|
1
|
Ciaramicoli LM, Kwon HY, Im CY, Kim N, Oh Y, Chang YT, Kang NY. Label-Free Enrichment of Highly Metastatic Tumor-Initiating Cells up to a Monoclonal State. Biomater Res 2025; 29:0168. [PMID: 40177028 PMCID: PMC11964298 DOI: 10.34133/bmr.0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/30/2024] [Accepted: 02/25/2025] [Indexed: 04/05/2025] Open
Affiliation(s)
- Larissa M. Ciaramicoli
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Haw-Young Kwon
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Chun Y. Im
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Namhui Kim
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Yoojin Oh
- New Drug Development Center,
Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), Daegu 41061, Republic of Korea
| | - Young-Tae Chang
- Department of Chemistry,
Pohang University of Science and Technology, Pohang 37673, Republic of Korea
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Nam-Young Kang
- SenPro Inc.,
Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
- Department of Convergence I.T. Engineering,
Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea
| |
Collapse
|
|
2
|
Li J, Jiang Y, Xue W, Liu L, Yu H, Zhang X, Ye X, Miao J, Liu J, Chen Y, Lan X, Liu X, Yao W, Sun J, Zheng J, Xiao J. Effects of transplantation of umbilical cord blood mononuclear cells into the scrotum on sexual function in elderly mice. Regen Med 2023; 18:695-706. [PMID: 37554102 DOI: 10.2217/rme-2022-0191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023] Open
Abstract
Aim: This study investigated the effect of allografting umbilical cord blood mononuclear cells (UCBMCs) into the scrotum on sexual function in male elderly mice. Methods: UCBMCs were injected once into the scrotal sheath cavity of elderly mice. Results: The transplanted UCBMCs survived in the scrotal sheath cavity for 1 month. The mice had significantly increased blood testosterone concentrations, cyclic guanosine monophosphate (cGMP) levels and total nitric oxide synthase (T-NOS) activity in the corpus cavernosum and an increase in the number of mouse matings within 30 min (all p = 0.000). Conclusion: Scrotum-implanted UCBMCs improve the sexual function of male elderly mice through testosterone production and the NOS/cGMP pathway, which may provide an innovative transplantation approach for the treatment of erectile dysfunction.
Collapse
Affiliation(s)
- Jun Li
- Medical School, Ningde Normal University, Ningde, 352100, China
- Medical School, Kunming University, Kunming, 650214, China
| | - Yinghong Jiang
- Medical School, Kunming University, Kunming, 650214, China
| | - Wei Xue
- Medical School, Kunming University, Kunming, 650214, China
| | - Lejiang Liu
- Medical School, Kunming University, Kunming, 650214, China
| | - Hua Yu
- Medical School, Kunming University, Kunming, 650214, China
| | - Xuemei Zhang
- Medical School, Kunming University, Kunming, 650214, China
| | - Xiao Ye
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Jianrong Miao
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Jianling Liu
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Yueen Chen
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Xingbin Lan
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Xiaoqing Liu
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Wensong Yao
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Jianchuan Sun
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Jing Zheng
- Medical School, Ningde Normal University, Ningde, 352100, China
| | - Jianzhong Xiao
- Medical School, Ningde Normal University, Ningde, 352100, China
| |
Collapse
|
|
3
|
Yehya A, Youssef J, Hachem S, Ismael J, Abou-Kheir W. Tissue-specific cancer stem/progenitor cells: Therapeutic implications. World J Stem Cells 2023; 15:323-341. [PMID: 37342220 PMCID: PMC10277968 DOI: 10.4252/wjsc.v15.i5.323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/14/2023] [Accepted: 04/12/2023] [Indexed: 05/26/2023] Open
Abstract
Surgical resection, chemotherapy, and radiation are the standard therapeutic modalities for treating cancer. These approaches are intended to target the more mature and rapidly dividing cancer cells. However, they spare the relatively quiescent and intrinsically resistant cancer stem cells (CSCs) subpopulation residing within the tumor tissue. Thus, a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs' resistant features. Based on their unique expression profile, the identification, isolation, and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence. Yet, targeting CSCs is limited mainly by the irrelevance of the utilized cancer models. A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids (PDOs) as a tool for establishing pre-clinical tumor models. Herein, we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors. Additionally, we highlight the advantage and relevance of the three-dimensional PDOs culture model as a platform for modeling cancer, evaluating the efficacy of CSC-based therapeutics, and predicting drug response in cancer patients.
Collapse
Affiliation(s)
- Amani Yehya
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Joe Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Sana Hachem
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jana Ismael
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon.
| |
Collapse
|
|
4
|
Cheng LH, Hsu CC, Tsai HW, Liao WY, Yang PM, Liao TY, Hsieh HY, Chan TS, Tsai KK. ASPM Activates Hedgehog and Wnt Signaling to Promote Small Cell Lung Cancer Stemness and Progression. Cancer Res 2023; 83:830-844. [PMID: 36638332 DOI: 10.1158/0008-5472.can-22-2496] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/14/2022] [Accepted: 01/11/2023] [Indexed: 01/15/2023]
Abstract
Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18-encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the Wnt-DVL3-β-catenin signaling axis. Functional studies verified that the ASPM-I1-regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1-mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target. SIGNIFICANCE ASPM promotes SCLC stemness and aggressiveness by stabilizing the expression of GLI1, DVL3, and SMO, representing a novel regulatory hub of Hh and Wnt signaling and targetable vulnerability.
Collapse
Affiliation(s)
- Li-Hsin Cheng
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Chung-Chi Hsu
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Wen-Ying Liao
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Pei-Ming Yang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan
| | - Tai-Yan Liao
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Hsiao-Yen Hsieh
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Tze-Sian Chan
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
- Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
- School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Kelvin K Tsai
- Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
- Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei City, Taiwan
| |
Collapse
|
|
5
|
Zhao J, Li M, Xu J, Cheng W. The modulation of ion channels in cancer chemo-resistance. Front Oncol 2022; 12:945896. [PMID: 36033489 PMCID: PMC9399684 DOI: 10.3389/fonc.2022.945896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/19/2022] [Indexed: 11/25/2022] Open
Abstract
Ion channels modulate the flow of ions into and out of a cell or intracellular organelle, leading to generation of electrical or chemical signals and regulating ion homeostasis. The abundance of ion channels in the plasma and intracellular membranes are subject to physiological and pathological regulations. Abnormal and dysregulated expressions of many ion channels are found to be linked to cancer and cancer chemo-resistance. Here, we will summarize ion channels distribution in multiple tumors. And the involvement of ion channels in cancer chemo-resistance will be highlighted.
Collapse
|
|
6
|
Tryggestad AMA, Axcrona K, Axcrona U, Bigalke I, Brennhovd B, Inderberg EM, Hønnåshagen TK, Skoge LJ, Solum G, Saebøe-Larssen S, Josefsen D, Olaussen RW, Aamdal S, Skotheim RI, Myklebust TÅ, Schendel DJ, Lilleby W, Dueland S, Kvalheim G. Long-term first-in-man Phase I/II study of an adjuvant dendritic cell vaccine in patients with high-risk prostate cancer after radical prostatectomy. Prostate 2022; 82:245-253. [PMID: 34762317 DOI: 10.1002/pros.24267] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/02/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Patients with high-risk prostate cancer (PC) can experience biochemical relapse (BCR), despite surgery, and develop noncurative disease. The present study aimed to reduce the risk of BCR with a personalized dendritic cell (DC) vaccine, given as adjuvant therapy, after robot-assisted laparoscopic prostatectomy (RALP). METHODS Twelve weeks after RALP, 20 patients with high-risk PC and undetectable PSA received DC vaccinations for 3 years or until BCR. The primary endpoint was the time to BCR. The immune response was assessed 7 weeks after surgery (baseline) and at one-time point during the vaccination period. RESULTS Among 20 patients, 11 were BCR-free over a median of 96 months (range: 84-99). The median time from the end of vaccinations to the last follow-up was 57 months (range: 45-60). Nine patients developed BCR, either during (n = 4) or after (n = 5) the vaccination period. Among five patients diagnosed with intraductal carcinoma, three experienced early BCR during the vaccination period. All patients that developed BCR remained in stable disease within a median of 99 months (range: 74-99). The baseline immune response was significantly associated with the immune response during the vaccination period (p = 0.015). For patients diagnosed with extraprostatic extension (EPE), time to BCR was longer in vaccine responders than in non-responders (p = 0.09). Among 12 patients with the International Society of Urological Pathology (ISUP) grade 5 PC, five achieved remission after 84 months, and all mounted immune responses. CONCLUSION Patients diagnosed with EPE and ISUP grade 5 PC were at particularly high risk of developing postsurgical BCR. In this subgroup, the vaccine response was related to a reduced BCR incidence. The vaccine was safe, without side effects. This adjuvant first-in-man Phase I/II DC vaccine study showed promising results. DC vaccines after curative surgery should be investigated further in a larger cohort of patients with high-risk PC.
Collapse
Affiliation(s)
| | - Karol Axcrona
- Department of Urology, Oslo University Hospital HF, Oslo, Norway
- Department of Urology, Akershus University Hospital HF, Oslo, Norway
| | - Ulrika Axcrona
- Department of Pathology, Oslo University Hospital HF, Oslo, Norway
| | - Iris Bigalke
- Department of Oncology, Oslo University Hospital HF, Oslo, Norway
- BioNTech IMFS GmbH, Idar-Oberstein, Germany
| | - Bjørn Brennhovd
- Department of Urology, Oslo University Hospital HF, Oslo, Norway
| | - Else M Inderberg
- Department of Oncology, Oslo University Hospital HF, Oslo, Norway
| | | | - Lisbeth J Skoge
- Department of Oncology, Oslo University Hospital HF, Oslo, Norway
| | - Guri Solum
- Department of Oncology, Oslo University Hospital HF, Oslo, Norway
| | | | - Dag Josefsen
- Department of Oncology, Oslo University Hospital HF, Oslo, Norway
| | | | - Steinar Aamdal
- Department for Clinical Research, Oslo University Hospital HF, Oslo, Norway
| | - Rolf I Skotheim
- Department of Molecular Oncology, Oslo University Hospital HF, Oslo, Norway
| | - Tor Å Myklebust
- Department of Registration, Cancer Registry Norway, Oslo, Norway
- Department of Research and Innovation, Møre and Romsdal Hospital Trust, Ålesund, Norway
| | | | - Wolfgang Lilleby
- Department of Oncology, Oslo University Hospital HF, Oslo, Norway
| | - Svein Dueland
- Department for Clinical Research, Oslo University Hospital HF, Oslo, Norway
| | - Gunnar Kvalheim
- Department of Oncology, Oslo University Hospital HF, Oslo, Norway
| |
Collapse
|
|
7
|
Shahoumi LA. Oral Cancer Stem Cells: Therapeutic Implications and Challenges. FRONTIERS IN ORAL HEALTH 2022; 2:685236. [PMID: 35048028 PMCID: PMC8757826 DOI: 10.3389/froh.2021.685236] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is currently one of the 10 most common malignancies worldwide, characterized by a biologically highly diverse group of tumors with non-specific biomarkers and poor prognosis. The incidence rate of HNSCC varies widely throughout the world, with an evident prevalence in developing countries such as those in Southeast Asia and Southern Africa. Tumor relapse and metastasis following traditional treatment remain major clinical problems in oral cancer management. Current evidence suggests that therapeutic resistance and metastasis of cancer are mainly driven by a unique subpopulation of tumor cells, termed cancer stem cells (CSCs), or cancer-initiating cells (CICs), which are characterized by their capacity for self-renewal, maintenance of stemness and increased tumorigenicity. Thus, more understanding of the molecular mechanisms of CSCs and their behavior may help in developing effective therapeutic interventions that inhibit tumor growth and progression. This review provides an overview of the main signaling cascades in CSCs that drive tumor repropagation and metastasis in oral cancer, with a focus on squamous cell carcinoma. Other oral non-SCC tumors, including melanoma and malignant salivary gland tumors, will also be considered. In addition, this review discusses some of the CSC-targeted therapeutic strategies that have been employed to combat disease progression, and the challenges of targeting CSCs, with the aim of improving the clinical outcomes for patients with oral malignancies. Targeting of CSCs in head and neck cancer (HNC) represents a promising approach to improve disease outcome. Some CSC-targeted therapies have already been proven to be successful in pre-clinical studies and they are now being tested in clinical trials, mainly in combination with conventional treatment regimens. However, some studies revealed that CSCs may not be the only players that control disease relapse and progression of HNC. Further, clinical research studying a combination of therapies targeted against head and neck CSCs may provide significant advances.
