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Activation of the hedgehog pathway in gastroesophageal cancers  [cached]
Ling Yang,Jingwu Xie,Xiulan Su
Journal of Solid Tumors , 2011, DOI: 10.5430/jst.v1n3p137
Abstract: The hedgehog pathway is a major regulator for cell differentiation, tissue polarity and cell proliferation in embryonic development and homeostasis in adult tissue. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas, medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last two years in our understanding of hedgehog signaling activation in human gastroesophageal cancer, and their potential in clinical treatment with hedgehog pathway inhibitors.
Hedgehog Signaling Pathway in Ovarian Cancer  [PDF]
Joanna Szkandera,Tobias Kiesslich,Johannes Haybaeck,Armin Gerger,Martin Pichler
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms14011179
Abstract: Despite advances in surgical and chemotherapeutic treatment options, less than 50% of patients with advanced-stage ovarian cancer survive five years after initial diagnosis. In this regard, novel treatment approaches are warranted utilizing molecularly targeted therapies directed against particular components of specific signaling pathways which are required for tumor development and progression. One molecular pathway of interest is the hedgehog (Hh) signaling pathway. Activation of the Hh pathway has been observed in several cancer types, including ovarian cancer. This review highlights the crucial role of Hh signaling in the development and progression of ovarian cancer and might lead to a better understanding of the Hh signaling in ovarian tumorigenesis, thus encouraging the investigation of novel targeted therapies.
Hedgehog pathway inhibitors – current status and future prospects  [cached]
Sheikh Asfandyar,Alvi Arsalan,Aslam Hafiz,Haseeb Abdul
Infectious Agents and Cancer , 2012, DOI: 10.1186/1750-9378-7-29
Abstract: The Hedgehog (Hh) proteins comprise a group of secreted proteins that regulate cell growth, differentiation and survival. Inappropriate activation of the Hh signaling pathway has been implicated in the development of a variety of cancers. Hedgehog pathway inhibitors are a relatively new class of therapeutic agents that act by targeting the proteins involved in the regulation of Hh pathway (PTCH, SMO and Gli). Together, they serve as exciting new prospects, with a bright future, both alone or as an adjuvant to the more traditional anti-cancer drugs.
Activation of the hedgehog pathway in advanced prostate cancer
Tao Sheng, Chengxin Li, Xiaoli Zhang, Sumin Chi, Nonggao He, Kai Chen, Frank McCormick, Zoran Gatalica, Jingwu Xie
Molecular Cancer , 2004, DOI: 10.1186/1476-4598-3-29
Abstract: Here we report that activation of the hedgehog pathway occurs frequently in advanced human prostate cancer. We find that high levels of hedgehog target genes, PTCH1 and hedgehog-interacting protein (HIP), are detected in over 70% of prostate tumors with Gleason scores 8–10, but in only 22% of tumors with Gleason scores 3–6. Furthermore, four available metastatic tumors all have high expression of PTCH1 and HIP. To identify the mechanism of the hedgehog signaling activation, we examine expression of Su(Fu) protein, a negative regulator of the hedgehog pathway. We find that Su(Fu) protein is undetectable in 11 of 27 PTCH1 positive tumors, two of them contain somatic loss-of-function mutations of Su(Fu). Furthermore, expression of sonic hedgehog protein is detected in majority of PTCH1 positive tumors (24 out of 27). High levels of hedgehog target genes are also detected in four prostate cancer cell lines (TSU, DU145, LN-Cap and PC3). We demonstrate that inhibition of hedgehog signaling by smoothened antagonist, cyclopamine, suppresses hedgehog signaling, down-regulates cell invasiveness and induces apoptosis. In addition, cancer cells expressing Gli1 under the CMV promoter are resistant to cyclopamine-mediated apoptosis. All these data suggest a significant role of the hedgehog pathway for cellular functions of prostate cancer cells.Our data indicate that activation of the hedgehog pathway, through loss of Su(Fu) or overexpression of sonic hedgehog, may involve tumor progression and metastases of prostate cancer. Thus, targeted inhibition of hedgehog signaling may have significant implications of prostate cancer therapeutics.The hedgehog (Hh) pathway plays a critical role in embryonic development and tissue polarity [1]. Secreted Hh molecules bind to the receptor patched (PTC-PTCH1, PTCH2), thereby alleviating PTC-mediated suppression of smoothened (SMO), a putative seven-transmembrane protein. SMO signaling triggers a cascade of intracellular events, leading to activ
