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The roles of Hedgehog signalling and NF-B activity in pancreatic cancer and opportunities for treatment

The roles of Hedgehog signalling and NF-B activity in pancreatic cancer and opportunities for... BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu004 Review The roles of Hedgehog signalling and NF-κB activity in pancreatic cancer and opportunities for treatment Jake Ranson University of Exeter Medical School, St. Luke’s Campus, University of Exeter, Heavitree Road, Exeter, Devon EX1 2LU, England *Corresponding author: Jake Ranson, University of Exeter Medical School, St. Luke’s Campus, University of Exeter, Heavitree Road, Exeter, Devon EX1 2LU, England. Email: jr371@exeter.ac.uk Project Supervisor: Kevin Brandom, University of Exeter Medical School, St. Luke’s Campus, University of Exeter, Heavitree Road, Exeter, Devon EX1 2LU, UK; Email: k.g.brandom@exeter.ac.uk. Pancreatic cancer is the seventh most common form of cancer-related death in the world, affecting hundreds of thousands of people worldwide every year. Treatment for this type of cancer is largely ineffective and future treatments are likely to involve targeting signalling pathways involved in the proliferation of pluripotent stem cells. There are a variety of signalling pathways involved in the pathogenesis of the disease, including Hedgehog (Hh) and nuclear factor-kappaB (NF-κB). Overexpression of Hh ligands or alterations in other areas of the Hh signalling pathway may lead to tumour formation. Inhibition of Hh ligands, Smoothened or Gli proteins, or up-regulation of Patched expression, could form the basis of new treatments. NF-κB is often active in pancreatic cancer cells and down-regulation of NF-κB activating molecules can inhibit tumour progression in cell culture studies. Clinical trials show some promising results in novel drugs. There is growing evidence to suggest the interac- tion between these two signalling pathways. NF-κB appears to play a role upstream of the Hh pathway. This article looks at the roles these pathways play in pancreatic cancer and explores current research into targeting them for treatment. Key words: hedgehog, NF-κB, pancreatic cancer, mechanisms, treatment Received 13 August 2013; revised 15 April 2014; accepted 17 April 2014 Introduction There are many different pathways that lead to the cellular effects and tumour formation seen in pancreatic cancer. Pancreatic cancer is one of the most deadly and aggressive can- Changes in the Hedgehog (Hh) signalling pathway activity and cers, with a poor prognosis and swiftly fatal progression the nuclear factor-kappaB (NF-κB) pathway have been impli- (Thayer et al., 2003). As the seventh most common cause of cated in the pathogenesis of the disease (Berman et al., 2003; death by cancer in the world (Bosetti et al., 2012), it causes Liptay et al., 2003; Thayer et al., 2003; Karin, 2006; tens of thousands of deaths every year in Europe alone (Ferlay Nakashima et al., 2006). Hh signalling was first discovered in et al., 2010; Malvezzi et al., 2013), and had a 5-year survival the fruit fly Drosophila melanogaster in 1980s (Nüsslein- rate (post-diagnosis) of only ~6% between 2001 and 2007 Volhard and Wieschaus, 1980), and is heavily involved in the (Siegel, Naishadham and Jemal, 2012). This incurable nature embryonic development of many species (Thayer et al., 2003; can be attributed to a combination of rapid tumour metastasis, Berman et al., 2003; Ng and Curran, 2011). The NF-κB family poor response to drugs (Thayer et al., 2003; Sarkar, Banerjee of proteins were identified in the 1980s ( Sen and Baltimore, and Li, 2007) and the fact that treatment is so ineffectual it is 1986), and are known to be heavily involved in infection and prescribed for only 10% of patients (Iovanna et al., 2012). inflammation ( Gilmore, 1999). Involvement of many other © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.  Review Bioscience Horizons • Volume 7 2014 pathways has also been observed, including epidermal growth factor receptor and COX-2 (Sarkar, Banerjee, and Li, 2007). These processes do not act independently of each other; the interaction between the pathways plays a significant role in the cancer formation (Nakashima et al., 2006). Further under- standing of these pathways and their interactions may lead to new and improved treatments for pancreatic cancer. This article will examine the mechanisms of Hh signalling and NF-κB in the formation of pancreatic cancer, and how they might be targeted to improve treatment. The role of the Hh signalling pathway As a driver of cell proliferation and differentiation, Hh sig- nalling has been identified as an important factor in the pathogenesis of several cancers, including pancreatic cancer (Berman et al., 2003; Thayer et al., 2003; Caro and Low, 2010). There are three Hh ligands in mammals: desert, Indian and Sonic (DHh, IHh and SHh, respectively). In the absence of an Hh ligand, the 12-transmembrane protein Patched (on the cell membrane) prevents translocation of pro-mitotic Smoothened (Caro and Low, 2010). In the presence of Hh ligands, Patched is inhibited, allowing Smoothened to trans- locate and cause a cascade of events including the Gli protein family (Thayer et al., 2003; Wang et al., 2013a,b; Caro and Low, 2010); ultimately leading to transcription of a variety of genes, including PTCH1 (the gene encoding the Patched pro- tein) and other cell proliferation genes (see Fig. 1) (Caro