|
1
|
Shevchenko JA, Nazarov KV, Alshevskaya AA, Sennikov SV. Erythroid Cells as Full Participants in the Tumor Microenvironment. Int J Mol Sci 2023; 24:15141. [PMID: 37894821 PMCID: PMC10606658 DOI: 10.3390/ijms242015141] [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: 09/12/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
The tumor microenvironment is an important factor that can determine the success or failure of antitumor therapy. Cells of hematopoietic origin are one of the most important mediators of the tumor-host interaction and, depending on the cell type and functional state, exert pro- or antitumor effects in the tumor microenvironment or in adjacent tissues. Erythroid cells can be full members of the tumor microenvironment and exhibit immunoregulatory properties. Tumor growth is accompanied by the need to obtain growth factors and oxygen, which stimulates the appearance of the foci of extramedullary erythropoiesis. Tumor cells create conditions to maintain the long-term proliferation and viability of erythroid cells. In turn, tumor erythroid cells have a number of mechanisms to suppress the antitumor immune response. This review considers current data on the existence of erythroid cells in the tumor microenvironment, formation of angiogenic clusters, and creation of optimal conditions for tumor growth. Despite being the most important life-support function of the body, erythroid cells support tumor growth and do not work against it. The study of various signaling mechanisms linking tumor growth with the mobilization of erythroid cells and the phenotypic and functional differences between erythroid cells of different origin allows us to identify potential targets for immunotherapy.
Collapse
Affiliation(s)
- Julia A. Shevchenko
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution, Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (J.A.S.); (K.V.N.)
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution, Ministry of Health of the Russian Federation, Higher Education I.M. Sechenov First Moscow State Medical University, Sechenov University, 119048 Moscow, Russia;
| | - Kirill V. Nazarov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution, Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (J.A.S.); (K.V.N.)
| | - Alina A. Alshevskaya
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution, Ministry of Health of the Russian Federation, Higher Education I.M. Sechenov First Moscow State Medical University, Sechenov University, 119048 Moscow, Russia;
| | - Sergey V. Sennikov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution, Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (J.A.S.); (K.V.N.)
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution, Ministry of Health of the Russian Federation, Higher Education I.M. Sechenov First Moscow State Medical University, Sechenov University, 119048 Moscow, Russia;
| |
Collapse
|
|
2
|
Tang DG. Understanding and targeting prostate cancer cell heterogeneity and plasticity. Semin Cancer Biol 2022; 82:68-93. [PMID: 34844845 PMCID: PMC9106849 DOI: 10.1016/j.semcancer.2021.11.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/01/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022]
Abstract
Prostate cancer (PCa) is a prevalent malignancy that occurs primarily in old males. Prostate tumors in different patients manifest significant inter-patient heterogeneity with respect to histo-morphological presentations and molecular architecture. An individual patient tumor also harbors genetically distinct clones in which PCa cells display intra-tumor heterogeneity in molecular features and phenotypic marker expression. This inherent PCa cell heterogeneity, e.g., in the expression of androgen receptor (AR), constitutes a barrier to the long-term therapeutic efficacy of AR-targeting therapies. Furthermore, tumor progression as well as therapeutic treatments induce PCa cell plasticity such that AR-positive PCa cells may turn into AR-negative cells and prostate tumors may switch lineage identity from adenocarcinomas to neuroendocrine-like tumors. This induced PCa cell plasticity similarly confers resistance to AR-targeting and other therapies. In this review, I first discuss PCa from the perspective of an abnormal organ development and deregulated cellular differentiation, and discuss the luminal progenitor cells as the likely cells of origin for PCa. I then focus on intrinsic PCa cell heterogeneity in treatment-naïve tumors with the presence of prostate cancer stem cells (PCSCs). I further elaborate on PCa cell plasticity induced by genetic alterations and therapeutic interventions, and present potential strategies to therapeutically tackle PCa cell heterogeneity and plasticity. My discussions will make it clear that, to achieve enduring clinical efficacy, both intrinsic PCa cell heterogeneity and induced PCa cell plasticity need to be targeted with novel combinatorial approaches.
Collapse
Affiliation(s)
- Dean G Tang
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Experimental Therapeutics (ET) Graduate Program, The University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| |
Collapse
|
|
3
|
She X, Qin S, Jing B, Jin X, Sun X, Lan X, An R. Radiotheranostic Targeting Cancer Stem Cells in Human Colorectal Cancer Xenografts. Mol Imaging Biol 2021; 22:1043-1053. [PMID: 32125599 DOI: 10.1007/s11307-019-01467-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE The aim of this study was to perform radiotheranostics with radioiodinated monoclonal antibodies (mAbs) for targeting cancer stem cells (CSCs) in human colorectal cancer xenografts and evaluate the relative advantage of a cocktail containing both [131I]CD133 mAb and [131I]CD44 mAb. PROCEDURES Tumor-bearing mice were randomly divided into eight groups: [131I]CD133mAb, [131I]CD44 mAb, [131I]IgG isotype control, radioiodinated mAb cocktail, CD133 mAb, CD44 mAb, unradioiodinated mAb cocktail, and saline groups. In vivo single photon emission computed tomography (SPECT) imaging was used to monitor dynamically changes in the CSC population after treatment. The radioactivity uptake of tumors was quantified ex vivo. The expression of CD133 and CD44 after treatment was also assessed by immunohistochemistry and western blot. Tumor growth curves and survival curves were generated to assess treatment efficacy. Cell apoptosis and proliferation in xenografts 30 days after treatment were measured by TdT-mediated dUTP-biotin nick end labeling (aka, TUNEL) and Ki67 staining. The expression levels of biomarkers in xenografts 30 days after treatment were measured by flow cytometry. RESULTS The radioimmunoimaging (RII) with in vivo SPECT showed that the CSC-targeting radioimmunotherapy (RIT) groups ([131I]CD133 mAb, [131I]CD44 mAb, and radioiodinated mAb cocktail groups) had intense accumulations of radiolabeled agents in the tumor areas. The ex vivo biodistribution confirmed these findings. In the CSC-targeting RIT groups, immunohistochemistry and western blot indicated significant reduction of specific target expression in the xenografts. The tumor growth curves and survival curves showed that the CSC-targeting RIT significantly inhibited tumor growth and prolonged mean survival, respectively. Significantly increased apoptosis and decreased proliferation in xenografts further confirmed the therapeutic efficacy of CSC-targeting RIT. Flow cytometry showed that the decreases in CSCs correlated with the presence of the corresponding antibodies. CONCLUSIONS Our results suggest that the CSC-targeting RIT can effectively reduce CSCs which consequently inhibits tumor development. The radioiodinated mAb cocktail may generate enhanced CSC-targeting specificity.
