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Li W, Hu Q, Lin C, Li X, Bai Y, Ma M. A positive feedback loop between FOSB and miR-133b controls colon cancer cell proliferation. Acta Biochim Biophys Sin (Shanghai) 2025. [PMID: 40151144 DOI: 10.3724/abbs.2025041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025] Open
Abstract
FOSB, a member of the FOS gene family, forms heterodimers with JUN family proteins to engage in diverse cellular processes. Its biological impacts vary among different types of tumors, yet its specific function in colon cancer (CC) remains ambiguous. In this study, quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) are applied to measure FOSB expression levels, followed by an analysis of the association between FOSB expression and patients' clinical parameters. In vitro experiments are performed to assess cell proliferation, including growth rate, cell cycle distribution, and apoptosis. A subcutaneous xenograft model in nude mice is utilized to monitor tumor growth in vivo. Additionally, chromatin immunoprecipitation (ChIP) and luciferase reporter assays are conducted to dissect the interactions among FOSB, miR-133b, and POU2F1. The results indicate that FOSB expression is downregulated in CC tissues relative to normal controls. Overexpression of FOSB suppresses proliferation and promotes apoptosis in CC cells. Mechanistically, FOSB binds to the promoter region of miR-133b, enhancing its transcription and subsequently repressing POU2F1 expression. Notably, decreased POU2F1 expression also alleviates the transcriptional repression of the FOSB promoter region, establishing a FOSB-miR-133b-POU2F1 feedback loop that inhibits CC proliferation. In summary, our findings suggest that FOSB acts as a tumor suppressor gene in CC and may exert its inhibitory effects on CC growth via the FOSB-miR-133b-POU2F1 feedback loop.
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Affiliation(s)
- Wanwan Li
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital of Central South University, Changsha 410013, China
- Department of General Surgery, the Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Qionggui Hu
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Changwei Lin
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Xiaorong Li
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Yang Bai
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital of Central South University, Changsha 410013, China
- Postdoctoral Station of Basic Medicine, the Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Min Ma
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital of Central South University, Changsha 410013, China
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Mizoo T, Oka T, Sugahara O, Minato T, Higa T, Nakayama KI. GPLD1+ cancer stem cells contribute to chemotherapy resistance and tumour relapse in intestinal cancer. J Biochem 2025; 177:105-119. [PMID: 39743241 DOI: 10.1093/jb/mvae082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 01/04/2025] Open
Abstract
Cancer stem cells (CSCs) play a central role in cancer progression, therapy resistance, and disease recurrence. With the use of a quadruple-mutant mouse intestinal cancer organoid model and single-cell RNA-sequencing analysis, we have now identified glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), an enzyme that catalyzes the cleavage of glycosylphosphatidylinositol (GPI) anchors of membrane proteins, as a marker of slowly cycling CSCs. Ablation of Gpld1+ cells in combination with 5-fluorouracil treatment greatly attenuated cell viability in and regrowth of the intestinal cancer organoids. In addition, we identified serine protease 8 (PRSS8) as a key substrate of GPLD1 in human colorectal cancer cells. GPLD1 cleaves the GPI anchor of PRSS8 and thereby mediates release of the protease from the plasma membrane, resulting in the activation of Wnt signalling and promotion of the epithelial-mesenchymal transition (EMT) in the cancer cells. Pharmacological inhibition of GPLD1 suppressed Wnt signalling activity and EMT in association with upregulation of the amount of functional PRSS8 at the plasma membrane. Our findings suggest that targeting of GPLD1 in colorectal cancer might contribute to a new therapeutic strategy that is based on suppression of Wnt signalling and EMT-related cancer progression driven by CSCs.
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Affiliation(s)
- Taisuke Mizoo
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Takeru Oka
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Osamu Sugahara
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Takafumi Minato
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Tsunaki Higa
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Keiichi I Nakayama
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
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Sinha S, Alcantara J, Perry K, Castillo V, Espinoza CR, Taheri S, Vidales E, Tindle C, Adel A, Amirfakhri S, Sawires JR, Yang J, Bouvet M, Sahoo D, Ghosh P. Machine-Learning Identifies a Strategy for Differentiation Therapy in Solid Tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.09.13.557628. [PMID: 37745574 PMCID: PMC10515918 DOI: 10.1101/2023.09.13.557628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
BACKGROUND Although differentiation therapy can cure some hematologic malignancies, its curative potential remains unrealized in solid tumors. This is because conventional computational approaches succumb to the thunderous noise of inter-/intratumoral heterogeneity. Using colorectal cancers (CRCs) as an example, here we outline a machine learning(ML)-based approach to track, differentiate, and selectively target cancer stem cells (CSCs). METHODS A transcriptomic network was built and validated using healthy colon and CRC tissues in diverse gene expression datasets (~5,000 human and >300 mouse samples). Therapeutic targets and perturbation strategies were prioritized using ML, with the goal of reinstating the expression of a transcriptional identifier of the differentiated colonocyte, CDX2, whose loss in poorly differentiated (CSC-enriched) CRCs doubles the risk of relapse/death. The top candidate target was then engaged with a clinical-grade drug and tested on 3 models: CRC lines in vitro, xenografts in mice, and in a prospective cohort of healthy (n = 3) and CRC (n = 23) patient-derived organoids (PDOs). RESULTS The drug shifts the network predictably, induces CDX2 and crypt differentiation, and shows cytotoxicity in all 3 models, with a high degree of selectivity towards all CDX2-negative cell lines, xenotransplants, and PDOs. The potential for effective pairing of therapeutic efficacy (IC50) and biomarker (CDX2-low state) is confirmed in PDOs using multivariate analyses. A 50-gene signature of therapeutic response is derived and tested on 9 independent cohorts (~1700 CRCs), revealing the impact of CDX2-reinstatement therapy could translate into a ~50% reduction in the risk of mortality/recurrence. CONCLUSIONS Findings not only validate the precision of the ML approach in targeting CSCs, and objectively assess its impact on clinical outcome, but also exemplify the use of ML in yielding clinical directive information for enhancing personalized medicine.
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Facey COB, Hunsu VO, Zhang C, Osmond B, Opdenaker LM, Boman BM. CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC. Cancers (Basel) 2024; 16:264. [PMID: 38254755 PMCID: PMC10813786 DOI: 10.3390/cancers16020264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/02/2024] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
APC mutation is the main driving mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. Hypotheses: A functional link exists between the WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induce wt-APC expression in APC-mutant CRC cells, and we assess the ability of all-trans retinoic acid (ATRA) to induce differentiation. We found that ATRA increased expression of the WNT target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, the RA and WNT pathways crosstalk to modulate CYP26A1, which metabolizes retinoids. Moreover, inducing wt-APC augments ATRA-induced cell differentiation by: (i) decreasing cell proliferation; (ii) suppressing ALDH1A1 expression; (iii) decreasing ALDH+ SCs; and (iv) increasing neuroendocrine cell differentiation. A novel CYP26A1-based network that links WNT and RA signaling was also identified by NanoString profiling/bioinformatics analysis. Furthermore, CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Notably, in wt-APC-CRCs, decreased CYP26A1 improved patient survival. These findings have strong potential for clinical translation.
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Affiliation(s)
- Caroline O. B. Facey
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
| | - Victoria O. Hunsu
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
- Department Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Chi Zhang
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
- Department Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Brian Osmond
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
- Department Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Lynn M. Opdenaker
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
| | - Bruce M. Boman
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
- Department Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Department Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [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] [Received: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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Zeng T, Ling C, Liang Y. Exploring active ingredients and mechanisms of Coptidis Rhizoma-ginger against colon cancer using network pharmacology and molecular docking. Technol Health Care 2024; 32:523-542. [PMID: 38759074 PMCID: PMC11191530 DOI: 10.3233/thc-248046] [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: 05/19/2024]
Abstract
BACKGROUND Colon cancer is the most prevalent and rapidly increasing malignancy globally. It has been suggested that some of the ingredients in the herb pair of Coptidis Rhizoma and ginger (Zingiber officinale), a traditional Chinese medicine, have potential anti-colon cancer properties. OBJECTIVE This study aimed to investigate the molecular mechanisms underlying the effects of the Coptidis Rhizoma-ginger herb pair in treating colon cancer, using an integrated approach combining network pharmacology and molecular docking. METHODS The ingredients of the herb pair Coptidis Rhizoma-ginger, along with their corresponding protein targets, were obtained from the Traditional Chinese Medicine System Pharmacology and Swiss Target Prediction databases. Target genes associated with colon cancer were retrieved from the GeneCards and OMIM databases. Then, the protein targets of the active ingredients in the herb pair were identified, and the disease-related overlapping targets were determined using the Venn online tool. The protein-protein interaction (PPI) network was constructed using STRING database and analyzed using Cytoscape 3.9.1 to identify key targets. Then, a compound-target-disease-pathway network map was constructed. The intersecting target genes were subjected to Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for colon cancer treatment. Molecular docking was performed using the Molecular Operating Environment (MOE) software to predict the binding affinity between the key targets and active compounds. RESULTS Besides 1922 disease-related targets, 630 targets associated with 20 potential active compounds of the herb pair Coptidis Rhizoma-ginger were collected. Of these, 229 intersection targets were obtained. Forty key targets, including STAT3, Akt1, SRC, and HSP90AA1, were further analyzed using the ClueGO plugin in Cytoscape. These targets are involved in biological processes such as miRNA-mediated gene silencing, phosphatidylinositol 3-kinase (PI3K) signaling, and telomerase activity. KEGG enrichment analysis showed that PI3K-Akt and hypoxia-inducible factor 1 (HIF-1) signaling pathways were closely related to colon cancer prevention by the herb pair Coptidis Rhizoma-ginger. Ten genes (Akt1, TP53, STAT3, SRC, HSP90AA1, JAK2, CASP3, PTGS2, BCl2, and ESR1) were identified as key genes for validation through molecular docking simulation. CONCLUSIONS This study demonstrated that the herb pair Coptidis Rhizoma-ginger exerted preventive effects against colon cancer by targeting multiple genes, utilizing various active compounds, and modulating multiple pathways. These findings might provide the basis for further investigations into the molecular mechanisms underlying the therapeutic effects of Coptidis Rhizoma-ginger in colon cancer treatment, potentially leading to the development of novel drugs for combating this disease.
