. The differing consequences of impaired Smad signaling in human cancers and the molecular mechanisms that underpin these differences will have important implications for the design and application of novel targeted therapies.

Figure 1. TGFβ/BMP signaling

TGFβ/BMP ligands mediate their signals through Smad family members.

Figure 2. Roles of Smads identified in SCCs

In non-malignant epithelial tissues, Smads function as tumor suppression. Smad2 loss promotes tumor progression through increased EMT and increased HGF while Smad4 loss promotes tumor progression through increased angiogenesis and inflammation mediated by increased VEGF and TGFβ expression, respectively. In addition, Smad4 loss initiates SCC formation in stratified epithelial layers via downregulation of Fanc/Brca family members.