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     

Colorectal carcinoma: from tumorigenesis to treatment

Colorectal carcinoma (CRC) is a complicated and often fatal genetic disease. Fortunately, owing to rapid expansion of knowledge and technology development in oncology, much progress has been made regarding the diagnosis, understanding of the molecular genetics and malignant progression, as well as the novel regimens of CRC. In this review, we summarize the staging system, the most critical genetic and epigenetic alterations, the pleiotropic effects of MMP-7, the controversial roles of Hedgehog signaling, the intriguing involvement of thymosin β-4, and the possible contribution of the putative colon (cancer) stem cells in CRC tumorigenesis. Current treatments as well as several potentially applicable therapeutic strategies for CRC are also discussed. Received 15 September 2005; received after revision 3 November 2005; accepted 25 November 2005     

Hedgehog signaling in pancreas development and disease

Since its discovery, numerous studies have shown that the Hedgehog (Hh) signaling pathway plays an instrumental role during diverse processes of cell differentiation and organ development. More recently, it has become evident that Hh signaling is not restricted to developmental events, but retains some of its activity during adult life. In mature tissues, Hh signaling has been implicated in the maintenance of stem cell niches in the brain, renewal of the gut epithelium and differentiation of hematopoietic cells. In addition to the basal function in adult tissue, deregulated signaling has been implicated in a variety of cancers, including basal cell carcinoma, glioma and small cell lung cancer. Here, we will focus on the role of Hh signaling in pancreas development and pancreatic diseases, including diabetes mellitus, chronic pancreatitis and pancreatic cancer. Received 5 August 2005; received after revision 4 November 2005; accepted 22 November 2005     

Hedgehog signaling in vertebrate and invertebrate limb patterning

Invertebrate and vertebrate limbs have very different anatomies and modes of development. Despite these differences, recent studies demonstrate that a significant overlap exists in the signals used to pattern invertebrate and vertebrate limbs. One of these signaling molecules is Hedgehog, a secreted protein that functions to coordinate growth and proliferation along the anterior-posterior axis of developing limbs. Recent studies indicate that the mechanism of action, regulation and function of Hedgehog signaling in Drosophila and vertebrate limb development are often quite similar, yet at other times are distinct. Here we highlight the similarities and differences between the use of Hedgehog signaling in these two systems.     

Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes

Since the 1960s, when the first tricyclic and monoamine oxidase inhibitor antidepressant drugs were introduced, most of the ensuing agents were designed to target similar brain pathways that elevate serotonin and/or norepinephrine signaling. Fifty years later, the main goal of the current depression research is to develop faster-acting, more effective therapeutic agents with fewer side effects, as currently available antidepressants are plagued by delayed therapeutic onset and low response rates. Clinical and basic science research studies have made significant progress towards deciphering the pathophysiological events within the brain involved in development, maintenance, and treatment of major depressive disorder. Imaging and postmortem brain studies in depressed human subjects, in combination with animal behavioral models of depression, have identified a number of different cellular events, intracellular signaling pathways, proteins, and target genes that are modulated by stress and are potentially vital mediators of antidepressant action. In this review, we focus on several neural mechanisms, primarily within the hippocampus and prefrontal cortex, which have recently been implicated in depression and treatment response.     

The epidermal growth factor receptor family: Biology driving targeted therapeutics

The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.     

Biomarkers for predicting future metastasis of human gastrointestinal tumors

The recent advances in surgery and radiation therapy have significantly improved the prognosis of patients with primary cancer, and the major challenge of cancer treatment now is metastatic disease development. The 5-year survival rate of cancer patients who have distant metastasis at diagnosis is extremely low, suggesting that prediction and early detection of metastasis would definitely improve their prognosis because suitable patient therapeutic management and treatment strategy can be provided. Cancer cells from a primary site give rise to a metastatic tumor via a number of steps which require the involvement and altered expression of many regulators. These regulators may serve as biomarkers for predicting metastasis. Over the past few years, numerous regulators have been found correlating with metastasis. In this review, we summarize the findings of a number of potential biomarkers that are involved in cadherin–catenin interaction, integrin signaling, PI3K/Akt/mTOR signaling and cancer stem cell identification in gastrointestinal cancers. We will also discuss how certain biomarkers are associated with the tumor microenvironment that favors cancer metastasis.     