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Affiliation(s)
- Ting Zeng
- Institute of Systems Engineering and Collaborative Laboratory for Intelligent Science and Systems, Macau University of Science and Technology, Taipa, Macao, China
| | - Caijin Ling
- Faculty of Information Technology, Macau University of Science and Technology, Taipa, Macao, China
| | - Yong Liang
- Peng Cheng Laboratory, Shenzhen, Guangdong, China
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Kasprzak A. Prognostic Biomarkers of Cell Proliferation in Colorectal Cancer (CRC): From Immunohistochemistry to Molecular Biology Techniques. Cancers (Basel) 2023; 15:4570. [PMID: 37760539 PMCID: PMC10526446 DOI: 10.3390/cancers15184570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/04/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., APC, KRAS/BRAF, TGF-β, and TP53). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients' overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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Hao J, Huang J, Hua C, Zuo Y, Yu W, Wu X, Li L, Xue G, Wan X, Ru L, Guo Z, Han S, Deng W, Lin F, Guo W. A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance. PLoS Biol 2023; 21:e3002256. [PMID: 37708089 PMCID: PMC10501593 DOI: 10.1371/journal.pbio.3002256] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 07/17/2023] [Indexed: 09/16/2023] Open
Abstract
The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.
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Affiliation(s)
- Jiaojiao Hao
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Jinsheng Huang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Chunyu Hua
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yan Zuo
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Wendan Yu
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Xiaojun Wu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Liren Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Guoqing Xue
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Xinyu Wan
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Liyuan Ru
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Ziyue Guo
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Shilong Han
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Wuguo Deng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Fei Lin
- Department of Oncology, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine; The Affiliated Nanhai Hospital of Traditional Chinese Medicine of Jinan University, Foshan, China
| | - Wei Guo
- Institute of Cancer Stem Cells & The First Affiliated Hospital, Dalian Medical University, Dalian, China
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9
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Cui G, Li G, Pang Z, Florholmen J, Goll R. The presentation and regulation of the IL-8 network in the epithelial cancer stem-like cell niche in patients with colorectal cancer. Biomed Pharmacother 2022; 152:113252. [PMID: 35687912 DOI: 10.1016/j.biopha.2022.113252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/02/2022] [Accepted: 06/02/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Accumulative evidence suggests that the biological behavior of cancer stem-like cells (CSCs) is regulated by their surrounding niche, in which cytokines function as one of the main mediators for the interaction between CSCs and their microenvironment in the colorectal cancer (CRC). METHODS We characterized the presentation of CSCs and the interleukin (IL)- 8 network in the adenoma/CRC epithelium using quantitative real-time PCR (q-PCR), immunohistochemistry (IHC) and double immunofluorescence. In addition, the capacity of IL-1β to stimulate epithelial IL-8 production in colon cancer Caco-2 cells was examined in vitro and the IL-8 product was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS IHC observation showed increased expression of both CSCs and IL-8 in the adenoma and CRC epithelium, and q-PCR results revealed that increased expression of IL-1β transcript was strongly correlated with increased IL-8 transcript levels in both adenoma and CRC tissues. Double immunofluorescence images demonstrated the coexpression of the IL-8 receptors IL-8RA and IL-8RB with LGR5 labeled CSCs in CRC tissue sections. Consistently, in vitro experiments showed that coculture of Caco-2 cells with IL-1β at concentrations of 1, 5, 10 and 20 ng/ml resulted in a dose-dependent release of IL-8, which could be specifically inhibited by cotreatment with the IL-1β receptor antagonist. CONCLUSIONS These results demonstrate activation of the IL-8 network in the niche of CSCs from the precancerous adenoma stage to the CRC stage, which is potentially stimulated by IL-1β in CRC cells.
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Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Faculty of Health Science, Nord University, Campus Levanger, Levanger, Norway.
| | - Gui Li
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Pang
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jon Florholmen
- Department of Gastroenterology, University Hospital of North Norway, University of Tromsø, Tromsø, Norway
| | - Rasmus Goll
- Department of Gastroenterology, University Hospital of North Norway, University of Tromsø, Tromsø, Norway
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Zhang M, Peng Y, Yang Z, Zhang H, Xu C, Liu L, Zhao Q, Wu J, Wang H, Liu J. DAB2IP down-regulates HSP90AA1 to inhibit the malignant biological behaviors of colorectal cancer. BMC Cancer 2022; 22:561. [PMID: 35590292 PMCID: PMC9118737 DOI: 10.1186/s12885-022-09596-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 04/22/2022] [Indexed: 12/15/2022] Open
Abstract
Background Studies have shown that DAB2IP inhibits cancer progression, while HSP90AA1 promotes cancer progression. However, the specific regulatory mechanism of DAB2IP and HSP90AA1 in colorectal cancer (CRC) is not clear. Our aim is to investigate the role and mechanism of DAB2IP and HSP90AA1 in the development of CRC. Methods We used bioinformation to analyze the interaction between DAB2IP and HSP90AA1 and predict their downstream pathways. Then, a series of in vitro and in vivo experiments were conducted to reveal the role of DAB2IP and HSP90AA1 in the invasion and metastasis of colorectal cancer, and flow cytometry was used to explore their effects on apoptosis. Results Loss of DAB2IP was associated with poor prognosis of CRC. In contrast, elevated expression of HSP90AA1 was associated with the malignant behavior of CRC. The present study demonstrated a negative correlation between DAB2IP and HSP90AA1. Using bioinformatic analysis, we scanned SRP9 which was highly expressed in CRC, as a co-related gene of DAB2IP and HSP90AA1. Mechanistically, DAB2IP promoted apoptosis through HSP90AA1/SRP9/ASK1/JNK signaling axis in CRC. Conclusions These findings provide evidence that DAB2IP-based therapy may enhance the anticancer effect of HSP90AA1 inhibitors, and combined targeting of DAB2IP and HSP90AA1 may be a powerful treatment strategy to combat CRC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09596-z.
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Affiliation(s)
- Mengna Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, WuhanHubei Province, 430071, China.,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Yanan Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, WuhanHubei Province, 430071, China.,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Zhenwei Yang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, WuhanHubei Province, 430071, China.,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Hailin Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, WuhanHubei Province, 430071, China.,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Cong Xu
- Tongji Hospital of Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, WuhanHubei Province, 430071, China.,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, WuhanHubei Province, 430071, China.,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Jixiong Wu
- Department of Gastroenterology, Huanggang Central Hospital, Huangzhou District, No.11, Kaopeng Street, HuanggangHubei Province, 438000, China.
| | - Hongling Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, WuhanHubei Province, 430071, China. .,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China.
| | - Jing Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, WuhanHubei Province, 430071, China. .,Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China.
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11
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Xu Z, Qu H, Ren Y, Gong Z, Ri HJ, Zhang F, Shao S, Chen X, Chen X. Systematic Analysis of E2F Expression and Its Relation in Colorectal Cancer Prognosis. Int J Gen Med 2022; 15:4849-4870. [PMID: 35585998 PMCID: PMC9109810 DOI: 10.2147/ijgm.s352141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/22/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- ZhaoHui Xu
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Graduate School of Dalian Medical University, Dalian, People’s Republic of China
| | - Hui Qu
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Graduate School of Dalian Medical University, Dalian, People’s Republic of China
| | - YanYing Ren
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - ZeZhong Gong
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Graduate School of Dalian Medical University, Dalian, People’s Republic of China
| | - Hyok Ju Ri
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Graduate School of Dalian Medical University, Dalian, People’s Republic of China
| | - Fan Zhang
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Shuai Shao
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - XiaoLiang Chen
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Xin Chen
- Department of Hernia and Colorectal Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Correspondence: Xin Chen, Tel +86 17709872266, Email
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12
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Lee JW, Lee HY. Targeting Cancer Stem Cell Markers or Pathways: A Potential Therapeutic Strategy for Oral Cancer Treatment. Int J Stem Cells 2021; 14:386-399. [PMID: 34711702 PMCID: PMC8611309 DOI: 10.15283/ijsc21084] [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: 04/30/2021] [Revised: 05/14/2021] [Accepted: 06/05/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cancer cells with stem cell-like properties, self-renewal potential, and differentiation capacity into multiple cell types. Critical genetic alterations or aberrantly activated signaling pathways associated with drug resistance and recurrence have been observed in multiple types of CSCs. In this context, CSCs are considered to be responsible for tumor initiation, growth, progression, therapeutic resistance, and metastasis. Therefore, to effectively eradicate CSCs, tremendous efforts have been devoted to identify specific target molecules that play a critical role in regulating their distinct functions and to develop novel therapeutics, such as proteins, monoclonal antibodies, selective small molecule inhibitors, and small antisense RNA (asRNA) drugs. Similar to other CSC types, oral CSCs can be characterized by certain pluripotency-associated markers, and oral CSCs can also survive and form 3D tumor spheres in suspension culture conditions. These oral CSC-targeting therapeutics selectively suppress specific surface markers or key signaling components and subsequently inhibit the stem-like properties of oral CSCs. A large number of new therapeutic candidates have been tested, and some products are currently in the pre-clinical or clinical development phase. In the present study, we review new oral CSC-targeted therapeutic strategies and discuss the various specific CSC surface markers and key signaling components involved in the stem-like properties, growth, drug resistance, and tumorigenicity of oral CSCs.
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Affiliation(s)
- Jin Woo Lee
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Korea
| | - Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, Goesan, Korea.,Division of Science Education, Kangwon National University, Chuncheon, Korea
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13
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Silva VR, Santos LDS, Dias RB, Quadros CA, Bezerra DP. Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells. Cancer Commun (Lond) 2021; 41:1275-1313. [PMID: 34791817 PMCID: PMC8696218 DOI: 10.1002/cac2.12235] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/28/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells (CSCs), which present both pluripotency and self-renewal properties. These cells are considered responsible for the progression of the disease, recurrence and tumor resistance. Interestingly, some cell signaling pathways participate in CRC survival, proliferation, and self-renewal properties, and most of them are dysregulated in CSCs, including the Wingless (Wnt)/β-catenin, Notch, Hedgehog, nuclear factor kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), peroxisome proliferator-activated receptor (PPAR), phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR), and transforming growth factor-β (TGF-β)/Smad pathways. In this review, we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways, which will contribute to the study of potential therapeutic schemes, combining conventional drugs with CSC-targeting drugs, and allowing better cure rates in anti-CRC therapy.