Collapse
Affiliation(s)
- Xianliang She
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Saimei Qin
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Boping Jing
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xueyan Jin
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xun Sun
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China. .,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Rui An
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave., Wuhan, 430022, Hubei Province, China. .,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| |
Collapse
|
|
4
|
Slow-cycling (dormant) cancer cells in therapy resistance, cancer relapse and metastasis. Semin Cancer Biol 2021; 78:90-103. [PMID: 33979674 DOI: 10.1016/j.semcancer.2021.04.021] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/26/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
It is increasingly appreciated that cancer cell heterogeneity and plasticity constitute major barriers to effective clinical treatments and long-term therapeutic efficacy. Research in the past two decades suggest that virtually all treatment-naive human cancers harbor subsets of cancer cells that possess many of the cardinal features of normal stem cells. Such stem-like cancer cells, operationally defined as cancer stem cells (CSCs), are frequently quiescent and dynamically change and evolve during tumor progression and therapeutic interventions. Intrinsic tumor cell heterogeneity is reflected in a different aspect in that tumors also harbor a population of slow-cycling cells (SCCs) that are not in the proliferative cell cycle and thus are intrinsically refractory to anti-mitotic drugs. In this Perspective, we focus our discussions on SCCs in cancer and on various methodologies that can be employed to enrich and purify SCCs, compare the similarities and differences between SCCs, CSCs and cancer cells undergoing EMT, and present evidence for the involvement of SCCs in surviving anti-neoplastic treatments, mediating tumor relapse, maintaining tumor dormancy and mediating metastatic dissemination. Our discussions make it clear that an in-depth understanding of the biological properties of SCCs in cancer will be instrumental to developing new therapeutic strategies to prevent tumor relapse and distant metastasis.
Collapse
|
|
5
|
Bhoopathi P, Mannangatti P, Emdad L, Das SK, Fisher PB. The quest to develop an effective therapy for neuroblastoma. J Cell Physiol 2021; 236:7775-7791. [PMID: 33834508 DOI: 10.1002/jcp.30384] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/27/2021] [Accepted: 03/22/2021] [Indexed: 12/18/2022]
Abstract
Neuroblastoma (NB) is a common solid extracranial tumor developing in pediatric populations. NB can spontaneously regress or grow and metastasize displaying resistance to therapy. This tumor is derived from primitive cells, mainly those of the neural crest, in the sympathetic nervous system and usually develops in the adrenal medulla and paraspinal ganglia. Our understanding of the molecular characteristics of human NBs continues to advance documenting abnormalities at the genome, epigenome, and transcriptome levels. The high-risk tumors have MYCN oncogene amplification, and the MYCN transcriptional regulator encoded by the MYCN oncogene is highly expressed in the neural crest. Studies on the biology of NB has enabled a more precise risk stratification strategy and a concomitant reduction in the required treatment in an expanding number of cases worldwide. However, newer treatment strategies are mandated to improve outcomes in pediatric patients who are at high-risk and display relapse. To improve outcomes and survival rates in such high-risk patients, it is necessary to use a multicomponent therapeutic approach. Accuracy in clinical staging of the disease and assessment of the associated risks based on biological, clinical, surgical, and pathological criteria are of paramount importance for prognosis and to effectively plan therapeutic approaches. This review discusses the staging of NB and the biological and genetic features of the disease and several current therapies including targeted delivery of chemotherapy, novel radiation therapy, and immunotherapy for NB.
Collapse
Affiliation(s)
- Praveen Bhoopathi
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.,VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Padmanabhan Mannangatti
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Luni Emdad
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.,VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.,VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Swadesh K Das
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.,VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.,VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.,VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.,VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| |
Collapse
|
|
6
|
The Intratumoral Heterogeneity of Cancer Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1311:149-160. [PMID: 34014541 DOI: 10.1007/978-3-030-65768-0_11] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer is one of the deadliest diseases in the world, causing over half a million deaths a year in the USA alone. Despite recent advances made in the field of cancer biology and the therapies that have been developed [1, 2], it is clear that more advances are necessary for us to classify cancer as curable. The logical question that arises is simple: Why, despite all the technologies and medical innovations of our time, has a complete cure eluded us? This chapter sheds light on one of cancer's most impactful attributes: its heterogeneity and, more specifically, the intratumoral heterogeneity of cancer metabolism. Simply put, what makes cancer one of the deadliest diseases is its ability to change and adapt. Cancer cells' rapid evolution, coupled with their irrepressible ability to divide, gives most of them the advantage over our immune systems. In this chapter, we delve into the complexities of this adaptability and the vital role that metabolism plays in the rise and progression of this heterogeneity.
Collapse
|
|
7
|
Terraneo N, Jacob F, Dubrovska A, Grünberg J. Novel Therapeutic Strategies for Ovarian Cancer Stem Cells. Front Oncol 2020; 10:319. [PMID: 32257947 PMCID: PMC7090172 DOI: 10.3389/fonc.2020.00319] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 02/21/2020] [Indexed: 12/12/2022] Open
Abstract
Ovarian cancer (OC) is one of the most lethal gynecologic malignancies. Due to the lack of specific symptoms and screening methods, this disease is usually diagnosed only at an advanced and metastatic stage. The gold-standard treatment for OC patients consists of debulking surgery followed by taxane combined with platinum-based chemotherapy. Most patients show complete clinical remission after first-line therapy, but the majority of them ultimately relapse, developing radio- and chemoresistant tumors. It is now proposed that the cause of recurrence and reduced therapy efficacy is the presence of small populations of cancer stem cells (CSCs). These cells are usually resistant against conventional cancer therapies and for this reason, effective targeted therapies for the complete eradication of CSCs are urgently needed. In this review article, we highlight the mechanisms of CSC therapy resistance, epithelial-to-mesenchymal transition, stemness, and novel therapeutic strategies for ovarian CSCs.
