Hedgehog signaling pathway: the must, the maybe and the unknown (original) (raw)
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Activation of the hedgehog pathway in a subset of lung cancers
Cancer Letters, 2006
Activation of the hedgehog pathway is reported in lung cancer, but its frequency remains unknown. We examine activation of this pathway in lung cancers by in situ hybridization and immunohistochemstry, and find that less than 10% of the tumors have elevated hedgehog target gene expression. We further identify a cell line NCI-H209 and two primary tumors with no detectable Su(Fu), a negative regulator of the pathway. Ectopic expression of Su(Fu) in NCI-H209 cells down-regulates hedgehog target gene expression and leads to inhibition of cell proliferation. These data indicate that activation of the hedgehog pathway is activated through Shh over-expression or Su(Fu) inactivation in only a subset of lung cancers.
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.
Hedgehog Signaling: An emerging targeting therapy in Cancer
Asian Journal of Pharmacy and Pharmacology
Stem cell biology has come of an age. During the past few years, CSCs have been increasingly found in many malignancies. Tumor relapse and metastasis remains major hurdle for improving overall cancer survival. CSCs basically have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting CSCs can be developed. Various stem cell maintenance pathways such as Notch, Wnt and Hedgehog are found to be activated in the various cancers stem cells. Hedgehog signaling is most active during the embryonic development and aberrant reactivation of the pathway in adult tissue can lead to development of cancer. A variety of cancers such as brain, gastrointestinal, lung, breast and prostate cancer shows possible signs of activation of Hedgehog pathway. Targeted inhibition of Hedgehog signaling can be found effective in the treatment and prevention of many types of human cancers. Hence, the discovery and synthesis of specific Hedgehog pathway inhibitors may have significant clinical implications in novel cancer therapeutics. In this review, we have discussed Hedgehog signaling and its activation in different types of cancers and the development of its targeted therapies.
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.
Wnt and Hedgehog Are Critical Mediators of Cigarette Smoke-Induced Lung Cancer
PLoS ONE, 2006
Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood. Methodology/Principal Findings. Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype. Conclusions/ Significance. These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.
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.
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),...
Scientific Reports , 2020
Lung malignancies comprise lethal and aggressive tumours that remain the leading cancer-related death cause worldwide. Regarding histological classification, lung squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD) account for the majority of cases. Surgical resection and various combinations of chemo-and radiation therapies are the golden standards in the treatment of lung cancers, although the five-year survival rate remains very poor. Notch, Hedgehog, Wnt and Erbb signalling are evolutionarily conserved pathways regulating pivotal cellular processes such as differentiation, proliferation, and angiogenesis during embryogenesis and post-natal life. However, to date, there is no study comprehensively revealing signalling networks of these four pathways in LUSC and LUAD. Therefore, the aim of the present study was the investigation profiles of downstream target genes of pathways that differ between LUSC and LUAD biology. Our results showed a few co-expression modules, identified through weighted gene co-expression network analysis (WGCNA), which significantly differentiated downstream signaling of Notch, ErbB, Hedgehog, and Wnt in LUSC and LUAD. Among co-expressed genes essential regulators of the cell cycle, DNA damage response, apoptosis, and proliferation have been found. Most of them were upregulated in LUSC compared to LUAD. In conclusion, identified downstream networks revealed distinct biological mechanisms underlying cancer development and progression in LUSC and LUAD that may diversify the clinical outcome of the disease. Lung carcinomas remain one of the most aggressive malignancies characterized by the highest mortality rate among men and women worldwide 1,2. Regarding histological classification lung squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD) account for the majority of lung tumours in non-small cell carcinomas (NSCLCs). In general, the NSCLCs are treated with surgery, which remains the key treatment option, accompanied by various modalities of chemotherapy and radiation. Nevertheless, the five-year survival rate is very poor 3 and patients experience early events of relapse, metastasis and death 4. Despite that both LUAD and LUSC, belong to the family of NSCLCs, they seem very distinct in terms of prognosis as well as the composition of gene expression and signalling pathways profiles. Importantly, more and more often they are being considered as separate clinical entities 5. LUAD comprises about 40% of all lung cancer cases. In the majority of patients, LUAD mostly affects non-smokers but is also observed among smokers. Usually, the tumour is located more peripherally and grows slower than the other types, although it tends to form metastasis at the early stages of the disease. LUSC, in turn, is the second most common lung malignancy among tobacco smokers. Its pathogenesis is strongly associated with airway lesions that arise with smoking and is mostly located in the central parts of the lung. LUSC is also regarded as a very heterogeneous entity, among which two major subtypes may be distinguished such as basaloid and non-basaloid tumours 6. Interestingly, lung cancer shows one of the most diverse genetic landscape harbouring numbers of mutations and copy number
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.
Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers
International Journal of Radiation Oncology*Biology*Physics, 2013
Hedgehog pathway has been implicated in tumor growth and survival. Whether Hedgehog inhibition can impact radiation efficacy in vivo has not been reported. We evaluated effects of a Hedgehog inhibitor (HhAntag) and radiation on in vitro and in vivo models of non-small cell lung cancer. Although HhAntag showed little radiosensitization in vitro, in human xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy. This effect seems to be stromal rather than cancer cell specific. Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras G12D-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.