Collapse
Affiliation(s)
- Linah A Shahoumi
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
| |
Collapse
|
|
8
|
Joshi J, Patel H, Bhavnagari H, Tarapara B, Pandit A, Shah F. Eliminating Cancer Stem-Like Cells in Oral Cancer by Targeting Elementary Signaling Pathways. Crit Rev Oncog 2022; 27:65-82. [PMID: 37199303 DOI: 10.1615/critrevoncog.2022047207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Oral cancer is a heterogeneous, aggressive, and complex entity. Current major treatment options for the disease are surgery, chemo, and/or radiotherapy either alone or in combination with each other. Each treatment method has its own limitations such as a significant journey with deformities and a protracted rehabilitation process leading to loss of self-esteem, loss of tolerance, and therapeutic side effects. Conventional therapies are frequently experienced with regimen resistance and recurrence attributed to the cancer stem cells (CSCs). Given that CSCs exert their tumorigenesis by affecting several cellular and molecular targets and pathways an improved understanding of CSCs' actions is required. Hence, more research is recommended to fully understand the fundamental mechanisms driving CSC-mediated treatment resistance. Despite the difficulties and disagreements surrounding the removal of CSCs from solid tumors, a great amount of knowledge has been derived from the characterization of CSCs. Various efforts have been made to identify the CSCs using several cell surface markers. In the current review, we will discuss numerous cell surface markers such as CD44, ALDH1, EPCAM, CD24, CD133, CD271, CD90, and Cripto-1 for identifying and isolating CSCs from primary oral squamous cell carcinoma (OSCC). Further, a spectrum of embryonic signaling pathways has been thought to be the main culprit of CSCs' active state in cancers, resulting in conventional therapeutic resistance. Hence, we discuss the functional and molecular bases of several signaling pathways such as the Wnt/beta;-catenin, Notch, Hedgehog, and Hippo pathways and their associations with disease aggressiveness. Moreover, numerous inhibitors targeting the above mentioned signaling pathways have already been identified and some of them are already undergoing clinical trials. Hence, the present review encapsulates the characterization and effectiveness of the prospective potential targeted therapies for eradicating CSCs in oral cancers.
Collapse
Affiliation(s)
- Jigna Joshi
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Hitarth Patel
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Hunayna Bhavnagari
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Bhoomi Tarapara
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Apexa Pandit
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Franky Shah
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| |
Collapse
|
|
9
|
Pongol Methyl Ether Inhibits Akt and Suppresses Cancer Stem Cell Phenotypes in Lung Cancer Cells. Pharmaceuticals (Basel) 2021; 14:ph14111085. [PMID: 34832867 PMCID: PMC8624902 DOI: 10.3390/ph14111085] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/19/2021] [Accepted: 10/23/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) are an important therapeutic target. The therapeutic agents targeting CSCs should lead to improved clinical outcomes. Here we have demonstrated the CSC-suppressing activity of pongol methyl ether (PME), a pure compound from Millettia erythrocalyx. METHODS CSC-suppressing effects were evaluated by spheroid formation assay and detection of CSC markers. The related CSC cell signals were evaluated by Western blot, immunofluorescence and molecular docking analysis. Proteins affected by PME treatment were subjected to bioinformatic analysis. Protein-protein interaction (PPI) networks were constructed by the Search Tool for Interactions of Chemicals (STITCH). The Kyoto Encyclopedia of Genes and Genomes (KEGG) mapper were used to confirm the underlying pathways. RESULTS PME (5-25 µM) significantly suppressed the ability of lung cancer cells to form colonies, grow in an anchorage-independent manner and generate tumour spheroids. PME at 25 µM significantly decreased the CSC markers (CD133 and ALDH1A1) and pluripotent transcription factors (Oct4 and Nanog). Akt, the key upstream signal of CSC control, was significantly decreased by the PME treatment. The molecular docking indicated that PME was bound to Akt-1 with a binding affinity of -9.2 kcal/mol greater than the Akt-1 inhibitor (reference compound; CQW). The STITCH network identified a total of 15 proteins interacted in PPI networks, and Akt-1 was identified as a central protein. The KEGG mapper indicated that the selected CSC markers were mostly involved in the 'signalling pathways regulating pluripotency of stem cells' pathway map and Akt, Oct4 and Nanog were the regulatory proteins in the dominant pathway. In addition, PME (10-25 µM) can suppress spheroid formation and reduce CSC-specific marker expression in patient-derived primary lung cancer cells. CONCLUSIONS Our study revealed a novel pharmacological effect and the underlying mechanism of PME that can attenuate CSC phenotypes in lung cancer cells and may be developed for lung cancer therapy.
Collapse
|
|
10
|
Zhou HM, Zhang JG, Zhang X, Li Q. Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents. Signal Transduct Target Ther 2021; 6:62. [PMID: 33589595 PMCID: PMC7884707 DOI: 10.1038/s41392-020-00430-1] [Citation(s) in RCA: 247] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/26/2020] [Accepted: 10/08/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) show a self-renewal capacity and differentiation potential that contribute to tumor progression and therapy resistance. However, the underlying processes are still unclear. Elucidation of the key hallmarks and resistance mechanisms of CSCs may help improve patient outcomes and reduce relapse by altering therapeutic regimens. Here, we reviewed the identification of CSCs, the intrinsic and extrinsic mechanisms of therapy resistance in CSCs, the signaling pathways of CSCs that mediate treatment failure, and potential CSC-targeting agents in various tumors from the clinical perspective. Targeting the mechanisms and pathways described here might contribute to further drug discovery and therapy.
Collapse
Affiliation(s)
- He-Ming Zhou
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Ji-Gang Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Xue Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Qin Li
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China.
| |
Collapse
|
|
11
|
Raniszewska A, Vroman H, Dumoulin D, Cornelissen R, Aerts JGJV, Domagała-Kulawik J. PD-L1 + lung cancer stem cells modify the metastatic lymph-node immunomicroenvironment in nsclc patients. Cancer Immunol Immunother 2021; 70:453-461. [PMID: 32808188 PMCID: PMC7889682 DOI: 10.1007/s00262-020-02648-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 06/18/2020] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Cancer stem cells (CSCs) are implicated in tumor initiation and development of metastasis. However, whether CSCs also affect the immune system is not fully understood. We investigated correlations between the PD-L1+ CSCs, changes in T-cell phenotype in metastatic and non-metastatic lymph nodes (LNs) and response to treatment. METHODS LNs' aspirates were obtained during the EBUS/TBNA procedure of 20 NSCLC patients at different stages of the disease. CSCs and T-cell characteristics were determined by flow cytometry. RESULTS PD-L1+ CSCs positively correlated with the percentage of Tregs, PD-1+ CD4 T cells and Tim3+ CD4+ T cells, whereas PD-L1+ CSCs were negatively correlated with CD4+ T cells and CD28+ CD4+ T cells. The percentage of PD-L1+ CSCs was higher in patients with progressive disease (PD) as compared to patients with stable disease (SD) or partial response (PR). Among T cells, only PD-1+ CD4+ T cells and Tim3+ CD4+ T-cell frequencies were higher in patients with PD as compared to patients with SD or PR. CONCLUSION The frequency of PD-L1+ CSCs associates with an altered T-cell frequency and phenotype indicating that CSCs can affect the immune system. The higher percentage of PD-L1+ CSCs in patients with PD may confirm their resistance to conventional therapy, suggesting that CSCs may be an interesting target for immunotherapy.
Collapse
Affiliation(s)
- A Raniszewska
- Department of Pathology, Medical University of Warsaw, Pawinskiego 7 Street, 02-106, Warsaw, Poland
| | - H Vroman
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
| | - D Dumoulin
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - R Cornelissen
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - J G J V Aerts
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - J Domagała-Kulawik
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Banacha 1a Street, 02-097, Warsaw, Poland
| |
Collapse
|
|
12
|
Zhang C, Zhao Y, Yang Y, Zhong C, Ji T, Duan J, Wang Y. RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells. Biochem Biophys Res Commun 2021; 534:254-260. [PMID: 33288197 DOI: 10.1016/j.bbrc.2020.11.101] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 11/25/2020] [Indexed: 01/02/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells. To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs, RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM+CD44+HCT-116 cells (CCSCs). We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA. Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in CCSCs. In addition, the invasive ability of CCSCs was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice. In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.
Collapse
Affiliation(s)
- Chen Zhang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China; Institute of Oceanography, Minjiang University, Fuzhou, Fujian, 350108, China
| | - Yuanyuan Zhao
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Yongjing Yang
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, China
| | - Chunlian Zhong
- Institute of Oceanography, Minjiang University, Fuzhou, Fujian, 350108, China
| | - Tianju Ji
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Jinyue Duan
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China.
| |
Collapse
|
|
13
|
Maity AK, Carroll RJ, Mallick BK. Integration of Survival and Binary Data for Variable Selection and Prediction: A Bayesian Approach. J R Stat Soc Ser C Appl Stat 2020; 68:1577-1595. [PMID: 33311813 DOI: 10.1111/rssc.12377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
We consider the problem where the data consist of a survival time and a binary outcome measurement for each individual, as well as corresponding predictors. The goal is to select the common set of predictors which affect both the responses, and not just only one of them. In addition, we develop a survival prediction model based on data integration. This article is motivated by the Cancer Genomic Atlas (TCGA) databank, which is currently the largest genomics and transcriptomics database. The data contain cancer survival information along with cancer stages for each patient. Furthermore, it contains Reverse-phase Protein Array (RPPA) measurements for each individual, which are the predictors associated with these responses. The biological motivation is to identify the major actionable proteins associated with both survival outcomes and cancer stages. We develop a Bayesian hierarchical model to jointly model the survival time and the classification of the cancer stages. Moreover, to deal with the high dimensionality of the RPPA measurements, we use a shrinkage prior to identify significant proteins. Simulations and TCGA data analysis show that the joint integrated modeling approach improves survival prediction.
