Jinghui Zhang, Jiajun Fan, Xian Zeng, Mingming Nie, Jingyun Luan, Yichen Wang, Dianwen Ju, Kai Yin. Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 609-620

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment
Jinghui Zhanga,b, Jiajun Fanb,c, Xian Zengb,c, Mingming Niea, Jingyun Luanb,c, Yichen Wangb,c, Dianwen Jub,c, Kai Yina
a Department of Gastrointestinal Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China;
b Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China;
c Shanghai Engineering Research Center of Immunotherapeutics, Shanghai 201203, China
The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.
Key words:    Hedgehog    Carcinogenesis    Tumor microenvironment    Gastrointestinal cancer    Cancer stem cells    Drug resistance   
Received: 2020-06-01     Revised: 2020-07-29
DOI: 10.1016/j.apsb.2020.10.022
Funds: This work was supported by Scientific Research Project of Shanghai Health and Family Planning Committee (Grant No. 201640017, China), National Science and Technology Major Project (Grant No. 2017ZX09304030, China), and Shanghai Science and Technology Funds (Grant No. 19ZR1456100, China).
Corresponding author: Dianwen Ju, Kai Yin;
Author description:
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Jinghui Zhang
Jiajun Fan
Xian Zeng
Mingming Nie
Jingyun Luan
Yichen Wang
Dianwen Ju
Kai Yin

1. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell 2008;15:801-12.
2. Merchant JL. Hedgehog signalling in gut development, physiology and cancer. J Physiol 2012;590:421-32.
3. van den Brink GR. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol Rev 2007;87:1343-75.
4. Hanna A, Shevde LA. Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment. Mol Canc 2016;15:24.
5. Noah TK, Donahue B, Shroyer NF. Intestinal development and differentiation. Exp Cell Res 2011;317:2702-10.
6. Kolterud A, Grosse AS, Zacharias WJ, Walton KD, Kretovich KE, Madison BB, et al. Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. Gastroenterology 2009;137:618-28.
7. Konstantinou D, Bertaux-Skeirik N, Zavros Y. Hedgehog signaling in the stomach. Curr Opin Pharmacol 2016;31:76-82.
8. Waszak SM, Robinson GW, Gudenas BL, Smith KS, Forget A, Kojic M, et al. Germline elongator mutations in Sonic Hedgehog medulloblastoma. Nature 2020;580:396-401.
9. Polizio AH, Chinchilla P, Chen X, Manning DR, Riobo NA. Sonic Hedgehog activates the GTPases Rac1 and RhoA in a Gliindependent manner through coupling of smoothened to Gi proteins. Sci Signal 2011;4:pt7.
10. Carballo GB, Honorato JR, de Lopes GPF, Spohr T. A highlight on Sonic hedgehog pathway. Cell Commun Signal 2018;16:11.
11. Will AJ, Cova G, Osterwalder M, Chan WL, Wittler L, Brieske N, et al. Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog). Nat Genet 2017;49:1539-45.
12. Gong X, Qian H, Cao P, Zhao X, Zhou Q, Lei J, et al. Structural basis for the recognition of Sonic Hedgehog by human Patched1. Science 2018;361:eaas8935.
13. Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol 2011;27:513-37.
14. Huang P, Zheng S, Wierbowski BM, Kim Y, Nedelcu D, Aravena L, et al. Structural basis of smoothened activation in Hedgehog signaling. Cell 2018;174:312-324 e16.
15. Zhang Y, Fu L, Qi X, Zhang Z, Xia Y, Jia J, et al. Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci. Nat Commun 2013;4:2608.
16. Infante P, Faedda R, Bernardi F, Bufalieri F, Lospinoso Severini L, Alfonsi R, et al. Itch/beta-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis. Nat Commun 2018;9:976.
17. Lex RK, Ji Z, Falkenstein KN, Zhou W, Henry JL, Ji H, et al. GLI transcriptional repression regulates tissue-specific enhancer activity in response to Hedgehog signaling. Elife 2020;9:e50670.