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Affiliation(s)
- Valdenizia R Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Luciano de S Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Rosane B Dias
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Claudio A Quadros
- São Rafael Hospital, Rede D'Or/São Luiz, Salvador, Bahia, 41253-190, Brazil.,Bahia State University, Salvador, Bahia, 41150-000, Brazil
| | - Daniel P Bezerra
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
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14
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O.B. Facey C, M. Boman B. Retinoids in Treatment of Colorectal Cancer. COLORECTAL CANCER 2021. [DOI: 10.5772/intechopen.93699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Retinoids are vitamin A metabolites best known for their role in embryonic development. Indeed, retinoid acid (RA) signaling plays a key role in regulating the development of the embryo body-plan by controlling embryonic stem cells (SCs). Retinoids function through their ability to induce cellular differentiation. Mutations in RA signaling pathway genes occur in most human cancers. The classic example is the chromosomal translocation involving RA receptor alpha in acute promyelocytic leukemia (APL). Because all-trans retinoic acid (ATRA) is a highly effective and often curative treatment for APL patients, determining if retinoids are efficacious for other cancer types is imperative. We review the current research on retinoids in colorectal cancer (CRC) and provide bioinformatics analyses of RA signaling. Our results show that most RA pathway genes are overexpressed and often mutated in CRC. Moreover, aberrant expression of many RA signaling proteins predicts decreased CRC patient survival. We also review aldehyde dehydrogenase (ALDH) expression in CRC because ALDH is a key enzyme in RA signaling, which regulates colonic SCs. Further investigation of RA signaling mechanisms that regulate colon SCs and how dysregulation contributes to the SC overpopulation that drives CRC growth should provide insight into strategies for designing new SC-targeted therapies for CRC.
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15
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The Role of miRNAs, miRNA Clusters, and isomiRs in Development of Cancer Stem Cell Populations in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22031424. [PMID: 33572600 PMCID: PMC7867000 DOI: 10.3390/ijms22031424] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/17/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) during development and altered expression can cause developmental defects and/or disease. Indeed, aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has been linked to many cancers. Mounting evidence also indicates a role for miRNAs in the development of the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current research on miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentially expressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genes to influence CSC phenotype. Accordingly, we discuss the specific miRNA cluster classifications and isomiRs that are predicted to target the ALDH1, CD166, BMI1, LRIG1, and LGR5 SC genes. miR-23b and miR-92A are of particular interest because our previously reported studies on miRNA expression in isolated normal versus malignant human colonic SCs showed that miR-23b and miR-92a are regulators of the LGR5 and LRIG1 SC genes, respectively. We also identify additional miRNAs whose expression inversely correlated with mRNA levels of their target genes and associated with CRC patient survival. Altogether, our deliberation on miRNAs, their clusters, and isomiRs in regulation of SC genes could provide insight into how dysregulation of miRNAs leads to the emergence of different CSC populations and SC overpopulation in CRC.
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16
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Zhang T, Ahn K, Emerick B, Modarai SR, Opdenaker LM, Palazzo J, Schleiniger G, Fields JZ, Boman BM. APC mutations in human colon lead to decreased neuroendocrine maturation of ALDH+ stem cells that alters GLP-2 and SST feedback signaling: Clue to a link between WNT and retinoic acid signalling in colon cancer development. PLoS One 2020; 15:e0239601. [PMID: 33112876 PMCID: PMC7592776 DOI: 10.1371/journal.pone.0239601] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 09/09/2020] [Indexed: 12/15/2022] Open
Abstract
APC mutations drive human colorectal cancer (CRC) development. A major contributing factor is colonic stem cell (SC) overpopulation. But, the mechanism has not been fully identified. A possible mechanism is the dysregulation of neuroendocrine cell (NEC) maturation by APC mutations because SCs and NECs both reside together in the colonic crypt SC niche where SCs mature into NECs. So, we hypothesized that sequential inactivation of APC alleles in human colonic crypts leads to progressively delayed maturation of SCs into NECs and overpopulation of SCs. Accordingly, we used quantitative immunohistochemical mapping to measure indices and proportions of SCs and NECs in human colon tissues (normal, adenomatous, malignant), which have different APC-zygosity states. In normal crypts, many cells staining for the colonic SC marker ALDH1 co-stained for chromogranin-A (CGA) and other NEC markers. In contrast, in APC-mutant tissues from familial adenomatous polyposis (FAP) patients, the proportion of ALDH+ SCs progressively increased while NECs markedly decreased. To explain how these cell populations change in FAP tissues, we used mathematical modelling to identify kinetic mechanisms. Computational analyses indicated that APC mutations lead to: 1) decreased maturation of ALDH+ SCs into progenitor NECs (not progenitor NECs into mature NECs); 2) diminished feedback signaling by mature NECs. Biological experiments using human CRC cell lines to test model predictions showed that mature GLP-2R+ and SSTR1+ NECs produce, via their signaling peptides, opposing effects on rates of NEC maturation via feedback regulation of progenitor NECs. However, decrease in this feedback signaling wouldn't explain the delayed maturation because both progenitor and mature NECs are depleted in CRCs. So the mechanism for delayed maturation must explain how APC mutation causes the ALDH+ SCs to remain immature. Given that ALDH is a key component of the retinoic acid (RA) signaling pathway, that other components of the RA pathway are selectively expressed in ALDH+ SCs, and that exogenous RA ligands can induce ALDH+ cancer SCs to mature into NECs, RA signaling must be attenuated in ALDH+ SCs in CRC. Thus, attenuation of RA signaling explains why ALDH+ SCs remain immature in APC mutant tissues. Since APC mutation causes increased WNT signaling in FAP and we found that sequential inactivation of APC in FAP patient tissues leads to progressively delayed maturation of colonic ALDH+ SCs, the hypothesis is developed that human CRC evolves due to an imbalance between WNT and RA signaling.
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Affiliation(s)
- Tao Zhang
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, United States of America
- University of Delaware, Newark, DE, United States of America
- Thomas Jefferson University, Philadelphia, PA, United States of America
| | - Koree Ahn
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, United States of America
- University of Delaware, Newark, DE, United States of America
- Thomas Jefferson University, Philadelphia, PA, United States of America
| | - Brooks Emerick
- Center for Applications of Mathematics in Medicine, Department of Mathematical Sciences, University of Delaware, Newark, DE, United States of America
| | - Shirin R. Modarai
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, United States of America
- University of Delaware, Newark, DE, United States of America
| | - Lynn M. Opdenaker
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, United States of America
- University of Delaware, Newark, DE, United States of America
| | - Juan Palazzo
- Thomas Jefferson University, Philadelphia, PA, United States of America
| | - Gilberto Schleiniger
- Center for Applications of Mathematics in Medicine, Department of Mathematical Sciences, University of Delaware, Newark, DE, United States of America
| | | | - Bruce M. Boman
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, United States of America
- University of Delaware, Newark, DE, United States of America
- Thomas Jefferson University, Philadelphia, PA, United States of America
- Center for Applications of Mathematics in Medicine, Department of Mathematical Sciences, University of Delaware, Newark, DE, United States of America
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17
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Walker BS, Zarour LR, Wieghard N, Gallagher AC, Swain JR, Weinmann S, Lanciault C, Billingsley K, Tsikitis VL, Wong MH. Stem Cell Marker Expression in Early Stage Colorectal Cancer is Associated with Recurrent Intestinal Neoplasia. World J Surg 2020; 44:3501-3509. [PMID: 32647988 PMCID: PMC10659815 DOI: 10.1007/s00268-020-05586-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) ranks second in cancer deaths worldwide and presents multiple management challenges, one of which is identifying high risk stage II disease that may benefit from adjuvant therapy. Molecular biomarkers, such as ones that identify stem cell activity, could better stratify high-risk cohorts for additional treatment. METHODS To identify possible biomarkers of high-risk disease in early-stage CRC, a discovery set (n = 66) of advanced-stage tumors were immunostained with antibodies to stemness proteins (CD166, CD44, CD26, and LGR5) and then digitally analyzed. Using a second validation cohort (n = 54) of primary CRC tumors, we analyzed protein and gene expression of CD166 across disease stages, and extended our analyses to CD166-associated genes (LGR5, ASCL2, BMI1, POSTN, and VIM) by qRT-PCR. RESULTS Stage III and metastatic CRC tumors highly expressed stem cell-associated proteins, CD166, CD44, and LGR5. When evaluated across stages, CD166 protein expression was elevated in advanced-stage compared to early-stage tumors. Notably, a small subset of stage I and II cancers harbored elevated CD166 protein expression, which correlated with development of recurrent cancer or adenomatous polyps. Gene expression analyses of CD166-associated molecules revealed elevated ASCL2 in primary tumors from patients who recurred. CONCLUSIONS We identified a protein signature prognostic of aggressive disease in early stage CRC. Stem cell-associated protein and gene expression identified a subset of early-stage tumors associated with cancer recurrence and/or subsequent adenoma formation. Signatures for stemness offer promising fingerprints for stratifying early-stage patients at high risk of recurrence.
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Affiliation(s)
- Brett S Walker
- Department of Surgery, OHSU, 3181 SW Sam Jackson Park Rd, L619, Portland, OR, 97239, USA
| | - Luai R Zarour
- Department of Surgery, OHSU, 3181 SW Sam Jackson Park Rd, L619, Portland, OR, 97239, USA
| | - Nicole Wieghard
- Department of Surgery, OHSU, 3181 SW Sam Jackson Park Rd, L619, Portland, OR, 97239, USA
| | - Alexandra C Gallagher
- Department of Cell, Developmental, and Cancer Biology, OHSU, 2720 S Moody Ave., KR-CDCB, Portland, OR, 97201, USA
| | - John R Swain
- Department of Cell, Developmental, and Cancer Biology, OHSU, 2720 S Moody Ave., KR-CDCB, Portland, OR, 97201, USA
| | - Sheila Weinmann
- Kaiser Permanente Northwest Center for Health Research, 3800 N. Interstate Ave., Portland, OR, 97227, USA
| | - Christian Lanciault
- Department of Pathology, OHSU, 3181 SW Sam Jackson Park Rd, L-113, Portland, OR, 97239, USA
| | - Kevin Billingsley
- Department of Surgery, OHSU, 3181 SW Sam Jackson Park Rd, L619, Portland, OR, 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, 2720 S Moody Ave., Portland, OR, 97201, USA
| | - V Liana Tsikitis
- Department of Surgery, OHSU, 3181 SW Sam Jackson Park Rd, L619, Portland, OR, 97239, USA.
- Knight Cancer Institute, Oregon Health & Science University, 2720 S Moody Ave., Portland, OR, 97201, USA.
| | - Melissa H Wong
- Department of Cell, Developmental, and Cancer Biology, OHSU, 2720 S Moody Ave., KR-CDCB, Portland, OR, 97201, USA.
- Knight Cancer Institute, Oregon Health & Science University, 2720 S Moody Ave., Portland, OR, 97201, USA.
