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Filippi A, Deculescu-Ioniță T, Hudiță A, Baldasici O, Gălățeanu B, Mocanu MM. Molecular Mechanisms of Dietary Compounds in Cancer Stem Cells from Solid Tumors: Insights into Colorectal, Breast, and Prostate Cancer. Int J Mol Sci 2025; 26:631. [PMID: 39859345 PMCID: PMC11766403 DOI: 10.3390/ijms26020631] [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: 11/21/2024] [Revised: 01/10/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Cancer stem cells (CSC) are known to be the main source of tumor relapse, metastasis, or multidrug resistance and the mechanisms to counteract or eradicate them and their activity remain elusive. There are different hypotheses that claim that the origin of CSC might be in regular stem cells (SC) and, due to accumulation of mutations, these normal cells become malignant, or the source of CSC might be in any malignant cell that, under certain environmental circumstances, acquires all the qualities to become CSC. Multiple studies indicate that lifestyle and diet might represent a source of wellbeing that can prevent and ameliorate the malignant phenotype of CSC. In this review, after a brief introduction to SC and CSC, we analyze the effects of phenolic and non-phenolic dietary compounds and we highlight the molecular mechanisms that are shown to link diets to CSC activation in colon, breast, and prostate cancer. We focus the analysis on specific markers such as sphere formation, CD surface markers, epithelial-mesenchymal transition (EMT), Oct4, Nanog, Sox2, and aldehyde dehydrogenase 1 (ALDH1) and on the major signaling pathways such as PI3K/Akt/mTOR, NF-κB, Notch, Hedgehog, and Wnt/β-catenin in CSC. In conclusion, a better understanding of how bioactive compounds in our diets influence the dynamics of CSC can raise valuable awareness towards reducing cancer risk.
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Affiliation(s)
- Alexandru Filippi
- Department of Biochemistry and Biophysics, “Carol Davila” University of Medicine and Pharmacy of Bucharest, 050474 Bucharest, Romania;
| | - Teodora Deculescu-Ioniță
- Department of Pharmacognosy, Phytochemistry and Phytotherapy, “Carol Davila” University of Medicine and Pharmacy of Bucharest, 050474 Bucharest, Romania;
| | - Ariana Hudiță
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania; (A.H.); (B.G.)
| | - Oana Baldasici
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuță”, 400015 Cluj-Napoca, Romania;
| | - Bianca Gălățeanu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania; (A.H.); (B.G.)
| | - Maria-Magdalena Mocanu
- Department of Biochemistry and Biophysics, “Carol Davila” University of Medicine and Pharmacy of Bucharest, 050474 Bucharest, Romania;
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Lavudi K, Nuguri SM, Pandey P, Kokkanti RR, Wang QE. ALDH and cancer stem cells: Pathways, challenges, and future directions in targeted therapy. Life Sci 2024; 356:123033. [PMID: 39222837 DOI: 10.1016/j.lfs.2024.123033] [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: 06/11/2024] [Revised: 08/16/2024] [Accepted: 08/30/2024] [Indexed: 09/04/2024]
Abstract
Human ALDH comprise 19 subfamilies in which ALDH1A1, ALDH1A3, ALDH3A1, ALDH5A1, ALDH7A1, and ALDH18A1 are implicated in CSC. Studies have shown that ALDH can also be involved in drug resistance and standard chemotherapy regimens are ineffective in treating patients at the stage of disease recurrence. Existing chemotherapeutic drugs eliminate the bulk of tumors but are usually not effective against CSC which express ALDH+ population. Henceforth, targeting ALDH is convincing to treat the patient's post-relapse. Combination therapies that interlink signaling mechanisms seem promising to increase the overall disease-free survival rate. Therefore, targeting ALDH through ALDH inhibitors along with immunotherapies may create a novel platform for translational research. This review aims to fill in the gap between ALDH1 family members in relation to its cell signaling mechanisms, highlighting their potential as molecular targets to sensitize recurrent tumors and bring forward the future development concerning the current progress and draw backs. This review summarizes the role of cancer stem cells and their upregulation by maintaining the tumor microenvironment in which ALDH is specifically highlighted. It discusses the regulation of ALDH family proteins and the crosstalk between ALDH and CSC in relation to cancer metabolism. Furthermore, it establishes the correlation between ALDH involved signaling mechanisms and their specific targeted inhibitors, as well as their functional modularity, bioavailability, and mechanistic role in various cancers.
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Affiliation(s)
- Kousalya Lavudi
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States
| | - Shreya Madhav Nuguri
- Department of Food science and Technology, The Ohio State University, Columbus, OH, United States
| | - Prashant Pandey
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, U.P., India; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | | | - Qi-En Wang
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States.
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3
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Mezentsev A, Durymanov M, Makarov VA. A Comprehensive Review of Protein Biomarkers for Invasive Lung Cancer. Curr Oncol 2024; 31:4818-4854. [PMID: 39329988 PMCID: PMC11431409 DOI: 10.3390/curroncol31090360] [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: 07/25/2024] [Revised: 08/16/2024] [Accepted: 08/22/2024] [Indexed: 09/28/2024] Open
Abstract
Invasion and metastasis are important hallmarks of lung cancer, and affect patients' survival. Early diagnostics of metastatic potential are important for treatment management. Recent findings suggest that the transition to an invasive phenotype causes changes in the expression of 700-800 genes. In this context, the biomarkers restricted to the specific type of cancer, like lung cancer, are often overlooked. Some well-known protein biomarkers correlate with the progression of the disease and the immunogenicity of the tumor. Most of these biomarkers are not exclusive to lung cancer because of their significant role in tumorigenesis. The dysregulation of others does not necessarily indicate cell invasiveness, as they play an active role in cell division. Clinical studies of lung cancer use protein biomarkers to assess the invasiveness of cancer cells for therapeutic purposes. However, there is still a need to discover new biomarkers for lung cancer. In the future, minimally invasive techniques, such as blood or saliva analyses, may be sufficient for this purpose. Many researchers suggest unconventional biomarkers, like circulating nucleic acids, exosomal proteins, and autoantibodies. This review paper aims to discuss the advantages and limitations of protein biomarkers of invasiveness in lung cancer, to assess their prognostic value, and propose novel biomarker candidates.
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Affiliation(s)
- Alexandre Mezentsev
- Medical Informatics Laboratory, Yaroslav-the-Wise Novgorod State University, 173003 Veliky Novgorod, Russia; (M.D.); (V.A.M.)
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia
| | - Mikhail Durymanov
- Medical Informatics Laboratory, Yaroslav-the-Wise Novgorod State University, 173003 Veliky Novgorod, Russia; (M.D.); (V.A.M.)
| | - Vladimir A. Makarov
- Medical Informatics Laboratory, Yaroslav-the-Wise Novgorod State University, 173003 Veliky Novgorod, Russia; (M.D.); (V.A.M.)
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4
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Gou S, Wu A, Luo Z. Integrins in cancer stem cells. Front Cell Dev Biol 2024; 12:1434378. [PMID: 39239559 PMCID: PMC11375753 DOI: 10.3389/fcell.2024.1434378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/12/2024] [Indexed: 09/07/2024] Open
Abstract
Integrins are a class of adhesion receptors on cell membranes, consisting of α and β subunits. By binding to the extracellular matrix, integrins activate intracellular signaling pathways, participating in every step of cancer initiation and progression. Tumor stem cells possess self-renewal and self-differentiation abilities, along with strong tumorigenic potential. In this review, we discussed the role of integrins in cancer, with a focus on their impact on tumor stem cells and tumor stemness. This will aid in targeting tumor stem cells as a therapeutic approach, leading to the exploration of novel cancer treatment strategies.
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Affiliation(s)
- Siqi Gou
- The Second Affiliated Hospital, Department of urology, Hengyang Medical School, University of South China, Hengyang, China
| | - Anqi Wu
- The Second Affiliated Hospital, Department of Clinical Research Center, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhigang Luo
- The Second Affiliated Hospital, Department of urology, Hengyang Medical School, University of South China, Hengyang, China
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5
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Oliveira SM, Carvalho PD, Serra-Roma A, Oliveira P, Ribeiro A, Carvalho J, Martins F, Machado AL, Oliveira MJ, Velho S. Fibroblasts Promote Resistance to KRAS Silencing in Colorectal Cancer Cells. Cancers (Basel) 2024; 16:2595. [PMID: 39061234 PMCID: PMC11274566 DOI: 10.3390/cancers16142595] [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: 05/29/2024] [Revised: 07/06/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Colorectal cancer (CRC) responses to KRAS-targeted inhibition have been limited due to low response rates, the mechanisms of which remain unknown. Herein, we explored the cancer-associated fibroblasts (CAFs) secretome as a mediator of resistance to KRAS silencing. CRC cell lines HCT15, HCT116, and SW480 were cultured either in recommended media or in conditioned media from a normal colon fibroblast cell line (CCD-18Co) activated with rhTGF-β1 to induce a CAF-like phenotype. The expression of membrane stem cell markers was analyzed by flow cytometry. Stem cell potential was evaluated by a sphere formation assay. RNAseq was performed in KRAS-silenced HCT116 colonospheres treated with either control media or conditioned media from CAFs. Our results demonstrated that KRAS-silencing up-regulated CD24 and down-regulated CD49f and CD104 in the three cell lines, leading to a reduction in sphere-forming efficiency. However, CAF-secreted factors restored stem cell marker expression and increased stemness. RNA sequencing showed that CAF-secreted factors up-regulated genes associated with pro-tumorigenic pathways in KRAS-silenced cells, including KRAS, TGFβ, NOTCH, WNT, MYC, cell cycle progression and exit from quiescence, epithelial-mesenchymal transition, and immune regulation. Overall, our results suggest that resistance to KRAS-targeted inhibition might derive not only from cell-intrinsic causes but also from external elements, such as fibroblast-secreted factors.
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Affiliation(s)
- Susana Mendonça Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FMUP—Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- ESS|P.PORTO—Escola Superior de Saúde, Instituto Politécnico do Porto, Rua Dr. António Bernardino de Almeida 400, 4200-072 Porto, Portugal
| | - Patrícia Dias Carvalho
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - André Serra-Roma
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - Patrícia Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - Andreia Ribeiro
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - Joana Carvalho
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - Flávia Martins
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FMUP—Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Ana Luísa Machado
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- FMUP—Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- ESS|P.PORTO—Escola Superior de Saúde, Instituto Politécnico do Porto, Rua Dr. António Bernardino de Almeida 400, 4200-072 Porto, Portugal
| | - Maria José Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- FMUP—Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
- INEB—Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-177 Porto, Portugal
| | - Sérgia Velho
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (S.M.O.); (P.O.); (J.C.); (F.M.); (A.L.M.); (M.J.O.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
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Kim HS, Yoon JH, Baek GO, Yoon MG, Han JE, Cho HJ, Kim SS, Jeong JY, Cheong JY, Eun JW. Tumor Endothelial Cells-Associated Integrin Alpha-6 as a Promising Biomarker for Early Detection and Prognosis of Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4156. [PMID: 37627184 PMCID: PMC10453423 DOI: 10.3390/cancers15164156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/08/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
HCC remains a lethal cancer type, with early detection being critical for improved patient outcomes. This study introduces a comprehensive methodological approach to identify the ITGA6 gene as a potential blood marker for early HCC (eHCC) detection. We initially analyzed the GSE114564 dataset encompassing various stages of liver disease, identifying 972 differentially expressed genes in HCC. A refined analysis yielded 59 genes specifically differentially expressed in early HCC, including ITGA6. Subsequent validation in multiple datasets confirmed the consistent upregulation of ITGA6 in HCC. In addition, when analyzing progression-free survival (PFS) within the entire patient cohort and overall survival (OS) specifically among patients classified as tumor grade G1, the group of patients characterized by high expression levels of ITGA6 displayed an elevated risk ratio in relation to prognosis. Further analyses demonstrated the predominant expression of ITGA6 in TECs and its enrichment in angiogenesis-related pathways. Additionally, positive correlations were found between ITGA6 expression and pro-tumorigenic immune cells, but not with anti-tumorigenic immune cells. Our study elucidates the potential of ITGA6 as a blood-based marker for HCC early detection and diagnosis and its complex interplay with the tumor microenvironment. Further research may lead to novel strategies for HCC management and patient care.