18. Milenkovic L, Scott MP. Not lost in space: trafficking in the hedgehog signaling pathway. Sci Signal 2010;3:pe14.
19. He M, Subramanian R, Bangs F, Omelchenko T, Liem KF Jr, Kapoor TM, et al. The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nat Cell Biol 2014;16:663-72.
20. Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M, et al. Betaarrestin-mediated localization of smoothened to the primary cilium. Science 2008;320:1777-81.
21. Zhao Z, Lee RT, Pusapati GV, Iyu A, Rohatgi R, Ingham PW. An essential role for Grk2 in Hedgehog signalling downstream of Smoothened. EMBO Rep 2016;17:739-52.
22. Zhang W, Yu F, Wang Y, Zhang Y, Meng L, Chi Y. Rab23 promotes the cisplatin resistance of ovarian cancer via the Shh-Gli-ABCG2 signaling pathway. Oncol Lett 2018;15:5155-60.
23. Moore BS, Stepanchick AN, Tewson PH, Hartle CM, Zhang J, Quinn AM, et al. Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics. Proc Natl Acad Sci U S A 2016;113:13069-74.
24. Jagani Z, Mora-Blanco EL, Sansam CG, McKenna ES, Wilson B, Chen D, et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the HedgehogeGli pathway. Nat Med 2010;16:1429-33.
25. Li N, Truong S, Nouri M, Moore J, Al Nakouzi N, Lubik AA, et al. Non-canonical activation of hedgehog in prostate cancer cells mediated by the interaction of transcriptionally active androgen receptor proteins with Gli3. Oncogene 2018;37:2313-25.
26. Pelullo M, Zema S, Nardozza F, Checquolo S, Screpanti I, Bellavia D. Wnt, Notch, and TGF-beta pathways impinge on Hedgehog signaling complexity: an open window on cancer. Front Genet 2019;10:711.
27. Della Corte CM, Bellevicine C, Vicidomini G, Vitagliano D, Malapelle U, Accardo M, et al. SMO gene amplification and activation of the Hedgehog pathway as novel mechanisms of resistance to anti-epidermal growth factor receptor drugs in human lung cancer. Clin Canc Res 2015;21:4686-97.
28. Gerling M, Buller NV, Kirn LM, Joost S, Frings O, Englert B, et al. Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth. Nat Commun 2016;7:12321.
29. Yoon C, Park DJ, Schmidt B, Thomas NJ, Lee HJ, Kim TS, et al. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin Canc Res 2014;20:3974-88.
30. Cui ML, Yang HY, He GQ. Apoptosis induction of colorectal cancer cells HTL-9 in vitro by the transformed products of soybean isoflavones by Ganoderma lucidum. J Zhejiang Univ Sci B 2017;18: 1101-12.
31. Huang W, Wan C, Luo Q, Huang Z, Luo Q. Genistein-inhibited cancer stem cell-like properties and reduced chemoresistance of gastric cancer. Int J Mol Sci 2014;15:3432-43.
32. Jiang J, Dong L, Shi HT, Guo XY, Qin B, Wang Y, et al. Imiquimod inhibits the growth of SGC7901 cells in vitro through induction of autophagy and apoptosis. Mol Med Rep 2016;13:393-7.
33. Song Z, Yue W, Wei B, Wang N, Li T, Guan L, et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS One 2011;6:e17687.
34. Magistri P, Battistelli C, Strippoli R, Petrucciani N, Pellinen T, Rossi L, et al. SMO inhibition modulates cellular plasticity and invasiveness in colorectal cancer. Front Pharmacol 2017;8:956.
35. Berlin J, Bendell JC, Hart LL, Firdaus I, Gore I, Hermann RC, et al. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Canc Res 2013;19:258-67.
36. Baek S, Lee YS, Shim HE, Yoon S, Baek SY, Kim BS, et al. Vitamin D3 regulates cell viability in gastric cancer and cholangiocarcinoma. Anat Cell Biol 2011;44:204-9.
37. Bi X, Shi Q, Zhang H, Bao Y, Hu D, Pohl N, et al. c-Jun NH2-teminal kinase 1 interacts with vitamin D receptor and affects vitamin Dmediated inhibition of cancer cell proliferation. J Steroid Biochem Mol Biol 2016;163:164-72.