Collapse
Affiliation(s)
- Arnab Kumar Maity
- Early Clinical Development Oncology Statistics, 10777 Science Center Drive, Pfizer Inc., San Diego, CA 92121
| | - Raymond J Carroll
- Department of Statistics, Texas A&M University, 3143 TAMU, College Station, TX, 77843-3143, and School of Mathematical and Physical Sciences, University of Technology, Sydney, Broadway NSW 2007, Australia
| | - Bani K Mallick
- Department of Statistics, Texas A&M University, 3143 TAMU, College Station, TX, 77843-3143
| |
Collapse
|
|
14
|
Lee SH, Reed-Newman T, Anant S, Ramasamy TS. Regulatory Role of Quiescence in the Biological Function of Cancer Stem Cells. Stem Cell Rev Rep 2020; 16:1185-1207. [DOI: 10.1007/s12015-020-10031-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
15
|
Targeting of Lung Cancer Stem Cell Self-Renewal Pathway by a Small Molecule Verrucarin J. Stem Cell Rev Rep 2020; 15:601-611. [PMID: 30835047 DOI: 10.1007/s12015-019-09874-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite considerable advances made in understanding of lung cancer biology, there has been meek improvement in lung cancer treatment outcome with 4% to 5% increase in 5-year survival rates in the last four decades. Underlying problem of lung cancer recurrence and poor prognosis is attributed to the presence of cancer stem cells (CSCs) which possess the potential to differentiate, proliferate and trigger chemo-resistance, tumor progression and metastasis, despite initial elimination of the tumor. To address specific targeting of CSCs, we investigated the effects of a small molecule Verrucarin J (VJ) on lung cancer cell lines A549 and H1793. VJ significantly inhibited cell proliferation of both cell lines, with IC50 values of approximately 10 nM for A549 and 20 nM for H1793 respectively after 48 h of treatment. A549 cell line when treated with VJ, induced cell apoptosis with concomitant down regulation of key CSC specific genes- ALDH1, LGR5, OCT4 and CD133 in a dose-dependent manner. To delineate the molecular mechanism by which VJ targets lung cancer cells and CSCs, we determined the effects of VJ on CSC self-renewal pathways Wnt1/β-catenin and Notch1. Treatment of A549 cell line with VJ inhibited significantly both the signalling pathways, suggesting inhibition of expression of CSC genes by VJ through the inhibition of CSC self-renewal signalling pathways. Taken together, our results suggest that VJ may serve as a potent anticancer drug to target cancer cells and CSCs.
Collapse
|
|
16
|
Mcgrath NA, Fu J, Gu SZ, Xie C. Targeting cancer stem cells in cholangiocarcinoma (Review). Int J Oncol 2020; 57:397-408. [PMID: 32468022 PMCID: PMC7307587 DOI: 10.3892/ijo.2020.5074] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023] Open
Abstract
The incidence of cholangiocarcinoma has been increasing steadily over the past 50 years, but the survival rates remained low due to the disease being highly resistant to non-surgical treatment interventions. Cancer stem cell markers are expressed in cholangiocarcinoma, suggesting that they serve a significant role in the physiology of the disease. Cancer stem cells are frequently implicated in tumor relapse and acquired resistance to a number of therapeutic strategies, including chemotherapy, radiation and immune checkpoint inhibitors. Novel targeted therapies to eradicate cancer stem cells may assist in overcoming treatment resistance in cholangiocarcinoma and reduce the rates of relapse and recurrence. Several signaling pathways have been previously documented to regulate the development and survival of cancer stem cells, including Notch, janus kinase/STAT, Hippo/yes-associated protein 1 (YAP1), Wnt and Hedgehog signaling. Although pharmacological agents have been developed to target these pathways, only modest effects were reported in clinical trials. The Hippo/YAP1 signaling pathway has come to the forefront in the field of cancer stem cell research due to its reported involvement in epithelium-mesenchymal transition, cell adhesion, organogenesis and tumorigenesis. In the present article, recent findings in terms of cancer stem cell research in cholangiocarcinoma were reviewed, where the potential therapeutic targeting of cancer stem cells in this disease was discussed.
Collapse
Affiliation(s)
- Nicole A Mcgrath
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
| | - Jianyang Fu
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
| | - Sophie Z Gu
- Johns Hopkins University School of Medicine, Baltimore, MD 20215, USA
| | - Changqing Xie
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
| |
Collapse
|
|
17
|
Retraction: Identification and Characterization of Cells with Cancer Stem Cell Properties in Human Primary Lung Cancer Cell Lines. PLoS One 2020; 15:e0232726. [PMID: 32348376 PMCID: PMC7190134 DOI: 10.1371/journal.pone.0232726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
|
|
18
|
Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Sighinolfi P, Stefani A, Morandi U, Dominici M, Aramini B. CD44+/EPCAM+ cells detect a subpopulation of ALDH high cells in human non-small cell lung cancer: A chance for targeting cancer stem cells? Oncotarget 2020; 11:1545-1555. [PMID: 32391123 PMCID: PMC7197447 DOI: 10.18632/oncotarget.27568] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 04/03/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Several studies demonstrated that aldehyde dehydrogenase (ALDH) and CD44 are the most considered cancer stem cells (CSC) markers. However, a comparison between ALDH high cells and CD44+ cells have been previously described with no significant correlation. Indeed, the aim of the present research is to identify a superficial marker able to match with ALDH high cells population in freshly isolated human lung cancer cells. MATERIALS AND METHODS This cross-sectional study analyzed the expression of ALDHhigh/low cells and the positivity for CD44 and epithelium cell adhesion molecule (EPCAM) antigens in surgical lung cancer tissues. The main approach was a cytofluorimetric analysis of ALDH expression and positivity for CD44/EPCAM on primary cell population obtained from 23 patients harboring NSCLC. RESULTS There was a highly positive correlation between the expressions of ALDHhigh and CD44+/EPCAM+ cells, with a Pearson's correlation coefficient equal to 0.69 (95% CI 0.39-0.86; P = 0.0002), and Spearman's correlation coefficient equal to 0.52 (P = 0.0124). The average paired difference between the expression of ALDHhigh and CD44+/EPCAM+ cells was very close to 0, being 0.1% (SD 2.5%); there was no difference between these subpopulations in terms of means (95% CI = -1.0; 1.2%, P = 0.8464). These results highlight a strong similarity between ALDHhigh and CD44+/EPCAM+ cells. CONCLUSIONS Our study is the first attempt which identifies a high correlation between the ALDHhigh and the CD44+/EPCAM+ cells, thus suggesting the possibility to use this superficial marker for future target treatments against lung cancer stem cells.
Collapse
Affiliation(s)
- Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.,Co-first/last authors
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.,Co-first/last authors
| | - Federico Banchelli
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.,Co-first/last authors
| | - Roberto D'Amico
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Pamela Sighinolfi
- Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Stefani
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.,Co-first/last authors
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.,Co-first/last authors
| |
Collapse
|
|
19
|
Alhabbab RY. Targeting Cancer Stem Cells by Genetically Engineered Chimeric Antigen Receptor T Cells. Front Genet 2020; 11:312. [PMID: 32391048 PMCID: PMC7188929 DOI: 10.3389/fgene.2020.00312] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 03/16/2020] [Indexed: 12/11/2022] Open
Abstract
The term cancer stem cell (CSC) starts 25 years ago with the evidence that CSC is a subpopulation of tumor cells that have renewal ability and can differentiate into several distinct linages. Therefore, CSCs play crucial role in the initiation and the maintenance of cancer. Moreover, it has been proposed throughout several studies that CSCs are behind the failure of the conventional chemo-/radiotherapy as well as cancer recurrence due to their ability to resist the therapy and their ability to re-regenerate. Thus, the need for targeted therapy to eliminate CSCs is crucial; for that reason, chimeric antigen receptor (CAR) T cells has currently been in use with high rate of success in leukemia and, to some degree, in patients with solid tumors. This review outlines the most common CSC populations and their common markers, in particular CD133, CD90, EpCAM, CD44, ALDH, and EGFRVIII, the interaction between CSCs and the immune system, CAR T cell genetic engineering and signaling, CAR T cells in targeting CSCs, and the barriers in using CAR T cells as immunotherapy to treat solid cancers.
Collapse
Affiliation(s)
- Rowa Y. Alhabbab
- Division of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
|
20
|
Immunomodulatory Molecules On Lung Cancer Stem Cells From Lymph Nodes Aspirates. Cancers (Basel) 2020; 12:cancers12040838. [PMID: 32244422 PMCID: PMC7226167 DOI: 10.3390/cancers12040838] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 03/26/2020] [Accepted: 03/30/2020] [Indexed: 12/18/2022] Open
Abstract
Over the past decade, immune checkpoint inhibitors have revolutionized the treatment of non-small cell lung cancer (NSCLC). Unfortunately, not all patients benefit from PD-(L)1 blockade, yet, the PD-L1 tumor cell expression is the only approved biomarker, and other biomarkers have been investigated. In the present study, we analyzed the presence of immunomodulatory molecules: PD-L1, CD47, CD73, Fas, and FasL on mature tumor cells (MTCs) and cancer stem cells (CSCs) in lymph nodes (LNs) aspirates and refer it to the lymphocyte subpopulation in peripheral blood (PB). PB samples and LNs aspirates obtained during the endobronchial ultrasound-guided transbronchial needle aspiration (EBUS/TBNA) procedure of 20 patients at different stages of NSCLC. The cells were analyzed by multiparameter flow cytometry. We reported the higher frequency of MTCs and CSCs expressing the investigated immunomodulating molecules in metastatic LNs than in nonmetastatic. The expression of CD47 and PD-L1 was significantly higher on CSCs than on MTCs. Among the lymphocyte subpopulation in PB, we observed a higher frequency of PD-1+ CD8 T cells and Fas+ CD8 T cells in patients with confirmed metastases than in nonmetastatic. Next, we found that the percentage of FasL+ MTCs correlated with the frequency of Fas+ CD3 T cells in LNs aspirates and Fas+ CD8 T cells in PB. Finally, we found that patients with metastatic disease had a significantly higher FasL+/Fas+ MTCs ratio than patients with nonmetastatic disease. Both MTCs and CSCs express different immunomodulatory molecules on their surface. The frequency of FasL+ MTCs associates with altered distribution of Fas+ lymphocyte subpopulations in LNs and PB.
Collapse
|
|
21
|
Sui JSY, Martin P, Gray SG. Pre-clinical models of small cell lung cancer and the validation of therapeutic targets. Expert Opin Ther Targets 2020; 24:187-204. [PMID: 32068452 DOI: 10.1080/14728222.2020.1732353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Small-cell lung cancer (SCLC) is an aggressive form of lung cancer that has a dismal prognosis. One of the factors hindering therapeutic developments for SCLC is that most SCLC is not surgically resected resulting in a paucity of material for analysis. To address this, significant efforts have been made by investigators to develop pre-clinical models of SCLC allowing for downstream target identification in this difficult to treat cancer.Areas covered: In this review, we describe the current pre-clinical models that have been developed to interrogate SCLC, and outline the benefits and limitations associated with each. Using examples we show how each has been used to (i) improve our knowledge of this intractable cancer, and (ii) identify and validate potential therapeutic targets that (iii) are currently under development and testing within the clinic.Expert opinion: The large numbers of preclinical models that have been developed have dramatically improved the ways in which we can examine SCLC and test therapeutic targets/interventions. The newer models are rapidly providing novel avenues for the design and testing of new therapeutics. Despite this many of these models have inherent flaws that limit the possibility of their use for individualized therapy decision-making for SCLC.