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Affiliation(s)
- Hyung Seok Kim
- Department of Biochemistry, College of Medicine, Kosin University, Seo-gu, Busan 49267, Republic of Korea; (H.S.K.); (J.-Y.J.)
| | - Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea;
| | - Geum Ok Baek
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Moon Gyeong Yoon
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Ji Eun Han
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Jee-Yeong Jeong
- Department of Biochemistry, College of Medicine, Kosin University, Seo-gu, Busan 49267, Republic of Korea; (H.S.K.); (J.-Y.J.)
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea; (G.O.B.); (M.G.Y.); (J.E.H.); (H.J.C.); (S.S.K.)
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7
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Khademi R, Malekzadeh H, Bahrami S, Saki N, Khademi R, Villa-Diaz LG. Regulation and Functions of α6-Integrin (CD49f) in Cancer Biology. Cancers (Basel) 2023; 15:3466. [PMID: 37444576 DOI: 10.3390/cancers15133466] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Over the past decades, our knowledge of integrins has evolved from being understood as simple cell surface adhesion molecules to receptors that have a complex range of intracellular and extracellular functions, such as delivering chemical and mechanical signals to cells. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Dysregulation of integrin signaling is a major factor in the development and progression of many tumors. Many reviews have covered the broader integrin family in molecular and cellular studies and its roles in diseases. Nevertheless, further understanding of the mechanisms specific to an individual subunit of different heterodimers is more useful. Thus, we describe the current understanding of and exploratory investigations on the α6-integrin subunit (CD49f, VLA6; encoded by the gene itga6) in normal and cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnosis biomarker, are discussed. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. In addition, exosomal ITGA6 also implies metastatic organotropism. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel prognostic or diagnostic marker and useful therapeutic target for better clinical outcomes.
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Affiliation(s)
- Rahele Khademi
- Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (Immuno_TACT), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
| | - Hossein Malekzadeh
- Department of Oral Medicine, Faculty of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Sara Bahrami
- Resident of Restorative Dentistry, Qazvin University of Medical Sciences, Qazvin 3419759811, Iran
| | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Reyhane Khademi
- Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (Immuno_TACT), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Laboratory Sciences, School of Para-Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Luis G Villa-Diaz
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
- Department of Bioengineering, Oakland University, Rochester, MI 48309, USA
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8
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Modvig S, Jeyakumar J, Marquart HV, Christensen C. Integrins and the Metastasis-like Dissemination of Acute Lymphoblastic Leukemia to the Central Nervous System. Cancers (Basel) 2023; 15:cancers15092504. [PMID: 37173970 PMCID: PMC10177281 DOI: 10.3390/cancers15092504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/23/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Acute lymphoblastic leukemia (ALL) disseminates with high prevalence to the central nervous system (CNS) in a process resembling aspects of the CNS surveillance of normal immune cells as well as aspects of brain metastasis from solid cancers. Importantly, inside the CNS, the ALL blasts are typically confined within the cerebrospinal fluid (CSF)-filled cavities of the subarachnoid space, which they use as a sanctuary protected from both chemotherapy and immune cells. At present, high cumulative doses of intrathecal chemotherapy are administered to patients, but this is associated with neurotoxicity and CNS relapse still occurs. Thus, it is imperative to identify markers and novel therapy targets specific to CNS ALL. Integrins represent a family of adhesion molecules involved in cell-cell and cell-matrix interactions, implicated in the adhesion and migration of metastatic cancer cells, normal immune cells, and leukemic blasts. The ability of integrins to also facilitate cell-adhesion mediated drug resistance, combined with recent discoveries of integrin-dependent routes of leukemic cells into the CNS, have sparked a renewed interest in integrins as markers and therapeutic targets in CNS leukemia. Here, we review the roles of integrins in CNS surveillance by normal lymphocytes, dissemination to the CNS by ALL cells, and brain metastasis from solid cancers. Furthermore, we discuss whether ALL dissemination to the CNS abides by known hallmarks of metastasis, and the potential roles of integrins in this context.
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Affiliation(s)
- Signe Modvig
- Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Jenani Jeyakumar
- Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
| | - Hanne Vibeke Marquart
- Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Claus Christensen
- Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
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9
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Okonechnikov K, Camgöz A, Chapman O, Wani S, Park DE, Hübner JM, Chakraborty A, Pagadala M, Bump R, Chandran S, Kraft K, Acuna-Hidalgo R, Reid D, Sikkink K, Mauermann M, Juarez EF, Jenseit A, Robinson JT, Pajtler KW, Milde T, Jäger N, Fiesel P, Morgan L, Sridhar S, Coufal NG, Levy M, Malicki D, Hobbs C, Kingsmore S, Nahas S, Snuderl M, Crawford J, Wechsler-Reya RJ, Davidson TB, Cotter J, Michaiel G, Fleischhack G, Mundlos S, Schmitt A, Carter H, Michealraj KA, Kumar SA, Taylor MD, Rich J, Buchholz F, Mesirov JP, Pfister SM, Ay F, Dixon JR, Kool M, Chavez L. 3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma. Nat Commun 2023; 14:2300. [PMID: 37085539 PMCID: PMC10121654 DOI: 10.1038/s41467-023-38044-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 04/13/2023] [Indexed: 04/23/2023] Open
Abstract
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.
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Affiliation(s)
- Konstantin Okonechnikov
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Aylin Camgöz
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- National Center for Tumor Diseases (NCT): German Cancer Research Center (DKFZ) Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
| | - Owen Chapman
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
| | - Sameena Wani
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
| | - Donglim Esther Park
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA
- Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Jens-Martin Hübner
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Abhijit Chakraborty
- Centers for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Meghana Pagadala
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
| | - Rosalind Bump
- Peptide Biology Labs, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Sahaana Chandran
- Peptide Biology Labs, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Katerina Kraft
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA
| | - Rocio Acuna-Hidalgo
- Max Planck Institute for Molecular Genetics, Berlin, Germany
- Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Derek Reid
- Arima Genomics, Inc, San Diego, CA, 92121, USA
| | | | - Monika Mauermann
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Edwin F Juarez
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
| | - Anne Jenseit
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - James T Robinson
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
| | - Kristian W Pajtler
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Till Milde
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
- CCU Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Natalie Jäger
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Petra Fiesel
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- CCU Neuropathology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Ling Morgan
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
| | - Sunita Sridhar
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
| | - Nicole G Coufal
- Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
- Department of Pediatrics, University of California, San Diego, San Diego, CA, 92093, USA
| | - Michael Levy
- Neurosurgery, University of California San Diego - Rady Children's Hospital, San Diego, CA, 92123, USA
| | - Denise Malicki
- Pathology, University of California San Diego - Rady Children's Hospital, San Diego, CA, 92123, USA
| | - Charlotte Hobbs
- Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA
| | - Stephen Kingsmore
- Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA
| | - Shareef Nahas
- Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA
| | - Matija Snuderl
- Department of Pathology, NYU Langone Health, NYU Grossman School of Medicine, 550 First Ave, New York, NY, 10016, USA
- Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - John Crawford
- Department of Neurosciences, University of California San Diego - Rady Children's Hospital, San Diego, CA, 92123, USA
| | - Robert J Wechsler-Reya
- Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
- Department of Pediatrics, University of California, San Diego, San Diego, CA, 92093, USA
- Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Tom Belle Davidson
- Division of Hematology-Oncology, Cancer and Blood Disease Institute and Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Jennifer Cotter
- Division of Hematology-Oncology, Cancer and Blood Disease Institute and Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - George Michaiel
- Division of Hematology-Oncology, Cancer and Blood Disease Institute and Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Gudrun Fleischhack
- German Cancer Consortium (DKTK), West German Cancer Center, Pediatrics III, University Hospital Essen, Essen, Germany
| | - Stefan Mundlos
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | | | - Hannah Carter
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
| | - Kulandaimanuvel Antony Michealraj
- Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, ONT, Canada
| | - Sachin A Kumar
- Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, ONT, Canada
| | - Michael D Taylor
- Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, ONT, Canada
| | - Jeremy Rich
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA
- Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
- Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Frank Buchholz
- National Center for Tumor Diseases (NCT): German Cancer Research Center (DKFZ) Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
- Medical Systems Biology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, 01307, Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Site Dresden, Dresden, Germany
| | - Jill P Mesirov
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, USA
| | - Stefan M Pfister
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Ferhat Ay
- Centers for Cancer Immunotherapy and Autoimmunity, La Jolla Institute for Immunology, La Jolla, CA, USA
- Department of Pediatrics, University of California, San Diego, San Diego, CA, 92093, USA
| | - Jesse R Dixon
- Peptide Biology Labs, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Marcel Kool
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Lukas Chavez
- Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego (UCSD), San Diego, USA.
- Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA.
- Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, USA.
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10
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Manni W, Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm (Beijing) 2022; 3:e176. [PMID: 36226253 PMCID: PMC9534377 DOI: 10.1002/mco2.176] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/07/2022] Open
Abstract
Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.
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Affiliation(s)
- Wang Manni
- Department of Biotherapy, Cancer Center, West China HospitalSichuan UniversityChengduP. R. China
| | - Wu Min
- Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksNorth DakotaUSA
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11
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Heumos S, Dehn S, Bräutigam K, Codrea MC, Schürch CM, Lauer UM, Nahnsen S, Schindler M. Multiomics surface receptor profiling of the NCI-60 tumor cell panel uncovers novel theranostics for cancer immunotherapy. Cancer Cell Int 2022; 22:311. [PMID: 36221114 PMCID: PMC9555072 DOI: 10.1186/s12935-022-02710-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 08/30/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Immunotherapy with immune checkpoint inhibitors (ICI) has revolutionized cancer therapy. However, therapeutic targeting of inhibitory T cell receptors such as PD-1 not only initiates a broad immune response against tumors, but also causes severe adverse effects. An ideal future stratified immunotherapy would interfere with cancer-specific cell surface receptors only. METHODS To identify such candidates, we profiled the surface receptors of the NCI-60 tumor cell panel via flow cytometry. The resulting surface receptor expression data were integrated into proteomic and transcriptomic NCI-60 datasets applying a sophisticated multiomics multiple co-inertia analysis (MCIA). This allowed us to identify surface profiles for skin, brain, colon, kidney, and bone marrow derived cell lines and cancer entity-specific cell surface receptor biomarkers for colon and renal cancer. RESULTS For colon cancer, identified biomarkers are CD15, CD104, CD324, CD326, CD49f, and for renal cancer, CD24, CD26, CD106 (VCAM1), EGFR, SSEA-3 (B3GALT5), SSEA-4 (TMCC1), TIM1 (HAVCR1), and TRA-1-60R (PODXL). Further data mining revealed that CD106 (VCAM1) in particular is a promising novel immunotherapeutic target for the treatment of renal cancer. CONCLUSION Altogether, our innovative multiomics analysis of the NCI-60 panel represents a highly valuable resource for uncovering surface receptors that could be further exploited for diagnostic and therapeutic purposes in the context of cancer immunotherapy.