and Low, 2010). In this way, PTCH1 can be considered a tumour suppressor gene as, when active, the cell will not respond to proliferative signals. The entire pathway also contains an interesting feedback mechanism. Patched is produced in the presence of Hh ligands (Chen, Carkner and Buttyan, 2011), which would infer a negative feedback loop as more suppressing proteins are produced in response to proliferative signals. However, this is negated in the case of overexpression of Hh ligands. This has been shown to be the case in pancreatic cancer. Figure 1. T he Hh signalling pathway. In normal adult physiology, A study by Thayer et al. in 2003 showed overexpression of smoothened (a 7-transmembrane protein on the membrane of SHh in 70% of tumours taken from patients suffering from endosomes) is suppressed from entering the primary cilium (a pancreatic cancer. The study went on to examine pancreatic structure common to many human cells) by the 12-transmembrane protein Patched (at the base of the cilium) (Caro and Low, 2010). This cells from four mice that had been genetically altered to over- suppression is prevented in the presence of Hh ligands (such as SHh), express SHh and found markers associated with early pan- which bind to and inhibit Patched. This allows Smoothened to creatic tumours. Though this study was only conducted on a translocate to the primary cilium where it activates repressed Gli very small sample of mice, it went some way towards demon- proteins (GliR) such as Gli1 and Gli2 into their active forms (GliA). These strating the effect of aberrant expression of SHh. As this can then translocate to the nucleus where they act as transcription ligand was found in high amounts in a large number of factors for genes encoding many proteins, including Patched, Gli1 and human pancreatic tumours, it suggests a correlation between cyclin-dependent kinases (Chen, Carkner and Buttyan, 2011). Hh ligand expression and pancreatic cancer, even in humans. Other studies have also demonstrated increased levels of produced through loss of Patched activity (Rodova et al., SHh, along with Patched, Smoothened and Gli proteins, in 2012). Some cancers have even been linked to activating human pancreatic cancers (Singh et al., 2011). mutations in the gene for Smoothened that allow it to break It is not necessary for Hh ligand expression to be altered in free from its suppression by Patched (Wang et al., 2013a,b). cancers linked to the pathway; a similar effect would be These would all have similar cellular effects that could lead to 2 Bioscience Horizons • Volume 7 2014 Review carcinogenesis, and could possibly be targeted by the same adult tissue; stem cells within tissues and organs differentiate drug, depending on the exact mechanism of action of the to form various cells necessary for the continued function of drug. If several of these mutations happened in tandem, it their specific tissue ( Tan et al., 2006). This similarity is unsur- may give rise to a complex genetic pathology, against which prising, and as such lends strength to the CSC theory. even advanced treatments may not be effective. Pancreatic cancer shows a high resilience to most contempo- rary treatments (Iovanna et al., 2012), and the problem may lie in stem cells that are somehow resistant to killing. It is Treating the Hh signalling pathway possible that targeting the pathways upon which these self- Treatments focussing on the Hh pathway may not be far renewing cells rely will increase efficacy of treatment. away from clinical practice. Thus far, the large majority of However, as the CSCs in this study were less susceptible to research into treatments targeting the Hh pathway has con- elimination by the smoothened inhibitor (Singh et al., 2011), cerned inhibition of Smoothened (Ng and Curran, 2011), this may not be the case. Some Smoothened-inhibiting com- although increasing therapeutic use of monoclonal antibod- pounds, however, do seem to have an effect on pancreatic ies may allow targeting of Hh ligands directly. A study by Lee CSCs, suggesting that there may be a difference in the activa- et al. in 2012 showed that mice treated daily with a specific tion of the Hh signalling pathway between CSCs and other Smoothened inhibitor, IPI-926 (also known as Saridegib), cancer cells (Tang et al., 2012). Many factors may play a role showed a unanimous reduction in the size of brain tumours in the efficacy of these drugs against CSCs: bioavailability of caused by overexpression of SHh. However, it was noted that the compounds, doses administered and interaction of the after 6 weeks of daily treatment, tumour progression began drug with the human body could all affect treatment. Further again in the treated mice, indicating that suppression of studies should look at methods of refining these processes Smoothened activity by the drug was not a long-term effect and investigate whether this has any improvement on the tar- (Wang et al., 2013a,b). There are obvious questions regard- geting of CSCs. ing the generalizability of this study to pancreatic cancer in humans. The cancer observed in this study is a rare form of The role of NF-κB brain tumour called a medulloblastoma. However, this NF-κB is formed by the dimerization of several subunits appears to have links to the Hh pathway in much the same including members of the Rel family (Ghosh and Karin, way as pancreatic cancer (Ng and Curran, 2011; Wang et al., 2002; Karin, 2006), one of which (v-rel) is known to be an 