38. Milczarek M, Psurski M, Kutner A, Wietrzyk J. Vitamin D analogs enhance the anticancer activity of 5-fluorouracil in an in vivo mouse colon cancer model. BMC Canc 2013;13:294.
39. Available from: on 10 2 2020).
40. Goldman J, Eckhardt SG, Borad MJ, Curtis KK, Hidalgo M, Calvo E, et al. Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors. Clin Canc Res 2015;21:1002-9.
41. Ma H, Tian Y, Yu X. Targeting smoothened sensitizes gastric cancer to chemotherapy in experimental models. Med Sci Monit 2017;23: 1493-500.
42. Hu Q, Hou YC, Huang J, Fang JY, Xiong H. Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells. J Exp Clin Canc Res 2017;36:50.
43. Popova SA, Buczacki SJA. Itraconazole perturbs colorectal cancer dormancy through SUFU-mediated WNT inhibition. Mol Cell Oncol 2018;5:e1494950.
44. Buczacki SJA, Popova S, Biggs E, Koukorava C, Buzzelli J, Vermeulen L, et al. Itraconazole targets cell cycle heterogeneity in colorectal cancer. J Exp Med 2018;215:1891-912.
45. Deng M, Zeng C, Lu X, He X, Zhang R, Qiu Q, et al. miR-218 suppresses gastric cancer cell cycle progression through the CDK6/Cyclin D1/E2F1 axis in a feedback loop. Canc Lett 2017;403: 175-85.
46. He X, Dong Y, Wu CW, Zhao Z, Ng SS, Chan FK, et al. MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene. Mol Med 2013;18:1491-8.
47. Lun W, Wu X, Deng Q, Zhi F. MiR-218 regulates epithelialmesenchymal transition and angiogenesis in colorectal cancer via targeting CTGF. Canc Cell Int 2018;18:83.
48. Roberg-Larsen H, Strand MF, Grimsmo A, Olsen PA, Dembinski JL, Rise F, et al. High sensitivity measurements of active oxysterols with automated filtration/filter backflush-solid phase extractioneliquid chromatographyemass spectrometry. J Chromatogr A 2012;1255: 291-7.
49. Gu H, Li XU, Zhou C, Wen Y, Shen Y, Zhou L, et al. Effects and mechanisms of blocking the hedgehog signaling pathway in human gastric cancer cells. Oncol Lett 2015;9:1997-2002.
50. Qualtrough D, Rees P, Speight B, Williams AC, Paraskeva C. The Hedgehog inhibitor cyclopamine reduces beta-catenin-Tcf transcriptional activity, induces E-cadherin expression, and reduces invasion in colorectal cancer cells. Cancers (Basel) 2015;7: 1885-99.
51. Yoo YA, Kang MH, Kim JS, Oh SC. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis 2008;29:480-90.
52. He W, Xia Y, Cao P, Hong L, Zhang T, Shen X, et al. Curcuminoid WZ35 synergize with cisplatin by inducing ROS production and inhibiting TrxR1 activity in gastric cancer cells. J Exp Clin Canc Res 2019;38:207.
53. Zhou X, Wang W, Li P, Zheng Z, Tu Y, Zhang Y, et al. Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in inducing gastric cancer cell apoptosis both in vitro and in vivo. Oncol Res 2016;23:29-34.
54. Li M, Yue GG, Tsui SK, Fung KP, Lau CB. Turmeric extract, with absorbable curcumin, has potent anti-metastatic effect in vitro and in vivo. Phytomedicine 2018;46:131-41.
55. Gao Q, Yuan Y, Gan HZ, Peng Q. Resveratrol inhibits the hedgehog signaling pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis. Oncol Lett 2015;9: 2381-7.
56. Yang S, Li W, Sun H, Wu B, Ji F, Sun T, et al. Resveratrol elicits anticolorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo. BMC Canc 2015;15:969.
57. Ran ZH, Xu Q, Tong JL, Xiao SD. Apoptotic effect of Epigallocatechin-3-gallate on the human gastric cancer cell line MKN45 via activation of the mitochondrial pathway. World J Gastroenterol 2007;13:4255-9.