Collapse
Affiliation(s)
- Nastassja Terraneo
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen, Switzerland
| | - Francis Jacob
- Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Anna Dubrovska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany
| | - Jürgen Grünberg
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen, Switzerland
| |
Collapse
|
|
8
|
Tuasha N, Petros B. Heterogeneity of Tumors in Breast Cancer: Implications and Prospects for Prognosis and Therapeutics. SCIENTIFICA 2020; 2020:4736091. [PMID: 33133722 PMCID: PMC7568790 DOI: 10.1155/2020/4736091] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/20/2020] [Accepted: 09/28/2020] [Indexed: 05/16/2023]
Abstract
Breast cancer is the most commonly diagnosed form of cancer in women comprising 16% of all female cancers. The disease shows high intertumoral and intratumoral heterogeneity posing diagnostic and therapeutic challenges with unpredictable clinical outcome and response to existing therapy. Mounting evidence is ascertaining that breast cancer stem cells (CSCs) are responsible for tumor initiation, progression, recurrence, evolution, metastasis, and drug resistance. Therapeutics selectively targeting the CSCs based on distinct surface molecular markers and enhanced intracellular activities of these cells continue to evolve and hold significant promise. Having plethora of heterogeneity accompanied with failure of existing conventional therapeutics and poor prognosis, the present review focuses on elucidating the main signaling pathways in breast CSCs as major therapeutic targets. The role of developments in nanomedicine and miRNA as targeted delivery of therapeutic anticancer agents is also highlighted.
Collapse
Affiliation(s)
- Nigatu Tuasha
- Addis Ababa University, College of Natural Science, Department of Microbial, Cellular and Molecular Biology, P.O. Box 1176, Addis Ababa, Ethiopia
| | - Beyene Petros
- Addis Ababa University, College of Natural Science, Department of Microbial, Cellular and Molecular Biology, P.O. Box 1176, Addis Ababa, Ethiopia
| |
Collapse
|
|
9
|
Goh JXH, Tan LTH, Goh JK, Chan KG, Pusparajah P, Lee LH, Goh BH. Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention. Cancers (Basel) 2019; 11:E867. [PMID: 31234411 PMCID: PMC6627117 DOI: 10.3390/cancers11060867] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 12/19/2022] Open
Abstract
The search for effective methods of cancer treatment and prevention has been a continuous effort since the disease was discovered. Recently, there has been increasing interest in exploring plants and fruits for molecules that may have potential as either adjuvants or as chemopreventive agents against cancer. One of the promising compounds under extensive research is nobiletin (NOB), a polymethoxyflavone (PMF) extracted exclusively from citrus peel. Not only does nobiletin itself exhibit anti-cancer properties, but its derivatives are also promising chemopreventive agents; examples of derivatives with anti-cancer activity include 3'-demethylnobiletin (3'-DMN), 4'-demethylnobiletin (4'-DMN), 3',4'-didemethylnobiletin (3',4'-DMN) and 5-demethylnobiletin (5-DMN). In vitro studies have demonstrated differential efficacies and mechanisms of NOB and its derivatives in inhibiting and killing of colon cancer cells. The chemopreventive potential of NOB has also been well demonstrated in several in vivo colon carcinogenesis animal models. NOB and its derivatives target multiple pathways in cancer progression and inhibit several of the hallmark features of colorectal cancer (CRC) pathophysiology, including arresting the cell cycle, inhibiting cell proliferation, inducing apoptosis, preventing tumour formation, reducing inflammatory effects and limiting angiogenesis. However, these substances have low oral bioavailability that limits their clinical utility, hence there have been numerous efforts exploring better drug delivery strategies for NOB and these are part of this review. We also reviewed data related to patents involving NOB to illustrate the extensiveness of each research area and its direction of commercialisation. Furthermore, this review also provides suggested directions for future research to advance NOB as the next promising candidate in CRC chemoprevention.
Collapse
Affiliation(s)
- Joanna Xuan Hui Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
| | - Loh Teng-Hern Tan
- Novel Bacteria and Drug Discovery (NBDD) Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
| | - Joo Kheng Goh
- School of Science, Monash University Malaysia, Jalan Lagoon Selatan, 47500, Bandar Sunway, Selangor Darul Ehsan, Malaysia.
| | - Kok Gan Chan
- Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia.
- International Genome Centre, Jiangsu University, Zhenjiang 212013, China.
| | - Priyia Pusparajah
- Medical Health and Translational Research Group, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia.
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery (NBDD) Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
- Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway 47500, Malaysia.
| | - Bey-Hing Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
- Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway 47500, Malaysia.
| |
Collapse
|
|
10
|
Wang Y, Leonard MK, Snyder DE, Fisher ML, Eckert RL, Kaetzel DM. NME1 Drives Expansion of Melanoma Cells with Enhanced Tumor Growth and Metastatic Properties. Mol Cancer Res 2019; 17:1665-1674. [PMID: 31123173 DOI: 10.1158/1541-7786.mcr-18-0019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 06/14/2018] [Accepted: 05/16/2019] [Indexed: 12/31/2022]
Abstract
Melanoma is a lethal skin cancer prone to progression and metastasis, and resistant to therapy. Metastasis and therapy resistance of melanoma and other cancers are driven by tumor cell plasticity, largely via acquisition/loss of stem-like characteristics and transitions between epithelial and mesenchymal phenotypes (EMT/MET). NME1 is a metastasis suppressor gene that inhibits metastatic potential when its expression is enforced in melanoma and other cancers. Herein, we have unmasked a novel role for NME1 as a driver of melanoma growth distinct from its canonical function as a metastasis suppressor. NME1 promotes expansion of stem-like melanoma cells that exhibit elevated expression of stem cell markers (e.g., Sox2, Sox10, Oct-4, KLF4, and Ccnb-1), enhanced growth as melanoma spheres in culture, and enhanced tumor growth and lung colonizing activities in vivo. In contrast, NME1 expression did not affect the proliferation of melanoma cell lines in monolayer culture conditions. Silencing of NME1 expression resulted in a dramatic reduction in melanoma sphere size, and impaired tumor growth and metastatic activities of melanoma sphere cells when xenografted in immunocompromised mice. Individual cells within melanoma sphere cultures displayed a wide range of NME1 expression across multiple melanoma cell lines. Cell subpopulations with elevated NME1 expression were fast cycling and displayed enhanced expression of stem cell markers. IMPLICATIONS: Our findings suggest the current model of NME1 as a metastasis-suppressing factor requires refinement, bringing into consideration its heterogeneous expression within melanoma sphere cultures and its novel role in promoting the expansion and tumorigenicity of stem-like cells.