Collapse
Affiliation(s)
- Jane S Y Sui
- Thoracic Oncology Research Group, Laboratory Medicine and Molecular Pathology, Central Pathology Laboratory, St. James's Hospital, Dublin, Ireland.,Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Petra Martin
- Thoracic Oncology Research Group, Laboratory Medicine and Molecular Pathology, Central Pathology Laboratory, St. James's Hospital, Dublin, Ireland
| | - Steven G Gray
- Thoracic Oncology Research Group, Laboratory Medicine and Molecular Pathology, Central Pathology Laboratory, St. James's Hospital, Dublin, Ireland.,Labmed Directorate, St. James's Hospital, Dublin, Ireland.,School of Biological Sciences, Dublin Institute of Technology, Dublin, Ireland
| |
Collapse
|
|
22
|
Potential of Thai Herbal Extracts on Lung Cancer Treatment by Inducing Apoptosis and Synergizing Chemotherapy. Molecules 2020; 25:molecules25010231. [PMID: 31935933 PMCID: PMC6983161 DOI: 10.3390/molecules25010231] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 01/03/2020] [Accepted: 01/04/2020] [Indexed: 12/18/2022] Open
Abstract
The incidence of lung cancer has increased while the mortality rate has continued to remain high. Effective treatment of this disease is the key to survival. Therefore, this study is a necessity in continuing research into new effective treatments. In this study we determined the effects of three different Thai herbs on lung cancer. Bridelia ovata, Croton oblongifolius, and Erythrophleum succirubrum were extracted by ethyl acetate and 50% ethanol. The cytotoxicity was tested with A549 lung cancer cell line. We found four effective extracts that exhibited toxic effects on A549 cells. These extracts included ethyl acetate extracts of B. ovata (BEA), C. oblongifolius (CEA), and E. succirubrum (EEA), and an ethanolic extract of E. succirubrum (EE). Moreover, these effective extracts were tested in combination with chemotherapeutic drugs. An effective synergism of these treatments was found specifically through a combination of BEA with methotrexate, EE with methotrexate, and EE with etoposide. Apoptotic cell death was induced in A549 cells by these effective extracts via the mitochondria-mediated pathway. Additionally, we established primary lung cancer and normal epithelial cells from lung tissue of lung cancer patients. The cytotoxicity results showed that EE had significant potential to be used for lung cancer treatment. In conclusion, the four effective extracts possessed anticancer effects on lung cancer. The most effective extract was found to be E. succirubrum (EE).
Collapse
|
|
23
|
Luo Y, Tian Z, Hua X, Huang M, Xu J, Li J, Huang H, Cohen M, Huang C. Isorhapontigenin (ISO) inhibits stem cell-like properties and invasion of bladder cancer cell by attenuating CD44 expression. Cell Mol Life Sci 2020; 77:351-363. [PMID: 31222373 PMCID: PMC6923629 DOI: 10.1007/s00018-019-03185-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/20/2019] [Accepted: 06/06/2019] [Indexed: 12/21/2022]
Abstract
Cancer stem cells (CSC) are highly associated with poor prognosis in cancer patients. Our previous studies report that isorhapontigenin (ISO) down-regulates SOX2-mediated cyclin D1 induction and stem-like cell properties in glioma stem-like cells. The present study revealed that ISO could inhibit stem cell-like phenotypes and invasivity of human bladder cancer (BC) by specific attenuation of expression of CD44 but not SOX-2, at both the protein transcription and degradation levels. On one hand, ISO inhibited cd44 mRNA expression through decreases in Sp1 direct binding to its promoter region-binding site, resulting in attenuation of its transcription. On the other hand, ISO also down-regulated USP28 expression, which in turn reduced CD44 protein stability. Further studies showed that ISO treatment induced miR-4295, which specific bound to 3'-UTR activity of usp28 mRNA and inhibited its translation and expression, while miR-4295 induction was mediated by increased Dicer protein to enhance miR-4295 maturation upon ISO treatment. Our results provide the first evidence that ISO has a profound inhibitory effect on human BC stem cell-like phenotypes and invasivity through the mechanisms distinct from those previously noted in glioma stem-like cells.
Collapse
Affiliation(s)
- Yisi Luo
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Zhongxian Tian
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Xiaohui Hua
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Maowen Huang
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Jiheng Xu
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Jingxia Li
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Haishan Huang
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Mitchell Cohen
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA
| | - Chuanshu Huang
- Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10100, USA.
| |
Collapse
|
|
24
|
Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Sighinolfi P, Stefani A, Morandi U, Dominici M, Aramini B. Isolation and Identification of Cancer Stem-Like Cells in Adenocarcinoma and Squamous Cell Carcinoma of the Lung: A Pilot Study. Front Oncol 2019; 9:1394. [PMID: 31921651 PMCID: PMC6930193 DOI: 10.3389/fonc.2019.01394] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 11/26/2019] [Indexed: 12/17/2022] Open
Abstract
Background: Lung cancer stem cells (CSCs) share many characteristics with normal stem cells, such as self-renewal and multipotentiality. High expression of aldehyde dehydrogenase (ALDH) has been detected in many tumors, particularly in the CSC compartment, and it plays an important role in tumor proliferation, metastasis, and drug resistance. CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumors. The aim of this study was to isolate and analyze cancer stem-like cells from surgically removed specimens to compare lung adenocarcinoma (ADENO) and squamous (SQUAMO) cell carcinoma. Methods: The ALDEFLUOR assay was used to identify and sort ALDHhigh and ALDHlow human lung cancer cells following tissue digestion. Fluorescence-activated cell sorting analysis for CD44 was performed with tumor cells. Quantitative real-time PCR was performed to assess the expression of SOX2 and NANOG as stemness markers. ALDH1A1 expression was additionally determined by immunohistochemistry. Anchorage-independent ALDHhigh cell growth was also evaluated. ALDHhigh ADENO and SQUAMO cells were cultured to analyze spheroid formation. Results: All specimens contained 0.5-12.5% ALDHhigh cells with 3.8-18.9% CD44-positive cells. SOX2 and NANOG relative expression in ALDHhigh compared to ALDHlow cells in ADENO and SQUAMO was analyzed and compared between the histotypes. Immunohistochemistry confirmed the presence of ALDH1A1 in the sections. SOX2 and NANOG were expressed at higher levels in the ALDHhigh subpopulation than in the ALDHlow subpopulation only in ADENO cells, and the opposite result was seen in SQUAMO cells. In vitro functional assays demonstrated that ALDHhigh cells exhibited migration capacity with distinct behaviors between ALDHhigh spheres in ADENO vs. SQUAMO samples. Conclusions: Our results highlight the importance of a better characterization of cancer stem-like cells in ADENO and SQUAMO histotypes. This may suggest new differential approaches for prognostic and therapeutic purposes in patients with non-small-cell lung cancer.
Collapse
Affiliation(s)
- Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy.,Rigenerand SRL, Modena, Italy
| | - Federico Banchelli
- Department of Medical and Surgical Sciences for Children & Adults, Center of Medical Statistic, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto D'Amico
- Department of Medical and Surgical Sciences for Children & Adults, Center of Medical Statistic, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Department of Medical and Surgical Sciences for Children & Adults, Institute of Pathology, University of Modena and Reggio Emilia, Modena, Italy
| | - Pamela Sighinolfi
- Department of Medical and Surgical Sciences for Children & Adults, Institute of Pathology, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Stefani
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| |
Collapse
|
|
25
|
Sigal D, Przedborski M, Sivaloganathan D, Kohandel M. Mathematical modelling of cancer stem cell-targeted immunotherapy. Math Biosci 2019; 318:108269. [DOI: 10.1016/j.mbs.2019.108269] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/17/2019] [Accepted: 10/05/2019] [Indexed: 12/15/2022]
|
|
26
|
Emetine Synergizes with Cisplatin to Enhance Anti-Cancer Efficacy against Lung Cancer Cells. Int J Mol Sci 2019; 20:ijms20235914. [PMID: 31775307 PMCID: PMC6928603 DOI: 10.3390/ijms20235914] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/18/2019] [Accepted: 11/23/2019] [Indexed: 02/07/2023] Open
Abstract
Cisplatin is still the primary therapeutic choice for advanced lung cancers without driver mutations. The occurrence of cisplatin resistance is a major clinical problem in lung cancer treatment. The natural extracted agent emetine reportedly has anticancer effects. This study aimed to explore the possible role of emetine in cisplatin resistance. We used cell viability, Western blot, and Wnt reporter assays to show that emetine suppresses proliferation, β-catenin expression, and Wnt/β-catenin signaling in non-small cell lung cancer (NSCLC). The synergism of emetine and cisplatin was assessed by constructing isobolograms and calculating combination index (CI) values using the Chou-Talalay method. Emetine effectively synergized with cisplatin to suppress the proliferation of cancer cells. Furthermore, nuclear β-catenin and cancer stem cell-related markers were upregulated in the cisplatin-resistant subpopulation of CL1-0 cells. Emetine enhanced the anticancer efficacy of cisplatin and synergized with cisplatin in the cisplatin-resistant subpopulation of CL1-0 cells. Taken together, these data suggest that emetine could suppress the growth of NSCLC cells through the Wnt/β-catenin pathway and contribute to a synergistic effect in combination with cisplatin.
Collapse
|
|
27
|
Mutated p53 Promotes the Symmetric Self-Renewal of Cisplatin-Resistant Lung Cancer Stem-Like Cells and Inhibits the Recruitment of Macrophages. J Immunol Res 2019; 2019:7478538. [PMID: 31781681 PMCID: PMC6875234 DOI: 10.1155/2019/7478538] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 10/12/2019] [Indexed: 12/12/2022] Open
Abstract
It has been proposed that mutant p53 is correlated with the recurrence of lung cancer. Recently, a small population of cells with asymmetric or symmetric self-renewal potential has been identified in lung cancer, which was termed as cancer stem-like cells (CSCs) and was speculated to be the reason for cancer recurrence after chemotherapy. In this study, we used lung cancer cell lines with different TP53 backgrounds to elucidate the potential role of mutant p53 in regulating lung CSC self-renewal and on lung cancer recurrence. Cisplatin-resistant lung cancer cells with different TP53 backgrounds were generated in vitro by exposing A549, H460, and H661 lung cancer cell lines repeatedly to cisplatin. CD44+/CD90+ stem-like cells were identified in above cisplatin-resistant lung cancers (termed as cisplatin-resistant lung cancer stem-like cells, (Cr-LCSCs)) and stained with PKH26 dye which was used to define the self-renewal pattern. The proportion of symmetric divisions was significantly higher in Cr-LCSCs with mutant (mt) p53 compared with Cr-LCSCs with wild-type (wt) p53, and forced expression of mt p53 promoted the symmetric division of Cr-LCSCs. Furthermore, fewer macrophages accumulated in subcutaneously implanted xenografts consisting of mt p53 Cr-LCSCs compared with wt p53 Cr-LCSCs. These results indicated that mt p53 might accelerate the recurrence of lung cancer by regulating the self-renewal kinetics of Cr-LCSCs as well as the recruitment of macrophages.