58. Jin G, Yang Y, Liu K, Zhao J, Chen X, Liu H, et al. Combination curcumin and (e)-epigallocatechin-3-gallate inhibits colorectal carcinoma microenvironment-induced angiogenesis by JAK/STAT3/IL-8 pathway. Oncogenesis 2017;6:e384.
59. Chen Z, Zhang H, Yang L, Jiang H, Guo S, Li Y, et al. Construction of a metabolomics profile of arsenic trioxide effect in gastric carcinoma cell line SGC7901. Acta Biochim Biophys Sin (Shanghai) 2016;48:474-81.
60. Sun XP, Zhang X, He C, Qiao H, Jiang X, Jiang H, et al. ABT-737 synergizes with arsenic trioxide to induce apoptosis of gastric carcinoma cells in vitro and in vivo. J Int Med Res 2012;40:1251-64.
61. Thomas-Schoemann A, Batteux F, Mongaret C, Nicco C, Chereau C, Annereau M, et al. Arsenic trioxide exerts antitumor activity through regulatory T cell depletion mediated by oxidative stress in a murine model of colon cancer. J Immunol 2012;189:5171-7.
62. Yan R, Peng X, Yuan X, Huang D, Chen J, Lu Q, et al. Suppression of growth and migration by blocking the Hedgehog signaling pathway in gastric cancer cells. Cell Oncol (Dordr) 2013;36:421-35.
63. Chakrabarti J, Holokai L, Syu L, Steele NG, Chang J, Wang J, et al. Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer. Oncotarget 2018;9:37439-57.
64. Mazumdar T, Devecchio J, Agyeman A, Shi T, Houghton JA. Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells. Canc Res 2011;71:5904-14.
65. Sithara T, Dhanya BP, Arun KB, Sini S, Dan M, Kokkuvayil Vasu R, et al. Zerumbone, a cyclic sesquiterpene from Zingiber zerumbet induces apoptosis, cell cycle arrest, and antimigratory effects in SW480 colorectal cancer cells. J Agric Food Chem 2018;66:602-12.
66. Othumpangat S, Kashon M, Joseph P. Sodium arsenite-induced inhibition of eukaryotic translation initiation factor 4E (eIF4E) results in cytotoxicity and cell death. Mol Cell Biochem 2005;279:123-31.
67. Usui T, Sakurai M, Umata K, Elbadawy M, Ohama T, Yamawaki H, et al. Hedgehog signals mediate anti-cancer drug resistance in threedimensional primary colorectal cancer organoid culture. Int J Mol Sci 2018;19:1098.
68. Xin M, Ji X, de La Cruz LK, Thareja S, Wang B. Strategies to target the Hedgehog signaling pathway for cancer therapy. Med Res Rev 2018;38:870-913.
69. Bhateja P, Cherian M, Majumder S, Ramaswamy B. The Hedgehog signaling pathway: a viable target in breast cancer?. Cancers (Basel) 2019;11.
70. Hanna A, Metge BJ, Bailey SK, Chen D, Chandrashekar DS, Varambally S, et al. Inhibition of Hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer. OncoImmunology 2019;8:1548241.
71. Mpekris F, Papageorgis P, Polydorou C, Voutouri C, Kalli M, Pirentis AP, et al. Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy. J Control Release 2017;261:105-12.
72. Jeng KS, Chang CF, Lin SS. Sonic Hedgehog signaling in organogenesis, tumors, and tumor microenvironments. Int J Mol Sci 2020; 21:758.
73. Ding L, Hayes MM, Photenhauer A, Eaton KA, Li Q, Ocadiz-Ruiz R, et al. Schlafen 4-expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia. J Clin Invest 2016;126: 2867-80.
74. Merchant JL, Ding L. Hedgehog signaling links chronic inflammation to gastric cancer precursor lesions. Cell Mol Gastroenterol Hepatol 2017;3:201-10.
75. Schumacher MA, Donnelly JM, Engevik AC, Xiao C, Yang L, Kenny S, et al. Gastric sonic Hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori. Gastroenterology 2012;142:1150-1159 e6.