Collapse
Affiliation(s)
- Ying Wang
- School of Medicine, University of Maryland-Baltimore, Department of Biochemistry and Molecular Biology, Baltimore, Maryland
| | - M Kathryn Leonard
- School of Medicine, University of Maryland-Baltimore, Department of Biochemistry and Molecular Biology, Baltimore, Maryland
| | - Devin E Snyder
- School of Medicine, University of Maryland-Baltimore, Department of Biochemistry and Molecular Biology, Baltimore, Maryland
| | - Matthew L Fisher
- School of Medicine, University of Maryland-Baltimore, Department of Biochemistry and Molecular Biology, Baltimore, Maryland
| | - Richard L Eckert
- School of Medicine, University of Maryland-Baltimore, Department of Biochemistry and Molecular Biology, Baltimore, Maryland.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland-Baltimore, Baltimore, Maryland
| | - David M Kaetzel
- School of Medicine, University of Maryland-Baltimore, Department of Biochemistry and Molecular Biology, Baltimore, Maryland. .,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland-Baltimore, Baltimore, Maryland
| |
Collapse
|
|
11
|
Scalable Culture Strategies for the Expansion of Patient-Derived Cancer Stem Cell Lines. Stem Cells Int 2019; 2019:8347595. [PMID: 30918523 PMCID: PMC6409046 DOI: 10.1155/2019/8347595] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 11/15/2018] [Indexed: 12/26/2022] Open
Abstract
Cancer stem cells (CSCs) have recently raised great interest as a promising biological system for designing effective cancer therapies. The scarcity of CSCs in vivo and the consequent low numbers obtained from biopsies represent a major hurdle to the development of such strategies. It is therefore necessary to design robust scalable methods to enable efficient expansion of bona fide CSCs in vitro. Here, we evaluated the applicability of computer-controlled bioreactors combined with 3D aggregate culture and microcarrier technology, widely used in stem cell bioprocessing, for the expansion and enrichment of CSCs isolated from different types of solid tumors—colorectal cancer (CRC) and non-small-cell lung cancer (NSCLC) from two patients. Results show that these culture strategies improved cell expansion and CSC enrichment. Both patient-derived CSC lines were able to grow on microcarriers, the best results being achieved for PPlus 102-L, Pro-F 102-L, Fact 102-L, and CGEN 102-L beads (5-fold and 40-fold increase in total cell concentration for CRC and NSCLC cells, respectively, in 6 days). As for 3D aggregate culture strategy, the cell proliferation profile was donor dependent. NSCLC cells were the only cells able to form aggregates and proliferate, and the flat-bottom bioreactor vessel equipped with a trapezoid-shaped paddle impeller was the most efficient configuration for cell growth (21-fold increase in cell concentration achieved in 8 days). Serum-free medium promotes CSC enrichment in both 3D aggregate and microcarrier cultures. The protocols developed herein for CSC expansion have the potential to be transferred to clinical and industrial settings, providing key insights to guide bioprocess design towards the production of enriched CSC cultures in higher quantity and improved quality.
Collapse
|
|
12
|
Abstract
Life starts with a zygote, which is formed by the fusion of a haploid sperm and egg. The formation of a blastomere by cleavage division (nuclear division without an increase in cell size) is the first step in embryogenesis, after the formation of the zygote. Blastomeres are responsible for reprogramming the parental genome as a new embryonic genome for generation of the pluripotent stem cells which then differentiate by Waddington's epigenetic landscape to create a new life. Multiple authors over the past 150 years have proposed that tumors arises from development gone awry at a point within Waddington's landscape. Recent discoveries showing that differentiated somatic cells can be reprogrammed into induced pluripotent stem cells, and that somatic cell nuclear transfer can be used to successfully clone animals, have fundamentally reshaped our understanding of tumor development and origin. Differentiated somatic cells are plastic and can be induced to dedifferentiate into pluripotent stem cells. Here, I review the evidence that suggests somatic cells may have a previously overlooked endogenous embryonic program that can be activated to dedifferentiate somatic cells into stem cells of various potencies for tumor initiation. Polyploid giant cancer cells (PGCCs) have long been observed in cancer and were thought originally to be nondividing. Contrary to this belief, recent findings show that stress-induced PGCCs divide by endoreplication, which may recapitulate the pattern of cleavage-like division in blastomeres and lead to dedifferentiation of somatic cells by a programmed process known as "the giant cell cycle", which comprise four distinct but overlapping phases: initiation, self-renewal, termination and stability. Depending on the intensity and type of stress, different levels of dedifferentiation result in the formation of tumors of different grades of malignancy. Based on these results, I propose a unified dualistic model to demonstrate the origin of human tumors. The tenet of this model includes four points, as follows. 1. Tumors originate from a stem cell at a specific developmental hierarchy, which can be achieved by dualistic origin: dedifferentiation of the zygote formed by two haploid gametes (sexual reproduction) via the blastomere during normal development, or transformation from damaged or aged mature somatic cells via a blastomere-like embryonic program (asexual reproduction). 2. Initiation of the tumor begins with a stem cell that has uncoupled the differentiation from the proliferation program which results in stem cell maturation arrest. 3. The developmental hierarchy at which stem cells arrest determines the degree of malignancy: the more primitive the level at which stem cells arrest, the greater the likelihood of the tumor being malignant. 4. Environmental factors and intrinsic genetic or epigenetic alterations represent the risk factors or stressors that facilitate stem cell arrest and somatic cell dedifferentiation. However, they, per se, are not the driving force of tumorigenesis. Thus, the birth of a tumor can be viewed as a triad that originates from a stem cell via dedifferentiation through a blastomere or blastomere-like program, which then differentiates along Waddington's landscape, and arrests at a developmental hierarchy. Blocking the PGCC-mediated dedifferentiation process and inducing their differentiation may represent a novel alternative approach to eliminate the tumor occurrence and therapeutic resistance.