Vimentin in cancer and its potential as a molecular target for cancer therapy

Vimentin, a major constituent of the intermediate filament family of proteins, is ubiquitously expressed in normal mesenchymal cells and is known to maintain cellular integrity and provide resistance against stress. Vimentin is overexpressed in various epithelial cancers, including prostate cancer, gastrointestinal tumors, tumors of the central nervous system, breast cancer, malignant melanoma, and lung cancer. Vimentin’s overexpression in cancer correlates well with accelerated tumor growth, invasion, and poor prognosis; however, the role of vimentin in cancer progression remains obscure. In recent years, vimentin has been recognized as a marker for epithelial–mesenchymal transition (EMT). Although EMT is associated with several tumorigenic events, vimentin’s role in the underlying events mediating these processes remains unknown. By virtue of its overexpression in cancer and its association with tumor growth and metastasis, vimentin serves as an attractive potential target for cancer therapy; however, more research would be crucial to evaluate its specific role in cancer. Our recent discovery of a vimentin-binding mini-peptide has generated further impetus for vimentin-targeted tumor-specific therapy. Furthermore, research directed toward elucidating the role of vimentin in various signaling pathways would reveal new approaches for the development of therapeutic agents. This review summarizes the expression and functions of vimentin in various types of cancer and suggests some directions toward future cancer therapy utilizing vimentin as a potential molecular target.     

Targeting abnormal DNA double strand break repair in cancer

A major challenge in cancer treatment is the development of therapies that target cancer cells with little or no toxicity to normal tissues and cells. Alterations in DNA double strand break (DSB) repair in cancer cells include both elevated and reduced levels of key repair proteins and changes in the relative contributions of the various DSB repair pathways. These differences can result in increased sensitivity to DSB-inducing agents and increased genomic instability. The development of agents that selectively inhibit the DSB repair pathways that cancer cells are more dependent upon will facilitate the design of therapeutic strategies that exploit the differences in DSB repair between normal and cancer cells. Here, we discuss the pathways of DSB repair, alterations in DSB repair in cancer, inhibitors of DSB repair and future directions for cancer therapies that target DSB repair.     

Therapeutic Protein Kinase Inhibitors

Protein kinase inhibitors represent an important and still emerging class of targeted therapeutic agents. Drug discovery and development strategies have explored numerous approaches to target the inhibition of protein kinase signaling. This review will highlight some of the strategies that have led to the successful clinical development of therapeutic protein kinase inhibitors, particularly as anticancer drugs. Some notable advances have been made in the development of novel protein and oligonucleotide-based biologics that target growth factor or receptor tyrosine kinases. Also, advances have been made in the rational design of small-molecule inhibitors that target unique kinase conformational forms and binding sites, and have specific kinase selectivity profiles. A review will also be given of some of the potential clinical toxicities and adverse side-effects associated with these kinase-targeted drugs. Therapeutic protein kinase inhibitors have been highly beneficial to cancer patients and offer the promise of future therapies for other diseases as well. Received 02 September 2008; received after revision 13 October 2008; accepted 15 October 2008     

Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development

Phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide signaling with diverse physiological functions. Because of their great market potential and therapeutic importance, PDE inhibitors became recognized as important therapeutic agents in the treatment of various diseases. Currently, there are seven PDE inhibitors on the market, and the pharmacological and safety evaluations of many drug candidates are in progress. Three-dimensional (3D) structures of catalytic domains of PDE 1, -3, -4, -5 and -9 in the presence of their inhibitors are now available, and can be utilized for rational drug design. Recent advances in molecular pharmacology of PDE isoenzymes resulted in identification of new potential applications of PDE inhibitors in various therapeutic areas, including dementia, depression and schizophrenia. This review will describe the latest advances in PDE research on 3D structural studies, the potential of therapeutic applications and the development of drug candidates.Received 30 November 2004; received after revision 24 January 2005; accepted 5 February 2005     

Protein arginine deiminase 4: a target for an epigenetic cancer therapy

The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted the important role that epigenetics plays in human diseases, and suggested that the factors controlling gene expression are novel drug targets. Protein arginine deiminase 4 (PAD4) is one such target because its effects on gene expression parallel those observed for the histone deacetylases. We demonstrated that F- and Cl-amidine, two potent PAD4 inhibitors, display micromolar cytotoxic effects towards several cancerous cell lines (HL-60, MCF7 and HT-29); no effect was observed in noncancerous lines (NIH 3T3 and HL-60 granulocytes). These compounds also induced the differentiation of HL-60 and HT29 cells. Finally, these compounds synergistically potentiated the cell killing effects of doxorubicin. Taken together, these findings suggest PAD4 inhibition as a novel epigenetic approach for the treatment of cancer, and suggest that F- and Cl-amidine are candidate therapeutic agents for this disease.     

Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer

Evidence is accumulating that breast cancer is not one disease but many separate diseases. DNA microarray-based gene expression profiling has demonstrated subtypes with distinct phenotypic features and clinical responses. Prominent among the new subtypes is 'basal-like' breast cancer, one of the 'intrinsic' subtypes defined by negativity for the estrogen, progesterone, and HER2/neu receptors and positivity for cytokeratins-5/6. Focusing on basal-like breast cancer, we discuss how molecular technologies provide new chemotherapy targets, optimising treatment whilst sparing patients from unnecessary toxicity. Clinical trials are needed that incorporate long-term follow-up of patients with well-characterised tumour markers. Whilst the absence of an obvious dominant oncogene driving basal-like breast cancer and the lack of specific therapeutic agents are serious stumbling blocks, this review will highlight several promising therapeutic candidates currently under evaluation. Thus, new molecular technologies should provide a fundamental foundation for better understanding breast and other cancers which may be exploited to save lives. (Part of a Multi-author Review).     

The neurotrophic receptor TrkB: a drug target in anti-cancer therapy?

Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target, and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer. Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006     

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     

Adaptation to antiangiogenic therapy in neurological tumors

Because tumors require a vascular supply for their survival and growth, angiogenesis is considered an important therapeutic target in most human cancers including cancer of the central nervous system. Antiangiogenic therapy has focused on inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway. VEGF pathway-targeted drugs have shown therapeutic efficacy in several CNS tumors and have been tried most frequently in glioblastoma. These therapies, however, have been less effective than anticipated as some patients do not respond to therapy and some receive only modest benefit. Underlying this suboptimal response are multiple mechanisms of drug resistance involving changes in both tumor cells and their microenvironment. In this review, we discuss the multiple proposed mechanisms by which neurological tumors evolve to become resistant to antiangiogenic therapies. A better understanding of these mechanisms, their context, and their interplay will likely facilitate improvements in pharmacological strategies for the targeted treatment of neurological tumors.     

Multidrug-resistant cancer cells and cancer stem cells hijack cellular systems to circumvent systemic therapies,can natural products reverse this?

Chemotherapy is one of the most effective and broadly used approaches for cancer management and many modern regimes can eliminate the bulk of the cancer cells. However, recurrence and metastasis still remain a major obstacle leading to the failure of systemic cancer treatments. Therefore, to improve the long-term eradication of cancer, the cellular and molecular pathways that provide targets which play crucial roles in drug resistance should be identified and characterised. Multidrug resistance (MDR) and the existence of tumor-initiating cells, also referred to as cancer stem cells (CSCs), are two major contributors to the failure of chemotherapy. MDR describes cancer cells that become resistant to structurally and functionally unrelated anti-cancer agents. CSCs are a small population of cells within cancer cells with the capacity of self-renewal, tumor metastasis, and cell differentiation. CSCs are also believed to be associated with chemoresistance. Thus, MDR and CSCs are the greatest challenges for cancer chemotherapy. A significant effort has been made to identify agents that specifically target MDR cells and CSCs. Consequently, some agents derived from nature have been developed with a view that they may overcome MDR and/or target CSCs. In this review, natural products-targeting MDR cancer cells and CSCs are summarized and clustered by their targets in different signaling pathways.     

Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis

New blood vessel formation, a process referred to as angiogenesis, is essential for embryonic development and for many physiological and pathological processes during postnatal life, including cancer progression. Endothelial cell adhesion molecules of the integrin family have emerged as critical mediators and regulators of angiogenesis and vascular homeostasis. Integrins provide the physical interaction with the extracellular matrix necessary for cell adhesion, migration and positioning, and induction of signaling events essential for cell survival, proliferation and differentiation. Antagonists of integrin alpha V beta 3 suppress angiogenesis in many experimental models and are currently tested in clinical trials for their therapeutic efficacy against angiogenesis-dependent diseases, including cancer. Furthermore, interfering with signaling pathways downstream of integrins results in suppression of angiogenesis and may have relevant therapeutic implications. In this article we review the role of integrins in endothelial cell function and angiogenesis. In the light of recent advances in the field, we will discuss their relevance as a therapeutic target to suppress tumor angiogenesis.     

New concepts in regulation and function of the insulin-like growth factors: implications for understanding normal growth and neoplasia

The insulin-like growth factors (IGFs) are a ubiquitous family of growth factors, binding proteins and receptors that are involved in normal growth and development. They are also implicated in numerous pathological states, including malignancy. IGF-II is a commonly expressed growth factor in many tumors and may enhance tumor growth, acting via the overexpressed IGF-I receptor, a cell-surface tyrosine kinase receptor. The IGF-I receptor may be overexpressed due to mutations in tumor suppression gene products such as p53 and WT-1 or growth factors such as bFGF and PDGF. Thus, this family of growth factors, especially the IGF-I receptor, may present an excellent target for new therapeutic agents in the treatment of cancer and other disorders of excessive cellular proliferation.