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Affiliation(s)
- Simon Heumos
- Quantitative Biology Center (QBiC), University of Tübingen, 72076, Tübingen, Germany.,Biomedical Data Science, Dept. of Computer Science, University of Tübingen, 72076, Tübingen, Germany
| | - Sandra Dehn
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | | | - Marius C Codrea
- Quantitative Biology Center (QBiC), University of Tübingen, 72076, Tübingen, Germany
| | - Christian M Schürch
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Ulrich M Lauer
- Department of Internal Medicine VIII, Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital Tübingen, 72076, Tübingen, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, 72076, Tübingen, Germany
| | - Sven Nahnsen
- Quantitative Biology Center (QBiC), University of Tübingen, 72076, Tübingen, Germany.,Biomedical Data Science, Dept. of Computer Science, University of Tübingen, 72076, Tübingen, Germany
| | - Michael Schindler
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.
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12
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Ojha PS, Maste MM, Tubachi S, Patil VS. Human papillomavirus and cervical cancer: an insight highlighting pathogenesis and targeting strategies. Virusdisease 2022; 33:132-154. [DOI: 10.1007/s13337-022-00768-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 05/07/2022] [Indexed: 11/29/2022] Open
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13
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Generation of Cancer Stem/Initiating Cells by Cell-Cell Fusion. Int J Mol Sci 2022; 23:ijms23094514. [PMID: 35562905 PMCID: PMC9101717 DOI: 10.3390/ijms23094514] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/10/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
CS/ICs have raised great expectations in cancer research and therapy, as eradication of this key cancer cell type is expected to lead to a complete cure. Unfortunately, the biology of CS/ICs is rather complex, since no common CS/IC marker has yet been identified. Certain surface markers or ALDH1 expression can be used for detection, but some studies indicated that cancer cells exhibit a certain plasticity, so CS/ICs can also arise from non-CS/ICs. Another problem is intratumoral heterogeneity, from which it can be inferred that different CS/IC subclones must be present in the tumor. Cell–cell fusion between cancer cells and normal cells, such as macrophages and stem cells, has been associated with the generation of tumor hybrids that can exhibit novel properties, such as an enhanced metastatic capacity and even CS/IC properties. Moreover, cell–cell fusion is a complex process in which parental chromosomes are mixed and randomly distributed among daughter cells, resulting in multiple, unique tumor hybrids. These, if they have CS/IC properties, may contribute to the heterogeneity of the CS/IC pool. In this review, we will discuss whether cell–cell fusion could also lead to the origin of different CS/ICs that may expand the overall CS/IC pool in a primary tumor.
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14
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Harryman WL, Marr KD, Nagle RB, Cress AE. Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers. Front Cell Dev Biol 2022; 10:837585. [PMID: 35300411 PMCID: PMC8921537 DOI: 10.3389/fcell.2022.837585] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/04/2022] [Indexed: 11/18/2022] Open
Abstract
Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.
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Affiliation(s)
- William L Harryman
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States
| | - Kendra D Marr
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United States.,Medical Scientist Training Program, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Ray B Nagle
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Department of Pathology, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Anne E Cress
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Department of Cellular and Molecular Medicine and Department of Radiation Oncology, College of Medicine, University of Arizona, Tucson, AZ, United States
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15
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Identification, Culture and Targeting of Cancer Stem Cells. Life (Basel) 2022; 12:life12020184. [PMID: 35207472 PMCID: PMC8879966 DOI: 10.3390/life12020184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance, tumor progression, and metastasis are features that are frequently seen in cancer that have been associated with cancer stem cells (CSCs). These cells are a promising target in the future of cancer therapy but remain largely unknown. Deregulation of pathways that govern stemness in non-tumorigenic stem cells (SCs), such as Notch, Wnt, and Hedgehog pathways, has been described in CSC pathogenesis, but it is necessary to conduct further studies to discover potential new therapeutic targets. In addition, some markers for the identification and characterization of CSCs have been suggested, but the search for specific CSC markers in many cancer types is still under development. In addition, methods for CSC cultivation are also under development, with great heterogeneity existing in the protocols used. This review focuses on the most recent aspects of the identification, characterization, cultivation, and targeting of human CSCs, highlighting the advances achieved in the clinical implementation of therapies targeting CSCs and remarking those potential areas where more research is still required.
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16
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Al-Obaide M, Ishmakej A, Brown C, Mazzella M, Agosta P, Perez-Cruet M, Chaudhry GR. The potential role of integrin alpha 6 in human mesenchymal stem cells. Front Genet 2022; 13:968228. [PMID: 36212156 PMCID: PMC9535380 DOI: 10.3389/fgene.2022.968228] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
Human mesenchymal stem cells (MSCs) are isolated from various adult and perinatal tissues. Although mesenchymal stem cells from multiple sources exhibit similar morphology and cell surface markers, they differ in their properties. In this study, we determined that the expression of integrin alpha 6 (ITGA6) and ITGA6 antisense RNA (ITGA6-AS1) correlates with the proliferation, cell size, and differentiation potential. The expression of ITGA6 was inversely correlated with ITGA6-AS1 in MSCs. The expression of ITGA6 was higher, but ITGA6-AS1 was lower in MSCs from cord placenta junction, cord tissue, and Wharton's jelly. In contrast, ITGA6 expression was lower, while ITGA6-AS1 was higher in MSCs from the placenta. The bioinformatic analysis showed that ITGA6 genomic DNA transcribes ITGA6-AS1 from the reverse strand, overlapping ITGA6 exon-2. Additionally, we identify several putative promoters (P1-P10) of ITGA6. ITGA6-P10 is CG rich and contains CGI. EMBOSS Cpgplot software revealed a CGI length of 180 bp that extends from nucleotide 125 to 304 of the P10 sequence. We suggest that the post-transcriptional regulation of the ITGA6 in mesenchymal stem cells is controlled by the ITGA6-AS1, which could be a critical factor responsible for the heterogeneity in function and cell fate of human MSCs. These results may provide further impetus for investigations to unravel the mechanisms of ITGA6 regulation that could help maintain or improve the properties of mesenchymal stem cells.
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Affiliation(s)
- Mohammed Al-Obaide
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
| | - Albi Ishmakej
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
| | - Christina Brown
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
| | - Matteo Mazzella
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
| | - Patrina Agosta
- Ascension Providence Hospital, Southfield, MI, United States
| | - Mick Perez-Cruet
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States.,Department of Neurosurgery, Beaumont Health, Royal Oak, MI, United States
| | - G Rasul Chaudhry
- Department of Biological Sciences, Oakland University, Rochester, MI, United States.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, United States
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17
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An JS, Moon JH, Kim C, No JK, Eun YG, Chang Lim Y. Integrin alpha 6 as a stemness driver is a novel promising target for HPV (+) head and neck squamous cell carcinoma. Exp Cell Res 2021; 407:112815. [PMID: 34496296 DOI: 10.1016/j.yexcr.2021.112815] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 07/31/2021] [Accepted: 09/03/2021] [Indexed: 12/14/2022]
Abstract
Although the incidence rates of head and neck squamous cell carcinoma (HNSCC) associated with human papilloma virus (HPV) infection have recently been on the rise, the underlying mechanism of its tumorigenesis remains largely unknown. Here, we investigated whether HNSCC cells with high expression of integrin alpha 6 (ITGα6), one of the HPV receptors, have a preference during HPV infection. In addition, we examined the gain or loss of function of the ITGα6 gene in HPV + ve HNSCC cells, as well as its prognostic value in patients with HNSCC. HPV pseudovirus was found to be more infective, with HNSCC cells featuring an overexpressed ITGα6 gene compared to the control cells. Overexpression and suppression of ITGα6 respectively increases and decreases stemness phenotypes of HPV + ve HNSCC cells. Furthermore, ITGα6 can regulate stemness by partially mediating AKT pathway in HPV + ve HNSCC cells. Finally, patients with HPV + ve HNSCC had a poor prognosis in cases of elevated ITGα6 expression; however, the expression levels of ITGα6 did not influence the survival rates of HPV-negative HNSCC patients. In conclusion, ITGα6 can serve as a potential therapeutic target for HPV + ve HNSCC cancer-like stem cells (CSCs).
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Affiliation(s)
- Jin Seol An
- Department of Otorhinolaryngology - Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
| | - Jung Hwa Moon
- Department of Otorhinolaryngology - Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
| | - Chayeon Kim
- Department of Otorhinolaryngology - Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
| | - Joo Kyung No
- Department of Otorhinolaryngology - Head and Neck Surgery, Kyunghee University School of Medicine, Seoul, South Korea
| | - Young Gyu Eun
- Department of Otorhinolaryngology - Head and Neck Surgery, Kyunghee University School of Medicine, Seoul, South Korea
| | - Young Chang Lim
- Department of Otorhinolaryngology - Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea.
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18
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Mohan A, Raj Rajan R, Mohan G, Kollenchery Puthenveettil P, Maliekal TT. Markers and Reporters to Reveal the Hierarchy in Heterogeneous Cancer Stem Cells. Front Cell Dev Biol 2021; 9:668851. [PMID: 34150761 PMCID: PMC8209516 DOI: 10.3389/fcell.2021.668851] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/30/2021] [Indexed: 12/12/2022] Open
Abstract
A subpopulation within cancer, known as cancer stem cells (CSCs), regulates tumor initiation, chemoresistance, and metastasis. At a closer look, CSCs show functional heterogeneity and hierarchical organization. The present review is an attempt to assign marker profiles to define the functional heterogeneity and hierarchical organization of CSCs, based on a series of single-cell analyses. The evidences show that analogous to stem cell hierarchy, self-renewing Quiescent CSCs give rise to the Progenitor CSCs with limited proliferative capacity, and later to a Progenitor-like CSCs, which differentiates to Proliferating non-CSCs. Functionally, the CSCs can be tumor-initiating cells (TICs), drug-resistant CSCs, or metastasis initiating cells (MICs). Although there are certain marker profiles used to identify CSCs of different cancers, molecules like CD44, CD133, ALDH1A1, ABCG2, and pluripotency markers [Octamer binding transcriptional factor 4 (OCT4), SOX2, and NANOG] are used to mark CSCs of a wide range of cancers, ranging from hematological malignancies to solid tumors. Our analysis of the recent reports showed that a combination of these markers can demarcate the heterogeneous CSCs in solid tumors. Reporter constructs are widely used for easy identification and quantification of marker molecules. In this review, we discuss the suitability of reporters for the widely used CSC markers that can define the heterogeneous CSCs. Since the CSC-specific functions of CD44 and CD133 are regulated at the post-translational level, we do not recommend the reporters for these molecules for the detection of CSCs. A promoter-based reporter for ABCG2 may also be not relevant in CSCs, as the expression of the molecule in cancer is mainly regulated by promoter demethylation. In this context, a dual reporter consisting of one of the pluripotency markers and ALDH1A1 will be useful in marking the heterogeneous CSCs. This system can be easily adapted to high-throughput platforms to screen drugs for eliminating CSCs.
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Affiliation(s)
- Amrutha Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.,Manipal Academy of Higher Education, Manipal, India
| | - Reshma Raj Rajan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Gayathri Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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19
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Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded. Cancers (Basel) 2020; 12:cancers12103067. [PMID: 33096662 PMCID: PMC7589733 DOI: 10.3390/cancers12103067] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) has remained an enigmatic component of the tumor microenvironment. It drives metastasis via its interaction with the integrin signaling pathway, contributes to tumor progression and confers therapy resistance by providing a physical barrier around the tumor. The complexity of the ECM lies in its heterogeneous composition and complex glycosylation that can provide a support matrix as well as trigger oncogenic signaling pathways by interacting with the tumor cells. In this review, we attempt to dissect the role of the ECM in enriching for the treatment refractory cancer stem cell population and how it may be involved in regulating their metabolic needs. Additionally, we discuss how the ECM is instrumental in remodeling the tumor immune microenvironment and the potential ways to target this component in order to develop a viable therapy.