Collapse
|
|
28
|
Aboubakar Nana F, Vanderputten M, Ocak S. Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target. Cancers (Basel) 2019; 11:E1683. [PMID: 31671774 PMCID: PMC6895835 DOI: 10.3390/cancers11111683] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 10/22/2019] [Accepted: 10/24/2019] [Indexed: 02/07/2023] Open
Abstract
Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC.
Collapse
Affiliation(s)
- Frank Aboubakar Nana
- Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL et Dermatologie (PNEU), Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
- Division of Pneumology, Cliniques Universitaires St-Luc, UCL, 1200 Brussels, Belgium.
| | - Marie Vanderputten
- Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL et Dermatologie (PNEU), Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
| | - Sebahat Ocak
- Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL et Dermatologie (PNEU), Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
- Division of Pneumology, CHU UCL Namur (Godinne Site), UCL, 5530 Yvoir, Belgium.
| |
Collapse
|
|
29
|
Huang TH, Wu ATH, Cheng TS, Lin KT, Lai CJ, Hsieh HW, Chang PMH, Wu CW, Huang CYF, Chen KY. In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer. J Cell Mol Med 2019; 23:8184-8195. [PMID: 31638335 PMCID: PMC6850923 DOI: 10.1111/jcmm.14689] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/15/2019] [Accepted: 07/23/2019] [Indexed: 12/15/2022] Open
Abstract
Cancer stem cells (CSCs) play an important role in cancer treatment resistance and disease progression. Identifying an effective anti-CSC agent may lead to improved disease control. We used CSC-associated gene signatures to identify drug candidates that may inhibit CSC growth by reversing the CSC gene signature. Thiostrepton, a natural cyclic oligopeptide antibiotic, was the top-ranked candidate. In non-small-cell lung cancer (NSCLC) cells, thiostrepton inhibited CSC growth in vitro and reduced protein expression of cancer stemness markers, including CD133, Nanog and Oct4A. In addition, metastasis-associated Src tyrosine kinase signalling, cell migration and epithelial-to-mesenchymal transition (EMT) were all inhibited by thiostrepton. Mechanistically, thiostrepton treatment led to elevated levels of tumour suppressor miR-98. Thiostrepton combined with gemcitabine synergistically suppressed NSCLC cell growth and induced apoptosis. The inhibition of NSCLC tumours and CSC growth by thiostrepton was also demonstrated in vivo. Our findings indicate that thiostrepton, an established drug identified in silico, is an inhibitor of CSC growth and a potential enhancer of chemotherapy in NSCLC.
Collapse
Affiliation(s)
- Tse-Hung Huang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.,School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan.,School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.,Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.,Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Alexander T H Wu
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Tai-Shan Cheng
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Kuan-Ting Lin
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Chia-Jou Lai
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Hao-Wen Hsieh
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Peter Mu-Hsin Chang
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Wen Wu
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chi-Ying F Huang
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kuan-Yu Chen
- Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
30
|
Lung tumorspheres reveal cancer stem cell-like properties and a score with prognostic impact in resected non-small-cell lung cancer. Cell Death Dis 2019; 10:660. [PMID: 31506430 PMCID: PMC6737160 DOI: 10.1038/s41419-019-1898-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/22/2019] [Accepted: 08/26/2019] [Indexed: 02/06/2023]
Abstract
The high resistance against current therapies found in non-small-cell lung cancer (NSCLC) has been associated to cancer stem-like cells (CSCs), a population for which the identification of targets and biomarkers is still under development. In this study, primary cultures from early-stage NSCLC patients were established, using sphere-forming assays for CSC enrichment and adherent conditions for the control counterparts. Patient-derived tumorspheres showed self-renewal and unlimited exponential growth potentials, resistance against chemotherapeutic agents, invasion and differentiation capacities in vitro, and superior tumorigenic potential in vivo. Using quantitative PCR, gene expression profiles were analyzed and NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 were selected to distinguish tumorspheres from adherent cells. Immunoblot and immunofluorescence analyses confirmed that proteins encoded by these genes were consistently increased in tumorspheres from adenocarcinoma patients and showed differential localization and expression patterns. The prognostic role of genes significantly overexpressed in tumorspheres was evaluated in a NSCLC cohort (N = 661) from The Cancer Genome Atlas. Based on a Cox regression analysis, CDKN1A, SNAI1, and ITGA6 were found to be associated with prognosis and used to calculate a gene expression score, named CSC score. Kaplan–Meier survival analysis showed that patients with high CSC score have shorter overall survival (OS) in the entire cohort [37.7 vs. 60.4 months (mo), p = 0.001] and the adenocarcinoma subcohort [36.6 vs. 53.5 mo, p = 0.003], but not in the squamous cell carcinoma one. Multivariate analysis indicated that this gene expression score is an independent biomarker of prognosis for OS in both the entire cohort [hazard ratio (HR): 1.498; 95% confidence interval (CI), 1.167–1.922; p = 0.001] and the adenocarcinoma subcohort [HR: 1.869; 95% CI, 1.275–2.738; p = 0.001]. This score was also analyzed in an independent cohort of 114 adenocarcinoma patients, confirming its prognostic value [42.90 vs. not reached (NR) mo, p = 0.020]. In conclusion, our findings provide relevant prognostic information for lung adenocarcinoma patients and the basis for developing novel therapies. Further studies are required to identify suitable markers and targets for lung squamous cell carcinoma patients.
Collapse
|
|
31
|
Akbarzadeh M, Maroufi NF, Tazehkand AP, Akbarzadeh M, Bastani S, Safdari R, Farzane A, Fattahi A, Nejabati HR, Nouri M, Samadi N. Current approaches in identification and isolation of cancer stem cells. J Cell Physiol 2019; 234:14759-14772. [PMID: 30741412 DOI: 10.1002/jcp.28271] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 01/17/2019] [Accepted: 01/22/2019] [Indexed: 01/24/2023]
Abstract
Cancer stem cells (CSCs) are tumor cells with initiating ability, self-renewal potential, and intrinsic resistance to conventional therapeutics. Efficient isolation and characterization of CSCs pave the way for more comprehensive knowledge about tumorigenesis, heterogeneity, and chemoresistance. Also a better understanding of CSCs will lead to novel era of both basic and clinical cancer research, reclassification of human tumors, and development of innovative therapeutic strategies. Finding novel diagnostic and effective therapeutic strategies also enhance the success of treatment in cancer patients. There are various methods based on the characteristics of the CSCs to detect and isolate these cells, some of which have recently developed. This review summarized current techniques for effective isolation and characterization of CSCs with a focus on advantages and limitations of each method with clinical applications.
Collapse
Affiliation(s)
- Maryam Akbarzadeh
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Fathi Maroufi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Pirpour Tazehkand
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Moloud Akbarzadeh
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Cellular and Molecular Biology, Faculty of Biological Science, Azarbaijan Shahid Madani University, Tabriz, Iran
| | - Sepideh Bastani
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Safdari
- Department of Health Information Management, School of Allied Medical Science, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Farzane
- Department of Health Information Management, School of Allied Medical Science, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Fattahi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Reza Nejabati
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
32
|
Hochmair M, Rath B, Klameth L, Ulsperger E, Weinlinger C, Fazekas A, Plangger A, Zeillinger R, Hamilton G. Effects of salinomycin and niclosamide on small cell lung cancer and small cell lung cancer circulating tumor cell lines. Invest New Drugs 2019; 38:946-955. [PMID: 31446534 PMCID: PMC7340652 DOI: 10.1007/s10637-019-00847-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023]
Abstract
Tumor dissemination and recurrence is attributed to highly resistant cancer stem cells (CSCs) which may constitute a fraction of circulating tumor cells (CTCs). Small cell lung cancer (SCLC) constitutes a suitable model to investigate the relation of CTCs and CSCs due to rapid tumor spread and a high number of CTCs. Expansion of five SCLC CTC lines (BHGc7, 10, 16, 26 and UHGc5) in vitro at our institution allowed for the analysis of CSC markers and cytotoxicity of the CSC-selective drugs salinomycin and niclosamide against CTC single cell suspensions or CTC spheroids/ tumorospheres (TOS). Salinomycin exerted dose-dependent cytotoxicity against the SCLC lines but, with exception of BHGc7 TOS, there was no markedly enhanced activity against TOS. Similarly, niclosamide exhibits high activity against BHGc7 TOS and UHGc5 TOS but not against the other CTC spheroids. High expression of the CSC marker CD133 was restricted to three SCLC tumor lines and the BHGc10 CTC line. All SCLC CTCs are CD24-positive but lack expression of CD44 and ABCG2 in contrast to the SCLC tumor lines which show a phenotype more similar to that of CSCs. The stem cell marker SOX2 was found in all CTC lines and SCLC GLC14/16, whereas elevated expression of Oct-3/4 and Nanog was restricted to BHGc26 and UHGc5. In conclusion, the SCLC CTCs established from patients with relapsed disease lack a typical CSC phenotype in respect to chemosensitivity to CSC-selective drugs, surface markers, expression of pluripotent stem cell and transcription factors.
Collapse
Affiliation(s)
- Maximilian Hochmair
- Respiratory Oncology Unit, Otto Wagner Hospital, Baumgartner Höhe, Vienna, Austria
| | - Barbara Rath
- Department of Surgery, Medical University of Vienna, Spitalgasse, Vienna, Austria
| | - Lukas Klameth
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | | | - Christoph Weinlinger
- Respiratory Oncology Unit, Otto Wagner Hospital, Baumgartner Höhe, Vienna, Austria
| | - Andreas Fazekas
- Respiratory Oncology Unit, Otto Wagner Hospital, Baumgartner Höhe, Vienna, Austria
| | - Adelina Plangger
- Department of Surgery, Medical University of Vienna, Spitalgasse, Vienna, Austria
| | - Robert Zeillinger
- Department of Gynecology and Obstetrics, Molecular Oncology Group, Medical University of Vienna, Vienna, Austria
| | - Gerhard Hamilton
- Department of Surgery, Medical University of Vienna, Spitalgasse, Vienna, Austria.
| |
Collapse
|
|
33
|
Feng YH, Su YC, Lin SF, Lin PR, Wu CL, Tung CL, Li CF, Shieh GS, Shiau AL. Oct4 upregulates osteopontin via Egr1 and is associated with poor outcome in human lung cancer. BMC Cancer 2019; 19:791. [PMID: 31399076 PMCID: PMC6688208 DOI: 10.1186/s12885-019-6014-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 08/05/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Roles of cancer stem cells and early growth response gene 1 (Egr1) in carcinogenesis have been extensively studied in lung cancer. However, the role of Egr1 in the metastasis of lung cancer remains undetermined, especially in regard to stem cell-related pathways. METHODS Egr1, osteopontin (OPN) and Oct4 expression in human lung cancer was determined by performing immunohistochemistry. Immunoblotting, ELISA, luciferase reporter assay, chromatin immunoprecipitation assay and RT-PCR were performed to validate the regulation of Oct4-Egr1-OPN axis. Moreover, the effect of Oct4-Egr1-OPN axis on lung cancer progression was evaluated by cell migration assay and mice study. RESULTS We detected Oct4, Egr1, and OPN expression in clinical specimens from 79 lung cancer patients, including 72 adenocarcinomas and 7 squamous cell carcinomas. High expression of Oct4, Egr1, and OPN accounted for 53, 51, and 57% of the patients, respectively. All of the three biomarkers were positively correlated in clinical human lung cancer. Patients with high expression of OPN were significantly associated with shorter disease-free survivals than those with low expression of OPN (p < 0.05). In lung cancer cells, Oct4 transactivated the Egr1 promoter and upregulated Egr1 expression. In a human lung cancer xenograft model, Oct4-overexpressing tumors expressed elevated levels of Egr1. Furthermore, overexpression of Oct4 in lung cancer cells increased the metastatic potential. CONCLUSIONS Egr1 exerts a promoting effect on cancer metastasis in Oct4-overexpressing lung cancer. Thus, therapeutic strategies targeting the Oct4/Egr1/OPN axis may be further explored for the treatment of lung cancer, especially when lung cancer is refractory to conventional treatment due to cancer stem cells.
