High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors
Paul Takam KamgaAurélie SwalduzAdrien CostantiniCatherine JuliéJean-François EmileM. PérolVirginie AvrillonSandra Ortiz-CuaránPierre SaintignyEtienne Giroux‐Leprieur
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Growing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context.We investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients' outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh-Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline).Among the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients' biopsies. Shh was significantly (p < 0.05) enriched in youth (age < 68), male, nonsmokers, patients with a PS > 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response.These data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI.Keywords:
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目的 将 Shh 基因用慢病毒载体转染甲状腺乳头状癌（PTC）原代细胞中，观察 Shh 对 PTC 细胞体外生物学性状的影响。方法 在建立慢病毒载体 pGC-FU-Shh-GFP 转染 PTC 细胞，稳定过表达 Shh 蛋白模型基础上，设立转染实验组和阴性对照组。MTT 法检测细胞增殖能力，流式细胞术检测细胞周期，Transwell 实验检测细胞迁移能力，检测 Sonic hedgehog 通路相关基因 mRNA 与蛋白表达变化，与阴性对照组检测结果进行比较。结果 高表达Shh 细胞生长曲线较陡直，生长速度较阴性对照组显著提高（P ＜0．05）；Shh-PTC 细胞24 h 后 S 期上升至20．88％， Shh-PTC 细胞48 h 后 G1期上升至83．78％；实验组穿透滤过膜细胞数量明显增加（P ＜0．05）。转染后 SMO、Gli1、PTCH 蛋白的表达均高于对照组，表达量分别是对照组的1．154倍，1．062倍和1．205倍。结论 Shh 明显促进 PTC细胞的增殖、迁移和侵袭能力。在 PTC 的发生、发展中 Sonic hedgehog 通路激活是激发或促进因素，该信号通路可能促进 PTC 的生长、转移。
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Sonic Hedgehog (Shh) is a critical signaling factor for a variety of developmental pathways during embryogenesis, including the specification of left-right asymmetry in the heart. Mice that lack Hedgehog signaling show a delay in the induction of cardiomyogenesis, as indicated by a delayed expression of Nkx2-5. To further examine a role for Shh in cardiomyogenesis, clonal populations of P19 cells that stably express Shh, termed P19(Shh) cells, were isolated. In monolayer P19(Shh) cultures the Shh pathway was functional as shown by the up-regulation of Ptc1 and Gli1 expression, but no cardiac muscle markers were activated. However, Shh expression induced cardiomyogenesis following cellular aggregation, resulting in the expression of factors expressed in cardiac muscle including GATA-4, MEF2C, and Nkx2-5. Furthermore, aggregated P19 cell lines expressing Gli2 or Meox1 also up-regulated the expression of cardiac muscle factors, leading to cardiomyogenesis. Meox1 up-regulated the expression of Gli1 and Gli2 and, thus, can modify the Shh signaling pathway. Finally, Shh, Gli2, and Meox1 all up-regulated BMP-4 expression, implying that activation of the Hedgehog pathway can regulate bone morphogenetic protein signals. Taken together, we propose a model in which Shh, functioning via Gli1/2, can specify mesodermal cells into the cardiac muscle lineage.
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Medulloblastoma (MB) is the most common malignant brain tumor of childhood arising from deregulated cerebellar development. Sonic Hedgehog (Shh) pathway plays a critical role in cerebellar development and its aberrant expression has been identified in MB. Gene expression profiling of cerebella from 1- to 14-day-old mice unveiled a cluster of genes whose expression correlates with the levels of Hedgehog (HH) activity. From this cluster, we identified Insm1 and Nhlh1/NSCL1 as novel HH targets induced by Shh treatment in cultured cerebellar granule cell progenitors. Nhlh1 promoter was found to be bound and activated by Gli1 transcription factor. Remarkably, the expression of these genes is also upregulated in mouse and human HH-dependent MBs, suggesting that they may be either a part of the HH-induced tumorigenic process or a specific trait of HH-dependent tumor cells.
