Membrane-bound Full-length Sonic Hedgehog Identifies Cancer Stem Cells in Human Non-small Cell Lung Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Dec 22

PMID 29262597

Citations 17

Authors

Etienne Giroux Leprieur

Bhairavi Tolani

Hui Li

Fleur Leguay

Ngoc T Hoang

Luis A Acevedo

Joy Q Jin

Hsin-Hui Tseng

Dongsheng Yue

Il-Jin Kim

Marie Wislez

Changli Wang

David M Jablons

Biao He

Affiliations

Soon will be listed here.

Abstract

The mechanism of Sonic Hedgehog (Shh) pathway activation in non-small cell lung cancer (NSCLC) is poorly described. Using an antibody against the Shh C-terminal domain, we found a small population of Shh-positive (Shh+) cells in NSCLC cells. The objective of this study was to characterize these Shh+ cells. Shh+ and Shh- cells were sorted by using Fluorescence Activated Cell Sorting (FACS) on 12 commercial NSCLC cell lines. Functional analyses on sorted cells were performed with gene expression assays (qRT-PCR and microarray) and cells were treated with cytotoxic chemotherapy and a targeted inhibitor of Shh signaling (GDC0449). We used models of nude mice inoculated with Shh+ and Shh- sorted cells and drug-treated cells. Finally, we confirmed our results in fresh human NSCLC samples (n=48) paired with normal lung tissue. We found that Shh+ cells produced an uncleaved, full-length Shh protein detected on the membranes of these cells. Shh+ cells exerted a paracrine effect on Shh- cells, inducing their proliferation and migration. Shh+ cells were chemo-resistant and showed features of cancer stem cells (CSCs) and . Pharmacological inhibition of the Shh pathway suppressed their CSC features. A high percentage of Shh+ cells was associated with poor prognosis in early-stage NSCLC patients. In conclusion, we describe for the first time the presence of an abnormal membrane-bound full-length Shh protein in human cancer cells that allows the identification of CSCs and .

Citing Articles

Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies.

Jing J, Wu Z, Wang J, Luo G, Lin H, Fan Y Signal Transduct Target Ther. 2023; 8(1):315.

PMID: 37596267 PMC: 10439210. DOI: 10.1038/s41392-023-01559-5.

Re-Sensitizing Cancer Stem Cells to Conventional Chemotherapy Agents.

Kim M, Bakyt L, Akhmetkaliyev A, Toktarkhanova D, Bulanin D Int J Mol Sci. 2023; 24(3).

PMID: 36768445 PMC: 9917165. DOI: 10.3390/ijms24032122.

Hedgehog Autoprocessing: From Structural Mechanisms to Drug Discovery.

Kandel N, Wang C Front Mol Biosci. 2022; 9:900560.

PMID: 35669560 PMC: 9163320. DOI: 10.3389/fmolb.2022.900560.

The Patient-Derived Cancer Organoids: Promises and Challenges as Platforms for Cancer Discovery.

Bae J, Choi Y, Cho G, Jang S Cancers (Basel). 2022; 14(9).

PMID: 35565273 PMC: 9105149. DOI: 10.3390/cancers14092144.

Gene expression profile of high PD-L1 non-small cell lung cancers refractory to pembrolizumab.

Talb J, Takam Kamga P, Mayenga M, Costantini A, Julie C, Dumenil C Cancer Immunol Immunother. 2022; 71(11):2791-2799.

PMID: 35435450 PMC: 10992407. DOI: 10.1007/s00262-022-03206-4.