Collapse
Affiliation(s)
- Yin-Hsun Feng
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, 901 Chung-Hwa Road, Tainan, 71004 Taiwan
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Yu-Chu Su
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shuo-Fu Lin
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 70101 Taiwan
| | - Pey-Ru Lin
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 70101 Taiwan
| | - Chao-Liang Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chao-Ling Tung
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, 901 Chung-Hwa Road, Tainan, 71004 Taiwan
| | - Chien-Feng Li
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Gia-Shing Shieh
- Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan
| | - Ai-Li Shiau
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 70101 Taiwan
| |
Collapse
|
|
34
|
Pankova D, Jiang Y, Chatzifrangkeskou M, Vendrell I, Buzzelli J, Ryan A, Brown C, O'Neill E. RASSF1A controls tissue stiffness and cancer stem-like cells in lung adenocarcinoma. EMBO J 2019; 38:e100532. [PMID: 31268606 PMCID: PMC6600643 DOI: 10.15252/embj.2018100532] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 04/23/2019] [Accepted: 04/29/2019] [Indexed: 01/03/2023] Open
Abstract
Lung cancer remains the leading cause of cancer-related death due to poor treatment responses and resistance arising from tumour heterogeneity. Here, we show that adverse prognosis associated with epigenetic silencing of the tumour suppressor RASSF1A is due to increased deposition of extracellular matrix (ECM), tumour stiffness and metastatic dissemination in vitro and in vivo. We find that lung cancer cells with RASSF1A promoter methylation display constitutive nuclear YAP1 accumulation and expression of prolyl 4-hydroxylase alpha-2 (P4HA2) which increases collagen deposition. Furthermore, we identify that elevated collagen creates a stiff ECM which in turn triggers cancer stem-like programming and metastatic dissemination in vivo. Re-expression of RASSF1A or inhibition of P4HA2 activity reverses these effects and increases markers of lung differentiation (TTF-1 and Mucin 5B). Our study identifies RASSF1A as a clinical biomarker associated with mechanical properties of ECM which increases the levels of cancer stemness and risk of metastatic progression in lung adenocarcinoma. Moreover, we highlight P4HA2 as a potential target for uncoupling ECM signals that support cancer stemness.
Collapse
Affiliation(s)
| | - Yanyan Jiang
- Department of OncologyUniversity of OxfordOxfordUK
- Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | | | - Iolanda Vendrell
- Department of OncologyUniversity of OxfordOxfordUK
- TDI Mass Spectrometry LaboratoryNuffield Department of MedicineTarget Discovery Institute University of OxfordOxfordUK
| | - Jon Buzzelli
- Department of OncologyUniversity of OxfordOxfordUK
| | - Anderson Ryan
- Department of OncologyUniversity of OxfordOxfordUK
- Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Cameron Brown
- School of Chemistry, Physics and Mechanical EngineeringQueensland University of TechnologyBrisbaneQldAustralia
| | - Eric O'Neill
- Department of OncologyUniversity of OxfordOxfordUK
- Systems Biology IrelandUniversity College DublinDublin 4Ireland
| |
Collapse
|
|
35
|
Nguyen JT, Haidar FS, Fox AL, Ray C, Mendonça DB, Kim JK, Krebsbach PH. mEAK-7 Forms an Alternative mTOR Complex with DNA-PKcs in Human Cancer. iScience 2019; 17:190-207. [PMID: 31288154 PMCID: PMC6614755 DOI: 10.1016/j.isci.2019.06.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 04/30/2019] [Accepted: 06/19/2019] [Indexed: 12/31/2022] Open
Abstract
MTOR associated protein, eak-7 homolog (mEAK-7), activates mechanistic target of rapamycin (mTOR) signaling in human cells through an alternative mTOR complex to regulate S6K2 and 4E-BP1. However, the role of mEAK-7 in human cancer has not yet been identified. We demonstrate that mEAK-7 and mTOR signaling are strongly elevated in tumor and metastatic lymph nodes of patients with non-small-cell lung carcinoma compared with those of patients with normal lung or lymph tissue. Cancer stem cells, CD44+/CD90+ cells, yield elevated mEAK-7 and activated mTOR signaling. mEAK-7 is required for clonogenic potential and spheroid formation. mEAK-7 associates with DNA-dependent protein kinase catalytic subunit isoform 1 (DNA-PKcs), and this interaction is increased in response to X-ray irradiation to regulate S6K2 signaling. DNA-PKcs pharmacologic inhibition or genetic knockout reduced S6K2, mEAK-7, and mTOR binding with DNA-PKcs, resulting in loss of S6K2 activity and mTOR signaling. Therefore, mEAK-7 forms an alternative mTOR complex with DNA-PKcs to regulate S6K2 in human cancer cells.
Collapse
Affiliation(s)
- Joe Truong Nguyen
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA
| | - Fatima Sarah Haidar
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA
| | - Alexandra Lucienne Fox
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA
| | - Connor Ray
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA
| | | | - Jin Koo Kim
- Section of Periodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Paul H Krebsbach
- Section of Periodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| |
Collapse
|
|
36
|
Zito Marino F, Bianco R, Accardo M, Ronchi A, Cozzolino I, Morgillo F, Rossi G, Franco R. Molecular heterogeneity in lung cancer: from mechanisms of origin to clinical implications. Int J Med Sci 2019; 16:981-989. [PMID: 31341411 PMCID: PMC6643125 DOI: 10.7150/ijms.34739] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 05/05/2019] [Indexed: 12/13/2022] Open
Abstract
Molecular heterogeneity is a frequent event in cancer responsible of several critical issues in diagnosis and treatment of oncologic patients. Lung tumours are characterized by high degree of molecular heterogeneity associated to different mechanisms of origin including genetic, epigenetic and non-genetic source. In this review, we provide an overview of recognized mechanisms underlying molecular heterogeneity in lung cancer, including epigenetic mechanisms, mutant allele specific imbalance, genomic instability, chromosomal aberrations, tumor mutational burden, somatic mutations. We focus on the role of spatial and temporal molecular heterogeneity involved in therapeutic implications in lung cancer patients.
Collapse
Affiliation(s)
| | - Roberto Bianco
- Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy
| | - Marina Accardo
- Pathology Unit, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Andrea Ronchi
- Pathology Unit, University of Campania “L. Vanvitelli”, Naples, Italy
| | | | - Floriana Morgillo
- Medical Oncology, Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Giulio Rossi
- Pathology Unit, Hospital S. Maria delle Croci, Azienda Romagna, Ravenna, Italy
| | - Renato Franco
- Pathology Unit, University of Campania “L. Vanvitelli”, Naples, Italy
| |
Collapse
|
|
37
|
Targeting Cancer Stem Cells: A Strategy for Effective Eradication of Cancer. Cancers (Basel) 2019; 11:cancers11050732. [PMID: 31137841 PMCID: PMC6562442 DOI: 10.3390/cancers11050732] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/19/2019] [Accepted: 05/23/2019] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells (CSCs) are subpopulations of tumor cells with the ability to self-renew, differentiate, and initiate and maintain tumor growth, and they are considered to be the main drivers of intra- and inter-tumoral heterogeneity. While conventional chemotherapy can eradicate the majority of non-CSC tumor cells, CSCs are often drug-resistant, leading to tumor recurrence and metastasis. The heterogeneity of CSCs is the main challenge in developing CSC-targeting therapy; therefore, we and other investigators have focused on developing novel therapeutic strategies that combine conventional chemotherapy with inhibitors of CSC-regulating pathways. Encouraging preclinical findings have suggested that CSC pathway blockade can indeed enhance cellular sensitivity to non-targeted conventional therapy, and this work has led to several ongoing clinical trials of CSC pathway inhibitors. Our studies in bladder cancer and lung adenocarcinoma have demonstrated a crucial role of YAP1, a transcriptional regulator of genes that promote cell survival and proliferation, in regulating CSC phenotypes. Moreover, using cell lines and patient-derived xenograft models, we showed that inhibition of YAP1 enhances the efficacy of conventional therapies by attenuating CSC stemness features. In this review, we summarize the therapeutic strategies for targeting CSCs in several cancers and discuss the potential and challenges of the approach.
Collapse
|
|
38
|
Organista-Nava J, Gómez-Gómez Y, Garibay-Cerdenares OL, Leyva-Vázquez MA, Illades-Aguiar B. Cervical cancer stem cell-associated genes: Prognostic implications in cervical cancer. Oncol Lett 2019; 18:7-14. [PMID: 31289465 PMCID: PMC6540231 DOI: 10.3892/ol.2019.10307] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 03/18/2019] [Indexed: 12/14/2022] Open
Abstract
Cervical cancer is the fourth most common type of gynecological malignancy to affect females, worldwide. Although high-risk human papillomavirus (HR-HPV) infection is the primary etiologic agent associated with the development of cervical cancer, cancer stem cells (CSCs) also serve a prominent role in the development, metastasis, recurrence and prognosis of the disease. CSCs are a small subpopulation of cells that have the ability to self-renew and are present in the majority of tumors, including cervical cancer. Studies describing the phenotype of cervical CSCs (CCSCs) vary in their definition of the expression pattern of principal biomarkers, including Musashi-1, aldehyde dehydrogenase 1, Oct3/4, Sox2 and CD49f. However, these markers are not observed in all cancers, although several may be present in multiple tumor types. The present review describes the potential biomarkers of CSCs in cervical cancer. These CCSC biomarkers may serve as molecular targets to enhance the efficacy and reduce the side effects associated with chemotherapeutic treatment in HR-HPV-positive cervical cancer.