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The Sonic hedgehog (Shh) signaling pathway plays a critical role in normal cerebellar development and has been implicated in medulloblastomas, common malignant childhood tumors of the cerebellum. To test whether Shh mis-expression is sufficient for medulloblastoma formation, we used ultrasound biomicroscopy-guided in utero injection of a Shh-expressing retrovirus into the cerebellum of 13.5-day mouse embryos to show that direct activation of the Shh pathway can lead to tumor formation. Significantly, medulloblastomas were observed in 76% of the mice infected with Shh-expressing retrovirus. Furthermore, contrary to recent suggestions that the Shh transcriptional target Gli1 plays a critical role in Shh-induced tumorigenesis, we found that medulloblastomas form in Gli1 null mutant mice. We have developed an efficient mouse model of medulloblastoma and shown that Gli1 is not required for tumorigenesis when Shh signaling is activated upstream in the pathway.
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AIM:To investigate the role of Sonic hedgehog(Shh) signaling pathway in renal interstitial fibrosis in the rats with unilateral ureteral obstruction(UUO).METHODS: Forty-eight male Sprague-Dawley rats were divided randomly into sham operation group and UUO model group with 24 rats each.The kidneys were excised on day 3,7,and 14,and the deposition of collagen fiber in the kidneys was detected with HE and Masson staining.Immunohistochemical analysis was performed to evaluate the expression of Shh signaling pathway-related proteins,including Shh,Smo,Ptch1 and Gli1.The contents of TGF-β1 and Shh in the kidney tissues were determined by ELISA.Real-time RT-PCR was used to detect the mRNA expression of TGF-β1,Col I,Col Ⅲ and Shh signaling-related genes.RESULTS: Fibrosis observed with HE and Masson staining was obviously increased in UUO kidneys,and aggravated as time prolonged.The contents of TGF-β1,Col I and Col Ⅲ were also increased.In addition,the expression of Shh,Smo and Gli1 was markedly increased in obstructive kidneys,and the expression of Ptch1 was decreased(P0.01),suggesting that Shh signaling was activated.The level of Shh in UUO rats was associated with the content of TGF-β1.CONCLUSION: Shh signaling is activated in the progress of renal interstitial fibrosis in UUO rats,and the possible mechanism triggering the fibrogenic response is that Shh signaling promotes the expression of TGF-β1.
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The sonic hedgehog (Shh) signaling pathway is not only critical for brain development but also contributes to glioma growth. It was reported that glioma samples showed high expression of Gli1/Gli2 transcription factors. There was even a positive correlation between Shh and Gli1 expression, which suggests the role of the Shh signaling pathway in brain tumor development (Fig. 5.1) (Dahmane et al. 2001).
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The hedgehog pathway plays a critical role in the development of the foregut. Recent studies indicate that the hedgehog pathway activation occurs in the stomach and other gastrointestinal cancers. However, the association of hedgehog pathway activation with tumor stage, differentiation and tumor subtype is not well documented. Here, we report our findings that the elevated expression of hedgehog target genes human patched gene 1 (PTCH1) or Gli1 occurs in 63 of the 99 primary gastric cancers. Activation of the hedgehog pathway is associated with poorly differentiated and more aggressive tumors. The sonic hedgehog (Shh) transcript is localized to the cancer tissue, whereas expression of Gli1 and PTCH1 is observed both in the cancer and in the surrounding stroma. Treatment of gastric cancer cells with KAAD-cyclopamine, a hedgehog signaling inhibitor, decreases expression of Gli1 and PTCH1, resulting in cell growth inhibition and apoptosis. Overexpression of Gli1 under the control of the cytomegalovirus (CMV) promoter renders these cells resistant to cyclopamine-induced apoptosis. Thus, our analysis of in vivo tissues indicates that the hedgehog pathway is frequently activated in advanced gastric adenocarcinomas; our in vitro studies suggest that hedgehog signaling contributes to gastric cancer cell growth. These data predict that targeted inhibition of the hedgehog pathway may be effective in the prevention and treatment of advanced gastric adenocarcinomas.
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The effects of Sonic hedgehog(Shh) signaling pathway activation on S-type neuroblastoma(NB) cell lines and its role in NB tumorigenesis were investigated.Immunohistochemistry was used to detect the expression of Shh pathway components- Patched1(PTCH1) and Gli1 in 40 human primary NB samples.Western blotting and RT-PCR were used to examine the protein expression and mRNA levels of PTCH1 and Gli1 in three kinds of S-type NB cell lines(SK-N-AS,SK-N-SH and SHEP1),respectively.Exogenous Shh was administrated to ...
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