2013a,b). The study used a mouse model, and in small num- oncogene, suggesting a potential link with cancer (Karin, bers; five originally, moving up to 37 after promising findings 2006). NF-κB is a transcription factor, activation of which (Lee et al., 2012). Whilst this may otherwise be considered to results in the secretion of growth factors such as the cytokine be less generalizable to the population at large, this is not IL-6, anti-apoptotic molecules and survival factors, such as uncommon in drug trials. In fact it is necessary to perform Bcl-2 and angiogenesis-inducing factors such as vascular initial tests on an animal model before clinical trials in endothelial growth factor (VEGF) (Karin, 2006) (see Fig. 2). humans can be considered. Therefore, this study may still be Whilst these are desirable in infection, allowing the recruit- considered valid, if basic, and further studies may be con- ment of immune cells and the repair of damaged tissues, they ducted based on this research. Another study, by Singh et al. are also characteristic of cancerous cells (Hanahan and in 2011, focused on a different Smoothened inhibitor: GDC- Weinberg, 2011). 0449 (Vismodegib). This study used human pancreatic can- cer cell lines and cancer stem cells (CSCs) in vitro, arguably a Inflammation has long been suspected as a factor in carci - more valid method when studying human cancers, though nogenesis, going as far back as 1863 (Karin, 2006). It is new lacking potentially vital evidence of in vivo interaction. The evidence that finally allows this to be confirmed. A study by results showed that the drug induced apoptosis and pre- Liptay et al. in 2003 examined 11 pancreatic tissue samples vented proliferation in all the cell lines, and to a lesser extent taken from patients with confirmed pancreatic cancer. in the CSCs themselves (Singh et al., 2011), by inducing the Immunohistochemical analysis revealed that seven of these expression of pro-apoptotic molecules such as Fas and inhib- contained markers of NF-κB activity, signifying a potential iting anti-apoptotic proteins such as Bcl-2 (Singh et al., role of this protein in pancreatic cancer (Liptay et al., 2003). 2011). This is a promising result, as it suggests that smooth- However, this is only a small sample, and this result alone ened inhibitors may be useful in delaying disease progression does not represent a causal link, only a correlation. and lessening the symptoms of pancreatic tumours. However, the drug did have a lesser effect on the stem cells (Singh et al., A key regulator of NF-κB, Notch-1 (Wang et al., 2006), 2011), and it may not therefore offer a complete cure for has also been implicated in pancreatic cancer (Sarkar, pancreatic cancer. There is growing evidence to support the Banerjee and Li, 2007). A study by Wang et al. in 2006 hypothesis that the driving force behind tumour growth is the looked at the mechanism behind the involvement of Notch-1 proliferation of a small minority population of ‘cancer stem in cancer using some of the same human pancreatic cancer cells’ (CSCs) within the tumour, which will cause re-occur- cell lines (BxPc3) as Liptay et al.’s study in 2003, and found rence of cancer if not eliminated (Tan et al., 2006; Wang that, amongst other things, decreased levels of Notch-1 lead et al., 2013a,b). This model bears a close similarity to healthy to decreased binding of NF-κB to DNA. Whilst this study 3 Review Bioscience Horizons • Volume 7 2014 with the drug Belinostat. While the mechanism of action of the drug is still not well understood, the data suggest that this suppression was accomplished indirectly via feedback from other components of the pathway, such as TNF-α, which were directly affected by Belinostat (Chien et al., 2013). This was accompanied by induction of apoptosis and autophagy in some cells, as well as an arrest of growth in the remaining cells (Chien et al., 2013). This is a positive result, and suggests that the link between NF-κB and cell proliferation and survival can be manipulated in the treatment of pancreatic cancer. Each of the previously mentioned studies used several different cell lines originating from pancreatic cancers, some of which were common to all of the studies. This suggests a good degree of corroboration between the studies’ results and potentially between in vitro and in vivo experiments, as the cell lines used originated from human tumours (Liptay et al., 2003; Wang et al., 2006; Chien et al., 2013). Treatments targeting NF-κB Few drugs targeting this pathway have reached the clinical trial stage. One drug that inhibits the activity of the protea- some, involved in the activation of NF-κB in response to spe- cific stimuli, is PS-341 (also known as bortezomib and marketed as Velcade), and has been shown to have some effi - cacy in the reduction of tumour size (Dy et al., 2005). It is assumed that this inhibition is preventing the degradation of I-kappa B (IκB), and the subsequent cleavage and activation of NF-κB (Dy et al., 2005), though it should be noted that the trial does not appear to check directly for this, and so it is only an assumed link. The trial also focuses on multiple myeloma, and so may not be valid when applied to treatment of pancre- atic cancer. However, the target (CSCs) is the same in both cases, and these should behave similarly in all cancers. Interactions between the Hh pathway and NF-κB Figure 2. Activation of NF-κB. Activation of nuclear factor-kappa B (NF-κB) involves