Collapse
Affiliation(s)
- Jorge Organista-Nava
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39090, Mexico
| | - Yazmín Gómez-Gómez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39090, Mexico
| | - Olga Lilia Garibay-Cerdenares
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39090, Mexico.,Consejo Nacional de Ciencia y Tecnología, Mexico City 03940, Mexico
| | - Marco Antonio Leyva-Vázquez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39090, Mexico
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39090, Mexico
| |
Collapse
|
|
39
|
Datta S, Choudhury D, Das A, Mukherjee DD, Dasgupta M, Bandopadhyay S, Chakrabarti G. Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway. Apoptosis 2019; 24:414-433. [DOI: 10.1007/s10495-019-01526-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
40
|
Tiwari N, Srivastava AN, Tandon N, Lal N, Yadav S, Kant S, Jain M. A prospective study of association of cancer stem cell marker aldehyde dehydrogenase 1 with clinicopathological profile in lung carcinoma patients. INDIAN J PATHOL MICR 2019; 61:489-494. [PMID: 30303135 DOI: 10.4103/ijpm.ijpm_318_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Context In India, lung carcinoma is the fifth-most common tumor and second-most common tumor in the males as per the Indian Council of Medical Research registry of 2002. It has been seen that ALDH1 expression in non-small cell lung cancer (NSCLC) and the presence of marker was linked to a more tumorigenic potential in the in vivo assessment and shorter disease-free survival in NSCLC patients with platinum treatment. Aims Hence, our objective was to detect association of cancer stem cell (CSC) marker aldehyde dehydrogenase 1 (ALDH1) with clinicopathological profile in lung carcinoma patients. Settings and Design This is a Pilot study. Subjects and Methods It was a Pilot study where biopsies from 55 fresh previously untreated lung cancer patients visiting the Pulmonary Medicine Department of Era's Lucknow Medical College and Hospital Lucknow and King George's Medical University were taken for 18 months November 2014-April 2016, after taking proper informed consent from them. Paraffin blocks were taken and stained by hematoxylin and eosin (Sigma) to make the histopathological diagnosis and immunohistochemistry was done for detection of CSC marker ALDH1 (Daco). Statistical Analysis Used The statistical analysis was done using Statistical Package for Social Sciences Version 15.0 Statistical Analysis Software. The values were represented in number (%) and mean ± standard deviation. Results Expression of stem cell marker ALDH1 with the staging of the tumor was observed in 62.5% of Stage I, 80% of Stage II, 94.1% of Stage III, and 100% of Stage IV cases. Statistically, there was a significant association between ALDH1expression and stage of disease (P < 0.001). Diagnostic efficacy of ALDH1 expression in the detection of any positive clinical stage, it was found to be 88.6% sensitive and 90.9% specific. Conclusions Strong ALDH1 expression correlates with higher stage of lung carcinoma making it a prognostic marker needing in-depth study.
Collapse
Affiliation(s)
- Neema Tiwari
- Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Anand N Srivastava
- Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Nishi Tandon
- Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Nirupma Lal
- Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Shailendra Yadav
- Department of CTVS and Pulmonary Medicine, King George Medical University, Lucknow, Uttar Pradesh, India
| | - Surya Kant
- Department of CTVS and Pulmonary Medicine, King George Medical University, Lucknow, Uttar Pradesh, India
| | - Manoj Jain
- Department of Pathology, SGPGI, Lucknow, Uttar Pradesh, India
| |
Collapse
|
|
41
|
Heterogeneity of Small Cell Lung Cancer Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1139:41-57. [PMID: 31134494 DOI: 10.1007/978-3-030-14366-4_3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Small cell lung cancer, a subtype of lung cancer is an extremely malignant disease due to its metastases and recurrence. Patients with SCLC develop resistance to chemotherapy and the disease relapses. This relapse and resistance are attributed to the heterogeneity of SCLC. Various factors such as recurrent mutations in key regulatory genes such as TP53, RB1, and myc, epigenetic changes, and cancer stem cells contribute to the observed heterogeneity. Cancer stem cell models predict neuroendocrine origin of SCLC. Though an unambiguous established CSC marker has not been assigned, markers CD133, CD44 have been found associated with SCLC. Genetically engineered mouse models (GEMMs) allow the validation of driver mutations and are necessary for design of targeted therapy. This chapter outlines the factors contributing to SCLC heterogeneity, detection methods, and the current therapy trials.
Collapse
|
|
42
|
Ortiz RC, Lopes NM, Amôr NG, Ponce JB, Schmerling CK, Lara VS, Moyses RA, Rodini CO. CD44 and ALDH1 immunoexpression as prognostic indicators of invasion and metastasis in oral squamous cell carcinoma. J Oral Pathol Med 2018; 47:740-747. [PMID: 29791975 DOI: 10.1111/jop.12734] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Tumour metastasis has been associated with cancer stem cells, a small population with stem-like cells properties, higher rate of migration and metastatic potential compared to cells from the tumour bulk. Our aim was to evaluate the immunoexpression of the putative cancer stem cell biomarkers ALDH1 and CD44 in primary tumour and corresponding metastatic lymph nodes. METHODS Tumour tissue specimens (n = 50) and corresponding metastatic lymph nodes (n = 25) were surgically obtained from 50 patients with oral squamous cell carcinoma and submitted to immunohistochemistry. CD44 and ALDH1 were semi-quantitatively scored according to the proportion and intensity of positive cells within the invasive front and metastatic lymph nodes as a whole. A combined score was obtained by multiplying both parameters and later dichotomized into a final score classified as low (≤2) or high (>2) immunoexpression. RESULTS ALDH1 immunoexpression and CD44 immunoexpression were detected in both tumour sites, although the means of ALDH1 (P = .0985) and CD44 (P = .4220) cells were higher in metastasis compared to primary tumours. ALDH1high was positively associated (P = .0184) with angiolymphatic invasion, while CD44high was positively associated (P = .0181) with metastasis (N+). At multivariate analysis, CD44 significantly increased the odds of lymph node metastasis, regardless of T stage (OR = 8.24; 1.64-65.64, P = .0088). CONCLUSIONS CD44 immunoexpression was a significant predictor of lymph node metastasis, while ALDH1high immunostaining was associated with angiolymphatic invasion. Altogether, it suggests that immunoexpression of CD44 and ALDH1 links the cancer stem cell phenotype with oral squamous cell carcinoma invasion and metastasis.
Collapse
Affiliation(s)
- Rafael C Ortiz
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Nathália M Lopes
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Nádia G Amôr
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - José B Ponce
- Department of Pathology, University Centre of Adamantina, Adamantina, São Paulo, Brazil
| | - Cláudia K Schmerling
- Department of Anatomical Pathology, Clinical Hospital, School of Medicine of São Paulo, São Paulo, Brazil
| | - Vanessa S Lara
- Department of Surgery, Stomatology, Pathology and Radiology, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Raquel A Moyses
- Department of Head and Neck Surgery, LIM28, Clinical Hospital HCFMUSP, School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Camila O Rodini
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| |
Collapse
|
|
43
|
Satar NA, Fakiruddin KS, Lim MN, Mok PL, Zakaria N, Fakharuzi NA, Abd Rahman AZ, Zakaria Z, Yahaya BH, Baharuddin P. Novel triple‑positive markers identified in human non‑small cell lung cancer cell line with chemotherapy-resistant and putative cancer stem cell characteristics. Oncol Rep 2018; 40:669-681. [PMID: 29845263 PMCID: PMC6072294 DOI: 10.3892/or.2018.6461] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 04/03/2018] [Indexed: 02/06/2023] Open
Abstract
Through the specific identification and direct targeting of cancer stem cells (CSCs), it is believed that a better treatment efficacy of cancer may be achieved. Hence, the present study aimed to identify a CSC subpopulation from adenocarcinoma cells (A549) as a model of non-small cell lung cancer (NSCLC). Initially, we sorted two subpopulations known as the triple-positive (EpCAM+/CD166+/CD44+) and triple-negative (EpCAM−/CD166−/CD44−) subpopulation using fluorescence-activated cell sorting (FACS). Sorted cells were subsequently evaluated for proliferation and chemotherapy-resistance using a viability assay and were further characterized for their clonal heterogeneity, self-renewal characteristics, cellular migration, alkaline dehydrogenase (ALDH) activity and the expression of stemness-related genes. According to our findings the triple-positive subpopulation revealed significantly higher (P<0.01) proliferation activity, exhibited better clonogenicity, was mostly comprised of holoclones and had markedly bigger (P<0.001) spheroid formation indicating a better self-renewal capacity. A relatively higher resistance to both 5-fluouracil and cisplatin with 80% expression of ALDH was observed in the triple-positive subpopulation, compared to only 67% detected in the triple-negative subpopulation indicated that high ALDH activity contributed to greater chemotherapy-resistance characteristics. Higher percentage of migrated cells was observed in the triple-positive subpopulation with 56% cellular migration being detected, compared to only 19% in the triple-negative subpopulation on day 2. This was similarly observed on day 3 in the triple-positive subpopulation with 36% higher cellular migration compared to the triple-negative subpopulation. Consistently, elevated levels of the stem cell genes such as REX1 and SSEA4 were also found in the triple-positive subpopulation indicating that the subpopulation displayed a strong characteristic of pluripotency. In conclusion, our study revealed that the triple-positive subpopulation demonstrated similar characteristics to CSCs compared to the triple-negative subpopulation. It also confirmed the feasibility of using the triple-positive (EpCAM+/CD166+/CD44+) marker as a novel candidate marker that may lead to the development of novel therapies targeting CSCs of NSCLC.
Collapse
Affiliation(s)
- Nazilah Abdul Satar
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200 Penang, Malaysia
| | - Kamal Shaik Fakiruddin
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), 50588 Kuala Lumpur, Malaysia
| | - Moon Nian Lim
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), 50588 Kuala Lumpur, Malaysia
| | - Pooi Ling Mok
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor
| | - Norashikin Zakaria
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200 Penang, Malaysia
| | - Noor Atiqah Fakharuzi
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), 50588 Kuala Lumpur, Malaysia
| | - Ahmad Zuhairi Abd Rahman
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), 50588 Kuala Lumpur, Malaysia
| | - Zubaidah Zakaria
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), 50588 Kuala Lumpur, Malaysia
| | - Badrul Hisham Yahaya
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200 Penang, Malaysia
| | - Puteri Baharuddin
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), 50588 Kuala Lumpur, Malaysia
| |
Collapse
|
|
44
|
Zakaria N, Mohd Yusoff N, Zakaria Z, Widera D, Yahaya BH. Inhibition of NF-κB Signaling Reduces the Stemness Characteristics of Lung Cancer Stem Cells. Front Oncol 2018; 8:166. [PMID: 29868483 PMCID: PMC5966538 DOI: 10.3389/fonc.2018.00166] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 04/30/2018] [Indexed: 12/29/2022] Open
Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells that play a pivotal role in tumor development, invasion, metastasis, and recurrence. We and others have reported significant involvement of the NF-κB pathway in regulating CSCs of non-small cell lung cancer (NSCLC). In this study, we evaluated the effects of NF-κB inhibition on self-renewal, stemness, migration, and expression of genes involved in the epithelial to mesenchymal transition (EMT) and apoptosis resistance in lung CSCs. Different concentrations of the NF-κB inhibitor BMS-345541 (0.4, 4.0, and 10.0 µM), an inhibitor the NF-κB upstream kinase IKKβ, were used to treat both lung CSCs (CD166+CD44+, CD166+EpCAM+) and non-CSC NSCLC cells (CD166−CD44−, CD166−EpCAM−) in A549 and H2170 cell lines. We assessed the impact of BMS-345541 on the ability to form tumorspheres (self-renewal assay), expression of stemness genes (SOX2, OCT4, NANOG, SCA-1, and KLF4), migration, and expression of EMT and apoptosis-related genes. Inhibition of NF-κB by BMS-345541 effectively reduced the stemness, self-renewal, and migration capacity of lung CSCs. Moreover, expression of genes involved in the EMT (SNAI1 and TWIST) and apoptosis resistance (BCL-2, BAX, and BIRC5) was significantly reduced following the treatments, suggesting that NF-κB inhibition is sufficient to prevent the EMT and induce apoptosis in lung CSCs. Our findings suggest that NF-κB inhibition could reduce the capability of CSCs to maintain their population within the tumor mass, potentially decelerating cancer progression, relapse, and chemotherapy resistance.
