Current Drug Targets - Volume 9, Issue 7, 2008

Canonical Wnt signaling has emerged as an important pathway that underlies the initiation of prostate cancer. Both human cancers and mouse models have confirmed that mutations or altered expression of components of this pathway are associated with prostate tumors. Additionally, several reports suggest that this pathway plays a key role in the establishment of skeletal metastasis. This review discusses our current knowledge of the Wnt signaling pathway in the development of prostate cancer. First, we will overview the Wnt signaling pathway to provide background for the rest of the discussion. We will then review the literature on the role of this pathway and the downstream effector, β-catenin, in the development and progression of prostate cancer and skeletal metastasis. We will also discuss reports that suggest that β-- catenin can directly interact with the androgen receptor to modulate its activity. These recent developments may provide insight into how tumor growth can be achieved under androgen deprivation. Finally, we speculate on how the pathway may be targeted for therapeutic treatment and what agents may be available to achieve this goal.

Signaling pathways are ubiquitously present in organisms ranging from the simple metazoan Hydra to vertebrates. These pathways play a pivotal role in tightly regulating cell-cell communication that coordinates various biological activities, such as embryogenesis, development, tissue homeostasis and regeneration. Among the myriad signaling pathways elucidated, the Wnt signaling pathway has made a tremendous impact by not only increasing our understanding of development, but also towards understanding cellular perturbations that promote human degenerative diseases and cancer. Components of the Wnt signaling pathway have a rich evolutionary history, pre-dated about 650 million years ago. Investigators have identified several bilaterian Wnt gene subfamilies in cnidarians, drosophila, C. elegans and mammals indicating a common ancestral cluster of Wnt genes. There is extensive amount of conservation of the Wnt gene cluster making orthologous recognition easy, suggesting similar biological and biochemical activities. The Wnts are composed of a large family of highly conserved growth factors or ligands that bind to the Frizzled/LRP receptor complex, and relays their signals to the nucleus via several transduction intermediates. One of the most focused aspects of Wnt signaling has been the canonical pathway in which the cytoplasmic stabilization of β-catenin is controlled by a destruction complex, and its subsequent nuclear translocation and activity plays a central role. This well-defined model of Wnt signaling is also referred to as the β-catenin-dependent pathway. In the absence of Wnt, the destruction complex, which consists of Axin/Adenomatous Polyposis Coli (APC)/Glycogen Synthase Kinase-3 (GSK3) degrades β-catenin. Presence of Wnt ligands in association with the signaling intermediate Dishevelled blocks the activity of the destruction complex causing stabilization and accumulation of β-catenin. In the nucleus β-catenin interacts with the TCF/LEF-1 transcriptional activators resulting in the expression of specific Wnt target genes. However, the Wnt ligands are pleiotropic, and participate in signaling cascade events that are β-catenin-independent or the noncanonical pathway(s) that operates through a network of intermediates that are calcium-dependent or require GTPases. Depending on the interaction of Wnts with different surface receptors various cellular outcomes have been observed. Some atypical members of the receptor tyrosine kinase family, such as RYK can associate with Wnt, and elicit axon repulsion providing directional guidance to extending axons during mammalian central nervous system development. Another noncanonical pathway, now known as the planar cell polarity (PCP) pathway utilizes both Frizzled and Dishevelled, along with c-Jun N-terminal kinase, and a number of novel signaling molecules to regulate PCP. Paradoxically in this pathway the specific role of Wnt is not fully understood. Furthermore, the Wnt/PCP pathway via Frizzled7 and Dishevelled can regulate convergent extension (CE) movements in Xenopus embryos. Both the Wnt pathways have been presented in considerable details in the ensuing articles. Though in a given cell only a subset of Wnts can stimulate the canonical signaling pathway there is cross-talk between the two pathways, whereby the noncanonical pathway can directly antagonize the canonical pathway to regulate signals critical for vertebrate body axis determination, limb development, and possibly oncogenesis. Given the diverse functions of Wnt ligands it is not surprising Wnt function gone awry would lead to dire consequences in humans. Some of the disorders associated with dysfunctional Wnt signaling are cancers, bone density defects, and defects in retinal angiogenesis. In this special issue dedicated to Wnt signaling, all articles illustrate in detail the multifaceted functions potentiated by the Wnt ligands. The first article by Coombs and colleagues gives a lucid description on the history of Wnt signaling. It also introduces the reader on the role of Wnts in development, cancers, bone diseases and neuropsychiatric disorders. The article by Ewan and Dale focuses on cellular events triggered by ligand/receptor interaction with a view to exploit different players of this pathway for therapeutic purposes in oncogenic therapy. Aberrant Wnt signaling in colorectal cancer and associated genetic changes have been addressed by Qi and Zhu. They have also described structured therapeutic intervention at different levels of the Wnt pathway. Parmalee and Kitajewski have explained the role of Wnt through Frizzled4 on the newly discovered angiogenic factor Norrin with respect to retinal angiogenesis. The article by Katoh describes the role of Wnt signaling along with different signaling partners on a variety of stem cells, such as embryonic, neural, mesenchymal, hematopoietic and intestinal stem cells. Thus, enabling investigators to gain insights towards developing tissue engineering and regeneration technology.

Wnt signaling regulates a multitude of critical processes in development and tissue homeostasis. The wingless (wg) gene product was first identified in Drosophila in 1973. Subsequently, the proto-oncogene INT-1 was identified in mice in 1984 when its activation by mouse mammary tumor virus' proviral insertion was found to induce tumor formation. The discovery in 1987 that wg and INT-1 are orthologues contributed to an appreciation of the intimate connection between oncogenic and developmental processes. Diverse diseases including cancer, diabetes, osteoporosis and psychiatric disorders may be amenable to treatment via modulation of Wnt-mediated signaling pathways. There are a number of attractive targets that are the object of ongoing drug development studies aiming to capitalize on these opportunities. In this review, we present a historical overview of key events in this field that have elucidated the known signaling cascades associated with Wnt ligands and shaped our understanding of the roles of these cascades in physiological and pathological processes.