76. Echizen K, Horiuchi K, Aoki Y, Yamada Y, Minamoto T, Oshima H, et al. NF-kappaB-induced NOX1 activation promotes gastric tumorigenesis through the expansion of SOX2-positive epithelial cells. Oncogene 2019;38:4250-63.
77. Wessler S, Krisch LM, Elmer DP, Aberger F. From inflammation to gastric cancerdthe importance of Hedgehog/GLI signaling in Helicobacter pylori-induced chronic inflammatory and neoplastic diseases. Cell Commun Signal 2017;15:15.
78. Merchant JL, Saqui-Salces M. Inhibition of Hedgehog signaling in the gastrointestinal tract: targeting the cancer microenvironment. Canc Treat Rev 2014;40:12-21.
79. Dong H, Liu H, Zhou W, Zhang F, Li C, Chen J, et al. GLI1 activation by non-classical pathway integrin αvβ3/ERK1/2 maintains stem cell-like phenotype of multicellular aggregates in gastric cancer peritoneal metastasis. Cell Death Dis 2019;10:574.
80. Holokai L, Chakrabarti J, Broda T, Chang J, Hawkins JA, Sundaram N, et al. Increased programmed death-ligand 1 is an early epithelial cell response to Helicobacter pylori infection. PLoS Pathog 2019;15:e1007468.
81. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 2015;12:445-64.
82. Batsaikhan BE, Yoshikawa K, Kurita N, Iwata T, Takasu C, Kashihara H, et al. Cyclopamine decreased the expression of Sonic Hedgehog and its downstream genes in colon cancer stem cells. Anticancer Res 2014;34:6339-44.
83. Zhou H, Xiong Y, Peng L, Wang R, Zhang H, Fu Z. LncRNA-cCSC1 modulates cancer stem cell properties in colorectal cancer via activation of the Hedgehog signaling pathway. J Cell Biochem 2020;121: 2510-24.
84. Yu D, Shin HS, Lee YS, Lee D, Kim S, Lee YC. Genistein attenuates cancer stem cell characteristics in gastric cancer through the downregulation of Gli1. Oncol Rep 2014;31:673-8.
85. Xu M, Gong A, Yang H, George SK, Jiao Z, Huang H, et al. Sonic hedgehog-glioma associated oncogene homolog 1 signaling enhances drug resistance in CD44+/Musashi-1+ gastric cancer stem cells. Canc Lett 2015;369:124-33.
86. Chen JH, Zhai ET, Chen SL, Wu H, Wu KM, Zhang XH, et al. CD44, Sonic Hedgehog, and Gli1 expression are prognostic biomarkers in gastric cancer patients after radical resection. Gastroenterol Res Pract 2016;2016:1013045.
87. Syu LJ, Zhao X, Zhang Y, Grachtchouk M, Demitrack E, Ermilov A, et al. Invasive mouse gastric adenocarcinomas arising from Lgr5+ stem cells are dependent on crosstalk between the Hedgehog/GLI2 and mTOR pathways. Oncotarget 2016;7:10255-70.
88. Yang Z, Zhang C, Qi W, Cui Y, Xuan Y. GLI1 promotes cancer stemness through intracellular signaling pathway PI3K/Akt/NFkappaB in colorectal adenocarcinoma. Exp Cell Res 2018;373:145-54.
89. Ruiz i Altaba A. Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. Sci Signal 2011;4:pt9.
90. Regan JL, Schumacher D, Staudte S, Steffen A, Haybaeck J, Keilholz U, et al. Non-canonical Hedgehog signaling is a positive regulator of the WNT pathway and is required for the survival of colon cancer stem cells. Cell Rep 2017;21:2813-28.
91. Yan GN, Yang L, Lv YF, Shi Y, Shen LL, Yao XH, et al. Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway. J Pathol 2014;234:11-22.
92. Fu YZ, Yan YY, He M, Xiao QH, Yao WF, Zhao L, et al. Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway. Oncol Rep 2016; 35:912-22.
