CAF-mediated Inhibition of Anoikis
Weigel et al. Page 855
Carcinoma-associated fibroblasts (CAF) are known to contribute to tumor progression, but their ability to regulate anoikis has yet to be investigated. Here, using both in vitro and in vivo approaches, Weigel and colleagues have discovered that CAFs secrete factors that block anoikis. Furthermore, CAFs secrete elevated quantities of IGFBPs that stimulate a kinase cascade resulting in the stabilization of the antiapoptotic protein Mcl-1. This work unveils new mechanistic insight by which the tumor microenvironment contributes to cancer progression and identifies IGFBPs as potential targets for the development of novel chemotherapeutics designed to eliminate detached cancer cells.
Mutation Profiling in Human Colon ACF
Drew et al. Page 823
Most aberrant crypt foci (ACF) do not advance to cancer, yet the progression of a subset of ACF, particularly those formed in the proximal colon, may significantly contribute to “interval” cancers. A detailed understanding of these early colonic lesions has been limited due to their small size and complex architecture. This Rapid Impact article by Drew and colleagues establishes an effective colonoscopic approach (HD chromoendoscopy), in combination with an exquisitely sensitive mutational screen using DNA mass spectrometry, to identify somatic mutations in ACF. These data provide renewed focus on colonoscopic identification and molecular analysis of ACF and offer useful information for personalized colon cancer risk assessment.
ERβ Decreases NSCLC Survival via RAS
Nikolos et al. Page 843
In the context of NSCLC, Nikolos and colleagues found that ERβ1 enhanced apoptosis. Downregulation of EGFR and inactivation of RAS and ERK1/2 contributed to ERβ1-induced apoptosis. Manipulation of EGFR and RAS in ERβ1-expressing cells revealed the central role of oncogenic RAS inhibition in the ERβ1-mediated proapoptotic phenotype. This study provides the first demonstration that ERβ1 affects lung cancer cell survival by regulating oncogenic RAS. These results shed light on the mechanism of therapeutic resistance in lung cancer and explain the association of ERβ1 with better survival observed in NSCLC patients. The ability of ERβ1 to regulate oncogenic RAS strengthens its importance in the biology of NSCLC and its clinical management.
P53 Restoration in MDM2-Overexpressing Tumors
Li et al. Page 901
Many human malignancies express high levels of MDM2, an E3 ubiquitin ligase and potent inhibitor of the p53 tumor suppressor. Li and colleagues examined whether restoring functional p53 would suppress growth of such tumors. To this end, wild-type p53 expression was genetically restored in angiosarcomas with concomitant MDM2 overexpression and decreased p53 levels using animal models. Restoration of p53 activity in these angiosarcomas led to tumor stasis and regression by suppressing cell proliferation but not by inducing apoptosis. These findings suggest that restoration of functional p53 is a promising therapeutic strategy for MDM2-overexpressing tumors.