degradation of IκB proteins—inhibitors of NF-κB, There is evidence to suggest a physiological link between the which are usually bound to the molecule to keep it deactivated in the Hh signalling pathway and the NF-κB pathway. In a study by cytoplasm. When IκB is tagged by IκB kinases (IKK), ubiquitin ligase Nakashima et al. in 2006, it was demonstrated that SHh complexes target it and cause it to be cleaved by proteasomes, releasing NF-κB (Ghosh and Karin, 2002). This allows NF-κB to expression was up-regulated in cell lines originating from translocate to the nucleus, where it binds to its target genes and acts human pancreatic tumours in which NF-κB activation was as a transcription factor (Karin, 2006), sometimes in conjunction with high. This suggested a potential role of NF-κB upstream of Hh other transcription factors. The target genes encode many proteins signalling. The study confirmed that NF- κB-induced overex- involved in cell proliferation, resistance to apoptosis and angiogenesis pression of SHh did lead to activation of the Hh signalling and vascularization, including IL-6, VEGF and Bcl genes (Karin, 2006). pathway and proliferation of pancreatic cancer cell lines (Nakashima et al., 2006). This evidence was further supported in a study by Kasperczyk et al. in 2009, using both in vivo and was not designed to specifically investigate NF- κB activity, in vitro models, which showed that SHh promoters were acti- the result shows further evidence of a correlation between vated and SHh expression elevated in response to NF-κB (see this transcription factor and development of cancer. Fig. 3), and this had a direct effect on proliferative capabilities Inhibiting the ability of NF-κB to bind to DNA may allow and resistance to apoptosis in cancer cells. This study also for control and treatment of pancreatic cancer. A study by reported indirect effects on SHh expression via regulation of Chien et al. in 2013, again using the BxPc3 cell line (amongst TNF-α (see Fig. 3), which lead to increased protein expression others) showed a suppression of NF-κB activity in cells treated via effects on mRNA (Kasperczyk et al., 2009). 4 Bioscience Horizons • Volume 7 2014 Review of which have little chance of success and are only prescribed in 10% of patients (Iovanna et al., 2012). As the understand- ing of molecular pathways and underlying cellular biology behind pancreatic cancer increases, new opportunities for treatment may become available. In the future, it is likely that treatment of pancreatic cancer will become increasingly based on cellular pathways involved in proliferation and sur- vival of cancerous cells, as the efficacy of surgery and other treatments are unlikely to improve greatly. The translation into clinical practice has already begun, as clinical trials and in vivo analyses are being conducted alongside in vitro stud- ies on potential therapeutic agents, targeting Hh signalling molecules (Thayer et al., 2003; Singh et al., 2011; Lee et al., 2012), NF-κB proteins (Dy et al., 2005; Chien et al., 2013) and other related pathways (Wang et al., 2006; Chien et al., 2013). The early studies mentioned here are showing promis- ing results in all areas, but more research is necessary to improve efficacy of these drugs. Combined therapies may have a complementary and increased effect on tumour pro- gression, though as yet there is little evidence that this is the case. During the development of these treatments, it will be necessary to focus on ways of reducing the resistance of CSCs to death and inhibition, as these are likely to be the major focus of any effective treatment strategy. Author biography Jake Ranson is currently studying Medical Sciences at the University of Exeter Medical School, a translational science degree that looks at all aspects of science from the laboratory bench to the patient’s bedside. His main interest is neurosci- ence, but he also has an interest in both cancer and microbi- ology. In his later career, he would like to study medicine and practice neurology whilst still being involved in research, Figure 3. Interactions between NF-κB and the Hh signalling pathway. When NF-κB is activated, it translocates to the nucleus (Karin, 2006). potentially in a more clinical environment. He wrote up the Here, it binds to promoter regions on target genes, including SHh paper, and has primary responsibility for its final content. (Karin, 2006; Kasperczyk et al., 2009) leading to up-regulation of gene expression. In healthy tissue, this up-regulation of SHh is desirable, as it assists tissue repair during the final stages of inflammation References (Kasperczyk et al., 2009); however, when this proliferative signal is unchecked, it can lead to cancer formation. NF-κB activation can also Berman, D. M., Karhadkar, S. S., Maitra, A. et  al. (2003) Widespread indirectly lead to up-regulation of SHh through mechanisms such as requirement for Hedgehog ligand stimulation ingrowth of digestive regulating expression of tumour necrosis factor alpha (TNF-α). This tract tumours, Nature, 425 (6960), 846–851. increases protein expression of SHh via mRNA enhancement, and has been shown to be a factor in pancreatic cancer formation (Kasperczyk Bosetti, C., Bertuccio, P., Negri, E. et al. (2012) Pancreatic cancer: overview et al., 2009). of descriptive epidemiology, Molecular Carcinogenesis, 51 (1), 3–13. Caro, I. and Low, J. A. 