Collapse
Affiliation(s)
- Jinsong Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4095, United States.
| |
Collapse
|
|
13
|
Zhang Y, Yang H, Li Q, Duan X, Zhao X, Wei Y, Chen X. Three-Dimensional Ameliorated Biologics Elicit Thymic Renewal in Tumor-Bearing Hosts. THE JOURNAL OF IMMUNOLOGY 2018; 201:1975-1983. [DOI: 10.4049/jimmunol.1701727] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 07/23/2018] [Indexed: 12/31/2022]
|
|
14
|
Silva I, Estrada MF, V Pereira C, da Silva AB, Bronze MR, Alves PM, Duarte CMM, Brito C, Serra AT. Polymethoxylated Flavones from Orange Peels Inhibit Cell Proliferation in a 3D Cell Model of Human Colorectal Cancer. Nutr Cancer 2018; 70:257-266. [PMID: 29313727 DOI: 10.1080/01635581.2018.1412473] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Polymethoxylated flavones (PMFs) have been recognized to inhibit colorectal cancer proliferation through various mechanisms, however most of these studies have been performed on cells grown as monolayers that present limitations in mimicking the 3D tumor architecture and microenvironment. The main aim of this study was to investigate the anticancer potential of an orange peel extract (OPE) enriched in PMFs in a 3D cell model of colorectal cancer. The OPE was developed by supercritical fluid extraction and the anticancer effect was evaluated in HT29 spheroids cultures in a stirred-tank based system. Results showed that OPE inhibited cell proliferation, induced cell cycle arrest (G2/M phase), promoted apoptosis, and reduced ALDH+ population on HT29 spheroids. The antiproliferative activity was significantly lower than that obtained for 2D model (EC50 value of 0.43 ± 0.02 mg/mL) and this effect was dependent on diameter and cell composition/phenotype of spheroids derived from different culture days (day 3 - 0.53 ± 0.05 mg/mL; day 5 - 0.55 ± 0.03 mg/mL; day 7 - 1.24 ± 0.15 mg/mL). HT29 spheroids collected at day 7 presented typical characteristics of in vivo solid tumors including a necrotic/apoptotic core, hypoxia regions, presence of cancer stem cells, and a less differentiated invasive front. Nobiletin, sinesentin, and tangeretin were identified as the main compounds responsible for the anticancer activity.
Collapse
Affiliation(s)
- Inês Silva
- a IBET-Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal
| | - Marta F Estrada
- a IBET-Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal.,b ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Oeiras , Portugal
| | - Carolina V Pereira
- a IBET-Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal
| | - Andreia Bento da Silva
- b ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Oeiras , Portugal
| | - Maria R Bronze
- a IBET-Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal.,b ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Oeiras , Portugal.,c iMED, Faculdade de Farmácia da Universidade de Lisboa , Lisboa , Portugal
| | - Paula M Alves
- a IBET-Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal.,b ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Oeiras , Portugal
| | - Catarina M M Duarte
- a IBET-Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal.,b ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Oeiras , Portugal
| | - Catarina Brito
- a IBET-Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal.,b ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Oeiras , Portugal
| | - Ana Teresa Serra
- a IBET-Instituto de Biologia Experimental e Tecnológica , Oeiras , Portugal.,b ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Oeiras , Portugal
| |
Collapse
|
|
15
|
The Intratumoral Heterogeneity of Cancer Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1063:131-145. [DOI: 10.1007/978-3-319-77736-8_10] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
|
|
16
|
Xin Z, Yang Z, Xu J, Li C, Shao T, Wang G, Li C. Gene expression profiling and construction of a putative gene regulatory network of bladder cancer tumor-initiating cells. Oncotarget 2017; 8:111271-111280. [PMID: 29340052 PMCID: PMC5762320 DOI: 10.18632/oncotarget.22771] [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: 08/24/2017] [Accepted: 09/22/2017] [Indexed: 11/25/2022] Open
Abstract
Human bladder cancer tumors have been shown to contain a subpopulation of cells with stem-like characteristics that may trigger tumor growth, recurrence, and metastasis. These cells, known as tumor-initiating cells (TICs), would be effective diagnostic tools and valuable therapeutic targets. Here, we report the isolation of TICs from seven bladder cancer cell lines and show that TICs from different sources vary on their ability to form tumorspheres in vitro and generate xenografts in vivo, which suggest they are remarkably heterogeneous. We used the Affymetrix PrimeView™ Human Gene Expression Array to analyze gene expression profiles of bladder TICs, which may help understand their tumorigenic capacities and develop novel treatments specifically targeted toward these cells. We then constructed a transcription factor-gene regulatory network that includes three key transcription factors that are involved in cell survival, differentiation, proliferation, and apoptosis. We validated our findings by analyzing mRNA expression of the key genes in this network in 24 clinical tissues. Our results suggest that this transcription factor-gene regulatory network could be useful in the development of clinical diagnostic tools and therapy approaches for bladder cancer.
