It is well accepted that complex biological processes such as angiogenesis are not controlled by a single family of molecules or individually isolated signaling pathways. In this regard, new insight into the interconnected mechanisms that regulate angiogenesis might be gained by examining this process from a more global network perspective. The coordination of signaling cues from both outside and inside many different cell types is required for the successful completion of angiogenesis. Evidence is accumulating that the multifunctional integrin family of cell adhesion receptors represent an important group of molecules that play active roles in sensing, integrating, and distributing a diverse set of signals that regulate many cellular events required for angiogenesis. Given the ability of integrins to bind numerous extracellular ligands and transmit signals in a bi-directional fashion, we will discuss the multiple ways by which integrins may serve as a functional hub during pathological angiogenesis. In addition, we will highlight potential imaging and therapeutic strategies based on the expanding new insight into integrin function.

Purpose: The importance of cellular communication with the extracellular matrix in regulating cellular invasion is well established. Selective disruption of communication links between cells and the local microenvironment by specifically targeting non-cellular matrix-immobilized cryptic extracellular matrix epitopes may represent an effective new clinical approach to limit tumorassociated angiogenesis. Therefore, we sought to determine whether the HU177 cryptic collagen epitope plays a functional role in regulating angiogenesis in vivo. Experimental Design: We examined the expression and characterized the HU177 cryptic collagen epitope in vitro and in vivo using immunohistochemistry and ELISA. We examined potential mechanisms by which this cryptic collagen epitope may regulate angiogenesis using in vitro cell adhesion, migration, proliferation, and biochemical assays. Finally, we examined the whether blocking cellular interactions with the HU177 cryptic epitope plays a role in angiogenesis and tumor growth in vivo using the chick embryo model. Results: The HU177 cryptic epitope was selectively exposed within tumor blood vessel extracellular matrix, whereas little was associated with quiescent vessels. An antibody directed to this cryptic site selectively inhibited endothelial cell adhesion, migration, and proliferation on denatured collagen type IV and induced increased levels of cyclin-dependent kinase inhibitor p27 KIP1 . Systemic administration of mAb HU177 inhibited cytokine-and tumor-induced angiogenesis in vivo. Conclusions: We provide evidence for a new functional cryptic regulatory element within collagen IV that regulates tumor angiogenesis. These findings suggest a novel and highly selective approach for regulating angiogenesis by targeting a non-cellular cryptic collagen epitope.

Background:We examined the impact of insulin-like growth factor binding protein-4 (IGFBP-4) on growth factor-induced angiogenesis in vivo. Results: IGFBP-4 inhibited IGF-1 and FGF-2, but not VEGF-induced angiogenesis, and this inhibition depended on p38 MAPK activity. Conclusion:The anti-angiogenic activity of IGFBP-4 depends in part on p38 MAPK. Significance: New insight is provided into how blood vessels respond to endogenous inhibitors during growth factor-stimulated angiogenesis.

Prostate cancer is a very common disease in industrialized countries and it is known to be androgen-dependent. The human SRD5A2 gene encodes the prostatic (or type II) steroid 5a-reductase, which catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. We have sequenced the entire protein-coding region of this locus in 30 microdissected prostate adenocarcinomas. We identified a total of 17 de novo amino-acid substitutions in 13 of these tumors. We also identified six additional silent substitutions. In total, 18 out of 30 (60%) of the tumors examined had de novo somatic substitutions in the prostatic steroid 5a-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5a-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5a-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5a-reductase in vitro activity, while the third one is essentially neutral. These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients. Our pharmacologic studies also reveal substantial variability for each 5a-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5a-reductase inhibitors.