Activation of the hedgehog pathway in chronic myelogeneous leukemia patients
Bing Long, Huanling Zhu, Cuixia Zhu, Ting Liu, Wentong Meng
Journal of Experimental & Clinical Cancer Research , 2011, DOI: 10.1186/1756-9966-30-8
Abstract: The aim of this study was to determine the expression of Hedgehog signaling molecules in Chronic Myelogeneous Leukemia (CML) patients and normal people by semiquantitative polymerase chain reaction (PCR) and to correlate mRNA expression to patients' clinical data.Here, we showed that Sonic hedgehog (Shh), Smoothened (Smo), and Gli1 genes of Hh signaling were significantly upregulated in CML patients when compared with normal people (P < 0.001). The levels of Shh, Smo mRNA in chronic phase of CML patients were obviously lower than that in blast crisis (p < 0.05). There were no significant differences of Shh, Ptch1, Smo, Gli1 mRNA expression found when comparing CML patients of chronic phase(CP) with imatinib(IM) treated or not(p > 0.05).These findings suggested that activation of the Hh pathway maybe associated with CML progression. Treatment of CML with imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase inhibitor, has no significant influence on the inhibition of Hh pathway of CML-CP patients.Chronic myelogeneous leukemia (CML) is a clonal disease that originates from a single transformed hematopoietic stem cell (HSC) or multipotent progenitor cell harboring a chromosomal translocation between chromosome 9 and 22 [t(9;22)(q34;q11)], resulting in the formation of Philadelphia(Ph) chromosome and at the molecular level, a chimeric gene known as BCR-ABL responsible for CML initiation. CML often initiates in a chronic phase, and without intervention, eventually progresses to a terminal blastic phase. The introduction of imatinib mesylate, has revolutionized the disease management. However, imatinib does not cure CML, and one of the reasons is that imatinib does not kill leukemia stem cells (LSCs) in CML [1,2]. Recent studies suggest that developmental pathway like Hedgehog signaling pathway played a role during the expansion of BCR-ABL-positive leukemic stem cells [3,4]. Hedgehog ligands (Sonic hedgehog [Shh], Indian hedgehog [Ihh], and Desert hedgehog [Dhh])
Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors  [cached]
Chao Che,Song Li,Bo Yang,Shengchang Xin
Beilstein Journal of Organic Chemistry , 2012, DOI: 10.3762/bjoc.8.94
Abstract: Sant-75 is a newly identified potent inhibitor of the hedgehog pathway. We designed a diversity-oriented synthesis program, and synthesized a series of Sant-75 analogues, which lays the foundation for further investigation of the structure–activity relationship of this important class of hedgehog-pathway inhibitors.
Hedgehog Signalling Pathway: Carcinogenesis and Targeted Therapy
Abdolali Ebrahimi,Leila Larijani,Afshin Moradi,Mohamad Reza Ebrahimi
Iranian Journal of Cancer Prevention , 2013,
Abstract: Hedgehog signalling pathway has not only a critical role in cell proliferation, differentiation and tissue polarity at embryonic period but also has a vital role in stem cell proliferation, tissue healing and carcinogenesis. Recent research has increased our understanding of this pathway and its relation to other signalling pathways. In addition, a large number of studies confirmed the alteration of Hh signalling pathway in various types of human malignancies including basal cell carcinomas, medulloblastomas, lung, gastrointestinal, ovarian, breast, prostate cancers and leukemia. More than 50 small biomolecules have been introduced which have inhibitory effects on Hh signalling pathway. Although, in many tumors some acceptable results have been showed in phase I clinical trial, closer studies are required to improve drug bioavailability, to decrease the side effects and to find the right small molecules for specific types of cancers, considering patients overall benefits as well.