Collapse
Affiliation(s)
- Zhuoyuan Xin
- Cancer Centre, First Hospital of Jilin University, Changchun, China
- Department of Pathogenobiology, College of Basic Medical Science, Jilin University, Changchun, China
| | - Zhao Yang
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jianting Xu
- Cancer Centre, First Hospital of Jilin University, Changchun, China
| | - Chaoying Li
- Department of Pathogenobiology, College of Basic Medical Science, Jilin University, Changchun, China
| | - Tong Shao
- Department of Pathogenobiology, College of Basic Medical Science, Jilin University, Changchun, China
| | - Guoqing Wang
- Department of Pathogenobiology, College of Basic Medical Science, Jilin University, Changchun, China
| | - Chong Li
- Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Beijing Jianlan Institute of Medicine, Beijing, China
| |
Collapse
|
|
17
|
Voura EB, Montalvo MJ, Dela Roca KT, Fisher JM, Defamie V, Narala SR, Khokha R, Mulligan ME, Evans CA. Planarians as models of cadmium-induced neoplasia provide measurable benchmarks for mechanistic studies. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2017; 142:544-554. [PMID: 28482323 DOI: 10.1016/j.ecoenv.2017.04.044] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 04/02/2017] [Accepted: 04/19/2017] [Indexed: 06/07/2023]
Abstract
Bioassays of planarian neoplasia highlight the potential of these organisms as useful standards to assess whether environmental toxins such as cadmium promote tumorigenesis. These studies complement other investigations into the exceptional healing and regeneration of planarians - processes that are driven by a population of active stem cells, or neoblasts, which are likely transformed during planarian tumor growth. Our goal was to determine if planarian tumorigenesis assays are amenable to mechanistic studies of cadmium carcinogenesis. To that end we demonstrate, by examining both counts of cell populations by size, and instances of mitosis, that the activity of the stem cell population can be monitored. We also provide evidence that specific biomodulators can affect the potential of planarian neoplastic growth, in that an inhibitor of metalloproteinases effectively blocked the development of the lesions. From these results, we infer that neoblast activity does respond to cadmium-induced tumor growth, and that metalloproteinases are required for the progression of cancer in the planarian.
Collapse
Affiliation(s)
- Evelyn B Voura
- School of Science, Technology and Health Studies, Morrisville State College, 80 Eaton Street, Morrisville, New York 13408, USA.
| | - Melissa J Montalvo
- Department of Math and Science, Dominican College, 470 Western Highway South, Orangeburg, New York 10962, USA
| | - Kevin T Dela Roca
- Department of Math and Science, Dominican College, 470 Western Highway South, Orangeburg, New York 10962, USA
| | - Julia M Fisher
- Colgate University, 13 Oak Drive, Hamilton, New York 13346, USA
| | - Virginie Defamie
- Ontario Cancer Institute, University Health Network, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada
| | - Swami R Narala
- Ontario Cancer Institute, University Health Network, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada
| | - Rama Khokha
- Ontario Cancer Institute, University Health Network, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada
| | - Margaret E Mulligan
- Department of Math and Science, Dominican College, 470 Western Highway South, Orangeburg, New York 10962, USA
| | - Colleen A Evans
- Department of Math and Science, Dominican College, 470 Western Highway South, Orangeburg, New York 10962, USA
| |
Collapse
|
|
18
|
Marcucci F, Ghezzi P, Rumio C. The role of autophagy in the cross-talk between epithelial-mesenchymal transitioned tumor cells and cancer stem-like cells. Mol Cancer 2017; 16:3. [PMID: 28137290 PMCID: PMC5282816 DOI: 10.1186/s12943-016-0573-8] [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: 10/01/2016] [Accepted: 12/19/2016] [Indexed: 12/13/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) and cancer stem-like cells (CSC) are becoming highly relevant targets in anticancer drug discovery. A large body of evidence suggests that epithelial-mesenchymal transitioned tumor cells (EMT tumor cells) and CSCs have similar functions. There is also an overlap regarding the stimuli that can induce the generation of EMT tumor cells and CSCs. Moreover, direct evidence has been brought that EMT can give rise to CSCs. It is unclear however, whether EMT tumor cells should be considered CSCs or if they have to undergo further changes. In this article we summarize available evidence suggesting that, indeed, additional programs must be engaged and we propose that macroautophagy (hereafter, autophagy) represents a key trait distinguishing CSCs from EMT tumor cells. Thus, CSCs have often been reported to be in an autophagic state and blockade of autophagy inhibits CSCs. On the other hand, there is ample evidence showing that EMT and autophagy are distinct events. CSCs, however, represent, by themselves, a heterogeneous population. Thus, CSCs have been distinguished in predominantly non-cycling and cycling CSCs, the latter representing CSCs that self-renew and replenish the pool of differentiated tumor cells. We now suggest that the non-cycling CSC subpopulation is in an autophagic state. We propose also two models to explain the relationship between EMT tumor cells and these two major CSC subpopulations: a branching model in which EMT tumor cells can give rise to cycling or non-cycling CSCs, respectively, and a hierarchical model in which EMT tumor cells are first induced to become autophagic CSCs and, subsequently, cycling CSCs. Finally, we address the therapeutic consequences of these insights.
Collapse
Affiliation(s)
- Fabrizio Marcucci
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, via Trentacoste 2, 20133, Milan, Italy.
| | - Pietro Ghezzi
- Brighton & Sussex Medical School, Trafford Centre, University of Sussex, Falmer, Brighton, BN1 9RY, UK
| | - Cristiano Rumio
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, via Trentacoste 2, 20133, Milan, Italy
| |
Collapse
|
|
19
|
Munakata K, Uemura M, Tanaka S, Kawai K, Kitahara T, Miyo M, Kano Y, Nishikawa S, Fukusumi T, Takahashi Y, Hata T, Nishimura J, Takemasa I, Mizushima T, Ikenaga M, Kato T, Murata K, Carethers JM, Yamamoto H, Doki Y, Mori M. Cancer Stem-like Properties in Colorectal Cancer Cells with Low Proteasome Activity. Clin Cancer Res 2016; 22:5277-5286. [PMID: 27166395 DOI: 10.1158/1078-0432.ccr-15-1945] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 04/21/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE One of the main reasons for cancer treatment resistance is the existence of cancer stem-like cells (CSCs). Here, we elucidated the relationship between low proteasome activity cells (LPACs) and CSCs. EXPERIMENTAL DESIGN The human colorectal cancer cell lines HCT116, SW480, DLD1, and KM12SM were engineered to stably express a green fluorescent molecule fused to the degron of ornithine decarboxylase, resulting in an accumulation of the fluorescence in LPACs. LPACs were isolated by flow cytometry. Treatment resistance (radio- and chemotherapy) and the capacity of LPACs to act as CSCs were analyzed. Microarray analysis was performed to reveal genes related to treatment resistance. The prognostic impact of potent genes was examined in 190 patients with colorectal cancer. RESULTS LPACs had a significantly increased capacity for radioresistance and chemoresistance (5-fluorouracil and oxaliplatin), significantly lower reactive oxygen species activity, and significantly increased sphere formation capacity compared with non-LPACs. The number of cells in the G0-G1 phase was significantly higher among LPACs. Subcutaneous injection of as few as 20 LPACs led to tumor formation in immunologically incompetent mice. Microarray analysis revealed that the expression of EP300-interacting inhibitor of differentiation 3 (EID3) was significantly increased in LPACs. In vitro assay revealed that EID3 positively controlled cell proliferation and treatment resistance. The high expression of EID3 was an adverse prognostic indicator in patients with colorectal cancer (P = 0.0400). CONCLUSIONS LPACs have characteristic treatment resistance and act as CSCs in colorectal cancer. In addition, EID3 is one of the potential regulators of treatment resistance in colorectal cancer and may be a potential therapeutic target. Clin Cancer Res; 22(21); 5277-86. ©2016 AACR.