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Iovanna, J., Mallmann, M. C., Gonçalves, A. et  al. (2012) Current knowl- edge on pancreatic cancer, Frontiers in Oncology, 2, 6. Singh, B. N., Fu, J., Srivastava, R. K. et  al. (2011) Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem Karin, M. (2006) Nuclear factor-kappaB in cancer development and pro- cell characteristics: molecular mechanisms, PLoS One, 6 (11), e27306. gression, Nature, 441 (7092), 431–436. Tan, B. T., Park, C. Y., Ailles, L. E. et al. (2006) The cancer stem cell hypoth- Kasperczyk, H., Baumann, B., Debatin, K. M. et al. (2009) Characterization esis: a work in progress, Laboratory Investigation, 86 (12), 1203–1207. of sonic hedgehog as a novel NF-kappaB target gene that promotes NF-kappaB-mediated apoptosis resistance and tumor growth in Tang, S. N., Fu, J., Nall, D. et al. (2012) Inhibition of sonic Hedgehog path- vivo. 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The roles of Hedgehog signalling and NF-B activity in pancreatic cancer and opportunities for treatment

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BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu004 Review The roles of Hedgehog signalling and NF-κB activity in pancreatic cancer and opportunities for treatment Jake Ranson University of Exeter Medical School, St. Luke’s Campus, University of Exeter, Heavitree Road, Exeter, Devon EX1 2LU, England *Corresponding author: Jake Ranson, University of Exeter Medical School, St. Luke’s Campus, University of Exeter, Heavitree Road, Exeter, Devon EX1 2LU, England. Email: jr371@exeter.ac.uk Project Supervisor: Kevin Brandom, University of Exeter Medical School, St. Luke’s Campus, University of Exeter, Heavitree Road, Exeter, Devon EX1 2LU, UK; Email: k.g.brandom@exeter.ac.uk. Pancreatic cancer is the seventh most common form of cancer-related death in the world, affecting hundreds of thousands of people worldwide every year. Treatment for this type of cancer is largely ineffective and future treatments are likely to involve targeting signalling pathways involved in the proliferation of pluripotent stem cells. There are a variety of signalling pathways involved in the pathogenesis of the disease, including Hedgehog (Hh) and nuclear factor-kappaB (NF-κB). Overexpression of Hh ligands or alterations in other areas of the Hh signalling pathway may lead to tumour formation. Inhibition of Hh ligands, Smoothened or Gli proteins, or up-regulation of Patched expression, could form the basis of new treatments. NF-κB is often active in pancreatic cancer cells and down-regulation of NF-κB activating molecules can inhibit tumour progression in cell culture studies. Clinical trials show some promising results in novel drugs. There is growing evidence to suggest the interac- tion between these two signalling pathways. NF-κB appears to play a role upstream of the Hh pathway. This article looks at the roles these pathways play in pancreatic cancer and explores current research into targeting them for treatment. Key words: hedgehog, NF-κB, pancreatic cancer, mechanisms, treatment Received 13 August 2013; revised 15 April 2014; accepted 17 April 2014 Introduction There are many different pathways that lead to the cellular effects and tumour formation seen in pancreatic cancer. Pancreatic cancer is one of the most deadly and aggressive can- Changes in the Hedgehog (Hh) signalling pathway activity and cers, with a poor prognosis and swiftly fatal progression the nuclear factor-kappaB (NF-κB) pathway have been impli- (Thayer et al., 2003). As the seventh most common cause of cated in the pathogenesis of the disease (Berman et al., 2003; death by cancer in the world (Bosetti et al., 2012), it causes Liptay et al., 2003; Thayer et al., 2003; Karin, 2006; tens of thousands of deaths every year in Europe alone (Ferlay Nakashima et al., 2006). Hh signalling was first discovered in et al., 2010; Malvezzi et al., 2013), and had a 5-year survival the fruit fly Drosophila melanogaster in 1980s (Nüsslein- rate (post-diagnosis) of only ~6% between 2001 and 2007 Volhard and Wieschaus, 1980), and is heavily involved in the (Siegel, Naishadham and Jemal, 2012). This incurable nature embryonic development of many species (Thayer et al., 2003; can be attributed to a combination of rapid tumour metastasis, Berman et al., 2003; Ng and Curran, 2011). The NF-κB family poor response to drugs (Thayer et al., 2003; Sarkar, Banerjee of proteins were identified in the 1980s ( Sen and Baltimore, and Li, 2007) and the fact that treatment is so ineffectual it is 1986), and are known to be heavily involved in infection and prescribed for only 10% of patients (Iovanna et al., 2012). inflammation ( Gilmore, 1999). Involvement of many other © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.  