Activation of the hedgehog pathway in a subset of lung cancers (original) (raw)
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Frequent requirement of hedgehog signaling in non-small cell lung carcinoma
Oncogene, 2007
Although it had previously been suggested that the hedgehog (HH) pathway might be activated in some lung tumors, the dependence of non-small cell lung carcinomas (NSCLC) for HH activity had not been comprehensively studied. During a screen of a panel of 60 human tumor cell lines with an HH antagonist, we observed that the proliferation of a subset of NSCLC cell lines was inhibited. These NSCLC cell lines express HH, as well as key HH target genes, consistent with them being activated through an autocrine mechanism. Interestingly, we also identified a number of NSCLC cell lines that express high levels of the downstream transcription factor GLI1 and harbor enhanced levels of HH activity, but appear insensitive to known HH antagonists. We hypothesized that the high levels of GLI1 in these cells would function downstream of the HH antagonist target, allowing them to bypass the antagonist-mediated block in proliferation. Consistent with this hypothesis, when the levels of GLI1 are knocked down in such cells, they become sensitive to these inhibitors. We go on to show that a large percentage of primary NSCLC samples express GLI1, consistent with constitutive activation of the HH pathway in these samples. Taken together, these results establish the involvement of the HH signaling pathway in a subset of NSCLCs.
Overexpression of hedgehog pathway molecules and FOXM1 in non-small cell lung carcinomas
Lung Cancer, 2009
The Hedgehog (HH)-signaling pathway is implicated in developmental processes while its aberrant activation in adult tissues has been associated with malignancy. The aim of this study was to determine the expression pattern of HH-signaling molecules in non-small cell lung carcinomas (NSCLCs) as well as the involvement of the transcription factor FOXM1, that controls cell proliferation, in this process. Eighty cases of NSCLCs and adjacent non neoplastic lung parenchyma were immunohistochemically analyzed with anti-SHH, anti-Patched1 (PTCH1), anti-SMO, anti-GLI1, anti-GLI2 and anti-FOXM1 antibodies on paraffin tissue sections. Correlations of HH molecules with clinicopathological parameters and FOXM1 expression were evaluated. All the HH-signaling molecules examined were overexpressed in NSCLCs compared with the adjacent non-neoplastic lung parenchyma. Expression of PTCH1 and SMO as well as the HH pathway activation was significantly higher in squamous cell carcinoma subtype. PTCH1 expression and pathway activation was higher in low grade tumors. Expression of SMO in all NSCLC histologic types and of nuclear GLI1 in adenocarcinomas correlated with lymph node metastases.
Oncotarget, 2016
Hedgehog (HH) pathway plays an important role in embryonic development, but is largely inactive in adult except for tissue repair. Aberrant activation of HH pathway has been found in a variety of cancer types. In non-small cell lung cancer, however, the role and importance of HH pathway remain controversial. In the current study, we found that HH pathway was maintained in low activity in lung adenocarcinoma (LAC) cells under normal culture condition, but was highly induced in response to stress conditions. Activation of HH pathway promoted cell survival, growth, and invasion partially through HGF and MET signaling. Hedgehog-Interacting Protein (HHIP), a cell-surface negative regulator of HH pathway, was epigenetically silenced in LAC. Overexpression of HHIP blocked the activation of HH and HGF/MET pathways, and made cells significantly more susceptible to stress conditions. In LAC cells with acquired resistance to Epidermal Growth Factor Receptor Tyrosin Kinase Inhibitor (EGFR-TKI),...
Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas
Journal of Experimental Clinical Cancer Research Cr, 2014
Background: Squamous cell carcinomas (SCC) account for approximately 30% of non-small cell lung cancer. Investigation of the mechanism of invasion and metastasis of lung SCC will be of great help for the development of meaningful targeted therapeutics. This study is intended to understand whether the activation of Hedgehog (Hh) pathway is involved in lung SCC, and whether activated Hh signaling regulates metastasis through epithelial-mesenchymal transition (EMT) in lung SCC. Methods: Two cohorts of patients with lung SCC were studied. Protein expression was examined by immunohistochemistry, Western blot, or immunofluorescence. Protein expression levels in tissue specimens were scored and correlations were analyzed. Vismodegib and a Gli inhibitor were used to inhibit Shh/Gli activity, and recombinant Shh proteins were used to stimulate the Hh pathway in lung SCC cell lines. Cell migration assay was performed in vitro. Results: Shh/Gli pathway components were aberrantly expressed in lung SCC tissue samples. Gli1 expression was reversely associated with the expression of EMT markers E-Cadherin and β-Catenin in lung SCC specimens. Inhibition of the Shh/Gli pathway suppressed migration and up-regulated E-Cadherin expression in lung SCC cells. Stimulation of the pathway increased migration and down-regulated E-Cadherin expression in lung SCC cells. Conclusions: Our results suggested that the Shh/Gli pathway may be critical for lung SCC recurrence, metastasis and resistance to chemotherapy. Inhibition of the Shh/Gli pathway activity/function is a potential therapeutic strategy for the treatment of lung SCC patients.