93. Yao Y, Zhou D, Shi D, Zhang H, Zhan S, Shao X, et al. GLI1 overexpression promotes gastric cancer cell proliferation and migration and induces drug resistance by combining with the AKTmTOR pathway. Biomed Pharmacother 2019;111:993-1004.
94. Yu B, Gu D, Zhang X, Liu B, Xie J. The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer. J Genet Genomics 2017;44:375-83.
95. Zeng F, Wang F, Zheng Z, Chen Z, Wah To KK, Zhang H, et al. Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo. Acta Pharm Sin B 2020;10:799-811.
96. Tang YA, Chen YF, Bao Y, Mahara S, Yatim S, Oguz G, et al. Hypoxic tumor microenvironment activates GLI2 via HIF-1alpha and TGF-beta2 to promote chemoresistance in colorectal cancer. Proc Natl Acad Sci U S A 2018;115:E5990-9.
97. Zhang L, Song R, Gu D, Zhang X, Yu B, Liu B, et al. The role of GLI1 for 5-Fu resistance in colorectal cancer. Cell Biosci 2017;7: 17.
98. Zhao J, Xiao Z, Li T, Chen H, Yuan Y, Wang YA, et al. Stromal modulation reverses primary resistance to immune checkpoint blockade in pancreatic cancer. ACS Nano 2018;12:9881-93.
99. Cheng HS, Lee JXT, Wahli W, Tan NS. Exploiting vulnerabilities of cancer by targeting nuclear receptors of stromal cells in tumor microenvironment. Mol Canc 2019;18:51.
100. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci 2012;125:5591-6.
101. Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B 2015;5:402-18.
102. Xiao C, Feng R, Engevik AC, Martin JR, Tritschler JA, Schumacher M, et al. Sonic Hedgehog contributes to gastric mucosal restitution after injury. Lab Invest 2013;93:96-111.
103. Shaker A, Binkley J, Darwech I, Swietlicki E, McDonald K, Newberry R, et al. Stromal cells participate in the murine esophageal mucosal injury response. Am J Physiol Gastrointest Liver Physiol 2013;304:G662-72.
104. Shahi MH, Rey JA, Castresana JS. The sonic hedgehogeGLI1 signaling pathway in brain tumor development. Expert Opin Ther Targets 2012;16:1227-38.
105. Heller E, Hurchla MA, Xiang J, Su X, Chen S, Schneider J, et al. Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Canc Res 2012;72: 897-907.
106. Arcucci A, Ruocco MR, Granato G, Sacco AM, Montagnani S. Cancer: an oxidative crosstalk between solid tumor cells and cancer associated fibroblasts. BioMed Res Int 2016;2016:4502846.
107. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Canc 2020;20:174-86.
108. von Ahrens D, Bhagat TD, Nagrath D, Maitra A, Verma A. The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol 2017;10:76.
109. Valenti G, Quinn HM, Heynen G, Lan L, Holland JD, Vogel R, et al. Cancer stem cells regulate cancer-associated fibroblasts via activation of Hedgehog signaling in mammary gland tumors. Canc Res 2017;77:2134-47.
110. Walter K, Omura N, Hong SM, Griffith M, Vincent A, Borges M, et al. Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. Clin Canc Res 2010;16:1781-9.
111. Zhao J, Wang H, Hsiao CH, Chow DS, Koay EJ, Kang Y, et al. Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy. Biomaterials 2018;159:215-28.
112. Kinoshita H, Hirata Y, Nakagawa H, Sakamoto K, Hayakawa Y, Takahashi R, et al. Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. PLoS One 2013;8: e60914.
113. Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Canc Res 2015;128:95-139.
114. Shintani Y, Fujiwara A, Kimura T, Kawamura T, Funaki S, Minami M, et al. IL-6 secreted from cancer-associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelialmesenchymal transition signaling. J Thorac Oncol 2016;11: 1482-92.
115. Reyes-Ramos AM, Ramos-Cruz KP, Rodriguez-Merced NJ, Martinez-Montemayor MM, Franqui-Rios ND, Rios-Grant JP, et al. Mesenchymal cells support the oncogenicity and therapeutic response of the Hedgehog pathway in triple-negative breast cancer. Cancers (Basel) 2019;11:1522.