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18
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MicroRNA Expression Profiling of Normal and Malignant Human Colonic Stem Cells Identifies miRNA92a as a Regulator of the LRIG1 Stem Cell Gene. Int J Mol Sci 2020; 21:ijms21082804. [PMID: 32316543 PMCID: PMC7216254 DOI: 10.3390/ijms21082804] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 04/13/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) have a critical role in regulating stem cells (SCs) during development, and because aberrant expression of miRNAs occurs in various cancers, our goal was to determine if dysregulation of miRNAs is involved in the SC origin of colorectal cancer (CRC). We previously reported that aldehyde dehydrogenase (ALDH) is a marker for normal and malignant human colonic SCs and tracks SC overpopulation during colon tumorigenesis. MicroRNA expression was studied in ALDH-positive SCs from normal and malignant human colon tissues by Nanostring miRNA profiling. Our findings show that: (1) A unique miRNA signature distinguishes ALDH-positive CRC cells from ALDH-positive normal colonic epithelial cells, (2) Expression of four miRNAs (miRNA200c, miRNA92a, miRNA20a, miRNA93) are significantly altered in CRC SCs compared to normal colonic SCs, (3) miRNA92a expression is also upregulated in ALDH-positive HT29 CRC SCs as compared to ALDH-negative SCs, (4) miRNA92a targets the 3′UTR of LRIG1 SC gene, and (5) miRNA92a modulates proliferation of HT29 CRC cells. Thus, our findings indicate that overexpression of miRNA92a contributes to the SC origin of CRC. Strategies designed to modulate miRNA expression, such as miRNA92a, may provide ways to target malignant SCs and to develop more effective therapies against CRC.
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19
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Boman BM, Guetter A, Boman RM, Runquist OA. Autocatalytic Tissue Polymerization Reaction Mechanism in Colorectal Cancer Development and Growth. Cancers (Basel) 2020; 12:cancers12020460. [PMID: 32079164 PMCID: PMC7072410 DOI: 10.3390/cancers12020460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 02/07/2020] [Accepted: 02/13/2020] [Indexed: 01/12/2023] Open
Abstract
The goal of our study was to measure the kinetics of human colorectal cancer (CRC) development in order to identify aberrant mechanisms in tissue dynamics and processes that contribute to colon tumorigenesis. The kinetics of tumor development were investigated using age-at-tumor diagnosis (adenomas and CRCs) of familial adenomatous coli (FAP) patients and sporadic CRC patients. Plots of age-at-tumor diagnosis data as a function of age showed a distinct sigmoidal-shaped curve that is characteristic of an autocatalytic reaction. Consequently, we performed logistics function analysis and found an excellent fit (p < 0.05) of the logistic equation to the curves for age-at-tumor diagnoses. These findings indicate that the tissue mechanism that becomes altered in CRC development and growth involves an autocatalytic reaction. We conjecture that colonic epithelium normally functions as a polymer of cells which dynamically maintains itself in a steady state through an autocatalytic polymerization mechanism. Further, in FAP and sporadic CRC patients, mutation in the adenomatous polyposis coli (APC) gene increases autocatalytic tissue polymerization and induces tumor tissues to autocatalyze their own progressive growth, which drives tumor development in the colon.
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Affiliation(s)
- Bruce M. Boman
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19718, USA;
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Arthur Guetter
- Department of Mathematics, Hamline University, Saint Paul, MN 55104, USA;
| | - Ryan M. Boman
- Department of Materials Science & Engineering, Drexel University, Philadelphia, PA 19104, USA
- CATX, Inc., Princeton, NJ 08542, USA
- Correspondence: ; Tel.: +267-303-9241
| | - Olaf A. Runquist
- Department of Chemistry, Hamline University, Saint Paul, MN 55104, USA;
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20
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Mohd-Zahid MH, Mohamud R, Che Abdullah CA, Lim J, Alem H, Wan Hanaffi WN, Z. A. I. Colorectal cancer stem cells: a review of targeted drug delivery by gold nanoparticles. RSC Adv 2020. [DOI: 10.1039/c9ra08192e] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The proposed schematic mechanismviawhich 5-fluorouracil-loaded gold nanoparticles conjugated with CD133 antibody target colorectal cancer stem cells.
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Affiliation(s)
- Manali Haniti Mohd-Zahid
- Department of Chemical Pathology
- School of Medical Sciences
- Universiti Sains Malaysia
- 16150 Kubang Kerian
- Malaysia
| | - Rohimah Mohamud
- Department of Immunology
- School of Medical Sciences
- Universiti Sains Malaysia
- 16150 Kubang Kerian
- Malaysia
| | | | - JitKang Lim
- School of Chemical Engineering
- Universiti Sains Malaysia
- 14300 Nibong Tebal
- Malaysia
| | - Halima Alem
- Institut Jean Lamour (IJL, UMR 7198)
- Université de Lorraine
- CNRS
- F-54011 Nancy Cedex
- France
| | | | - Iskandar Z. A.
- Department of Chemical Pathology
- School of Medical Sciences
- Universiti Sains Malaysia
- 16150 Kubang Kerian
- Malaysia
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The Role of MicroRNAs upon Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease. Cells 2019; 8:cells8111461. [PMID: 31752264 PMCID: PMC6912477 DOI: 10.3390/cells8111461] [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: 10/13/2019] [Revised: 11/03/2019] [Accepted: 11/18/2019] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence suggest the significance of inflammation in the progression of cancer, for example the development of colorectal cancer in Inflammatory Bowel Disease (IBD) patients. Long-lasting inflammation in the gastrointestinal tract causes serious systemic complications and breaks the homeostasis of the intestine, where the altered expression of regulatory genes and miRNAs trigger malignant transformations. Several steps lead from acute inflammation to malignancies: epithelial-to-mesenchymal transition (EMT) and inhibitory microRNAs (miRNAs) are known factors during multistage carcinogenesis and IBD pathogenesis. In this review, we outline the interactions between EMT components and miRNAs that may affect cancer development during IBD.
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22
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Usui T, Sasaki K. [Study on colorectal cancer using air-liquid interface organoid culture method]. Nihon Yakurigaku Zasshi 2019; 154:50-55. [PMID: 31406042 DOI: 10.1254/fpj.154.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Colorectal cancer is a disease with high unmet medical needs. An increase in the number of cancer patients who are resistant to anti-cancer drugs is one of factors that increase the number of fatalities. Since there was no suitable experimental model to recapitulate the tumor environment in which various cells in the tissues exist, it was extremely difficult to develop a medicine that overcomes the anti-cancer drug resistance in each colorectal cancer patient. In this review, we describe the current status and problems of drug therapy for colorectal cancer patients, and introduce our study to develop the new targeting drugs using human colon tissue-derived air liquid interface organoid culture method.
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Affiliation(s)
- Tatsuya Usui
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology
| | - Kazuaki Sasaki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology
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23
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Sugimori M, Hayakawa Y, Tamura R, Kuroda S. The combined efficacy of OTS964 and temozolomide for reducing the size of power-law coded heterogeneous glioma stem cell populations. Oncotarget 2019; 10:2397-2415. [PMID: 31040930 PMCID: PMC6481323 DOI: 10.18632/oncotarget.26800] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 03/04/2019] [Indexed: 01/06/2023] Open
Abstract
Glioblastoma resists chemotherapy then recurs as a fatal space-occupying lesion. To improve the prognosis, the issues of chemoresistance and tumor size should be addressed. Glioma stem cell (GSC) populations, a heterogeneous power-law coded population in glioblastoma, are believed to be responsible for the recurrence and progressive expansion of tumors. Thus, we propose a therapeutic strategy of reducing the initial size and controlling the regrowth of GSC populations which directly facilitates initial and long-term control of glioblastoma recurrence. In this study, we administered an anti-glioma/GSC drug temozolomide (TMZ) and OTS964, an inhibitor for T-Lak cell originated protein kinase, in combination (T&O), investigating whether together they efficiently and substantially shrink the initial size of power-law coded GSC populations and slow the long-term re-growth of drug-resistant GSC populations. We employed a detailed quantitative approach using clonal glioma sphere (GS) cultures, measuring sphere survivability and changes to growth during the self-renewal. T&O eliminated self-renewing GS clones and suppressed their growth. We also addressed whether T&O reduced the size of self-renewed GS populations. T&O quickly reduced the size of GS populations via efficient elimination of GS clones. The growth of the surviving T&O-resistant GS populations was continuously disturbed, leading to substantial long-term shrinkage of the self-renewed GS populations. Thus, T&O reduced the initial size of GS populations and suppressed their later regrowth. A combination therapy of TMZ and OTS964 would represent a novel therapeutic paradigm with the potential for long-term control of glioblastoma recurrence via immediate and sustained shrinkage of power-law coded heterogeneous GSC populations.
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Affiliation(s)
- Michiya Sugimori
- Department of Integrative Neuroscience, University of Toyama, Toyama, Toyama 930-0194, Japan
| | - Yumiko Hayakawa
- Department of Neurosurgery, University of Toyama, Toyama, Toyama 930-0194, Japan
| | - Ryoi Tamura
- Department of Integrative Neuroscience, University of Toyama, Toyama, Toyama 930-0194, Japan
| | - Satoshi Kuroda
- Department of Neurosurgery, University of Toyama, Toyama, Toyama 930-0194, Japan
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24
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Asadzadeh Z, Mansoori B, Mohammadi A, Aghajani M, Haji‐Asgarzadeh K, Safarzadeh E, Mokhtarzadeh A, Duijf PHG, Baradaran B. microRNAs in cancer stem cells: Biology, pathways, and therapeutic opportunities. J Cell Physiol 2018; 234:10002-10017. [DOI: 10.1002/jcp.27885] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 11/13/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Marjan Aghajani
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | | | - Elham Safarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Microbiology & Immunology Faculty of Medicine, Ardabil University of Medical Sciences Ardabil Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Pascal H. G. Duijf
- Translational Research Institute, University of Queensland Diamantina Institute, The University of Queensland Brisbane Queensland Australia
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
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25
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Patel S, Waghela B, Shah K, Vaidya F, Mirza S, Patel S, Pathak C, Rawal R. Silibinin, A Natural Blend In Polytherapy Formulation For Targeting Cd44v6 Expressing Colon Cancer Stem Cells. Sci Rep 2018; 8:16985. [PMID: 30451890 PMCID: PMC6242811 DOI: 10.1038/s41598-018-35069-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 10/15/2018] [Indexed: 12/17/2022] Open
Abstract
Colon cancer stem cells have been attributed to poor prognosis, therapeutic resistance and aggressive nature of the malignancy. Recent reports associated CD44v6 expression with relapse, metastasis and reduced 5-year survival of colon cancer patients, thereby making it a potential therapeutic target. Thus, in this study, comprehensive prediction and screening of CD44v6 against 1674 lead compounds was conducted. Silibinin was identified as a potential compound targeting CD44v6. Inorder to substantiate these findings, the cytotoxic effect of 5FU, Silibinin and 5FU+ Silibinin was assessed on human colon carcinoma cell line HCT116 derived CD44+ subpopulation. 5FU+ Silibinin inhibited cell proliferation of CD44+ subpopulation at lower concentration than Silibinin standalone. Further, corresponding to CD44v6 knockdown cells, 5FU+ Silibinin treatment significantly decreased CD44v6, Nanog, CTNNB1 and CDKN2A expression whereas increased E-cadherin expression in HCT116 derived CD44+ cells. Moreover, synergistic effect of these drugs suppressed sphere formation, inhibited cell migration, triggered PARP cleavage and perturbation in mitochondrial membrane potential, thereby activating intrinsic apoptotic pathways and induced autophagic cell death. Importantly, 5FU+ Silibinin could inhibit PI3K/MAPK dual activation and arrest the cell cycle at G0/G1 phase. Thus, our study suggests that inhibition of CD44v6 attenuates stemness of colon cancer stem cells and holds a prospect of potent therapeutic target.