Review Bioscience Horizons • Volume 7 2014 pathways has also been observed, including epidermal growth factor receptor and COX-2 (Sarkar, Banerjee, and Li, 2007). These processes do not act independently of each other; the interaction between the pathways plays a significant role in the cancer formation (Nakashima et al., 2006). Further under- standing of these pathways and their interactions may lead to new and improved treatments for pancreatic cancer. This article will examine the mechanisms of Hh signalling and NF-κB in the formation of pancreatic cancer, and how they might be targeted to improve treatment. The role of the Hh signalling pathway As a driver of cell proliferation and differentiation, Hh sig- nalling has been identified as an important factor in the pathogenesis of several cancers, including pancreatic cancer (Berman et al., 2003; Thayer et al., 2003; Caro and Low, 2010). There are three Hh ligands in mammals: desert, Indian and Sonic (DHh, IHh and SHh, respectively). In the absence of an Hh ligand, the 12-transmembrane protein Patched (on the cell membrane) prevents translocation of pro-mitotic Smoothened (Caro and Low, 2010). In the presence of Hh ligands, Patched is inhibited, allowing Smoothened to trans- locate and cause a cascade of events including the Gli protein family (Thayer et al., 2003; Wang et al., 2013a,b; Caro and Low, 2010); ultimately leading to transcription of a variety of genes, including PTCH1 (the gene encoding the Patched pro- tein) and other cell proliferation genes (see Fig. 1) (Caro and Low, 2010). In this way, PTCH1 can be considered a tumour suppressor gene as, when active, the cell will not respond to proliferative signals. The entire pathway also contains an interesting feedback mechanism. Patched is produced in the presence of Hh ligands (Chen, Carkner and Buttyan, 2011), which would infer a negative feedback loop as more suppressing proteins are produced in response to proliferative signals. However, this is negated in the case of overexpression of Hh ligands. This has been shown to be the case in pancreatic cancer. Figure 1. T he Hh signalling pathway. In normal adult physiology, A study by Thayer et al. in 2003 showed overexpression of smoothened (a 7-transmembrane protein on the membrane of SHh in 70% of tumours taken from patients suffering from endosomes) is suppressed from entering the primary cilium (a pancreatic cancer. The study went on to examine pancreatic structure common to many human cells) by the 12-transmembrane protein Patched (at the base of the cilium) (Caro and Low, 2010). This cells from four mice that had been genetically altered to over- suppression is prevented in the presence of Hh ligands (such as SHh), express SHh and found markers associated with early pan- which bind to and inhibit Patched. This allows Smoothened to creatic tumours. Though this study was only conducted on a translocate to the primary cilium where it activates repressed Gli very small sample of mice, it went some way towards demon- proteins (GliR) such as Gli1 and Gli2 into their active forms (GliA). These strating the effect of aberrant expression of SHh. As this can then translocate to the nucleus where they act as transcription ligand was found in high amounts in a large number of factors for genes encoding many proteins, including Patched, Gli1 and human pancreatic tumours, it suggests a correlation between cyclin-dependent kinases (Chen, Carkner and Buttyan, 2011). Hh ligand expression and pancreatic cancer, even in humans. Other studies have also demonstrated increased levels of produced through loss of Patched activity (Rodova et al., SHh, along with Patched, Smoothened and Gli proteins, in 2012). Some cancers have even been linked to activating human pancreatic cancers (Singh et al., 2011). mutations in the gene for Smoothened that allow it to break It is not necessary for Hh ligand expression to be altered in free from its suppression by Patched (Wang et al., 2013a,b). cancers linked to the pathway; a similar effect would be These would all have similar cellular effects that could lead to 2 Bioscience Horizons • Volume 7 2014 Review carcinogenesis, and could possibly be targeted by the same adult tissue; stem cells within tissues and organs differentiate drug, depending on the exact mechanism of action of the to form various cells necessary for the continued function of drug. If several of these mutations happened in tandem, it their specific tissue ( Tan et al., 2006). This similarity is unsur- may give rise to a complex genetic pathology, against which prising, and as such lends strength to the CSC theory. even advanced treatments may not be effective. Pancreatic cancer shows a high resilience to most contempo- rary treatments (Iovanna et al., 2012), and the problem may lie in stem cells that are somehow resistant to killing. It is Treating the Hh signalling pathway possible that targeting the pathways upon which these self- Treatments focussing on the Hh pathway may not be far renewing cells rely will increase efficacy of treatment. away from clinical practice. Thus far, the large majority of However, as the CSCs in this study were less susceptible to research into treatments targeting the Hh pathway has con- elimination by the smoothened inhibitor (Singh et al., 2011), cerned inhibition of Smoothened (Ng and Curran, 2011), this may not be the case. Some Smoothened-inhibiting com- although increasing therapeutic use of monoclonal antibod- pounds, however, do seem to have an effect on pancreatic ies may allow targeting of Hh ligands directly. A study by Lee CSCs, suggesting that there may be a difference in the activa- et al. in 2012 showed that mice treated daily with a specific tion of the Hh signalling pathway between CSCs and other Smoothened inhibitor, IPI-926 (also known as Saridegib), cancer cells (Tang et al., 2012). Many factors may play a role showed a unanimous reduction in the size of brain tumours in the efficacy of these drugs against CSCs: bioavailability of caused by overexpression of SHh. However, it was noted that the compounds, doses administered and interaction of the after 6 weeks of daily treatment, tumour progression began drug with the human body could all affect treatment. Further again in the treated