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20
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Su CY, Li JQ, Zhang LL, Wang H, Wang FH, Tao YW, Wang YQ, Guo QR, Li JJ, Liu Y, Yan YY, Zhang JY. The Biological Functions and Clinical Applications of Integrins in Cancers. Front Pharmacol 2020; 11:579068. [PMID: 33041823 PMCID: PMC7522798 DOI: 10.3389/fphar.2020.579068] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/24/2020] [Indexed: 12/12/2022] Open
Abstract
Integrins are the adhesion molecules and receptors of extracellular matrix (ECM). They mediate the interactions between cells-cells and cells-ECM. The crosstalk between cancer cells and their microenvironment triggers a variety of critical signaling cues and promotes the malignant phenotype of cancer. As a type of transmembrane protein, integrin-mediated cell adhesion is essential in regulating various biological functions of cancer cells. Recent evidence has shown that integrins present on tumor cells or tumor-associated stromal cells are involved in ECM remodeling, and as mechanotransducers sensing changes in the biophysical properties of the ECM, which contribute to cancer metastasis, stemness and drug resistance. In this review, we outline the mechanism of integrin-mediated effects on biological changes of cancers and highlight the current status of clinical treatments by targeting integrins.
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Affiliation(s)
- Chao-yue Su
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jing-quan Li
- The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Ling-ling Zhang
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Hui Wang
- Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Feng-hua Wang
- Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yi-wen Tao
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yu-qing Wang
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Qiao-ru Guo
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jia-jun Li
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yun Liu
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yan-yan Yan
- Institute of Immunology and School of Medicine, Shanxi Datong University, Datong, China
| | - Jian-ye Zhang
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
- The First Affiliated Hospital, Hainan Medical University, Haikou, China
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21
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Chen B, Ye P, Chen Y, Liu T, Cha JH, Yan X, Yang WH. Involvement of the Estrogen and Progesterone Axis in Cancer Stemness: Elucidating Molecular Mechanisms and Clinical Significance. Front Oncol 2020; 10:1657. [PMID: 33014829 PMCID: PMC7498570 DOI: 10.3389/fonc.2020.01657] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 07/28/2020] [Indexed: 12/21/2022] Open
Abstract
Estrogen and progesterone regulate the growth and development of human tissues, including the reproductive system and breasts, through estrogen and progesterone receptors, respectively. These receptors are also important indicators for the clinical prognosis of breast cancer and various reproductive cancers. Many studies have reported that cancer stem cells (CSCs) play a key role in tumor initiation, progression, metastasis, and recurrence. Although the role of estrogen and progesterone in human organs and various cancers has been studied, the molecular mechanisms underlying the action of these hormones on CSCs remain unclear. Therefore, further elucidation of the effects of estrogen and progesterone on CSCs should provide a new direction for developing pertinent therapies. In this review, we summarize the current knowledge on the estrogen and progesterone axis involved in cancer stemness and discuss potential therapeutic strategies to inhibit CSCs by targeting relevant pathways.
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Affiliation(s)
- Bi Chen
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Peng Ye
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Yeh Chen
- Institute of New Drug Development, China Medical University, Taichung, Taiwan
| | - Tong Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.,The Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, China
| | - Jong-Ho Cha
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, South Korea
| | - Xiuwen Yan
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Wen-Hao Yang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
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22
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Pádua D, Figueira P, Ribeiro I, Almeida R, Mesquita P. The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication. Front Cell Dev Biol 2020; 8:442. [PMID: 32626705 PMCID: PMC7314965 DOI: 10.3389/fcell.2020.00442] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric and colorectal cancers have a high incidence and mortality worldwide. The presence of cancer stem cells (CSCs) within the tumor mass has been indicated as the main reason for tumor relapse, metastasis and therapy resistance, leading to poor overall survival. Thus, the elimination of CSCs became a crucial goal for cancer treatment. The identification of these cells has been performed by using cell-surface markers, a reliable approach, however it lacks specificity and usually differs among tumor type and in some cases even within the same type. In theory, the ideal CSC markers are those that are required to maintain their stemness features. The knowledge that CSCs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar transcription factors (TFs) including SOX2, OCT4, NANOG, KLF4 and c-Myc, and signaling pathways such as the Wnt/β-catenin, Hedgehog (Hh), Notch and PI3K/AKT/mTOR directed the attention to the use of these similarities to identify and target CSCs in different tumor types. Several studies have demonstrated that the abnormal expression of some TFs and the dysregulation of signaling pathways are associated with tumorigenesis and CSC phenotype. The disclosure of common and appropriate biomarkers for CSCs will provide an incredible tool for cancer prognosis and treatment. Therefore, this review aims to gather the new insights in gastric and colorectal CSC identification specially by using TFs as biomarkers and divulge promising drugs that have been found and tested for targeting these cells.
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Affiliation(s)
- Diana Pádua
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Paula Figueira
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Inês Ribeiro
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Raquel Almeida
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Patrícia Mesquita
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
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23
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El-Gowily AH, Abosheasha MA. Differential mechanisms of autophagy in cancer stem cells: Emphasizing gastrointestinal cancers. Cell Biochem Funct 2020; 39:162-173. [PMID: 32468609 DOI: 10.1002/cbf.3552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/17/2020] [Accepted: 05/03/2020] [Indexed: 12/15/2022]
Abstract
Gastrointestinal (GI) cancers are one of the most common forms of malignancies and still are the most important cause of cancer-related mortality worldwide. Autophagy is a conserved catabolic pathway involving lysosomal degradation and recycling of whole cellular components, which is essential for cellular homeostasis. For instance, it acts as a pivotal intracellular quality control and repair mechanism but also implicated in cell reformation during cell differentiation and development. Indeed, GI cancer stem cells (CSCs) are thought to be responsible for tumour initiation, traditional therapies resistance, metastasis and tumour recurrence. Molecular mechanisms of autophagy in normal vs CSCs gain great interest worldwide. Here, we shed light on the role of autophagy in normal stem cells differentiation for embryonic progression and its role in maintaining the activity and self-renewal capacity of CSCs which offer novel viewpoints on promising cancer therapeutic strategies based on the differential roles of autophagy in CSCs.
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Affiliation(s)
- Afnan H El-Gowily
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt.,Organ and Cell physiology Department, Juntendo University, Tokyo, Japan
| | - Mohammed A Abosheasha
- Cellular Genetics Laboratory, Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan
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24
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Chivu-Economescu M, Necula LG, Matei L, Dragu DL, Neagu AI, Alexiu I, Bleotu C, Diaconu CC. Gastrointestinal cancer stem cells as targets for innovative immunotherapy. World J Gastroenterol 2020; 26:1580-1593. [PMID: 32327907 PMCID: PMC7167409 DOI: 10.3748/wjg.v26.i14.1580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/22/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023] Open
Abstract
The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.
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MESH Headings
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Cancer Vaccines/administration & dosage
- Combined Modality Therapy/methods
- Dendritic Cells/immunology
- Drug Resistance, Neoplasm/immunology
- Gastrointestinal Neoplasms/immunology
- Gastrointestinal Neoplasms/pathology
- Gastrointestinal Neoplasms/therapy
- Humans
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Immunity, Innate/drug effects
- Immunity, Innate/immunology
- Immunotherapy/methods
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/prevention & control
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- Tumor Escape/drug effects
- Tumor Escape/immunology
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Nicolae Cajal Institute, Titu Maiorescu University, Bucharest 040441, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Laura Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Irina Alexiu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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25
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Bigoni-Ordóñez GD, Czarnowski D, Parsons T, Madlambayan GJ, Villa-Diaz LG. Integrin α6 (CD49f), The Microenvironment and Cancer Stem Cells. Curr Stem Cell Res Ther 2019; 14:428-436. [PMID: 30280675 DOI: 10.2174/1574888x13666181002151330] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 08/20/2018] [Accepted: 09/02/2018] [Indexed: 12/16/2022]
Abstract
Cancer is a highly prevalent and potentially terminal disease that affects millions of individuals worldwide. Here, we review the literature exploring the intricacies of stem cells bearing tumorigenic characteristics and collect evidence demonstrating the importance of integrin α6 (ITGA6, also known as CD49f) in cancer stem cell (CSC) activity. ITGA6 is commonly used to identify CSC populations in various tissues and plays an important role sustaining the self-renewal of CSCs by interconnecting them with the tumorigenic microenvironment.
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Affiliation(s)
- Gabriele D Bigoni-Ordóñez
- Division de Investigacion Basica, Instituto Nacional de Cancerologia, Secretaria de Salud, Mexico City, Mexico.,Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, UNAM, Mexico City, Mexico
| | - Daniel Czarnowski
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Tyler Parsons
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Gerard J Madlambayan
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Luis G Villa-Diaz
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
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26
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Shinji S, Sasaki N, Yamada T, Koizumi M, Ohta R, Matsuda A, Yokoyama Y, Takahashi G, Hotta M, Hara K, Takeda K, Ueda K, Kuriyama S, Ishiwata T, Ueda Y, Murakami T, Kanazawa Y, Yoshida H. Establishment and characterization of a novel neuroendocrine carcinoma cell line derived from a human ascending colon tumor. Cancer Sci 2019; 110:3708-3717. [PMID: 31648389 PMCID: PMC6890439 DOI: 10.1111/cas.14221] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 10/19/2019] [Accepted: 10/21/2019] [Indexed: 01/15/2023] Open
Abstract
The incidence of rare neuroendocrine tumors (NET) is rapidly increasing. Neuroendocrine carcinoma (NEC) is a NET with poorly differentiated histological features, high proliferative properties and associated poor prognoses. As these carcinomas are so rare and, thus, affect only a small number of patients allowing for few cell lines to be derived from patient biopsies, the histological, immunohistochemical, and clinical characteristics associated with colorectal NEC and NEC in other organs have yet to be clearly defined. Herein, we describe the establishment of a novel NEC cell line (SS‐2) derived from a tumor resection of the ascending colon from a 59‐year‐old Japanese woman. The histological, electron microscopic and immunohistochemical features of chromogranin A (CgA) as well as confirmation of synaptophysin positivity in this tumor were typical of those commonly observed in surgically resected colorectal NEC. Further, the Ki‐67 labeling index of the resected tumor was >20% and, thus, the tumor was diagnosed as an NEC of the ascending colon. The SS‐2 cell line maintained characteristic features to those of the resected tumor, which were further retained following implantation into subcutaneous tissues of nude mice. Additionally, when SS‐2 cells were seeded into ultra‐low attachment plates, they formed spheres that expressed higher levels of the cancer stem cell (CSC) marker CD133 compared to SS‐2 cells cultured under adherent conditions. SS‐2 cells may, therefore, contribute to the current knowledge on midgut NEC biological function while providing a novel platform for examining the effects of colorectal NEC drugs, including CSC.