116. Liu J, Chen S, Wang W, Ning BF, Chen F, Shen W, et al. Cancerassociated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-beta pathways. Canc Lett 2016;379:49-59.
117. Zhu Q, Zhang X, Zhang L, Li W, Wu H, Yuan X, et al. The IL6—STAT3 axis mediates a reciprocal crosstalk between cancerderived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. Cell Death Dis 2014;5:e1295.
118. Sternberg C, Gruber W, Eberl M, Tesanovic S, Stadler M, Elmer DP, et al. Synergistic cross-talk of hedgehog and interleukin-6 signaling drives growth of basal cell carcinoma. Int J Canc 2018;143: 2943-54.
119. Zhao G, Li H, Guo Q, Zhou A, Wang X, Li P, et al. Exosomal Sonic Hedgehog derived from cancer-associated fibroblasts promotes proliferation and migration of esophageal squamous cell carcinoma. Canc Med 2020;9:2500-13.
120. Li T, Yi S, Liu W, Jia C, Wang G, Hua X, et al. Colorectal carcinomaderived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Med Oncol 2013;30:663.
121. Margol AS, Robison NJ, Gnanachandran J, Hung LT, Kennedy RJ, Vali M, et al. Tumor-associated macrophages in SHH subgroup of medulloblastomas. Clin Canc Res 2015;21:1457-65.
122. Petty AJ, Li A, Wang X, Dai R, Heyman B, Hsu D, et al. Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8þ T cell recruitment. J Clin Invest 2019; 129:5151-62.
123. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity 2010;32:593-604.
124. Jin Q, Gui L, Niu F, Yu B, Lauda N, Liu J, et al. Macrophages in keloid are potent at promoting the differentiation and function of regulatory T cells. Exp Cell Res 2018;362:472-6.
125. Standing ASI, Yanez DC, Ross R, Crompton T, Furmanski AL. Frontline science: Shh production and Gli signaling is activated in vivo in lung, enhancing the Th2 response during a murine model of allergic asthma. J Leukoc Biol 2017;102:965-76.
126. Ryzhakov G, West NR, Franchini F, Clare S, Ilott NE, Sansom SN, et al. Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis. Nat Commun 2018;9:3797.
127. Nizzoli G, Krietsch J, Weick A, Steinfelder S, Facciotti F, Gruarin P, et al. Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses. Blood 2013;122:932-42.
128. Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Canc 2013;13:739-52.
129. Xie J. The hedgehog’s trick for escaping immunosurveillance: the molecular mechanisms driving myeloid-derived suppressor cell recruitment in hedgehog signaling-dependent tumors. OncoImmunology 2014;3:e29180.
130. Chen X, Pan X, Zhang W, Guo H, Cheng S, He Q, et al. Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses. Acta Pharm Sin B 2020;10: 723-33.
131. Fan F, Wang R, Boulbes DR, Zhang H, Watowich SS, Xia L, et al. Macrophage conditioned medium promotes colorectal cancer stem cell phenotype via the hedgehog signaling pathway. PLoS One 2018; 13:e0190070.
132. Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, DosakaAkita H, et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci U S A 2011;108:12425-30.
133. Otsuka A, Dreier J, Cheng PF, Nageli M, Lehmann H, Felderer L, et al. Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma. Clin Canc Res 2015;21:1289-97.
134. Katoh M. Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers. Clin Sci (Lond) 2019; 133:953-70.
135. Xu M, Li X, Liu T, Leng A, Zhang G. Prognostic value of hedgehog signaling pathway in patients with colon cancer. Med Oncol 2012;29: 1010-6.
136. Ertao Z, Jianhui C, Chuangqi C, Changjiang Q, Sile C, Yulong H, et al. Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cgamma1 and the ERK1/2 pathway. J Exp Clin Canc Res 2016;35:63.
137. Li T, Liao X, Lochhead P, Morikawa T, Yamauchi M, Nishihara R, et al. SMO expression in colorectal cancer: associations with clinical, pathological, and molecular features. Ann Surg Oncol 2014;21: 4164-73.