mice, indicating that suppression of studies should look at methods of refining these processes Smoothened activity by the drug was not a long-term effect and investigate whether this has any improvement on the tar- (Wang et al., 2013a,b). There are obvious questions regard- geting of CSCs. ing the generalizability of this study to pancreatic cancer in humans. The cancer observed in this study is a rare form of The role of NF-κB brain tumour called a medulloblastoma. However, this NF-κB is formed by the dimerization of several subunits appears to have links to the Hh pathway in much the same including members of the Rel family (Ghosh and Karin, way as pancreatic cancer (Ng and Curran, 2011; Wang et al., 2002; Karin, 2006), one of which (v-rel) is known to be an 2013a,b). The study used a mouse model, and in small num- oncogene, suggesting a potential link with cancer (Karin, bers; five originally, moving up to 37 after promising findings 2006). NF-κB is a transcription factor, activation of which (Lee et al., 2012). Whilst this may otherwise be considered to results in the secretion of growth factors such as the cytokine be less generalizable to the population at large, this is not IL-6, anti-apoptotic molecules and survival factors, such as uncommon in drug trials. In fact it is necessary to perform Bcl-2 and angiogenesis-inducing factors such as vascular initial tests on an animal model before clinical trials in endothelial growth factor (VEGF) (Karin, 2006) (see Fig. 2). humans can be considered. Therefore, this study may still be Whilst these are desirable in infection, allowing the recruit- considered valid, if basic, and further studies may be con- ment of immune cells and the repair of damaged tissues, they ducted based on this research. Another study, by Singh et al. are also characteristic of cancerous cells (Hanahan and in 2011, focused on a different Smoothened inhibitor: GDC- Weinberg, 2011). 0449 (Vismodegib). This study used human pancreatic can- cer cell lines and cancer stem cells (CSCs) in vitro, arguably a Inflammation has long been suspected as a factor in carci - more valid method when studying human cancers, though nogenesis, going as far back as 1863 (Karin, 2006). It is new lacking potentially vital evidence of in vivo interaction. The evidence that finally allows this to be confirmed. A study by results showed that the drug induced apoptosis and pre- Liptay et al. in 2003 examined 11 pancreatic tissue samples vented proliferation in all the cell lines, and to a lesser extent taken from patients with confirmed pancreatic cancer. in the CSCs themselves (Singh et al., 2011), by inducing the Immunohistochemical analysis revealed that seven of these expression of pro-apoptotic molecules such as Fas and inhib- contained markers of NF-κB activity, signifying a potential iting anti-apoptotic proteins such as Bcl-2 (Singh et al., role of this protein in pancreatic cancer (Liptay et al., 2003). 2011). This is a promising result, as it suggests that smooth- However, this is only a small sample, and this result alone ened inhibitors may be useful in delaying disease progression does not represent a causal link, only a correlation. and lessening the symptoms of pancreatic tumours. However, the drug did have a lesser effect on the stem cells (Singh et al., A key regulator of NF-κB, Notch-1 (Wang et al., 2006), 2011), and it may not therefore offer a complete cure for has also been implicated in pancreatic cancer (Sarkar, pancreatic cancer. There is growing evidence to support the Banerjee and Li, 2007). A study by Wang et al. in 2006 hypothesis that the driving force behind tumour growth is the looked at the mechanism behind the involvement of Notch-1 proliferation of a small minority population of ‘cancer stem in cancer using some of the same human pancreatic cancer cells’ (CSCs) within the tumour, which will cause re-occur- cell lines (BxPc3) as Liptay et al.’s study in 2003, and found rence of cancer if not eliminated (Tan et al., 2006; Wang that, amongst other things, decreased levels of Notch-1 lead et al., 2013a,b). This model bears a close similarity to healthy to decreased binding of NF-κB to DNA. Whilst this study 3 Review Bioscience Horizons • Volume 7 2014 with the drug Belinostat. While the mechanism of action of the drug is still not well understood, the data suggest that this suppression was accomplished indirectly via feedback from other components of the pathway, such as TNF-α, which were directly affected by Belinostat (Chien et al., 2013). This was accompanied by induction of apoptosis and autophagy in some cells, as well as an arrest of growth in the remaining cells (Chien et al., 2013). This is a positive result, and suggests that the link between NF-κB and cell proliferation and survival can be manipulated in the treatment of pancreatic cancer. Each of the previously mentioned studies used several different cell lines originating from pancreatic cancers, some of which were common to all of the studies. This suggests a good degree of corroboration between the studies’ results and potentially between in vitro and in vivo experiments, as the cell lines used originated from human tumours (Liptay et al., 2003; Wang et al., 2006; Chien et al., 2013). Treatments targeting NF-κB Few drugs targeting this pathway have reached the clinical trial stage. One drug that inhibits the activity of the protea- some, involved in the activation of NF-κB in response to spe- cific stimuli, is PS-341 (also