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Affiliation(s)
- Shanaya Patel
- Division of Biological & Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad, Gujarat, India.,Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Bhargav Waghela
- Department of Cell Biology, Indian Institute of Advanced Research, Gandhinagar, Gujarat, India
| | - Kanisha Shah
- Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Foram Vaidya
- Department of Cell Biology, Indian Institute of Advanced Research, Gandhinagar, Gujarat, India
| | - Sheefa Mirza
- Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Saumya Patel
- Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Chandramani Pathak
- Department of Cell Biology, Indian Institute of Advanced Research, Gandhinagar, Gujarat, India
| | - Rakesh Rawal
- Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India.
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26
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Zheng Y, Song Y, Han Q, Liu W, Xu J, Yu Z, Zhang R, Li N. Intestinal epithelial cell-specific IGF1 promotes the expansion of intestinal stem cells during epithelial regeneration and functions on the intestinal immune homeostasis. Am J Physiol Endocrinol Metab 2018; 315:E638-E649. [PMID: 29783855 DOI: 10.1152/ajpendo.00022.2018] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
It is well known that insulin-like growth factor 1 (IGF1) acts as a trophic factor in small intestine under both physiological and pathophysiological conditions. However, it still lacks direct in vivo evidence of the functions of intestinal epithelial cell (IEC)-specific IGF1 under both normal and pathological conditions. Using IEC-specific IGF1-knockout (cKO) mice and Lgr5-eGFP-CreERT mice, we demonstrate that IEC-specific IGF1 can enhance nutrient uptake, reduce protein catabolism and energy consumption, and promote the proliferation and expansion of intestinal epithelial cells, including intestinal epithelial stem cells and intestinal secretory cells. Next, we showed that IEC-specific IGF1 renders IECs resistant to irradiation and promotes epithelial regeneration. Strikingly, transcriptome profiling assay revealed that many differentially expressed genes involved in the differentiation and maturation of lymphoid lineages were significantly suppressed in the cKO mice as compared with the control mice. We demonstrated that deletion of IGF1 in IECs enhances bacterial translocation to the mesenteric lymph nodes and liver. Furthermore, high-throughput sequencing of 16S ribosomal RNA genes of gut microbiota revealed that IEC-specific IGF1 loss profoundly affected the gut microbial composition at various levels of classification. Therefore, our findings shed light on the in vivo roles of IEC-specific IGF1 in intestinal homeostasis, epithelial regeneration, and immunity, broadening our current insights on IGF1 functions.
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Affiliation(s)
- Yu Zheng
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University , Beijing , China
| | - Yongli Song
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University , Beijing , China
| | - Qi Han
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University , Beijing , China
| | - Wenjie Liu
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University , Beijing , China
| | - Jiuzhi Xu
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University , Beijing , China
| | - Zhengquan Yu
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University , Beijing , China
| | - Ran Zhang
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University , Beijing , China
| | - Ning Li
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University , Beijing , China
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4-Acetyl-Antroquinonol B Suppresses SOD2-Enhanced Cancer Stem Cell-Like Phenotypes and Chemoresistance of Colorectal Cancer Cells by Inducing hsa-miR-324 re-Expression. Cancers (Basel) 2018; 10:cancers10080269. [PMID: 30103475 PMCID: PMC6116152 DOI: 10.3390/cancers10080269] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/04/2018] [Accepted: 08/07/2018] [Indexed: 01/07/2023] Open
Abstract
Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit the niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. Experimental approach: In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, Western blot, real-time polymerase chain reaction (RT-PCR), and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. Results: This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-acetylantroquinonol B (4-AAQB), as evidenced by inhibited cell viability and proliferation, as well as attenuated migration, invasion, and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. Interestingly, 4-AAQB did not affect the viability and proliferation of normal colon cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA, reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates the FOLFOX (folinate (leucovorin), fluorouracil (5FU), and oxaliplatin) anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324, and inhibiting SOD2-mediated tumorigenicity. Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.
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Role of HOX Genes in Stem Cell Differentiation and Cancer. Stem Cells Int 2018; 2018:3569493. [PMID: 30154863 PMCID: PMC6081605 DOI: 10.1155/2018/3569493] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/08/2018] [Accepted: 05/15/2018] [Indexed: 02/07/2023] Open
Abstract
HOX genes encode an evolutionarily conserved set of transcription factors that control how the phenotype of an organism becomes organized during development based on its genetic makeup. For example, in bilaterian-type animals, HOX genes are organized in gene clusters that encode anatomic segment identity, that is, whether the embryo will form with bilateral symmetry with a head (anterior), tail (posterior), back (dorsal), and belly (ventral). Although HOX genes are known to regulate stem cell (SC) differentiation and HOX genes are dysregulated in cancer, the mechanisms by which dysregulation of HOX genes in SCs causes cancer development is not fully understood. Therefore, the purpose of this manuscript was (i) to review the role of HOX genes in SC differentiation, particularly in embryonic, adult tissue-specific, and induced pluripotent SC, and (ii) to investigate how dysregulated HOX genes in SCs are responsible for the development of colorectal cancer (CRC) and acute myeloid leukemia (AML). We analyzed HOX gene expression in CRC and AML using information from The Cancer Genome Atlas study. Finally, we reviewed the literature on HOX genes and related therapeutics that might help us understand ways to develop SC-specific therapies that target aberrant HOX gene expression that contributes to cancer development.
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29
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Elbadawy M, Usui T, Yamawaki H, Sasaki K. Development of an Experimental Model for Analyzing Drug Resistance in Colorectal Cancer. Cancers (Basel) 2018; 10:164. [PMID: 29843359 PMCID: PMC6025190 DOI: 10.3390/cancers10060164] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 05/24/2018] [Accepted: 05/26/2018] [Indexed: 12/30/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers, for which combination treatment of chemotherapy is employed. However, most patients develop drug resistance during the course of treatment. To clarify the mechanisms of drug resistance, various research models have been developed. Recently, we established a human CRC patients-derived three-dimensional (3D) culture system using an air-liquid interface organoid method. It contained numerous cancer stem cells and showed resistance to 5-fluorouracil and Irinotecan. In this review, we introduce conventional and our established models for studying drug resistance in CRC.
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Affiliation(s)
- Mohamed Elbadawy
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
- Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Elqaliobiya 13736, Egypt.
| | - Tatsuya Usui
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan.
| | - Kazuaki Sasaki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
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30
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Zhang Y, Qian C, Jing L, Ren J, Guan Y. Meta-analysis indicating that high ALCAM expression predicts poor prognosis in colorectal cancer. Oncotarget 2018; 8:48272-48281. [PMID: 28537909 PMCID: PMC5564645 DOI: 10.18632/oncotarget.17707] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 04/24/2017] [Indexed: 11/25/2022] Open
Abstract
Activated leukocyte cell adhesion molecule (ALCAM) has been linked to the development and progress of colorectal cancer (CRC). In this meta-analysis, we examined whether ALCAM expression is predictive of survival outcomes in CRC patients. We included 7 studies with 2048 patients in our meta-analysis after searching the PubMed, Cochrane Library, EMBASE, OVID and Web of Science databases. High ALCAM expression was associated with poor overall survival among CRC patients (HR = 1.94, 95%CI = 1.05–3.58, P = 0.03). High ALCAM expression was also associated with aggressive clinicopathological features such as tumor stage (T3,T4/T1,T2; HR = 2.66, 95%CI = 2.01–3.51, P < 0.00001), nodal status (Positive/Negative, HR = 2.12, 95%CI = 1.61–2.82, P < 0.00001), distant metastasis (M1/M0, HR = 3.30, 95%CI = 2,21–4.91, P < 0.00001), tumor grade (grade3/grade1,2, HR = 1,28, 95% CI = 1.00–1.62, P = 0.05), and patient age (> 60/< 60, HR = 1.29, 95%CI = 1.01–1.66, P = 0.05). These findings indicate that high ALCAM expression is associated with poor prognosis and advanced clinicopathological characteristics in CRC patients.
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Affiliation(s)
- Yeqing Zhang
- Department of Chinese Internal Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
| | - Chunmei Qian
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
| | - Lin Jing
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
| | - Jianlin Ren
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
| | - Yu Guan
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
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Testa U, Pelosi E, Castelli G. Colorectal cancer: genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells. Med Sci (Basel) 2018; 6:E31. [PMID: 29652830 PMCID: PMC6024750 DOI: 10.3390/medsci6020031] [Citation(s) in RCA: 161] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 03/24/2018] [Accepted: 04/03/2018] [Indexed: 02/08/2023] Open
Abstract
Colon cancer is the third most common cancer worldwide. Most colorectal cancer occurrences are sporadic, not related to genetic predisposition or family history; however, 20-30% of patients with colorectal cancer have a family history of colorectal cancer and 5% of these tumors arise in the setting of a Mendelian inheritance syndrome. In many patients, the development of a colorectal cancer is preceded by a benign neoplastic lesion: either an adenomatous polyp or a serrated polyp. Studies carried out in the last years have characterized the main molecular alterations occurring in colorectal cancers, showing that the tumor of each patient displays from two to eight driver mutations. The ensemble of molecular studies, including gene expression studies, has led to two proposed classifications of colorectal cancers, with the identification of four/five non-overlapping groups. The homeostasis of the rapidly renewing intestinal epithelium is ensured by few stem cells present at the level of the base of intestinal crypts. Various experimental evidence suggests that colorectal cancers may derive from the malignant transformation of intestinal stem cells or of intestinal cells that acquire stem cell properties following malignant transformation. Colon cancer stem cells seem to be involved in tumor chemoresistance, radioresistance and relapse.