Collapse
Affiliation(s)
- Koji Munakata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
- Department of Surgery, National Hospital Organization, Osaka National Hospital, Japan
| | - Shinji Tanaka
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Japan
| | - Kenji Kawai
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Tomohiro Kitahara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Masaaki Miyo
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Yoshihiro Kano
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Japan
| | - Shinpei Nishikawa
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Japan
| | - Takahito Fukusumi
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Japan
| | - Yusuke Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Taishi Hata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Junichi Nishimura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Ichiro Takemasa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | | | - Takeshi Kato
- Department of Surgery, Kansai Rosai Hospital, Japan
| | - Kohei Murata
- Department of Surgery, Suita Municipal Hospital, Japan
| | - John M Carethers
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Hirofumi Yamamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| |
Collapse
|
|
20
|
Abstract
Metastases that are resistant to conventional therapy are the major cause of death from cancer. In most patients, metastasis has already occurred by the time of diagnosis. Thus, the prevention of metastasis is unlikely to be of therapeutic benefit. The biological heterogeneity of metastases presents a major obstacle to treatment. However, the growth and survival of metastases depend on interactions between tumor cells and host homeostatic mechanisms. Targeting these interactions, in addition to the tumor cells, can produce synergistic therapeutic effects against existing metastases.
Collapse
Affiliation(s)
- Isaiah J Fidler
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 173, Houston, TX, 77030, USA.
| | - Margaret L Kripke
- Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 173, Houston, TX, 77030, USA
| |
Collapse
|
|
21
|
Bora-Singhal N, Perumal D, Nguyen J, Chellappan S. Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer. Neoplasia 2016; 17:538-51. [PMID: 26297432 PMCID: PMC4547412 DOI: 10.1016/j.neo.2015.07.001] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 06/22/2015] [Accepted: 07/02/2015] [Indexed: 12/21/2022] Open
Abstract
Non–small cell lung cancer (NSCLC) patients have very low survival rates because the current therapeutic strategies are not fully effective. Although EGFR tyrosine kinase inhibitors are effective for NSCLC patients harboring EGFR mutations, patients invariably develop resistance to these agents. Alterations in multiple signaling cascades have been associated with the development of resistance to EGFR inhibitors. Sonic Hedgehog and associated Gli transcription factors play a major role in embryonic development and have recently been found to be reactivated in NSCLC, and elevated Gli1 levels correlate with poor prognosis. The Hedgehog pathway has been implicated in the functions of cancer stem cells, although the underlying molecular mechanisms are not clear. In this context, we demonstrate that Gli1 is a strong regulator of embryonic stem cell transcription factor Sox2. Depletion of Gli1 or inhibition of the Hedgehog signaling significantly abrogated the self-renewal of stem-like side-population cells from NSCLCs as well as vascular mimicry of such cells. Gli1 was found to transcriptionally regulate Sox2 through its promoter region, and Gli1 could be detected on the Sox2 promoter. Inhibition of Hedgehog signaling appeared to work cooperatively with EGFR inhibitors in markedly reducing the viability of NSCLC cells as well as the self-renewal of stem-like cells. Thus, our study demonstrates a cooperative functioning of the EGFR signaling and Hedgehog pathways in governing the stem-like functions of NSCLC cancer stem cells and presents a novel therapeutic strategy to combat NSCLC harboring EGFR mutations.
Collapse
Affiliation(s)
- Namrata Bora-Singhal
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Deepak Perumal
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Jonathan Nguyen
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Srikumar Chellappan
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
| |
Collapse
|
|
22
|
Moreira D, Zhang Q, Hossain DMS, Nechaev S, Li H, Kowolik CM, D'Apuzzo M, Forman S, Jones J, Pal SK, Kortylewski M. TLR9 signaling through NF-κB/RELA and STAT3 promotes tumor-propagating potential of prostate cancer cells. Oncotarget 2016; 6:17302-13. [PMID: 26046794 PMCID: PMC4627309 DOI: 10.18632/oncotarget.4029] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 05/09/2015] [Indexed: 12/16/2022] Open
Abstract
Prostate cancer progression was associated with tumorigenic signaling activated by proinflammatory mediators. However, the etiology of these events remains elusive. Here, we demonstrate that triggering of the innate immune receptor, Toll-like Receptor 9 (TLR9), in androgen-independent prostate cancer cells initiates signaling cascade leading to increased tumor growth and progression. Using limited dilution/serial transplantation experiments, we show that TLR9 is essential for prostate cancer cells' potential to propagate and self-renew in vivo. Furthermore, low expression or silencing of TLR9 limits the clonogenic potential and mesenchymal stem cell-like properties of LNCaP- and PC3-derived prostate cancer cell variants. Genome-wide transcriptional analysis of prostate cancer cells isolated from xenotransplanted TLR9-positive and -negative tumors revealed a unique gene expression signature, with prominent upregulation of inflammation- and stem cell-related markers. TLR9 signaling orchestrated expression of critical stem cell-related genes such as NKX3.1, KLF-4, BMI-1 and COL1A1, at both mRNA and protein levels. Our further analysis identified that TLR9-induced NF-κB/RELA and STAT3 transcription factors co-regulated NKX3.1 and KLF4 gene expression by directly binding to both promoters. Finally, we demonstrated the feasibility of using TLR9-targeted siRNA delivery to block RELA- and STAT3-dependent prostate cancer cell self-renewal in vivo. The intratumoral administration of CpG-RELAsiRNA or CpG-STAT3siRNA but not control conjugates inhibited growth of established prostate tumors and reduced clonogenic potential of cancer cells. Overcoming cancer cell self-renewal and tumor-propagating potential by targeted inhibition of TLR9 signaling can provide therapeutic strategy for late-stage prostate cancer patients.