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Affiliation(s)
- Seiichi Shinji
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Norihiko Sasaki
- Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Takeshi Yamada
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Michihiro Koizumi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Ryo Ohta
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Akihisa Matsuda
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Yasuyuki Yokoyama
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Goro Takahashi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Masahiro Hotta
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Keisuke Hara
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Kohki Takeda
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Koji Ueda
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Sho Kuriyama
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Toshiyuki Ishiwata
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Yoshibumi Ueda
- Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan
| | - Takashi Murakami
- Department of Microbiology, Saitama Medical University, Saitama, Japan
| | - Yoshikazu Kanazawa
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Yoshida
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
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27
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Are Integrins Still Practicable Targets for Anti-Cancer Therapy? Cancers (Basel) 2019; 11:cancers11070978. [PMID: 31336983 PMCID: PMC6678560 DOI: 10.3390/cancers11070978] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 06/27/2019] [Accepted: 07/09/2019] [Indexed: 01/01/2023] Open
Abstract
Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells. In spite of compelling preclinical results demonstrating that the inhibition of integrin αVβ3/αVβ5 and α5β1 has therapeutic potential, clinical trials with integrin inhibitors targeting those integrins have repeatedly failed to demonstrate therapeutic benefits in cancer patients. Here, we review emerging integrin functions and their proposed contribution to tumor progression, discuss preclinical evidence of therapeutic significance, revisit clinical trial results, and consider alternative approaches for their therapeutic targeting in oncology, including targeting integrins in the other cells of the tumor microenvironment, e.g., cancer-associated fibroblasts and immune/inflammatory cells. We conclude that integrins remain a valid target for cancer therapy; however, agents with better pharmacological properties, alternative models for their preclinical evaluation, and innovative combination strategies for clinical testing (e.g., together with immuno-oncology agents) are needed.
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28
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Xu XF, Gao F, Wang JJ, Long C, Chen X, Tao L, Yang L, Ding L, Ji Y. BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathway. Cancer Cell Int 2019; 19:133. [PMID: 31130822 PMCID: PMC6525346 DOI: 10.1186/s12935-019-0847-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 05/02/2019] [Indexed: 12/19/2022] Open
Abstract
Background Cancer stem cells (CSCs), drug-resistant cancer cell subsets, are known to be responsible for tumor metastasis and relapse. The JAK/STAT pathway, activated by SH2 domain, is known to regulate the tumor growth in gastric cancer (GC). Now, this study was designed to examine whether BMX-ARHGAP affects the GC stem cell properties and the underlying regulatory network via JAK/STAT axis. Methods BMX-ARHGAP expression was characterized in GC tissues and cells by RT-qPCR and western blot assay. When BMX-ARHGAP was overexpressed or silenced via plasmids or siRNA transfection, the stem cell properties were assessed by determining stem cell markers CD133, CD44, SOX2 and Nanog, followed by cell sphere and colony formation assays. Subsequently, cell proliferation and invasion were examined by conducting EdU and Transwell assays. The JAK/STAT3 signaling pathway activation was inhibited using AG490. ARHGAP12, BMX exon 10-11, BXM-SH2, JAK2 and STAT3 expression patterns were all determined to examine the regulatory network. The stem cell property in nude mice was also tested. Results BMX-ARHGAP was determined to be enriched in the GC. Overexpression of BMX-ARHGAP resulted in increased expression of CD133, CD44, SOX2 and Nanog protein, and accelerated proliferation and invasion of CD133+CD44+ cells as well as facilitated self-renewal potential of GC cells. However, the inhibition of the JAK/STAT3 signaling pathway reversed the stimulating effect of BMX-ARHGAP on proliferative and invasion abilities of CD133+CD44+ cells. The overexpression of BMX-ARHGAP was suggested to increase the BMX-SH2 protein expression via ARHGAP 5'UTR, and activate the JAK/STAT3 signaling pathway. Also, BMX-ARHGAP promoted tumor growth in nude mice. Conclusions The aforementioned results demonstrated that the BMX-ARHGAP-dependent SH2 domain-JAK/STAT3 axis mediates the maintenance of GC stem cells, benefiting the development of new potential therapeutic targets for GC.
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Affiliation(s)
- Xiao-Feng Xu
- Clinical Laboratory, Jingjiang People's Hospital, Jingjiang, 214500 People's Republic of China
| | - Feng Gao
- Department of Surgery, Jingjiang People's Hospital, No. 28, Zhongzhou Road, Jingjiang, 214500 Jiangsu People's Republic of China
| | - Jian-Jiang Wang
- Department of Surgery, Jingjiang People's Hospital, No. 28, Zhongzhou Road, Jingjiang, 214500 Jiangsu People's Republic of China
| | - Cong Long
- Clinical Laboratory, Jingjiang People's Hospital, Jingjiang, 214500 People's Republic of China
| | - Xing Chen
- Department of Surgery, Jingjiang People's Hospital, No. 28, Zhongzhou Road, Jingjiang, 214500 Jiangsu People's Republic of China
| | - Lan Tao
- Central Laboratory, Jingjiang People's Hospital, Jingjiang, 214500 People's Republic of China
| | - Liu Yang
- Clinical Laboratory, Jingjiang People's Hospital, Jingjiang, 214500 People's Republic of China
| | - Li Ding
- Clinical Laboratory, Jingjiang People's Hospital, Jingjiang, 214500 People's Republic of China
| | - Yong Ji
- Department of Surgery, Jingjiang People's Hospital, No. 28, Zhongzhou Road, Jingjiang, 214500 Jiangsu People's Republic of China
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Sudhalkar N, Rathod NP, Mathews A, Chopra S, Sriram H, Shrivastava SK, Goda JS. Potential role of cancer stem cells as biomarkers and therapeutic targets in cervical cancer. Cancer Rep (Hoboken) 2019; 2:e1144. [PMID: 32721115 PMCID: PMC7941515 DOI: 10.1002/cnr2.1144] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Eradicating cancer stem cells (CSCs) that are termed as the "beating heart" of various malignant tumors, including cervical cancer, holds great importance in cancer therapeutics. CSCs not only confer chemo-radio resistance but also play an important role in tumor metastasis and thereby pose a potential barrier for the cure of cervical cancer. Cervical cancer, a common malignancy among females, is associated with high morbidity and mortality rates, and the study on CSCs residing in the niche is promising. RECENT FINDINGS Biomarker approach to screen the cervical CSCs has gained impetus since the past decade. Progress in identification and characterization of the stem cell biomarkers has led to many insights. For the diagnostic purpose, several biomarkers like viral (HPV16), stem cell markers, transcription factors (viz, SOX2, OCT 4, and c-Myc), and CSC surface markers (viz, ALDH1 and CD44) have been identified. The research so far has been directed to study the CSC stemness and demonstrates various gene expression signatures in cervical CSCs. Such studies hold a potential to improve diagnostic accuracy and predict therapeutic response and clinical outcome in patients. CONCLUSIONS Stem cell biomarkers have been validated and their therapeutic targets are being developed as "strategies to improve therapeutic ratio in personalized medicine." This review gives a brief overview of the cervical CSC biomarkers, their current and future diagnostic, prognostic, and therapeutic potential.
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Affiliation(s)
- Niyati Sudhalkar
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Nidul P. Rathod
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Ashwathi Mathews
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Supriya Chopra
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Harshini Sriram
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Shyam K. Shrivastava
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Jayant S. Goda
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
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Toledo-Guzmán ME, Bigoni-Ordóñez GD, Ibáñez Hernández M, Ortiz-Sánchez E. Cancer stem cell impact on clinical oncology. World J Stem Cells 2018; 10:183-195. [PMID: 30613312 PMCID: PMC6306557 DOI: 10.4252/wjsc.v10.i12.183] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/15/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer is a widespread worldwide chronic disease. In most cases, the high mortality rate from cancer correlates with a lack of clear symptoms, which results in late diagnosis for patients, and consequently, advanced tumor disease with poor probabilities for cure, since many patients will show chemo- and radio-resistance. Several mechanisms have been studied to explain chemo- and radio-resistance to anti-tumor therapies, including cell signaling pathways, anti-apoptotic mechanisms, stemness, metabolism, and cellular phenotypes. Interestingly, the presence of cancer stem cells (CSCs), which are a subset of cells within the tumors, has been related to therapy resistance. In this review, we focus on evaluating the presence of CSCs in different tumors such as breast cancer, gastric cancer, lung cancer, and hematological neoplasias, highlighting studies where CSCs were identified in patient samples. It is evident that there has been a great drive to identify the cell surface phenotypes of CSCs so that they can be used as a tool for anti-tumor therapy treatment design. We also review the potential effect of nanoparticles, drugs, natural compounds, aldehyde dehydrogenase inhibitors, cell signaling inhibitors, and antibodies to treat CSCs from specific tumors. Taken together, we present an overview of the role of CSCs in tumorigenesis and how research is advancing to target these highly tumorigenic cells to improve oncology patient outcomes.
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Affiliation(s)
- Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | | | - Miguel Ibáñez Hernández
- Departamento de Bioquímica, Laboratorio de Terapia Génica, Escuela Nacional de Ciencias Biológicas, Posgrado de Biomedicina y Biotecnología Molecular, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
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Fafińska J, Czech A, Sitz T, Ignatova Z, Hahn U. DNA Aptamers for the Malignant Transformation Marker CD24. Nucleic Acid Ther 2018; 28:326-334. [PMID: 30407110 DOI: 10.1089/nat.2018.0748] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Cluster of differentiation 24 (CD24) is a cell surface glycoprotein, which is largely present on hematopoietic cells and many types of solid tumor cells. CD24 is known to be involved in a wide range of downstream signaling pathways and neural development, yet the underlying mechanisms are poorly understood. Moreover, its production correlates with poor cancer prognosis, and targeting of CD24 with different antibodies has been shown to inhibit disease progression. Nucleic acid aptamers are oligonucleotides that are selected from random DNA or RNA libraries for high affinity and specific binding to a certain target. Thus, they can be used as an alternative to antibodies. To gain an insight on CD24 role and its interaction partners, we performed several SELEX (systematic evolution of ligands by exponential enrichment) experiments to select CD24-specfiic DNA aptamers. We found that the cell-SELEX approach was the most useful and that using HT-29 cell line presenting CD24 along with CD24 knockdown HT-29 cells has selected six aptamers. For the selected aptamers, we determined dissociation constants in the nanomolar range (18-709 nM) using flow cytometry. These aptamers can be applied as diagnostic tools to track cancer progression and bear a potential for therapeutic use for inhibiting signaling pathways that promote the metastatic process.
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Affiliation(s)
- Joanna Fafińska
- Hamburg University, MIN Faculty, Chemistry Department, Institute for Biochemistry & Molecular Biology, Hamburg, Germany
| | - Andreas Czech
- Hamburg University, MIN Faculty, Chemistry Department, Institute for Biochemistry & Molecular Biology, Hamburg, Germany
| | - Tobias Sitz
- Hamburg University, MIN Faculty, Chemistry Department, Institute for Biochemistry & Molecular Biology, Hamburg, Germany
| | - Zoya Ignatova
- Hamburg University, MIN Faculty, Chemistry Department, Institute for Biochemistry & Molecular Biology, Hamburg, Germany
| | - Ulrich Hahn
- Hamburg University, MIN Faculty, Chemistry Department, Institute for Biochemistry & Molecular Biology, Hamburg, Germany
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Bigoni-Ordóñez GD, Ortiz-Sánchez E, Rosendo-Chalma P, Valencia-González HA, Aceves C, García-Carrancá A. Molecular iodine inhibits the expression of stemness markers on cancer stem-like cells of established cell lines derived from cervical cancer. BMC Cancer 2018; 18:928. [PMID: 30257666 PMCID: PMC6158890 DOI: 10.1186/s12885-018-4824-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 09/14/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cancer stem cells (CSC) are characterized by deregulated self-renewal, tumorigenicity, metastatic potential, aberrant stemness signaling pathways, resistance to conventional therapy, and the ability to give rise to a progeny of proliferating cells that constitute the bulk of tumors. Targeting CSC will provide novel treatments for cancer. Different investigations have focused on developing complementary approaches that involve natural compounds that decrease chemo-resistance and reduce the side effects of conventional therapies. Since, it has been reported that molecular iodine (I2) exhibits antineoplastic effects and decreases tumor progression in some cancer models, we evaluated the potential effect of I2 on cell cultures enriched in cervical cancer stem-like cells. METHODS HeLa and SiHa cervical cancer cells were treated with 200uM I2 for 24 h. After time, cells were cultured in CSC-conditioned medium (cervospheres) and viability assays were performed. Following, tumorigenic capabilities in cervospheres treated with I2 were evaluated in NOD/SCID mice. HeLa monolayer cells untreated and their respective cervosphere cells treated or untreated with 200 μM of I2 for 24 h were xenotransplanted subcutaneously at different amounts and mice were monitored for at least 2 months. RESULTS In the present study, monolayer and CSC-enriched cultures (cervospheres) from cervical cancer-derived cell lines, HeLa and SiHa, showed that 200uM I2 supplementation inhibits proliferation of both and decreased their tumorigenic capacity, in vivo. This antineoplastic effect of I2 was accompanied by diminished expression of stemness markers including CD49f, CK17, OCT-4, NANOG, SOX2, and KLF4, as well as increased expression and activation of PPARγ receptors. CONCLUSIONS All this data led us to suggest a clinical potential use of I2 for targeting CSC and improve current treatments against cervical cancer.