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Affiliation(s)
- Ugo Testa
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Elvira Pelosi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Germana Castelli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
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32
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Bai HY, Liao YJ, Cai MY, Ma NF, Zhang Q, Chen JW, Zhang JX, Wang FW, Wang CY, Chen WH, Jin XH, Xu RH, Guan XY, Xie D. Eukaryotic Initiation Factor 5A2 Contributes to the Maintenance of CD133(+) Hepatocellular Carcinoma Cells via the c-Myc/microRNA-29b Axis. Stem Cells 2018; 36:180-191. [PMID: 29119708 DOI: 10.1002/stem.2734] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 09/28/2017] [Accepted: 10/22/2017] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs)/cancer-initiating cells (CICs) are suggested responsible for driving cancer resistance to conventional therapies and for cancer recurrence and/or metastasis. CD133 is served as a key biomarker to identify and characterize this subpopulation of cells in hepatocellular carcinoma (HCC). Our previous study indicated that overexpression of eukaryotic initiation factor 5A2 (EIF5A2) promotes HCC cell metastasis and angiogenesis. In this study, we demonstrated that EIF5A2 might play a crucial role in CSCs regulation and investigated its potential molecular mechanisms. Using quantitative real-time polymerase chain reaction assay, we observed that the expression of EIF5A2 positively correlated with CD133 levels in a cohort of cancerous and noncancerous liver tissues and cells. Next, HCC cells with high expression of EIF5A2 have a strong capacity to form undifferentiated tumor spheres in vitro and show elevated levels of stem cell-related genes, leading to an increased ability to develop tumors when subcutaneously injected into nude mice. Furthermore, differential microRNA expression was profiling between two EIF5A2-depleted HCC cell lines and their control one identified a decreased expression of miR-29b in EIF5A2-depleted cell lines. Further functional studies illustrated that downregulated miR-29b level is responsible for EIF5A2-maintained HCC cell stemness either in vitro or in vivo. Moreover, enforced expression of EIF5A2 in HCC cells largely enhanced the binding of c-Myc on the promoter of miR-29b and downregulation of miR-29b by EIF5A2 was dependent on c-Myc. Our findings, collectively, reveal that EIF5A2 contributes to the maintenance of CD133+ HCC cells via the c-Myc/miR-29b axis. Stem Cells 2018;36:180-191.
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Affiliation(s)
- Hai-Yan Bai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yi-Ji Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Mu-Yan Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Ning-Fang Ma
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Qi Zhang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jie-Wei Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jia-Xing Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Feng-Wei Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Chen-Yuan Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Wen-Hui Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Xiao-Han Jin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Dan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
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33
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Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers. Oncogene 2018; 37:1669-1684. [PMID: 29343849 PMCID: PMC6448595 DOI: 10.1038/s41388-017-0060-8] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 11/07/2017] [Accepted: 11/10/2017] [Indexed: 12/18/2022]
Abstract
Emerging notion in carcinogenesis ascribes tumor initiation and aggressiveness to cancer stem cells (CSCs). Specifically, colorectal cancer (CRC) development was shown to be compatible with CSCs hypothesis. Mutations in p53 are highly frequent in CRC, and are known to facilitate tumor development and aggressiveness. Yet, the fink between mutant p53 and colorectal CSCs is not well-established. In the present study, we set to examine whether oncogenic mutant p53 proteins may augment colorectal CSCs phenotype. By genetic manipulation of mutant p53 in several cellular systems, we demonstrated that mutant p53 enhances colorectal tumorigenesis. Moreover, mutant p53-expressing cell lines harbor larger sub-populationss of cells highly expressing the known colorectal CSCs markers: CD44, Lgr5, and ALDH. This elevated expression is mediated by mutant p53 binding to CD44, Lgr5, and ALDH1A1 promoter sequences. Furthermore, ALDH1 was found to be involved in mutant p53-dependent chemotherapy resistance. Finally, analysis of ALDH1 and CD44 in human CRC biopsies indicated a positive correlation between their expression and the presence of oncogenic p53 missense mutations. These findings suggest novel insights pertaining the mechanism by which mutant p53 enhances CRC development, which involves the expansion of CSCs sub-populations within CRC tumors, and underscore the importance of targeting these sub-populations for CRC therapy.
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34
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Emerick B, Schleiniger G, Boman BM. Multi-scale modeling of APC and [Formula: see text]-catenin regulation in the human colonic crypt. J Math Biol 2018; 76:1797-1830. [PMID: 29302705 DOI: 10.1007/s00285-017-1204-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 12/22/2017] [Indexed: 10/18/2022]
Abstract
Stem cell renewal and differentiation in the human colonic crypt are linked to the [Formula: see text]-catenin pathway. The spatial balance of Wnt factors in proliferative cells within the crypt maintain an appropriate level of cellular reproduction needed for normal crypt homeostasis. Mutational events at the gene level are responsible for deregulating the balance of Wnt factors along the crypt, causing an overpopulation of proliferative cells, a loss of structure of the crypt domain, and the initiation of colorectal carcinomas. We formulate a PDE model describing cell movement and reproduction in a static crypt domain. We consider a single cell population whose proliferative capabilities are determined by stemness, a quantity defined by intracellular levels of adenomatous polyposis coli (APC) scaffold protein and [Formula: see text]-catenin. We fit APC regulation parameters to biological data that describe normal protein gradients in the crypt. We also fit cell movement and protein flux parameters to normal crypt characteristics such as renewal time, total cell count, and proportion of proliferating cells. The model is used to investigate abnormal crypt dynamics when subjected to a diminished APC gradient, a scenario synonymous to mutations in the APC gene. We find that a 25% decrease in APC synthesis leads to a fraction of 0.88 proliferative, which is reflective of normal-appearing FAP crypts. A 50% drop in APC activity yields a fully proliferative crypt showing a doubling of the level of stemness, which characterizes the initial stages of colorectal cancer development. A sensitivity analysis of APC regulation parameters shows the perturbation of factors that is required to restore crypt dynamics to normal in the case of APC mutations.
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Affiliation(s)
- Brooks Emerick
- Department of Mathematics, Kutztown University, Kutztown, PA, 19530, USA.
| | - Gilberto Schleiniger
- Department of Mathematical Sciences, University of Delaware, Newark, DE, 19711, USA
| | - Bruce M Boman
- Department of Biological Sciences, University of Delaware, Newark, DE, 19711, USA.,Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, 19713, USA
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35
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Cicatiello AG, Ambrosio R, Dentice M. Thyroid hormone promotes differentiation of colon cancer stem cells. Mol Cell Endocrinol 2017; 459:84-89. [PMID: 28342853 DOI: 10.1016/j.mce.2017.03.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 03/16/2017] [Accepted: 03/18/2017] [Indexed: 01/14/2023]
Abstract
Tumor formation and maintenance depend on a small fraction of cancer stem cells (CSCs) that can self-renew and generate a wide variety of differentiated cells. CSCs are resistant to chemotherapy and radiation, and can represent a reservoir of cancer cells that often cause relapse after treatment. Evidence suggests that CSCs also give rise to metastases. Thyroid hormone (TH) controls a variety of biological processes including the development and functioning of most adult tissues. Recent years has seen the emergence of an intimate link between TH and multiple steps of tumorigenesis. Thyroid hormone controls the balance between the proliferation and differentiation of CSCs, and may thus be a druggable anti-cancer agent. Here, we review current understanding of the effects of TH on colorectal CSCs, including the cross regulatory loops between TH and regulators of CSC stemness. Targeting TH in the tumor microenvironment may improve treatment strategies.
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Affiliation(s)
| | | | - Monica Dentice
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Italy; CEINGE-Biotecnologie Avanzate S.c.ar.l., Naples, Italy.
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36
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Targeting the T-Lak cell originated protein kinase by OTS964 shrinks the size of power-law coded heterogeneous glioma stem cell populations. Oncotarget 2017; 9:3043-3059. [PMID: 29423027 PMCID: PMC5790444 DOI: 10.18632/oncotarget.23077] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 11/14/2017] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma resists chemoradiotherapy, then, recurs to be a fatal space-occupying lesion. The recurrence is caused by re-growing cell populations such as glioma stem cells (GSCs), suggesting that GSC populations should be targeted. This study addressed whether a novel anti-cancer drug, OTS964, an inhibitor for T-LAK cell originated protein kinase (TOPK), is effective in reducing the size of the heterogeneous GSC populations, a power-law coded heterogeneous GSC populations consisting of glioma sphere (GS) clones, by detailing quantitative growth properties. We found that OTS964 killed GS clones while suppressing the growth of surviving GS clones, thus identifying clone-eliminating and growth-disturbing efficacies of OTS964. The efficacies led to a significant size reduction in GS populations in a dose-dependent manner. The surviving GS clones reconstructed GS populations in the following generations; the recovery of GS populations fits a recurrence after the chemotherapy. The recovering GS clones resisted the clone-eliminating effect of OTS964 in sequential exposure during the growth recovery. However, surprisingly, the resistant properties of the recovered-GS clones had been plastically canceled during self-renewal, and then the GS clones had become re-sensitive to OTS964. Thus, OTS964 targets GSCs to eliminate them or suppress their growth, resulting in shrinkage of the power-law coded GSC populations. We propose a therapy focusing on long-term control in recurrence of glioblastoma via reducing the size of the GSC populations by OTS964.
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37
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Fadus MC, Lau C, Bikhchandani J, Lynch HT. Curcumin: An age-old anti-inflammatory and anti-neoplastic agent. J Tradit Complement Med 2017; 7:339-346. [PMID: 28725630 PMCID: PMC5506636 DOI: 10.1016/j.jtcme.2016.08.002] [Citation(s) in RCA: 175] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 08/09/2016] [Indexed: 01/19/2023] Open
Abstract
Curcumin is a natural anti-inflammatory agent that has been used for treating medical conditions for many years. Several experimental and pharmacologic trials have demonstrated its efficacy in the role as an anti-inflammatory agent. Curcumin has been shown to be effective in treating chronic conditions like rheumatoid arthritis, inflammatory bowel disease, Alzheimer's and common malignancies like colon, stomach, lung, breast, and skin cancers. As treatments in medicine become more and more complex, the answer may be something simpler. This is a review article written with the objective to systematically analyze the wealth of information regarding the medical use of curcumin, the "curry spice", and to understand the existent gaps which have prevented its widespread application in the medical community.