Collapse
Affiliation(s)
- Norashikin Zakaria
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia
| | - Narazah Mohd Yusoff
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia
| | - Zubaidah Zakaria
- Cancer Research Centre, Institute for Medical Research (IMR), Kuala Lumpur, Malaysia
| | - Darius Widera
- Stem Cell Biology and Regenerative Medicine, School of Pharmacy, University of Reading, Reading, United Kingdom
| | - Badrul Hisham Yahaya
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia
| |
Collapse
|
|
45
|
Yu J, Wang S, Zhao W, Duan J, Wang Z, Chen H, Tian Y, Wang D, Zhao J, An T, Bai H, Wu M, Wang J. Mechanistic Exploration of Cancer Stem Cell Marker Voltage-Dependent Calcium Channel α2δ1 Subunit-mediated Chemotherapy Resistance in Small-Cell Lung Cancer. Clin Cancer Res 2018; 24:2148-2158. [PMID: 29437792 DOI: 10.1158/1078-0432.ccr-17-1932] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Revised: 11/24/2017] [Accepted: 02/01/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Chemoresistance in small-cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSC). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. This study explored the role of the voltage-dependent calcium channel α2δ1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of α2δ1-mediated chemoresistance and strategies of overcoming the resistance.Experimental Design: α2δ1-positive cells were identified and isolated from SCLC cell lines and patient-derived xenograft (PDX) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western blotting were carried out to identify pathways involved in α2δ1-mediated chemoresistance in SCLC. In addition, possible interventions to overcome α2δ1-mediated chemoresistance were examined.Results: Different proportions of α2δ1+ cells were identified in SCLC cell lines and PDX models. α2δ1+ cells exhibited CSC-like properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of α2δ1+ cells instead of CD133+ cells in PDXs, and an increased proportion of α2δ1+ cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the α2δ1-positive H1048 cell line was identified at the protein level. mAb 1B50-1 was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models.Conclusions: SCLC cells expressing α2δ1 demonstrated CSC-like properties, and may contribute to chemoresistance. ERK may play a key role in α2δ1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. Clin Cancer Res; 24(9); 2148-58. ©2018 AACR.
Collapse
Affiliation(s)
- Jiangyong Yu
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shuhang Wang
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China
| | - Wei Zhao
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jianchun Duan
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhijie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hanxiao Chen
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanhua Tian
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Di Wang
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Jun Zhao
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China
| | - Tongtong An
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hua Bai
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Meina Wu
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China
| |
Collapse
|
|
46
|
Monterisi S, Lo Riso P, Russo K, Bertalot G, Vecchi M, Testa G, Di Fiore PP, Bianchi F. HOXB7 overexpression in lung cancer is a hallmark of acquired stem-like phenotype. Oncogene 2018; 37:3575-3588. [PMID: 29576613 DOI: 10.1038/s41388-018-0229-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 01/31/2018] [Accepted: 02/28/2018] [Indexed: 12/24/2022]
Abstract
HOXB7 is a homeodomain (HOX) transcription factor involved in regional body patterning of invertebrates and vertebrates. We previously identified HOXB7 within a ten-gene prognostic signature for lung adenocarcinoma, where increased expression of HOXB7 was associated with poor prognosis. This raises the question of how HOXB7 overexpression can influence the metastatic behavior of lung adenocarcinoma. Here, we analyzed publicly available microarray and RNA-seq lung cancer expression datasets and found that HOXB7-overexpressing tumors are enriched in gene signatures characterizing adult and embryonic stem cells (SC), and induced pluripotent stem cells (iPSC). Experimentally, we found that HOXB7 upregulates several canonical SC/iPSC markers and sustains the expansion of a subpopulation of cells with SC characteristics, through modulation of LIN28B, an emerging cancer gene and pluripotency factor, which we discovered to be a direct target of HOXB7. We validated this new circuit by showing that HOXB7 enhances reprogramming to iPSC with comparable efficiency to LIN28B or its target c-MYC, which is a canonical reprogramming factor.
Collapse
Affiliation(s)
- Simona Monterisi
- Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy.,IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy.,Humanitas Clinical and Research Center, 20089 Rozzano (MI), Italy
| | - Pietro Lo Riso
- Department of Experimental Oncology, European Institute of Oncology, 20141, Milan, Italy
| | - Karin Russo
- IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy
| | - Giovanni Bertalot
- Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy
| | - Manuela Vecchi
- IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy
| | - Giuseppe Testa
- Department of Experimental Oncology, European Institute of Oncology, 20141, Milan, Italy.,DIPO, Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, Italy
| | - Pier Paolo Di Fiore
- Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy.,IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy.,DIPO, Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, Italy
| | - Fabrizio Bianchi
- Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy. .,ISBREMIT, Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies, IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (FG), Italy.
| |
Collapse
|
|
47
|
In Silico Selection Approach to Develop DNA Aptamers for a Stem-like Cell Subpopulation of Non-small Lung Cancer Adenocarcinoma Cell Line A549. Radiol Oncol 2018; 52:152-159. [PMID: 30018518 PMCID: PMC6043879 DOI: 10.2478/raon-2018-0014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 02/26/2018] [Indexed: 11/29/2022] Open
Abstract
Background Detection of circulating lung cancer cells with cancer-stem like characteristics would represent an improved tool for disease prognosis. However, current antibodies based methods have some disadvantages and therefore cell SELEX (Systematic Evolution of Ligands by Exponential Enrichment) was used to develop DNA aptamers, recognizing cell surface markers of non-small lung carcinoma (NSLC) cells. Materials and methods The human adenocarcinoma cell line A549 was used for selection in seven cell SELEX cycles. We used human blood leukocytes for negative selection, and lung stem cell protein marker CD90 antibody binding A549 cells for positive selection. Results The obtained oligonucleotide sequences after the seventh SELEX cycle were subjected to in silico selection analysis based on three independent types of bioinformatics approaches, selecting two closely related aptamer candidates in terms of consensus sequences, structural motifs, binding affinity (Kd) and stability (ΔG). We selected and identified the aptamer A155_18 with very good binding characteristics to A459 cells, selected for CD90 antibody binding. The calculated phylogenetic tree showed that aptamers A155_18 and the known A549 cell aptamer S6 have a close structural relationship. MEME sequence analysis showed that they share two unique motifs, not present in other sequences. Conclusions The novel aptamer A155_18 has strong binding affinity for A549 lung carcinoma cell line subpopulation that is expressing stem cell marker CD90, indicating a possible stemness, characteristic for the A459 line, or a subpopulation present within this cell line. This aptamer can be applied as diagnostic tool, identifying NSLC circulating cells.
Collapse
|
|
48
|
Shue YT, Lim JS, Sage J. Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models. Transl Lung Cancer Res 2018. [PMID: 29535910 DOI: 10.21037/tlcr.2018.01.15] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth. We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents. A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients.
Collapse
Affiliation(s)
- Yan Ting Shue
- Department of Pediatrics, Stanford University, Stanford, CA, USA.,Department of Genetics, Stanford University, Stanford, CA, USA
| | - Jing Shan Lim
- Department of Pediatrics, Stanford University, Stanford, CA, USA.,Department of Genetics, Stanford University, Stanford, CA, USA
| | - Julien Sage
- Department of Pediatrics, Stanford University, Stanford, CA, USA.,Department of Genetics, Stanford University, Stanford, CA, USA
| |
Collapse
|
|
49
|
Serafim V, Shah A, Puiu M, Andreescu N, Coricovac D, Nosyrev AE, Spandidos DA, Tsatsakis AM, Dehelean C, Pinzaru I. Classification of cancer cell lines using matrix-assisted laser desorption/ionization time‑of‑flight mass spectrometry and statistical analysis. Int J Mol Med 2017; 40:1096-1104. [PMID: 28765873 PMCID: PMC5593469 DOI: 10.3892/ijmm.2017.3083] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 07/12/2017] [Indexed: 01/08/2023] Open
Abstract
Over the past decade, matrix-assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI‑TOF MS) has been established as a valuable platform for microbial identification, and it is also frequently applied in biology and clinical studies to identify new markers expressed in pathological conditions. The aim of the present study was to assess the potential of using this approach for the classification of cancer cell lines as a quantifiable method for the proteomic profiling of cellular organelles. Intact protein extracts isolated from different tumor cell lines (human and murine) were analyzed using MALDI‑TOF MS and the obtained mass lists were processed using principle component analysis (PCA) within Bruker Biotyper® software. Furthermore, reference spectra were created for each cell line and were used for classification. Based on the intact protein profiles, we were able to differentiate and classify six cancer cell lines: two murine melanoma (B16‑F0 and B164A5), one human melanoma (A375), two human breast carcinoma (MCF7 and MDA‑MB‑231) and one human liver carcinoma (HepG2). The cell lines were classified according to cancer type and the species they originated from, as well as by their metastatic potential, offering the possibility to differentiate non‑invasive from invasive cells. The obtained results pave the way for developing a broad‑based strategy for the identification and classification of cancer cells.
Collapse
Affiliation(s)
- Vlad Serafim
- Center of Genomic Medicine, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania
- Department of Natural Sciences, Middlesex University, London NW4 4BT, UK
| | - Ajit Shah
- Department of Natural Sciences, Middlesex University, London NW4 4BT, UK
| | - Maria Puiu
- Center of Genomic Medicine, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Nicoleta Andreescu
- Center of Genomic Medicine, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Dorina Coricovac
- Department of Toxicology, Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Alexander E. Nosyrev
- Central Chemical Laboratory of Toxicology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | | | - Aristides M. Tsatsakis
- Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Cristina Dehelean
- Department of Toxicology, Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Iulia Pinzaru
- Department of Toxicology, Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| |
Collapse
|
|
50
|
CD44v8-10 as a potential theranostic biomarker for targeting disseminated cancer cells in advanced gastric cancer. Sci Rep 2017; 7:4930. [PMID: 28694503 PMCID: PMC5503939 DOI: 10.1038/s41598-017-05247-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 05/25/2017] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer is the third most common cause of cancer mortality, and the survival rate of stage IV advanced gastric cancer (AGC) patients with distant metastasis is very low. Thus, the detection and eradication of disseminated cancer cells by targeting cell surface molecules in AGC would improve patient survival. The hyaluronic acid receptor, CD44, has various isoforms generated by alternative splicing, and some isoforms are known to be correlated to gastric cancer. In this study, to find out the most appropriate CD44v for targeting AGC, we analysed the expression differences of CD44 isoforms at the mRNA level in stomach cancer cell lines as well as in 74 patients with AGC by using exon-specific qRT-PCR. Among the CD44v isoforms, CD44v8-10 was determined as the most promising biomarker for the development of theranostic agents of gastric cancer. Next, we synthesised the conjugate of anti-CD44v9 antibody with near-infrared fluorophore or photosensitiser, and then demonstrated its feasibility for target cell-specific imaging and photoimmunotherapy in gastric cancer. As a result, these conjugates have clearly demarcated the surface of CD44v8-10 expressing cancer cells and showed efficient phototoxic effects. Therefore, this study revealed that CD44v8-10 is the efficient theranostic biomarker to target disseminated cancer cells in AGC.
Collapse
|