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Affiliation(s)
- Gabriele Davide Bigoni-Ordóñez
- División de Investigación Básica, Laboratory of Virus and Cancer, Instituto Nacional de Cancerología, Secretaria de Salud, Av. San Fernando No. 22, Sección XVI, Tlalpan, 14080 Ciudad de México, CP Mexico
- Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, UNAM, Mexico City, Mexico
| | - Elizabeth Ortiz-Sánchez
- División de Investigación Básica, Laboratory of Virus and Cancer, Instituto Nacional de Cancerología, Secretaria de Salud, Av. San Fernando No. 22, Sección XVI, Tlalpan, 14080 Ciudad de México, CP Mexico
| | - Pedro Rosendo-Chalma
- División de Investigación Básica, Laboratory of Virus and Cancer, Instituto Nacional de Cancerología, Secretaria de Salud, Av. San Fernando No. 22, Sección XVI, Tlalpan, 14080 Ciudad de México, CP Mexico
- Programa de Doctorado en Ciencias Biomédicas, UNAM, Mexico City, Mexico
| | - Heriberto A Valencia-González
- División de Investigación Básica, Laboratory of Virus and Cancer, Instituto Nacional de Cancerología, Secretaria de Salud, Av. San Fernando No. 22, Sección XVI, Tlalpan, 14080 Ciudad de México, CP Mexico
- Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, UNAM, Mexico City, Mexico
| | - Carmen Aceves
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla 3001, Juriquilla. Campus-Juriquilla., Querétaro, 76230 Qro Mexico
| | - Alejandro García-Carrancá
- División de Investigación Básica, Laboratory of Virus and Cancer, Instituto Nacional de Cancerología, Secretaria de Salud, Av. San Fernando No. 22, Sección XVI, Tlalpan, 14080 Ciudad de México, CP Mexico
- Instituto de Investigaciones Biomédicas, Universidad Naciona Autónoma de México, Mexico City, Mexico
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Transcriptomic but not genomic variability confers phenotype of breast cancer stem cells. Cancer Commun (Lond) 2018; 38:56. [PMID: 30231942 PMCID: PMC6146522 DOI: 10.1186/s40880-018-0326-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 09/08/2018] [Indexed: 12/19/2022] Open
Abstract
Background Breast cancer stem cells (BCSCs) are considered responsible for cancer relapse and drug resistance. Understanding the identity of BCSCs may open new avenues in breast cancer therapy. Although several discoveries have been made on BCSC characterization, the factors critical to the origination of BCSCs are largely unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs. Methods We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency, and then performed target deep DNA sequencing at bulk-cell and single-cell levels. To identify the transcriptional program associated with BCSCs, bulk-cell and single-cell RNA sequencing was performed. Results By using whole-genome sequencing of bulk cells, potential BCSC phenotype-associated mutation hotspot regions were detected. Validation by target deep DNA sequencing, at both bulk-cell and single-cell levels, revealed no genetic changes specifically associated with BCSC phenotype. Moreover, single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features. Notably, this transcriptomic variability was enriched during the transcription of 74 genes, revealed as BCSC markers. Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse, thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers. Conclusions Transcriptomic variability, not genetic mutations, distinguishes BCSCs from non-BCSCs. The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy. Electronic supplementary material The online version of this article (10.1186/s40880-018-0326-8) contains supplementary material, which is available to authorized users.
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Huang R, Rofstad EK. Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget 2018; 8:35351-35367. [PMID: 27343550 PMCID: PMC5471060 DOI: 10.18632/oncotarget.10169] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 06/12/2016] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence has shown that cancer stem cells (CSCs) have a tumour-initiating capacity and play crucial roles in tumour metastasis, relapse and chemo/radio-resistance. As tumour propagation initiators, CSCs are considered to be promising targets for obtaining a better therapeutic outcome. Cervical carcinoma is the most common gynaecological malignancy and has a high cancer mortality rate among females. As a result, the investigation of cervical cancer stem cells (CCSCs) is of great value. However, the numbers of cancer cells and corresponding CSCs in malignancy are dynamically balanced, and CSCs may reside in the CSC niche, about which little is known to date. Therefore, due to their complicated molecular phenotypes and biological behaviours, it remains challenging to obtain “purified” CSCs and continuously culture CSCs for further in vitro studies without the cells losing their stem properties. At present, CSC-related markers and functional assays are used to purify, identify and therapeutically target CSCs both in vitro and in vivo. Nevertheless, CSC-related markers are not universal to all tumour types, although some markers may be valid in multiple tumour types. Additionally, functional identifications based on CSC-specific properties are usually limited in in vivo studies. Furthermore, an optimal method for identifying potential CCSCs in CCSC studies has not been previously published, and these techniques are currently of great importance. This article updates our knowledge on CSCs and CCSCs, reviews potential stem cell markers and functional assays for identifying CCSCs, and describes the potential of targeting CCSCs in the treatment of cervical carcinoma.
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Affiliation(s)
- Ruixia Huang
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Einar K Rofstad
- Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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Resistance to Taxanes in Triple-Negative Breast Cancer Associates with the Dynamics of a CD49f+ Tumor-Initiating Population. Stem Cell Reports 2017; 8:1392-1407. [PMID: 28457887 PMCID: PMC5425727 DOI: 10.1016/j.stemcr.2017.03.026] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 03/31/2017] [Accepted: 03/31/2017] [Indexed: 12/04/2022] Open
Abstract
Taxanes are a mainstay of treatment for breast cancer, but resistance often develops followed by metastatic disease and mortality. Aiming to reveal the mechanisms underlying taxane resistance, we used breast cancer patient-derived orthoxenografts (PDX). Mimicking clinical behavior, triple-negative breast tumors (TNBCs) from PDX models were more sensitive to docetaxel than luminal tumors, but they progressively acquired resistance upon continuous drug administration. Mechanistically, we found that a CD49f+ chemoresistant population with tumor-initiating ability is present in sensitive tumors and expands during the acquisition of drug resistance. In the absence of the drug, the resistant CD49f+ population shrinks and taxane sensitivity is restored. We describe a transcriptional signature of resistance, predictive of recurrent disease after chemotherapy in TNBC. Together, these findings identify a CD49f+ population enriched in tumor-initiating ability and chemoresistance properties and evidence a drug holiday effect on the acquired resistance to docetaxel in triple-negative breast cancer.
PDX models mimic the clinical response to docetaxel in breast cancer patients Sensitivity to docetaxel can be regained in metastatic resistant TNBC A tumor-initiating CD49f chemoresistant population is present in TNBC Docetaxel resistance associates with the expansion of a CD49f+ population in TNBC
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Leight JL, Drain AP, Weaver VM. Extracellular Matrix Remodeling and Stiffening Modulate Tumor Phenotype and Treatment Response. ANNUAL REVIEW OF CANCER BIOLOGY-SERIES 2017. [DOI: 10.1146/annurev-cancerbio-050216-034431] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Jennifer L. Leight
- Department of Biomedical Engineering and The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210
| | - Allison P. Drain
- University of California, Berkeley–University of California, San Francisco Graduate Program in Bioengineering, Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, California 94143
| | - Valerie M. Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, Department of Anatomy, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California 94143
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Qureshi-Baig K, Ullmann P, Haan S, Letellier E. Tumor-Initiating Cells: a criTICal review of isolation approaches and new challenges in targeting strategies. Mol Cancer 2017; 16:40. [PMID: 28209178 PMCID: PMC5314476 DOI: 10.1186/s12943-017-0602-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 01/20/2017] [Indexed: 02/07/2023] Open
Abstract
Most cancers contain a subpopulation of highly tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Targeting TICs may be essential to achieve cure, because of their self-renewal and tumorigenic properties as well as their resistance to conventional therapies. Despite significant advances in TIC biology, their isolation and identification remain largely disputed and incompletely established. In this review, we discuss the latest developments in isolation and culturing approaches of TICs, with focus on colorectal cancer (CRC). We feature recent findings on TIC-relevant signaling pathways and the metabolic identity of TICs, as well as their current clinical implications. Lastly, we highlight the influence of inter- and intra-tumoral heterogeneity on TIC function and targeting approaches.
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Affiliation(s)
- Komal Qureshi-Baig
- Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, 6, Avenue du Swing, L-4367, Campus Belval, Belvaux, Luxembourg
| | - Pit Ullmann
- Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, 6, Avenue du Swing, L-4367, Campus Belval, Belvaux, Luxembourg
| | - Serge Haan
- Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, 6, Avenue du Swing, L-4367, Campus Belval, Belvaux, Luxembourg
| | - Elisabeth Letellier
- Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, 6, Avenue du Swing, L-4367, Campus Belval, Belvaux, Luxembourg.
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Pan T, Xu J, Zhu Y. Self-renewal molecular mechanisms of colorectal cancer stem cells. Int J Mol Med 2016; 39:9-20. [PMID: 27909729 PMCID: PMC5179189 DOI: 10.3892/ijmm.2016.2815] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 11/22/2016] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer stem cells (CCSCs) represent a small fraction of the colorectal cancer cell population that possess self-renewal and multi-lineage differentiation potential and drive tumorigenicity. Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood, the aberrant activation of signaling pathways, such as Wnt, Notch, transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) and Hedgehog-Gli (HH-GLI), specific roles mediated by cell surface markers and micro-environmental factors are involved in the regulation of self-renewal. The elucidation of the molecular mechanisms behind self-renewal may lead to the development of novel targeted interventions for the treatment of colorectal cancer.
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Affiliation(s)
- Tianhui Pan
- Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jinghong Xu
- Department of Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yongliang Zhu
- Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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Löffek S, Franzke CW, Helfrich I. Tension in Cancer. Int J Mol Sci 2016; 17:ijms17111910. [PMID: 27854331 PMCID: PMC5133907 DOI: 10.3390/ijms17111910] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 11/02/2016] [Accepted: 11/09/2016] [Indexed: 12/30/2022] Open
Abstract
Integrins represent a large family of cell receptors that mediate adhesion to the extracellular matrix (ECM), thereby modulating a variety of cellular functions that are required for proliferation, migration, malignant conversion and invasiveness. During tumorigenesis the conversion of a tumor cell from sessile, stationary phenotype to an invasive phenotype requires the ability of tumor cells to interact with their environment in order to transduce signals from the ECM into the cells. Hence, there is increasing evidence that changes in the composition, topography and tension of tumor matrix can be sensed by integrin receptors, leading to the regulation of intracellular signalling events which subsequently help to fuel cancer progression. The fact that intracellular signals perceived from integrin ligand binding impact on almost all steps of tumor progression, including tumor cell proliferation, survival, metastatic dissemination and colonization of a metastatic niche, renders integrins as ideal candidates for the development of therapeutic agents. In this review we summarize the role of integrins in cancer with the special focus on cancer therapies and the recent progress that has been made in the understanding of “integrin-induced tension in cancer”. Finally, we conclude with clinical evidence for the role of integrin-mediated mechanotransduction in the development of therapy-resistant tumors.