known as bortezomib and marketed as Velcade), and has been shown to have some effi - cacy in the reduction of tumour size (Dy et al., 2005). It is assumed that this inhibition is preventing the degradation of I-kappa B (IκB), and the subsequent cleavage and activation of NF-κB (Dy et al., 2005), though it should be noted that the trial does not appear to check directly for this, and so it is only an assumed link. The trial also focuses on multiple myeloma, and so may not be valid when applied to treatment of pancre- atic cancer. However, the target (CSCs) is the same in both cases, and these should behave similarly in all cancers. Interactions between the Hh pathway and NF-κB Figure 2. Activation of NF-κB. Activation of nuclear factor-kappa B (NF-κB) involves degradation of IκB proteins—inhibitors of NF-κB, There is evidence to suggest a physiological link between the which are usually bound to the molecule to keep it deactivated in the Hh signalling pathway and the NF-κB pathway. In a study by cytoplasm. When IκB is tagged by IκB kinases (IKK), ubiquitin ligase Nakashima et al. in 2006, it was demonstrated that SHh complexes target it and cause it to be cleaved by proteasomes, releasing NF-κB (Ghosh and Karin, 2002). This allows NF-κB to expression was up-regulated in cell lines originating from translocate to the nucleus, where it binds to its target genes and acts human pancreatic tumours in which NF-κB activation was as a transcription factor (Karin, 2006), sometimes in conjunction with high. This suggested a potential role of NF-κB upstream of Hh other transcription factors. The target genes encode many proteins signalling. The study confirmed that NF- κB-induced overex- involved in cell proliferation, resistance to apoptosis and angiogenesis pression of SHh did lead to activation of the Hh signalling and vascularization, including IL-6, VEGF and Bcl genes (Karin, 2006). pathway and proliferation of pancreatic cancer cell lines (Nakashima et al., 2006). This evidence was further supported in a study by Kasperczyk et al. in 2009, using both in vivo and was not designed to specifically investigate NF- κB activity, in vitro models, which showed that SHh promoters were acti- the result shows further evidence of a correlation between vated and SHh expression elevated in response to NF-κB (see this transcription factor and development of cancer. Fig. 3), and this had a direct effect on proliferative capabilities Inhibiting the ability of NF-κB to bind to DNA may allow and resistance to apoptosis in cancer cells. This study also for control and treatment of pancreatic cancer. A study by reported indirect effects on SHh expression via regulation of Chien et al. in 2013, again using the BxPc3 cell line (amongst TNF-α (see Fig. 3), which lead to increased protein expression others) showed a suppression of NF-κB activity in cells treated via effects on mRNA (Kasperczyk et al., 2009). 4 Bioscience Horizons • Volume 7 2014 Review of which have little chance of success and are only prescribed in 10% of patients (Iovanna et al., 2012). As the understand- ing of molecular pathways and underlying cellular biology behind pancreatic cancer increases, new opportunities for treatment may become available. In the future, it is likely that treatment of pancreatic cancer will become increasingly based on cellular pathways involved in proliferation and sur- vival of cancerous cells, as the efficacy of surgery and other treatments are unlikely to improve greatly. The translation into clinical practice has already begun, as clinical trials and in vivo analyses are being conducted alongside in vitro stud- ies on potential therapeutic agents, targeting Hh signalling molecules (Thayer et al., 2003; Singh et al., 2011; Lee et al., 2012), NF-κB proteins (Dy et al., 2005; Chien et al., 2013) and other related pathways (Wang et al., 2006; Chien et al., 2013). The early studies mentioned here are showing promis- ing results in all areas, but more research is necessary to improve efficacy of these drugs. Combined therapies may have a complementary and increased effect on tumour pro- gression, though as yet there is little evidence that this is the case. During the development of these treatments, it will be necessary to focus on ways of reducing the resistance of CSCs to death and inhibition, as these are likely to be the major focus of any effective treatment strategy. Author biography Jake Ranson is currently studying Medical Sciences at the University of Exeter Medical School, a translational science degree that looks at all aspects of science from the laboratory bench to the patient’s bedside. His main interest is neurosci- ence, but he also has an interest in both cancer and microbi- ology. In his later career, he would like to study medicine and practice neurology whilst still being involved in research, Figure 3. Interactions between NF-κB and the Hh signalling pathway. When NF-κB is activated, it translocates to the nucleus (Karin, 2006). potentially in a more clinical environment. He wrote up the Here, it binds to promoter regions on target genes, including SHh paper, and has primary responsibility for its final content. (Karin, 2006; Kasperczyk et al., 2009) leading to up-regulation of gene expression. 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Bioscience HorizonsOxford University Press

Published: Jun 28, 2014

Keywords: Hedgehog NF-κB pancreatic cancer mechanisms treatment

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