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Affiliation(s)
- Matthew C. Fadus
- Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States
| | - Cecilia Lau
- Duke University, Department of Psychiatry, Durham, NC, United States
| | - Jai Bikhchandani
- Creighton University, Department of Preventive Medicine, Omaha, NE 68178, United States
| | - Henry T. Lynch
- Creighton University, Department of Preventive Medicine, Omaha, NE 68178, United States
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38
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Gharib AF, Shalaby SM, Raafat N, Fawzy WMS, Abdel Hakim NH. Assessment of neutralizing interleukin-4 effect on CD133 gene expression in colon cancer cell line. Cytokine 2017; 97:66-72. [PMID: 28578295 DOI: 10.1016/j.cyto.2017.05.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 05/20/2017] [Accepted: 05/24/2017] [Indexed: 12/14/2022]
Abstract
Colorectal cancer may be maintained by cancer stem-like cells (CSCs) that express the cell surface marker CD133. CSCs (CD133+cells) exhibits greater resistance to the chemotherapy and this resistance may be mediated in part by an autocrine response to IL4. The aim of the study was to assess the effect of anti-IL4 antibody alone or in combination with chemotherapy on the CD133 expression andthe tumor growth. We used Caco cell line in our experiments and the samples were as the following; untreated colorectal cell line, cells treated by chemotherapy, cells treated by anti-IL4 antibody in 3doses (2.5, 5, 10μg/ml), cells treatedby combination of chemotherapy and anti-IL4 antibody in 3 doses. Results of our in vitro studies demonstrated that anti-IL4 inhibited growth of Caco cell line in a dose-dependent manner revealing a 32.11% inhibition at the highest concentration (10µg/ml). There was further significant inhibition by combination of anti IL4 and chemotherapy in a dose response manner when compared to group treated by chemotherapy only. These effects were associated with decreased expression of CD133 in tumor cells also. Lastly, anti-IL4 antibody stimulated apoptosis. Our study suggested that neutralizing of IL4 by anti IL4 antibody affect the CD133+ cells may be by increasing their apoptosis. The effects of anti IL4 antibody either, alone or in combination with chemotherapy, inhibited the tumor growth and decreased the viable tumor cells. Furthermore, neutralizing of IL4 increased the efficacy of chemotherapy treatment.
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Affiliation(s)
- Amal F Gharib
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sally M Shalaby
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Nermin Raafat
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Walaa M S Fawzy
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Nabila H Abdel Hakim
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Viswanathan V, Damle S, Zhang T, Opdenaker L, Modarai S, Accerbi M, Schmidt S, Green P, Galileo D, Palazzo J, Fields J, Haghighat S, Rigoutsos I, Gonye G, Boman BM. An miRNA Expression Signature for the Human Colonic Stem Cell Niche Distinguishes Malignant from Normal Epithelia. Cancer Res 2017; 77:3778-3790. [PMID: 28487386 DOI: 10.1158/0008-5472.can-16-2388] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 03/02/2017] [Accepted: 05/05/2017] [Indexed: 02/02/2023]
Abstract
Malignant transformation of tissue stem cells (SC) may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic SC niche to understand how cancer stem cells (CSC) may arise. In profiling miRNA expression in SC-enriched crypt subsections isolated from fresh, normal surgical specimens, we identified 16 miRNAs that were differentially expressed in the crypt bottom, creating an SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miR-206, miR-007-3, and miR-23b individually could distinguish colorectal cancer from NCE. Notably, miR-23b, which was increased in colorectal cancer, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miR-23b regulated CSC phenotypes globally at the level of proliferation, cell cycle, self-renewal, epithelial-mesenchymal transition, invasion, and resistance to the colorectal cancer chemotherapeutic agent 5-fluorouracil. In mechanistic experiments, we found that miR-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miR-23b are inversely correlated in ALDH+ CSCs and that distinct subpopulations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miR-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and colorectal cancer. Cancer Res; 77(14); 3778-90. ©2017 AACR.
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Affiliation(s)
- Vignesh Viswanathan
- Center for Translational Cancer Research, Helen F Graham Cancer Center and Research Institute, Newark, Delaware.,Department of Biological Sciences, University of Delaware, Newark, Delaware.,Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Shirish Damle
- Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, Pennsylvania
| | - Tao Zhang
- Center for Translational Cancer Research, Helen F Graham Cancer Center and Research Institute, Newark, Delaware.,Department of Biological Sciences, University of Delaware, Newark, Delaware.,Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, Pennsylvania
| | - Lynn Opdenaker
- Center for Translational Cancer Research, Helen F Graham Cancer Center and Research Institute, Newark, Delaware.,Department of Biological Sciences, University of Delaware, Newark, Delaware
| | - Shirin Modarai
- Center for Translational Cancer Research, Helen F Graham Cancer Center and Research Institute, Newark, Delaware.,Department of Biological Sciences, University of Delaware, Newark, Delaware
| | - Monica Accerbi
- Department of Plant and Soil Sciences, Delaware Biotechnology Institute, Newark, Delaware
| | - Skye Schmidt
- Department of Plant and Soil Sciences, Delaware Biotechnology Institute, Newark, Delaware
| | - Pamela Green
- Department of Plant and Soil Sciences, Delaware Biotechnology Institute, Newark, Delaware
| | - Deni Galileo
- Department of Biological Sciences, University of Delaware, Newark, Delaware
| | - Juan Palazzo
- Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, Pennsylvania
| | | | - Sepehr Haghighat
- Center for Translational Cancer Research, Helen F Graham Cancer Center and Research Institute, Newark, Delaware.,Department of Biological Sciences, University of Delaware, Newark, Delaware.,Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, Pennsylvania
| | - Isidore Rigoutsos
- Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, Pennsylvania
| | - Greg Gonye
- Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, Pennsylvania.,Nanostring Technologies, Seattle, Washington
| | - Bruce M Boman
- Center for Translational Cancer Research, Helen F Graham Cancer Center and Research Institute, Newark, Delaware. .,Department of Biological Sciences, University of Delaware, Newark, Delaware.,Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, Pennsylvania
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40
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Wei MF, Kuo SH. Inhibition of SOX9 may be an effective target for increasing radiosensitivity in gastrointestinal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:224. [PMID: 28603739 PMCID: PMC5451632 DOI: 10.21037/atm.2017.03.60] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Accepted: 01/18/2017] [Indexed: 12/31/2022]
Affiliation(s)
- Ming-Feng Wei
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sung-Hsin Kuo
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
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41
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Vadde R, Vemula S, Jinka R, Merchant N, Bramhachari PV, Nagaraju GP. Role of hypoxia-inducible factors (HIF) in the maintenance of stemness and malignancy of colorectal cancer. Crit Rev Oncol Hematol 2017; 113:22-27. [DOI: 10.1016/j.critrevonc.2017.02.025] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Indexed: 01/09/2023] Open
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42
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Emerick B, Schleiniger G, Boman BM. A kinetic model to study the regulation of β-catenin, APC, and Axin in the human colonic crypt. J Math Biol 2017; 75:1171-1202. [PMID: 28271271 DOI: 10.1007/s00285-017-1112-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 01/18/2017] [Indexed: 12/17/2022]
Abstract
The Wnt/[Formula: see text]-catenin pathway plays a crucial role in stem cell renewal and differentiation in the normal human colonic crypt. The balance between [Formula: see text]-catenin and APC along the crypt axis determines its normal functionality. The mechanism that deregulates this balance may give insight into the initiation of colorectal cancer. This is significant because the spatial dysregulation of [Formula: see text]-catenin by the mutated tumor suppressor gene/protein APC in human colonic crypts is responsible for the initiation and growth of colorectal cancer. We consider a regulatory function that promotes APC synthesis within the cell and its effect on the accumulation of the Wnt target protein, [Formula: see text]-catenin. It is evident that an APC gradient exists along the crypt axis; however, the mechanism by which APC expression is regulated within the cell is not well known. We investigate the dynamics of an APC regulatory mechanism with an increased level of Axin at the subcellular level. Model output shows an increase of APC for a diminished Wnt signal, which explains the APC gradient along the crypt. We find that the dynamic interplay between [Formula: see text]-catenin, APC, and Axin produces oscillatory behavior, which is controlled by the Wnt stimulus. In the presence of reduced functional APC, the oscillations are amplified, which suggests that the cell remains in a more proliferative state for longer periods of time. Increased Axin levels (typical of mammalian cells) reduce oscillatory behavior and minimize the levels of [Formula: see text]-catenin within the cell while raising the levels of APC.
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Affiliation(s)
- Brooks Emerick
- Department of Mathematics, Trinity College, Hartford, CT, 06106, USA.
| | - Gilberto Schleiniger
- Department of Mathematical Sciences, University of Delaware, Newark, DE, 19711, USA
| | - Bruce M Boman
- Department of Biological Sciences, University of Delaware, Newark, DE, 19711, USA
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, 19713, USA
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Salim EI, Hegazi MM, Kang JS, Helmy HM. Expression Patterns of Cancer Stem Cell Markers During Specific Celecoxib Therapy in Multistep Rat Colon Carcinogenesis Bioassays. Asian Pac J Cancer Prev 2017; 17:1023-35. [PMID: 27039721 DOI: 10.7314/apjcp.2016.17.3.1023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The purpose of this study was to investigate the role of colon cancer stem cells (CSCs) during chemicallyinduced rat multi-step colon carcinogenesis with or without the treatment with a specific cyclooxygenase-2 inhibitor drug (celecoxib). Two experiments were performed, the first, a short term 12 week colon carcinogenesis bioassay in which only surrogate markers for colon cancer, aberrant crypt foci (ACF) lesions, were formed. The other experiment was a medium term colon cancer rat assay in which tumors had developed after 32 weeks. Treatment with celecoxib lowered the numbers of ACF, as well as the tumor volumes and multiplicities after 32 weeks. Immunohistochemical proliferating cell nuclear antigen (PCNA) labeling indexes LI (%) were downregulated after treatment by celecoxib. Also different cell surface antigens known to associate with CSCs such as the epithelial cell adhesion molecule (EpCAM), CD44 and CD133 were compared between the two experiments and showed differential expression patterns depending on the stage of carcinogenesis and treatment with celecoxib. Flow cytometric analysis demonstrated that the numbers of CD133 cells were increased in the colonic epithelium after 12 weeks while those of CD44 but not CD133 cells were increased after 32 weeks. Moreover, aldehyde dehydrogenase-1 activity levels in the colonic epithelium (a known CSC marker) detected by ELISA assay were found down-regulated after 12 weeks, but were up-regulated after 32 weeks. The data have also shown that the protective effect of celecoxib on these specific markers and populations of CSCs and on other molecular processes such as apoptosis targeted by this drug may vary depending on the genetic and phenotypic stages of carcinogenesis. Therefore, uncovering these distinction roles of CSCs during different phases of carcinogenesis and during specific treatment could be useful for targeted therapy.