Hedgehog pathway activity in the LADY prostate tumor model
Jerry Gipp, Guangyu Gu, Curtis Crylen, Susan Kasper, Wade Bushman
Molecular Cancer , 2007, DOI: 10.1186/1476-4598-6-19
Abstract: We analyzed expression of Hh pathway components and conserved Hh target genes along with progenitor cell markers and selected markers of epithelial differentiation during tumor development in the LADY transgenic mouse model. Tumor development was associated with a selective increase in Ihh expression. In contrast Shh expression was decreased. Expression of the Hh target Patched (Ptc) was significantly decreased while Gli1 expression was not significantly altered. A survey of other relevant genes revealed significant increases in expression of Notch-1 and Nestin together with decreased expression of HNF3a/FoxA1, NPDC-1 and probasin.Our study shows no evidence for a generalized increase in Hh signaling during tumor development in the LADY mouse. It does reveal a selective increase in Ihh expression that is associated with increased expression of progenitor cell markers and decreased expression of terminal differentiation markers. These data suggest that Ihh expression may be a feature of a progenitor cell population that is involved in tumor development.Sonic hedgehog (Shh) is one of three mammalian hedgehog (Hh) genes [Sonic hedgehog, Desert hedgehog, Indian hedgehog]. Each of the Hh genes encodes a secreted signaling peptide that binds to a membrane bound receptor (Ptc). Binding of Hh ligand to the Ptc receptor on the target cell initiates an intracellular signal transduction cascade that ultimately activates expression of Hh target genes through the activity of a family of Gli transcription factors [1]. Previous studies have identified Shh as an important regulator of prostate development [2-7]. Shh is expressed exclusively in the epithelium of the developing prostate. Expression is most abundant during prostate ductal budding and postnatal ductal morphogenesis and diminishes to a low level in the adult. Ihh is also expressed in the prostate epithelium. It is expressed at relatively lower levels in the developing prostate but in a distinctive pattern and, in contra
Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo  [PDF]
Kathryn E. O'Reilly,Eleazar Vega-Saenz de Miera,Miguel F. Segura,Erica Friedman,Laura Poliseno,Sung Won Han,Judy Zhong,Jiri Zavadil,Anna Pavlick,Eva Hernando,Iman Osman
Pharmaceuticals , 2013, DOI: 10.3390/ph6111429
Abstract: Previous reports have demonstrated a role for hedgehog signaling in melanoma progression, prompting us to explore the therapeutic benefit of targeting this pathway in melanoma. We profiled a panel of human melanoma cell lines and control melanocytes for altered expression of hedgehog pathway members and determined the consequences of both genetic and pharmacological inhibition of the hedgehog pathway activator Smoothened (SMO) in melanoma, both in vitro and in vivo. We also examined the relationship between altered expression of hedgehog pathway mediators and survival in a well-characterized cohort of metastatic melanoma patients with prospectively collected follow up information. Studies revealed that over 40% of the melanoma cell lines examined harbored significantly elevated levels of the hedgehog pathway mediators SMO, GLI2, and PTCH1 compared to melanocytes ( p < 0.05). SMO inhibition using siRNA and the small molecule inhibitor, NVP-LDE-225, suppressed melanoma growth in vitro, particularly in those cell lines with moderate SMO and GLI2 expression. NVP-LDE-225 also induced apoptosis in vitro and inhibited melanoma growth in a xenograft model. Gene expression data also revealed evidence of compensatory up-regulation of two other developmental pathways, Notch and WNT, in response to hedgehog pathway inhibition. Pharmacological and genetic SMO inhibition also downregulated genes involved in human embryonic stem cell pluripotency. Finally, increased SMO expression and decreased expression of the hedgehog pathway repressor GLI3 correlated with shorter post recurrence survival in metastatic melanoma patients. Our data demonstrate that hedgehog pathway inhibition might be a promising targeted therapy in appropriately selected metastatic melanoma patients.
Role of sonic hedgehog signaling pathway in neuroblastoma development
Mehdi Hayat Shahi
Biology and Medicine , 2009,
Abstract: Malignant transformation of normal cells is a complex and accumulative process. Understanding this event givesinsight into mechanisms of developmental biology and physical interaction of cellular machinery with surroundingambient factors. However, the trend of embryonic malignancy is not interactive with ambient factors, rather a cause ofderegulations of internal developmental process. In this review, we have attempted to explore the possibility of sonichedgehog role in the development of neuroblastoma tumour. It is the major extra cranial tumour and develops in veryearly stage of childhood. Sonic hedgehog signaling is very well studied in another major childhood tumour i.e.medulloblastoma that contributes 20-25% of childhood tumours, and 1/4th of medulloblastoma is due of abnormality inthe Shh signaling pathway. Therefore, we would consider whether Shh could also contribute to the development ofneuroblastoma. Although scientists are coming up with role of Shh in the neuroblastoma, the sonic hedgehogsignaling is very much a promising pathway because of its multi-dimensional role not only in CNS development butalso in organogenesis and other major tumour development.
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