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Affiliation(s)
- Stefanie Löffek
- Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, 45147 Essen, Germany.
- German Cancer Consortium (DKTK), University Duisburg-Essen, 45147 Essen, Germany.
| | - Claus-Werner Franzke
- Department of Dermatology and Venerology, Medical Center, University of Freiburg, Hauptstraße 7, 79104 Freiburg, Germany.
| | - Iris Helfrich
- Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, 45147 Essen, Germany.
- German Cancer Consortium (DKTK), University Duisburg-Essen, 45147 Essen, Germany.
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Zhang DH, Yang ZL, Zhou EX, Miao XY, Zou Q, Li JH, Liang LF, Zeng GX, Chen SL. Overexpression of Thy1 and ITGA6 is associated with invasion, metastasis and poor prognosis in human gallbladder carcinoma. Oncol Lett 2016; 12:5136-5144. [PMID: 28105220 PMCID: PMC5228576 DOI: 10.3892/ol.2016.5341] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 10/14/2016] [Indexed: 02/07/2023] Open
Abstract
Gallbladder cancer (GBC) is a rare but highly aggressive cancer for which no well-accepted prognostic biomarkers have been identified. Thymus cell antigen 1 (Thy1), also known as cluster of differentiation (CD)90, and integrin α6 (ITGA6), also known as CD49f, are important molecules in cancer and putative markers of various stem cell types. However, their role in GBC remains to be elucidated. In the present study, Thy1 and ITGA6 expression status in clinical GBC samples, which comprised squamous cell/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC) subtypes, was investigated. The associations between Thy1 and ITGA6 expression and clinical parameters and survival rate were analyzed separately. The THY1 and ITGA6 messenger RNA levels were significantly higher in both SC/ASC and AC tissues than in adjacent non-tumor tissues (all P<0.001). These results were subsequently confirmed by immunohistochemical analyses. Overexpression of Thy1 and ITGA6 was correlated with poor differentiation, large tumor size, lymph node metastasis and great invasiveness in SC/ASC (Thy1, P=0.045, P=0.005, P=0.003 and P=0.009, respectively, and ITGA6, P=0.029, P=0.011, P=0.009 and P=0.004, respectively) and AC (Thy1, P=0.027, P<0.001, P=0.003 and P 0.004, respectively, and ITGA6, P=0.002, P=0.003, P=0.006 and P=0.006, respectively). Both Thy1 and ITGA6 were expressed at higher levels in AC with advanced tumor-node-metastasis stage (TNM) than in AC with low TNM stage (P=0.001 and P=0.018, respectively). In addition, patients with elevated Thy1 or ITGA6 expression had shorter overall survival than those with negative Thy1 or ITGA6 expression. Multivariate Cox regression analysis demonstrated that Thy1 (SC/ASC, P=0.001 and AC, P=0.005) and ITGA6 (both P=0.003) were independent predictors of poor prognosis in both SC/ASC and AC patients. In conclusion, Thy1 and ITGA6 could be clinical prognostic markers for GBC.
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Affiliation(s)
- Dan-Hua Zhang
- Research Laboratory of Hepatobiliary Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Zhu-Lin Yang
- Research Laboratory of Hepatobiliary Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - En-Xiang Zhou
- Research Laboratory of Hepatobiliary Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Xiong-Ying Miao
- Research Laboratory of Hepatobiliary Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Qiong Zou
- Department of Pathology, Changde Central Hospital, Changde, Hunan 415000, P.R. China
| | - Jing-He Li
- Department of Pathology, Basic Medical Science College, Central South University, Changsha, Hunan 410011, P.R. China
| | - Lu-Feng Liang
- Department of Hepatobiliary and Pancreatic Surgery, Hunan Provincial People's Hospital, Changsha, Hunan 410007, P.R. China
| | - Gui-Xiang Zeng
- Department of Pathology, Loudi Central Hospital, Loudi, Hunan 417011, P.R. China
| | - Sen-Lin Chen
- Department of Pathology, Hunan Provincial Tumor Hospital, Changsha, Hunan 410013, P.R. China
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Samardzija C, Luwor RB, Quinn MA, Kannourakis G, Findlay JK, Ahmed N. Coalition of Oct4A and β1 integrins in facilitating metastasis in ovarian cancer. BMC Cancer 2016; 16:432. [PMID: 27390927 PMCID: PMC4939035 DOI: 10.1186/s12885-016-2458-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 06/24/2016] [Indexed: 12/16/2022] Open
Abstract
Background Ovarian cancer is a metastatic disease and one of the leading causes of gynaecology malignancy-related deaths in women. Cancer stem cells (CSCs) are key contributors of cancer metastasis and relapse. Integrins are a family of cell surface receptors which allow interactions between cells and their surrounding microenvironment and play a fundamental role in promoting metastasis. This study investigates the molecular mechanism which associates CSCs and integrins in ovarian cancer metastasis. Methods The expression of Oct4A in high-grade serous ovarian tumors and normal ovaries was determined by immunofluorescence analysis. The functional role of Oct4A was evaluated by generating stable knockdown (KD) of Oct4A clones in an established ovarian cancer cell line HEY using shRNA-mediated silencing. The expression of integrins in cell lines was evaluated by flow cytometry. Spheroid forming ability, adhesion and the activities of matrix metalloproteinases 9/2 (MMP-9/2) was measured by in vitro functional assays and gelatin zymography. These observations were further validated in in vivo mouse models using Balb/c nu/nu mice. Results We report significantly elevated expression of Oct4A in high-grade serous ovarian tumors compared to normal ovarian tissues. The expression of Oct4A in ovarian cancer cell lines correlated with their CSC-related sphere forming abilities. The suppression of Oct4A in HEY cells resulted in a significant diminution of integrin β1 expression and associated α5 and α2 subunits compared to vector control cells. This was associated with a reduced adhesive ability on collagen and fibronectin and decreased secretion of pro-MMP2 in Oct4A KD cells compared to vector control cells. In vivo, Oct4A knock down (KD) cells produced tumors which were significantly smaller in size and weight compared to tumors derived from vector control cells. Immunohistochemical analyses of Oct4A KD tumor xenografts demonstrated a significant loss of cytokeratin 7 (CK7), Glut-1 as well as CD34 and CD31 compared to vector control cell-derived xenografts. Conclusion The expression of Oct4A may be crucial to promote and sustain integrin-mediated extracellular matrix (ECM) remodeling requisite for tumor metastasis in ovarian cancer patients.
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Affiliation(s)
- Chantel Samardzija
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia
| | - Rodney B Luwor
- Department of Surgery, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia
| | - Michael A Quinn
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia
| | - George Kannourakis
- Fiona Elsey Cancer Research Institute, Suites 23-26, 106-110 Lydiard Street South, Ballarat Technology Central Park, Ballarat, 3353, Australia.,Federation University Australia, Ballarat, VIC, 3010, Australia
| | - Jock K Findlay
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia.,The Hudson Institute of Medical Research, Clayton, Melbourne, VIC, 3168, Australia
| | - Nuzhat Ahmed
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Melbourne, VIC, 3052, Australia. .,Fiona Elsey Cancer Research Institute, Suites 23-26, 106-110 Lydiard Street South, Ballarat Technology Central Park, Ballarat, 3353, Australia. .,Federation University Australia, Ballarat, VIC, 3010, Australia. .,The Hudson Institute of Medical Research, Clayton, Melbourne, VIC, 3168, Australia.
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He L, Yang Z, Li Z. The clinical pathological significance of Thy1 and CD49f expression in chondrosarcomas. Pathol Res Pract 2016; 212:636-42. [PMID: 27155928 DOI: 10.1016/j.prp.2016.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Revised: 03/17/2016] [Accepted: 04/20/2016] [Indexed: 11/30/2022]
Abstract
OBJECTIVE This study investigated the protein expression and clinicopathological significance of Thy1 and CD49f in chondrosarcomas. METHODS Thy1 and CD49f protein expression in 59 chondrosarcomas and 33 osteochondromas were measured by immunohistochemical staining. RESULTS The percentage of positive Thy1 and CD49f expression was significantly higher in patients with chondrosarcoma than in patients with osteochondroma (P<0.01). The percentage of positive Thy1 and CD49f expression was significantly lower in patients with histological grade I, Enneking stage I, AJCC stage I/II stage, non-metastatic and non-invasive chondrosarcoma than in patients with histological grade III, Enneking stage II+III, AJCC stage III/IV, metastatic and invasive chondrosarcoma (P<0.05 or P<0.01). Thy1 expression was positively correlated with CD49f expression in chondrosarcoma. Kaplan-Meier survival analysis showed that histological grade, AJCC stage, Enneking stage, metastasis, invasion, and Thy1 and CD49f expression significantly correlated with shorter mean survival time in chondrosarcoma patients (P<0.05 or P<0.01). Cox multivariate analysis showed that positive Thy1 and CD49f expression was an independent prognostic factor that negatively correlated with overall postoperative survival. CONCLUSION Positive Thy1 and CD49f expression is significantly associated with the progression and poor prognosis of chondrosarcoma.
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Affiliation(s)
- Lile He
- Department of Orthopedics, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Zhulin Yang
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Zhihong Li
- Department of Orthopedics, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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Use of Cancer Stem Cells to Investigate the Pathogenesis of Colitis-associated Cancer. Inflamm Bowel Dis 2016; 22:976-83. [PMID: 26963566 PMCID: PMC4794128 DOI: 10.1097/mib.0000000000000756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Colitis-associated cancer (CAC) can develop in patients with inflammatory bowel disease with long-term uncontrolled inflammation. The mutational history and tumor microenvironment observed in CAC patients is distinct from that observed in sporadic colon cancer and suggests a different etiology. Recently, much attention has been focused on understanding the cellular origin of cancer and the cancer stem cells, which is key to growth and progression. Cancer stem cells are often chemo-resistant making them attractive targets for improving patient outcomes. New techniques have rapidly been evolving allowing for a better understanding of the normal intestinal stem cell function and behavior in the niche. Use of these new technologies will be crucial to understanding cancer stem cells in both sporadic and CAC. In this review, we will explore emerging methods related to the study of normal and cancer stem cells in the intestine, and examine potential avenues of investigation and application to understanding the pathogenesis of CAC.
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Ye F, Qiu Y, Li L, Yang L, Cheng F, Zhang H, Wei B, Zhang Z, Sun L, Bu H. The Presence of EpCAM(-)/CD49f(+) Cells in Breast Cancer Is Associated with a Poor Clinical Outcome. J Breast Cancer 2015; 18:242-8. [PMID: 26472974 PMCID: PMC4600688 DOI: 10.4048/jbc.2015.18.3.242] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Accepted: 08/04/2015] [Indexed: 02/05/2023] Open
Abstract
Purpose It is well established that breast cancer stem cells (BCSCs) play an essential role in tumor invasion for both local and distant metastasis. The aim of this study was to establish whether BCSCs could act as a prognostic and clinical marker. Methods We analyzed tumor tissues from 161 breast cancer patients. Dual immunohistochemistry and immunofluorescence were performed on all the slides, and we analyzed the relationship between EpCAM-/CD49f+ tumor cells and key clinical and prognostic factors. Results Univariate survival analysis using the Kaplan-Meier method showed that the presence of EpCAM-/CD49f+ tumor cells in breast cancer was significantly associated with shorter disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that the presence of EpCAM-/CD49f+ cells was associated with shorter DFS (p=0.010; hazard ratio [HR], 2.070) and OS (p=0.002; HR, 3.235). Tumors containing EpCAM-/CD49f+ cells were also more likely to metastasize after initial surgery (p=0.048). Conclusion Our study suggests that breast tumors containing EpCAM-/CD49f+ cells are more likely to undergo distant metastasis after initial surgery and are associated with a shorter DFS and OS.