138. Lu L, Wu M, Zhao F, Fu W, Li W, Li X, et al. Prognostic and clinicopathological value of Gli-1 expression in gastric cancer: a meta-analysis. Oncotarget 2016;7:69087-96.
139. Tang CT, Lin XL, Wu S, Liang Q, Yang L, Gao YJ, et al. NOX4-driven ROS formation regulates proliferation and apoptosis of gastric cancer cells through the GLI1 pathway. Cell Signal 2018;46:52-63.
140. Peng Y, Zhang X, Ma Q, Yan R, Qin Y, Zhao Y, et al. MiRNA-194 activates the Wnt/beta-catenin signaling pathway in gastric cancer by targeting the negative Wnt regulator, SUFU. Canc Lett 2017;385: 117-27.
141. Xu Y, Song S, Wang Z, Ajani JA. The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective. Cell Commun Signal 2019;17:157.
142. Bonilla X, Parmentier L, King B, Bezrukov F, Kaya G, Zoete V, et al. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat Genet 2016;48:398-406.
143. Wang XD, Inzunza H, Chang H, Qi Z, Hu B, Malone D, et al. Mutations in the hedgehog pathway genes SMO and PTCH1 in human gastric tumors. PLoS One 2013;8:e54415.
144. Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D, et al. Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS Med Chem Lett 2010;1:130-4.
145. Frampton JE, Basset-Seguin N. Vismodegib: a review in advanced basal cell carcinoma. Drugs 2018;78:1145-56.
146. Basset-Seguin N, Hauschild A, Kunstfeld R, Grob J, Dreno B, Mortier L, et al. Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE, an international, open-label trial. Eur J Canc 2017;86:334-48.
147. Basset-Seguin N, Hauschild A, Grob JJ, Kunstfeld R, Dreno B, Mortier L, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol 2015;16:729-36.
148. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012;366:2171-9.
149. Koelblinger P, Lang R. New developments in the treatment of basal cell carcinoma: update on current and emerging treatment options with a focus on vismodegib. OncoTargets Ther 2018;11:8327-40.
150. Zhang H, Sun Z, Liu Z, Song C. Overcoming the emerging drug resistance of smoothened: an overview of small-molecule SMO antagonists with antiresistance activity. Future Med Chem 2018;10: 2855-75.
151. Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. Targeting the Sonic Hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel) 2016;8:22.
152. Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLImediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A 2007;104:8455-60.
153. Maun HR, Wen X, Lingel A, de Sauvage FJ, Lazarus RA, Scales SJ, et al. Hedgehog pathway antagonist 5-1 binds hedgehog at the pseudo-active site. J Biol Chem 2010;285:26570-80.
154. Xiao C, Ogle SA, Schumacher MA, Schilling N, Tokhunts RA, OrrAsman MA, et al. Hedgehog signaling regulates E-cadherin expression for the maintenance of the actin cytoskeleton and tight junctions. Am J Physiol Gastrointest Liver Physiol 2010;299:G1252-65.
155. Raleigh DR, Reiter JF. Misactivation of Hedgehog signaling causes inherited and sporadic cancers. J Clin Invest 2019;129:465-75.
156. Zeng X, Ju D. Hedgehog signaling pathway and autophagy in cancer. Int J Mol Sci 2018;19:2279.
157. Wu F, Zhang Y, Sun B, McMahon AP, Wang Y. Hedgehog signaling: from basic biology to cancer therapy. Cell Chem Biol 2017;24: 252-80.
158. Zeng X, Zhao H, Li Y, Fan J, Sun Y, Wang S, et al. Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia. Autophagy 2015;11:355-72.
159. Fan J, Zhang X, Wang S, Chen W, Li Y, Zeng X, et al. Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production. Cell Death Dis 2019;10:626.
160. Christos CD, Paul J, Sparano JA, Kindler HL, Virgil D, Catenacci T, et al. Vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX for first-line therapy of patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: a New York Cancer Consortium led phase II randomized study. J Clin Oncol 2013;31(Suppl):abs4011.
161. Wu X, Hu W, Lu L, Zhao Y, Zhou Y, Xiao Z, et al. Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment. Acta Pharm Sin B 2019;9:203-19.
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