References

Leung E, Fiscus R, Tung J, Tin V, Cheng L, Sihoe A . Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One. 2010; 5(11):e14062. PMC: 2988826. DOI: 10.1371/journal.pone.0014062. View

Li C, Heidt D, Dalerba P, Burant C, Zhang L, Adsay V . Identification of pancreatic cancer stem cells. Cancer Res. 2007; 67(3):1030-7. DOI: 10.1158/0008-5472.CAN-06-2030. View

Merchant A, Matsui W . Targeting Hedgehog--a cancer stem cell pathway. Clin Cancer Res. 2010; 16(12):3130-40. PMC: 2888641. DOI: 10.1158/1078-0432.CCR-09-2846. View

Bumcrot D, Takada R, McMahon A . Proteolytic processing yields two secreted forms of sonic hedgehog. Mol Cell Biol. 1995; 15(4):2294-303. PMC: 230457. DOI: 10.1128/MCB.15.4.2294. View

Ho M, Ng A, Lam S, Hung J . Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 2007; 67(10):4827-33. DOI: 10.1158/0008-5472.CAN-06-3557. View

Jiang F, Qiu Q, Khanna A, Todd N, Deepak J, Xing L . Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res. 2009; 7(3):330-8. PMC: 4255559. DOI: 10.1158/1541-7786.MCR-08-0393. View

Goetz J, Singh S, Suber L, Kull F, Robbins D . A highly conserved amino-terminal region of sonic hedgehog is required for the formation of its freely diffusible multimeric form. J Biol Chem. 2005; 281(7):4087-93. DOI: 10.1074/jbc.M511427200. View

Pietanza M, Litvak A, Varghese A, Krug L, Fleisher M, Teitcher J . A phase I trial of the Hedgehog inhibitor, sonidegib (LDE225), in combination with etoposide and cisplatin for the initial treatment of extensive stage small cell lung cancer. Lung Cancer. 2016; 99:23-30. PMC: 5427482. DOI: 10.1016/j.lungcan.2016.04.014. View

Cui F, Wang J, Chen D, Chen Y . CD133 is a temporary marker of cancer stem cells in small cell lung cancer, but not in non-small cell lung cancer. Oncol Rep. 2010; 25(3):701-8. DOI: 10.3892/or.2010.1115. View

10.

Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A . Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2007; 15(3):504-14. DOI: 10.1038/sj.cdd.4402283. View

11.

Yuan Z, Goetz J, Singh S, Ogden S, Petty W, Black C . Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene. 2006; 26(7):1046-55. DOI: 10.1038/sj.onc.1209860. View

12.

Bender Kim C, Jackson E, Woolfenden A, Lawrence S, Babar I, Vogel S . Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005; 121(6):823-35. DOI: 10.1016/j.cell.2005.03.032. View

13.

Giroux Leprieur E, Vieira T, Antoine M, Rozensztajn N, Rabbe N, Ruppert A . Sonic Hedgehog Pathway Activation Is Associated With Resistance to Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Carcinoma. Clin Lung Cancer. 2016; 17(4):301-8. DOI: 10.1016/j.cllc.2015.12.007. View

14.

Karhadkar S, Bova G, Abdallah N, Dhara S, Gardner D, Maitra A . Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004; 431(7009):707-12. DOI: 10.1038/nature02962. View

15.

Chen X, Tukachinsky H, Huang C, Jao C, Chu Y, Tang H . Processing and turnover of the Hedgehog protein in the endoplasmic reticulum. J Cell Biol. 2011; 192(5):825-38. PMC: 3051819. DOI: 10.1083/jcb.201008090. View

16.

Lemjabbar-Alaoui H, Dasari V, Sidhu S, Mengistab A, Finkbeiner W, Gallup M . Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer. PLoS One. 2006; 1:e93. PMC: 1762353. DOI: 10.1371/journal.pone.0000093. View

17.

Roelink H, Augsburger A, Heemskerk J, Korzh V, Norlin S, Ruiz i Altaba A . Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell. 1994; 76(4):761-75. DOI: 10.1016/0092-8674(94)90514-2. View

18.

Patel M, Lu L, Zander D, Sreerama L, Coco D, Moreb J . ALDH1A1 and ALDH3A1 expression in lung cancers: correlation with histologic type and potential precursors. Lung Cancer. 2007; 59(3):340-9. DOI: 10.1016/j.lungcan.2007.08.033. View

19.

Watkins D, Berman D, Burkholder S, Wang B, Beachy P, Baylin S . Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 2003; 422(6929):313-7. DOI: 10.1038/nature01493. View

20.

Porter J, von Kessler D, Ekker S, Young K, Lee J, Moses K . The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature. 1995; 374(6520):363-6. DOI: 10.1038/374363a0. View