Sonic Hedgehog signaling in advanced prostate cancer

The Hedgehog family of growth factors activate a highly conserved signaling system for cell-cell communication that regulates cell proliferation and differentiation during development. Abnormal activation of the Hedgehog pathway has been demonstrated in a variety of human tumors, including those of the skin, brain, lung and digestive tract. Hedgehog pathway activity in these tumors is required for cancer cell proliferation and tumor growth. Recent studies have uncovered the role for Hedgehog signaling in advanced prostate cancer and demonstrated that autocrine signaling by tumor cells is required for proliferation, viability, and invasive behavior. The level of Hedgehog activity correlates with the severity of the tumor and is both necessary and sufficient for metastatic behavior. Blockade of Hedgehog signaling leads to tumor shrinkage and remission in preclinical tumor xenograft models. Thus, Hedgehog signaling represents a novel pathway in prostate cancer that offers opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring. Received 18 August 2005; received after revision 30 September 2005; accepted 1 November 2005     

Hedgehog signaling in vertebrate eye development: a growing puzzle

The vertebrate retina has been widely used as a model to study the development of the central nervous system. Its accessibility and relatively simple organization allow analysis of basic mechanisms such as cell proliferation, differentiation and death. For this reason, it could represent an ideal place to solve the puzzle of Hh signaling during neural development. However, the extensive wealth of data, sometimes apparently discordant, has made the retina one of the most complicated models for studying the role of the Hh cascade. Given the complexity of the field, a deep analysis of the data arising from different animal models is essential. In this review, we will compare and discuss all reported roles of Hh signaling in eye development to shed light on its multiple functions.Received 26 September 2003; received after revision 13 November 2003; accepted 19 November 2003     

Ontogenic development of peptide hormones in the mammalian fetal pancreas

Summary The ontogeny of insulin, glucagon, PP and somatostatin in the mammalian fetal pancreas has been examined in recent years largely by immunocytochemistry and in some instances by radioimmunoassay. Complete ontogenic data are available only for the rat, human pig and sheep. Figure 3 compares the time of appearance of the endocrine cell-types within the fetal pancreas when the periods of gestation of the four species are converted to a uniform scale. The striking ontogenic difference in the rat probably reflects the immaturity of the rodent fetus at birth compared with the human, pig and sheep. In the fetal pancreas, differences in cell number of glucagon and PP cells in the dorsal and ventral lobes become apparent from an early gestational period. Factors responsible for the functional and structural maturation of the fetal pancreatic endocrine cells and the processes involved in pancreatic organogenesis are poorly understood. Studies in these areas would have clinical implications since it may be possible in the future to employ agents for selective replication of fetal -cells for transplantation in patients with Type I diabetes, bearing in mind that such cells must have the capacity to respond to normal stimuli and repressors when transplanted. The presence of the other islet cell-types may be obligatory for these appropriate responses. This would require a more complete knowledge of those factors which produce the normal selectivity of the four hormonal cell-types.     

Decoding the Hedgehog signal in animal development

The Hedgehog (Hh) family of secreted proteins plays essential roles in a myriad of developmental processes via a complex signaling cascade conserved in species ranging from insects to mammals. In many developmental contexts, Hh acts as long-range morphogen to control distinct cellular outcomes as a function of its concentration. Here we review the current understanding of the Hh signaling mechanisms that govern the establishment of the Hh gradient and the transduction of the Hh signal with an emphasis on the intracellular signaling cascade from the receptor to the nuclear effector. We discuss how graded Hh signals are transduced to govern distinct developmental outcomes. Received 28 October 2005; received after revision 6 February 2006; accepted 15 February 2006     

Extracellular microfibrils in development and disease

Fibrillins are the structural components of extracellular microfibrils that impart physical properties to tissues, alone or together with elastin as elastic fibers. Genetic studies in mice have revealed that fibrillin-rich microfibrils are also involved in regulating developmental programs and homeostatic processes through the modulation of TGF-β/BMP signaling events. A new paradigm has thus emerged whereby the spatiotemporal organization of microfibrils dictates both the cellular activities and physical properties of connective tissues. These observations have paved the way to novel therapeutic approaches aimed at counteracting the life-threatening complications in human conditions caused by dysfunctions of fibrillin-rich microfibrils. Received 2 April 2007; received after revision 23 May 2007; accepted 24 May 2007