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Affiliation(s)
- Feng Ye
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Qiu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Libo Yang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Fei Cheng
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Hongying Zhang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Bing Wei
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhang Zhang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Linyong Sun
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Bu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China. ; Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
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45
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So JY, Suh N. Targeting cancer stem cells in solid tumors by vitamin D. J Steroid Biochem Mol Biol 2015; 148:79-85. [PMID: 25460302 PMCID: PMC4361233 DOI: 10.1016/j.jsbmb.2014.10.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/18/2014] [Accepted: 10/09/2014] [Indexed: 12/14/2022]
Abstract
Cancer stem cells (CSCs) are a small subset of cells that may be responsible for initiation, progression, and recurrence of tumors. Recent studies have demonstrated that CSCs are highly tumorigenic and resistant to conventional chemotherapies, making them a promising target for the development of preventive/therapeutic agents. A single or combination of various markers, such as CD44, EpCAM, CD49f, CD133, CXCR4, ALDH-1, and CD24, were utilized to isolate CSCs from various types of human cancers. Notch, Hedgehog, Wnt, and TGF-β signalingregulate self-renewal and differentiation of normal stem cells andare aberrantly activated in CSCs. In addition, many studies have demonstrated that these stem cell-associated signaling pathways are required for the maintenance of CSCs in different malignancies, including breast, colorectal, prostate, and pancreatic cancers. Accumulating evidence has shown inhibitory effects of vitamin D and its analogs on the cancer stem cell signaling pathways, suggesting vitamin D as a potential preventive/therapeutic agent against CSCs. In this review, we summarize recent findings about the roles of Notch, Hedgehog, Wnt, and TGF-β signaling in CSCs as well as the effects of vitamin D on these stem cell signaling pathways. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
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Affiliation(s)
- Jae Young So
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Nanjoo Suh
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
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46
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Schulenburg A, Blatt K, Cerny-Reiterer S, Sadovnik I, Herrmann H, Marian B, Grunt TW, Zielinski CC, Valent P. Cancer stem cells in basic science and in translational oncology: can we translate into clinical application? J Hematol Oncol 2015; 8:16. [PMID: 25886184 PMCID: PMC4345016 DOI: 10.1186/s13045-015-0113-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 01/14/2015] [Indexed: 02/08/2023] Open
Abstract
Since their description and identification in leukemias and solid tumors, cancer stem cells (CSC) have been the subject of intensive research in translational oncology. Indeed, recent advances have led to the identification of CSC markers, CSC targets, and the preclinical and clinical evaluation of the CSC-eradicating (curative) potential of various drugs. However, although diverse CSC markers and targets have been identified, several questions remain, such as the origin and evolution of CSC, mechanisms underlying resistance of CSC against various targeted drugs, and the biochemical basis and function of stroma cell-CSC interactions in the so-called ‘stem cell niche.’ Additional aspects that have to be taken into account when considering CSC elimination as primary treatment-goal are the genomic plasticity and extensive subclone formation of CSC. Notably, various cell fractions with different combinations of molecular aberrations and varying proliferative potential may display CSC function in a given neoplasm, and the related molecular complexity of the genome in CSC subsets is considered to contribute essentially to disease evolution and acquired drug resistance. In the current article, we discuss new developments in the field of CSC research and whether these new concepts can be exploited in clinical practice in the future.
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Affiliation(s)
- Axel Schulenburg
- Bone Marrow Transplantation Unit, Department of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, A-1090, Wien, Austria. .,Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Wien, Austria. .,Department of Medicine I, Stem Cell Transplantation Unit, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Wien, Austria.
| | - Katharina Blatt
- Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Wien, Austria.
| | - Sabine Cerny-Reiterer
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Wien, Austria. .,Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Wien, Austria.
| | - Irina Sadovnik
- Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Wien, Austria.
| | - Harald Herrmann
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Wien, Austria. .,Department of Radiation Therapy, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Wien, Austria.
| | - Brigitte Marian
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Wien, Austria. .,Department of Medicine I, Institute for Cancer Research, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Wien, Austria.
| | - Thomas W Grunt
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Wien, Austria. .,Department of Medicine I, Division of Clinical Oncology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Wien, Austria.
| | - Christoph C Zielinski
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Wien, Austria. .,Department of Medicine I, Division of Clinical Oncology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Wien, Austria.
| | - Peter Valent
- Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Spitalgasse 23, Vienna, 1090, Wien, Austria. .,Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Wien, Austria.
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Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol 2015; 25:234-40. [PMID: 25572304 DOI: 10.1016/j.tcb.2014.12.006] [Citation(s) in RCA: 542] [Impact Index Per Article: 54.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 12/03/2014] [Accepted: 12/05/2014] [Indexed: 12/17/2022]
Abstract
Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell-matrix adhesion, integrins present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations, but in some cases, these receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses. Understanding how integrin expression and function is regulated in this context will enable the development of new therapeutic approaches to sensitize tumors to therapy and suppress their metastatic phenotype.
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Affiliation(s)
- Laetitia Seguin
- Department of Pathology and the Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
| | - Jay S Desgrosellier
- Department of Pathology and the Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
| | - Sara M Weis
- Department of Pathology and the Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
| | - David A Cheresh
- Department of Pathology and the Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
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Sinha A, Cherba D, Bartlam H, Lenkiewicz E, Evers L, Barrett MT, Haab BB. Mesenchymal-like pancreatic cancer cells harbor specific genomic alterations more frequently than their epithelial-like counterparts. Mol Oncol 2014; 8:1253-65. [PMID: 24837184 PMCID: PMC4198499 DOI: 10.1016/j.molonc.2014.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 04/24/2014] [Accepted: 04/25/2014] [Indexed: 01/06/2023] Open
Abstract
The aggressiveness of pancreatic cancer is associated with the acquisition of mesenchymal characteristics by a subset of pancreatic cancer cells. The factors driving the development of this subset are not well understood. In this study, we tested the hypothesis that acquisition of a mesenchymal phenotype occurs selectively in tumor cells that harbor specific enabling genetic alterations. We obtained whole-genome comparative genomic hybridization (CGH) measurements on pancreatic cancer cell lines that have either an epithelial-like (17 cell lines) or a mesenchymal-like (9 cell lines) phenotype in vitro. The total amounts of amplifications and deletions were equivalent between the epithelial and mesenchymal groups, but 20 genes showed a major difference between the groups in prevalence of alterations. All 20 alterations (18 deletions and 2 amplifications) were more prevalent in the mesenchymal group, confirming the advanced nature of this cellular subtype. CDKN2A was altered in more than 50% of both groups, but co-deletions in neighboring genes, and concomitant loss of gene expression, were more prevalent in the mesenchymal group, suggesting that the size of the loss around CDKN2A affects cell phenotype. Whole-genome CGH on 11 primary cancer tissues revealed that the 20 genes were altered at a higher prevalence (up to 55% of the cases for certain genes) than randomly selected sets of 20 genes, with the same direction of alteration as in the cell lines. These findings support the concept that specific genetic alterations enable phenotype plasticity and provide promising candidate genes for further research.
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Affiliation(s)
- Arkadeep Sinha
- Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA; Genetics Program, Michigan State University, East Lansing, MI, USA
| | - David Cherba
- Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA
| | - Heather Bartlam
- Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA
| | - Elizabeth Lenkiewicz
- Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, USA
| | - Lisa Evers
- Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, USA
| | - Michael T Barrett
- Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, USA
| | - Brian B Haab
- Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA; Genetics Program, Michigan State University, East Lansing, MI, USA.
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Fukamachi H, Seol HS, Shimada S, Funasaka C, Baba K, Kim JH, Park YS, Kim MJ, Kato K, Inokuchi M, Kawachi H, Yook JH, Eishi Y, Kojima K, Kim WH, Jang SJ, Yuasa Y. CD49f(high) cells retain sphere-forming and tumor-initiating activities in human gastric tumors. PLoS One 2013; 8:e72438. [PMID: 24015244 PMCID: PMC3756075 DOI: 10.1371/journal.pone.0072438] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 07/09/2013] [Indexed: 12/18/2022] Open
Abstract
Identification of gastric tumor-initiating cells (TICs) is essential to explore new therapies for gastric cancer patients. There are reports that gastric TICs can be identified using the cell surface marker CD44 and that they form floating spheres in culture, but we could not obtain consistent results with our patient-derived tumor xenograft (PDTX) cells. We thus searched for another marker for gastric TICs, and found that CD49f(high) cells from newly-dissected gastric cancers formed tumors with histological features of parental ones while CD49f(low) cells did not when subcutaneously injected into immunodeficient mice. These results indicate that CD49f, a subunit of laminin receptors, is a promising marker for human gastric TICs. We established a primary culture system for PDTX cells where only CD49f(high) cells could grow on extracellular matrix (ECM) to form ECM-attaching spheres. When injected into immunodeficient mice, these CD49f(high) sphere cells formed tumors with histological features of parental ones, indicating that only TICs could grow in the culture system. Using this system, we found that some sphere-forming TICs were more resistant than gastric tumor cell lines to chemotherapeutic agents, including doxorubicin, 5-fluorouracil and doxifluridine. There was a patient-dependent difference in the tumorigenicity of sphere-forming TICs and their response to anti-tumor drugs. These results suggest that ECM plays an essential role for the growth of TICs, and that this culture system will be useful to find new drugs targeting gastric TICs.
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Affiliation(s)
- Hiroshi Fukamachi
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hyang Sook Seol
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Chikako Funasaka
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kanako Baba
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ji Hun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Mi Jeung Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Keiji Kato
- Department of Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mikito Inokuchi
- Department of Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroshi Kawachi
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jeong Hwan Yook
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yoshinobu Eishi
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuyuki Kojima
- Department of Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Se Jin Jang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yasuhito Yuasa
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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Lessons learned about human stem cell responses to ionizing radiation exposures: a long road still ahead of us. Int J Mol Sci 2013; 14:15695-723. [PMID: 23899786 PMCID: PMC3759881 DOI: 10.3390/ijms140815695] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/15/2013] [Accepted: 07/17/2013] [Indexed: 12/16/2022] Open
Abstract
Human stem cells (hSC) possess several distinct characteristics that set them apart from other cell types. First, hSC are self-renewing, capable of undergoing both asymmetric and symmetric cell divisions. Second, these cells can be coaxed to differentiate into various specialized cell types and, as such, hold great promise for regenerative medicine. Recent progresses in hSC biology fostered the characterization of the responses of hSC to genotoxic stresses, including ionizing radiation (IR). Here, we examine how different types of hSC respond to IR, with a special emphasis on their radiosensitivity, cell cycle, signaling networks, DNA damage response (DDR) and DNA repair. We show that human embryonic stem cells (hESCs) possess unique characteristics in how they react to IR that clearly distinguish these cells from all adult hSC studied thus far. On the other hand, a manifestation of radiation injuries/toxicity in human bodies may depend to a large extent on hSC populating corresponding tissues, such as human mesenchymal stem cells (hMSC), human hematopoietic stem cells (hHSC), neural hSC, intestine hSC, etc. We discuss here that hSC responses to IR differ notably across many types of hSC which may represent the distinct roles these cells play in development, regeneration and/or maintenance of homeostasis.
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