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Affiliation(s)
- Elsayed I Salim
- Department of Zoology, Faculty of Science, Tanta University, Research Lab. of Molecular Carcinogenesis, Tanta, Egypt E-mail : ,
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44
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Chen J, Shao R, Li F, Monteiro M, Liu JP, Xu ZP, Gu W. PI3K/Akt/mTOR pathway dual inhibitor BEZ235 suppresses the stemness of colon cancer stem cells. Clin Exp Pharmacol Physiol 2016; 42:1317-26. [PMID: 26399781 DOI: 10.1111/1440-1681.12493] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/13/2015] [Accepted: 09/17/2015] [Indexed: 12/21/2022]
Abstract
Colon cancer is one of the most common cancers worldwide with high mortality. A major issue in colon cancer treatment is drug-resistance and metastasis that have been ascribed to the cancer stem cells. In this study, colon cancer stem cells were isolated through sphere culture and verified with the cancer stem cell markers CD133, CD44, and CD24. It was demonstrated that the PI3K/Akt/mTOR signalling pathway was highly activated in the colon cancer stem cells and that inhibition of the PI3K/Akt/mTOR pathway by the inhibitor BEZ235 suppressed the colon cancer stem cell proliferation with reduced stemness indicated by CD133 and Lgr5 expressions. Treatment with insulin as a known activator of the PI3K/Akt pathway increased CD133 expression and decreased the effects of BEZ235 on colon cancer proliferation and survival. The data presented here collectively suggest that the PI3K/Akt/mTOR pathway underpins the stemness of colon cancer stem cells and BEZ235 is potentially a good drug candidate for treatment of colon cancer drug resistance and metastasis.
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Affiliation(s)
- Jiezhong Chen
- Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Qld, Australia.,School of Biomedical Sciences, University of Queensland, St Lucia, Qld, Australia
| | - Renfu Shao
- GeneCology Research Centre, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, Qld, Australia
| | - Feng Li
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezhi University, Xinjiang, China
| | - Michael Monteiro
- Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Qld, Australia
| | - Jun-Ping Liu
- Aging Research Institute, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zhi Ping Xu
- Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Qld, Australia
| | - Wenyi Gu
- Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Qld, Australia
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45
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Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, Moriyama H, Kashimoto S, Inoue T, Goto N, Okamoto K, Shirouzu M, Sawa M, Yamada T. TNIK inhibition abrogates colorectal cancer stemness. Nat Commun 2016; 7:12586. [PMID: 27562646 PMCID: PMC5007443 DOI: 10.1038/ncomms12586] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 07/14/2016] [Indexed: 12/11/2022] Open
Abstract
Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. TRAF2 and NCK-interacting protein kinase (TNIK) is a key regulatory component of the TCF4 and β-catenin transcriptional complex. In this study, the authors identify a TNIK inhibitor that blocks Wnt signalling and Wnt-driven colorectal tumorigenesis in mice.
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Affiliation(s)
- Mari Masuda
- Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Yuko Uno
- Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Naomi Ohbayashi
- Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Hirokazu Ohata
- Division of Cancer Differentiation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Ayako Mimata
- Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Mutsuko Kukimoto-Niino
- Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Hideki Moriyama
- Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Shigeki Kashimoto
- Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Tomoko Inoue
- Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Naoko Goto
- Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Koji Okamoto
- Division of Cancer Differentiation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Mikako Shirouzu
- Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Masaaki Sawa
- Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Tesshi Yamada
- Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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Bellamkonda K, Chandrashekar NK, Osman J, Selvanesan BC, Savari S, Sjölander A. The eicosanoids leukotriene D4 and prostaglandin E2 promote the tumorigenicity of colon cancer-initiating cells in a xenograft mouse model. BMC Cancer 2016; 16:425. [PMID: 27388564 PMCID: PMC4937611 DOI: 10.1186/s12885-016-2466-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 06/29/2016] [Indexed: 12/11/2022] Open
Abstract
Background Colorectal cancer is one of the most common types of cancers worldwide. Recent studies have identified cancer-initiating cells (CICs) as a subgroup of replication-competent cells in the development of colorectal cancer. Although it is understood that an inflammation-rich tumor microenvironment presumably supports CIC functions, the contributory factors are not very well defined. The present study advances our understanding of the role of the eicosanoids leukotriene D4 (LTD4) and prostaglandin E2 (PGE2) in the tumorigenic ability of CICs and investigates the consequential changes occurring in the tumor environment that might support tumor growth. Methods In this study we used human HCT-116 colon cancer ALDH+ cells in a nude mouse xenograft model. Protein expression and immune cell was determined in tumor-dispersed cells by flow cytometry and in tumor sections by immunohistochemistry. mRNA expressions were quantified using RT-q-PCR and plasma cytokine levels by Multiplex ELISA. Results We observed that LTD4 and PGE2 treatment augmented CIC-induced tumor growth. LTD4-and PGE2-treated xenograft tumors revealed a robust increase in ALDH and Dclk1 protein expression, coupled with activated β-catenin signaling and COX-2 up-regulation. Furthermore, LTD4 or PGE2 accentuated the accumulation of CD45 expressing cells within xenograft tumors. Further analysis revealed that these infiltrating immune cells consisted of neutrophils (LY6G) and M2 type macrophages (CD206+). In addition, LTD4 and PGE2 treatment significantly elevated the plasma levels of cysteinyl leukotrienes and PGE2, as well as levels of IL-1β, IL-2, IL-6, TNF-α and CXCL1/KC/GRO. In addition, increased mRNA expression of IL-1β, IL-6 and IL-10 were detected in tumors from mice that had been treated with LTD4 or PGE2. Conclusion Our data suggest that both LTD4 and PGE2 promote CICs in initiating tumor growth by allowing modifications in the tumor environment. Our data indicate that new therapeutic strategies targeting eicosanoids, specifically LTD4 and PGE2, could be tested for better therapeutic management of colon cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2466-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kishan Bellamkonda
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Naveen Kumar Chandrashekar
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Janina Osman
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Benson Chellakkan Selvanesan
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Sayeh Savari
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden
| | - Anita Sjölander
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden.
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D'Addio F, Fiorina P. Type 1 Diabetes and Dysfunctional Intestinal Homeostasis. Trends Endocrinol Metab 2016; 27:493-503. [PMID: 27185326 DOI: 10.1016/j.tem.2016.04.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 04/09/2016] [Accepted: 04/13/2016] [Indexed: 12/11/2022]
Abstract
Despite the relatively high frequency of gastrointestinal (GI) disorders in individuals with type 1 diabetes (T1D), termed diabetic enteropathy (DE), the pathogenic mechanisms of these disorders remain to be elucidated. While previous studies have assumed that DE is a manifestation of diabetic autonomic neuropathy, other contributing factors such as enteric hormones, inflammation, and microbiota were later recognized. More recently, the emerging role of intestinal stem cells (ISCs) in several GI diseases has led to a new understanding of DE. Given the absence of diagnostic methods and the lack of broadly efficacious therapeutic remedies in DE, targeting factors and pathways that control ISC homeostasis and are dysfunctional in DE may represent a new path for the detection and cure of DE.
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Affiliation(s)
- Francesca D'Addio
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Paolo Fiorina
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
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Fateh A, Feizi MAH, Safaralizadeh R, Azarbarzin S, Ravanbakhsh R. Diagnostic and Prognostic Value of miR-1287 in Colorectal Cancer. J Gastrointest Cancer 2016; 47:399-403. [DOI: 10.1007/s12029-016-9833-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Abstract
Cancer stem cells (CSCs) have been shown to be markedly resistant to conventional cancer treatments such as chemotherapy and radiation therapy. Therefore, therapeutic strategies that selectively target CSCs will ultimately lead to better cancer treatments. Currently, accessible conventional therapeutic agents mainly eliminate the bulk tumor but do not eliminate CSCs. Therefore, the discovery and improvement of CSC-targeting therapeutic agents are necessary. Nanoparticles effectively inhibit multiple types of CSCs by targeting specific signaling pathways (Wnt/β-catenin, Notch, transforming growth factor-β, and hedgehog signaling) and/or specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) critically involved in CSC function and maintenance. In this review article, we summarized a number of findings to provide current information about their therapeutic potential of nanoparticles in various cancer cell types and CSCs.
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Affiliation(s)
- In-Sun Hong
- Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea ; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Republic of Korea
| | - Gyu-Beom Jang
- Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea ; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Republic of Korea
| | - Hwa-Yong Lee
- The Faculty of Liberal Arts, Jungwon University, Chungbuk, Republic of Korea
| | - Jeong-Seok Nam
- Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea ; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Republic of Korea
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50
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Zhang C, Tian Y, Song F, Fu C, Han B, Wang Y. Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells. Oncol Rep 2015; 34:2469-76. [PMID: 26352531 DOI: 10.3892/or.2015.4253] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 07/23/2015] [Indexed: 12/19/2022] Open
Abstract
Salinomycin is a monocarboxylic polyether antibiotic that has been reported to induce apoptosis in various types of cancer cells with specificity for cancer stem cells. However, its anticancer effect in colorectal cancer stem cells has never been reported. In the present study, we examined the ability of salinomycin to induce cell death in the colorectal cancer stem cell line CD44+EpCAM+ HCT-116, and we measured its in vivo tumor inhibition capacity. Salinomycin dose-dependently induced cytotoxicity in the CD44+EpCAM+ HCT-116 cells and inhibited colony formation. Salinomycin treatment was shown to induce apoptosis, as evidenced by nuclear fragmentation, an increase in the proportion of acridine orange/ethidium bromide-positive cells and an increase in the percentage of Annexin V-positive cells. Apoptosis was induced in colorectal cancer stem cells in a caspase-dependent manner, as shown by an increase in the levels of cleaved caspase-3, -8 and -9. JC-1 staining further revealed that salinomycin induced colorectal cancer cell apoptosis via the mitochondrial pathway. In addition, salinomycin treatment of xenograft mice inhibited the growth of tumors derived from the CD44+EpCAM+ HCT-116 cells. The present study demonstrated that the antibiotic salinomycin exerts an anti-colorectal cancer effect in vitro and in vivo, suggesting salinomycin as a potential drug for colorectal cancer therapy.
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Affiliation(s)
- Chen Zhang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yaping Tian
- Department of Dermatology, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Feiyu Song
- Jilin Connell Pharmaceutical Company, Changchun, Jilin 130000, P.R. China
| | - Changhao Fu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Bo Han
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
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