There has been a surge of interest in the therapeutic targeting of the Wnt pathway following the demonstration that it is activated in a wide variety of tumors and that blocking aberrant signaling promoted tumor cell apoptosis or differentiation. This review describes recent therapeutic approaches and discusses potential opportunities for intervention at multiple levels within the Wnt pathway.

The Wnt signaling pathway has important functions in development, tissue homeostasis, and regeneration. Deregulation of canonical Wnt/β-catenin signaling is frequently found in various human cancers, particularly in colorectal cancer, and non-canonical Wnt signaling pathways also have been implicated in neoplasia. Colorectal cancer is a multipathway disease. Activation of Wnt signaling by both genetic and epigenetic alterations has been found to be important for both, initiation and progression of colorectal cancer. In addition, since Wnt signaling results in diverse downstream intracellular events, targeted inhibition of Wnt/β-catenin signaling at the most upstream site of this pathway is a rational and an advantageous new approach for the therapy of colorectal cancer.

Although progress has been made in understanding the role of growth factors and their receptors in angiogenesis, little is known about how the Wnt family of growth factors function in the vasculature. Wnts are multifunctional factors that act through the frizzled receptors to regulate proliferation, apoptosis, branching morphogenesis, inductive processes, and cell polarity. All of these processes must occur as developing vascular structures are formed and maintained. Recent evidence has linked the Wnt/Frizzled signaling pathway to proper vascular growth in murine and human retina. Here we review the literature describing the angiogenic functions for Wnt signaling and focus on a newly discovered angiogenic factor, Norrin, which acts through the Wnt receptor, Frizzled4.

WNT family members are secreted-type glycoproteins to orchestrate embryogenesis, to maintain homeostasis, and to induce pathological conditions. FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, and ROR2 are transmembrane receptors transducing WNT signals based on ligand-dependent preferentiality for caveolin- or clathrin-mediated endocytosis. WNT signals are transduced to canonical pathway for cell fate determination, and to non-canonical pathways for regulation of planar cell polarity, cell adhesion, and motility. MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 and Glucagon are target genes of canonical WNT signaling cascade, while CD44, Vimentin and STX5 are target genes of non-canonical WNT signaling cascades. However, target genes of WNT signaling cascades are determined in a context-dependent manner due to expression profile of transcription factors and epigenetic status. WNT signaling cascades network with Notch, FGF, BMP and Hedgehog signaling cascades to regulate the balance of stem cells and progenitor cells. Here WNT signaling in embryonic stem cells, neural stem cells, mesenchymal stem cells, hematopoietic stem cells, and intestinal stem cells will be reviewed. WNT3, WNT5A and WNT10B are expressed in undifferentiated human embryonic stem cells, while WNT6, WNT8B and WNT10B in endoderm precursor cells. Wnt6 is expressed in intestinal crypt region for stem or progenitor cells. TNFα-WNT10B signaling is a negative feedback loop to maintain homeostasis of adipose tissue and gastrointestinal mucosa with chronic inflammation. Recombinant WNT protein or WNT mimetic (circular peptide, small molecule compound, or RNA aptamer) in combination with Notch mimetic, FGF protein, and BMP protein opens a new window to tissue engineering for regenerative medicine.

In the United States, it is estimated that $10-15 billion is spent annually for the treatment of osteoporotic fracture. The worldwide annual incidence of osteoporotic hip fracture exceeds 1.7 million cases. Bone loss leading to osteoporosis and osteoporotic fractures are caused by an imbalance between osteoblast-mediated bone formation and osteoclastmediated bone resorption and numerous factors have been implicated in the development of osteoporosis. The prevention and treatment of osteoporosis traditionally involves the use of anti-resorptive agents, which target osteoclast function, but do not lead to a significant increase in bone mass and therefore only partially reduce risk of fractures. For these reasons, the search for anabolic agents, which target osteoblast function, represents an urgent medical need. Genetic studies have firmly established a link between bone mass in humans and Wnt signaling. Multiple genetic and pharmacological manipulations of Wnt signaling in mice have since then confirmed the central role of this pathway in regulating bone formation. The existence of many potential pharmacological targets in this pathway makes it attractive for bone anabolic drug discovery.

About one fourth of people diagnosed with kidney cancer in 2007, are expected to die of this disease within 5 years from the date of diagnosis. Recent years have produced novel drugs, some with FDA approval, and many in clinical trials, all showing very discrete results. Failure in finding effective treatments to improve survival with drugs mainly targeting VEGF and its downstream effectors, urges to shift the drug development targets to other unexploited pathways shown to be also involved in renal cancer. Several studies show alterations in the Wnt signaling pathway, many of which differ from those implicated in other human cancers. Unlike colorectal or hepatocellular carcinomas, where APC and axin mutations, respectively, are the main Wnt signaling deregulating event, renal carcinomas seem to be affected by other factors. Recent studies have presented VHL, a tumor suppressor gene strongly associated with renal cell carcinoma, as a beta-catenin target. This confirms that Wnt signaling is likely playing a central role during renal carcinoma development, which needs to be considered and addressed to treat this disease. This review outlines briefly the molecular biology of the most common renal cancers and the drug treatments currently used to treat the disease. The canonical Wnt pathway is reviewed more carefully adding specific features in a renal carcinoma context, which present potential targets for drug development and biomarker use.