Clinical and Experimental Medicine, 2012
The hedgehog (Hh) signaling pathway has been shown to be activated in the cancer stem cells of several tumor entities. The Hh inhibitor GDC-0449 has been proven to be effective in some cancers but not yet in lung cancer. We aimed at investigating whether GDC-0449 is effective in the lung cancer cell lines HCC (adenocarcinoma) and H1339 (small-cell-lung carcinoma), whether in these cell lines stem cell-like side populations (SPs) can be identified, and whether possible effects of GDC-0449 are mediated via SPs. SPs were identified by spectrum shift and decreased fluorescence after staining with 2.5 lg/ml Hoechst 33342. Expression of proteins was quantified by immunofluorescence. GDC-0449 (25 and 50 lM) inhibited concentration-dependent cell growth in HCC and H1339 cells. Further, the inhibitory effects of cisplatin on cell growth were augmented. In HCC and H1339 cell lines, SPs of 0.57 and 0.46% could be identified, respectively. SP, but not non-SP, cells were able to repopulate the original tumor population. The Hh receptor smoothened was detectable in SP but not in non-SP cells, showing the activation of the Hh pathway only in SPs. GDC-0449 considerably reduced SPs in HCC and H1339 cells. We demonstrate for the first time that GDC-0449 effectively reduces cell growth in lung cancer cell lines. This effect is mediated by the inhibition of stem cell-like SPs.
Journal of Carcinogenesis & Mutagenesis, 2014
Objective: Lung cancer still remains the leading cause of cancer deaths in the world and it lacks validated biomarkers to predict clinical outcome. The Hedgehog (Hh) pathway is critical for cell growth and differentiation. The aim of our study was to evaluate the role of the Hh signaling in the prediction of clinical outcome for advanced NSCLC. Methods: We determined the expression of Hh-related molecules including Ptch1 and Gli1 (nuclear and cytoplasmic) by immunohistochemistry in histologic samples (biopsies and surgical specimens) of advanced NSCLC patients. All the neoplastic area included in the slides was considered and both cytoplasmic and nuclear stainings were evaluated, according to the positive neoplastic cells. The intensity of the staining was evaluated and scored as follows: 0 (absent), 1+ (low), 2+ (medium) and 3+ (high). Results: We analyzed 35 lung cancer histological samples, 18 adenocarcinomas and 17 squamous cell carcinomas. Positivity of Gli1-cytoplasmic and Gli1-nuclear expression was expressed in adenocarcinoma at a significantly higher level and more frequently than compared to squamous cell carcinoma (p<0.05), while Ptch1 did not differ significantly in the two histotypes. Overall survival was longer in Gli1 and Ptch1 negative tumor samples compared to the positive group (p=0.02). The 18 patients with adenocarcinoma received erlotinib as second line therapy and those presenting a lower Gli1 and Ptch1 expression experienced a significant increase in progression free survival. Conclusion: At our best knowledge this represents the first study investigating the role of HH in NSCLC patients. Our results suggest that the Hh pathway might play a major prognostic role in NSCLC with significant differences between the histotypes.
The role of the Hedgehog signaling pathway in cancer A comprehensive review
The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1 , PTCH2 , and GLI1 . Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.
A crucial requirement for Hedgehog signaling in small cell lung cancer
2011
AUTHOR CONTRIBUTIONS A.N.K. analyzed the histopathology of all mouse lung tumors and edited the manuscript. A.S. performed and analyzed the immunohistochemistry. D.N.W. and L.G.M. edited the manuscript and analyzed the immunohistochemistry. L.G.M. performed experiments with Smo inhibitors and chemotherapy in culture and in xenografts. C.A.O. and J.K.C. generated HPI-1 for cell culture experiments. J.K.C. edited the manuscript. M.R.M. and T.S. designed, performed and analyzed the experiments related to the primary cilia in mouse cells. M.P., M.L.S. and R.K.T. designed and performed the experiments related to the genomic analysis of mousec and human tumors. K.-S.P. and K.B. quantified the proliferation and survival phenotypes in tumors treated with cyclopamine. K.-S.P. and J.F.C. analyzed gene and protein expression levels in tumor cells. K.-S.P. performed all the other experiments involving mouse cells. K.-S.P. and J.S. designed the experiments for the analysis of mouse SCLC cells in culture and in vivo, and generated the corresponding figures. C.D.P. designed and analyzed the research performed by A.M. and W.L.D. on the human SCLC cells in vitro.
Hedgehog signaling pathway: the must, the maybe and the unknown
Journal of thoracic disease, 2013
Lung cancer treatment consists from the basic chemotherapeutic drugs (e.g., platinum analogues) and from pharmaceuticals targeting the different genome of lung tumors (e.g., tyrosine kinase inhibitors). During the last years pharmaceuticals targeting the tumor mutations are approved for first line treatment since they have provided increased overall survival in comparison to standard chemotherapy treatment. Furthermore, due to the increased interest in unrevealing the mechanisms of cell mutation, tumor evolution and tumor cell maintenance the hedgehog pathway has been elicited. Along with Notch and Wnt these three pathways are responsible for progenitor cell development and pulmonary organogenesis. Inhibitors of this pathway have been discovered and their application in the clinical practice is being investigated. However, further understanding of the mechanisms of regulation is needed.
Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis
Experimental Cell Research, 2012
The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.