Collapse
Affiliation(s)
- Dayson Moreira
- Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Qifang Zhang
- Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Dewan Md S Hossain
- Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Sergey Nechaev
- Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA.,Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Haiqing Li
- Bioinformatics Core Facility, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Claudia M Kowolik
- Department of Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Massimo D'Apuzzo
- Department of Pathology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Stephen Forman
- Department of Hematologic Malignancies, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Jeremy Jones
- Department of Cell Biology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Sumanta K Pal
- Department of Medical Oncology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| | - Marcin Kortylewski
- Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
| |
Collapse
|
|
23
|
Strand DW, Aaron L, Henry G, Franco OE, Hayward SW. Isolation and analysis of discreet human prostate cellular populations. Differentiation 2016; 91:139-51. [PMID: 26546040 PMCID: PMC4854811 DOI: 10.1016/j.diff.2015.10.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 10/27/2015] [Indexed: 02/03/2023]
Abstract
The use of lineage tracing in transgenic mouse models has revealed an abundance of subcellular phenotypes responsible for maintaining prostate homeostasis. The ability to use fresh human tissues to examine the hypotheses generated by these mouse experiments has been greatly enhanced by technical advances in tissue processing, flow cytometry and cell culture. We describe in detail the optimization of protocols for each of these areas to facilitate research on solving human prostate diseases through the analysis of human tissue.
Collapse
Affiliation(s)
- Douglas W Strand
- Department of Urology, UT Southwestern University Medical Center, Dallas, TX, USA
| | - LaTayia Aaron
- Department of Cancer Biology, Meharry Medical College, Nashville, TN, USA
| | - Gervaise Henry
- Department of Urology, UT Southwestern University Medical Center, Dallas, TX, USA
| | - Omar E Franco
- Department of Surgery, NorthShore University Health System, Research Institute, Evanston, IL, USA
| | - Simon W Hayward
- Department of Surgery, NorthShore University Health System, Research Institute, Evanston, IL, USA.
| |
Collapse
|
|
24
|
Wei H, Fu P, Yao M, Chen Y, Du L. Breast cancer stem cells phenotype and plasma cell-predominant breast cancer independently indicate poor survival. Pathol Res Pract 2016; 212:294-301. [PMID: 26857534 DOI: 10.1016/j.prp.2016.01.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 12/20/2015] [Accepted: 01/24/2016] [Indexed: 01/28/2023]
Abstract
PURPOSE Cancer stem cell-tumor microenvironment ecosystem is proposed to drive tumor heterogeneity. Tumor-infiltrating lymphocytes (TILs) in breast cancer ecosystem were demonstrated to indicate better prognosis and benefit from chemotherapy. This study sought to detect the association between breast cancer stem cells and TILs. METHODS 92 patients with breast cancer were enrolled. Matched cancerous and paracancerous tissues were assembled in a tissue microarray and immunohistochemistry was employed to test expression of breast cancer stem cells (BCSCs) markers. TILs counts were estimated with global hematoxylin-eosin staining. The association between TILs and BCSCs phenotypes was analysed by multivariate analysis. RESULTS Although it was unable to find direct significant association between BCSCs phenotypes and TILs, the BCSCs phenotype with CD44(+)CD24(-)ALDH1A1(+)EpCAM(+)CD49f(+) was proved to be associated with worse DFS and OS (P=0.037 and 0.001). This result was confirmed by cox proportional-hazards regression model (for DFS and OS respectively, HR=2.438 and 3.383, P=0.019 [95%CI 1.418-3.457] and 0.025 [95%CI 1.162-9.843]). Additionally, in results of TILs, plasma cell-predominant breast cancer (PPBC) was unexpectedly found to indicate worse OS and HR was 2.686 (P=0.038 [95%CI 1.582-3.789]). CONCLUSIONS The BCSCs phenotype and PPBC may be helpful stratified factors in future clinical trials. The underlying mechanism needs further research.
Collapse
Affiliation(s)
- Haiyan Wei
- Breast Center, the Fist Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003 China.
| | - Peifen Fu
- Breast Center, the Fist Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003 China.
| | - Minya Yao
- Breast Center, the Fist Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003 China.
| | - Yaomin Chen
- Breast Center, the Fist Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003 China.
| | - Linlin Du
- Department of Intensive Care Unit, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310009 China.
| |
Collapse
|
|
25
|
Tume L, Paco K, Ubidia-Incio R, Moya J. CD133 in breast cancer cells and in breast cancer stem cells as another target for immunotherapy. GACETA MEXICANA DE ONCOLOGÍA 2016. [DOI: 10.1016/j.gamo.2016.01.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
|
|
26
|
Ganapathy V, Moghe PV, Roth CM. Targeting tumor metastases: Drug delivery mechanisms and technologies. J Control Release 2015; 219:215-223. [PMID: 26409123 PMCID: PMC4745901 DOI: 10.1016/j.jconrel.2015.09.042] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 09/22/2015] [Accepted: 09/22/2015] [Indexed: 12/17/2022]
Abstract
Primary sites of tumor are the focal triggers of cancers, yet it is the subsequent metastasis events that cause the majority of the morbidity and mortality. Metastatic tumor cells exhibit a phenotype that differs from that of the parent cells, as they represent a resistant, invasive subpopulation of the original tumor, may have acquired additional genetic or epigenetic alterations under exposure to prior chemotherapeutic or radiotherapeutic treatments, and reside in a microenvironment differing from that of its origin. This combination of resistant phenotype and distal location make tracking and treating metastases particularly challenging. In this review, we highlight some of the unique biological traits of metastasis, which in turn, inspire emerging strategies for targeted imaging of metastasized tumors and metastasis-directed delivery of therapeutics.
Collapse
Affiliation(s)
- Vidya Ganapathy
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, USA
| | - Prabhas V Moghe
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, USA; Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, USA
| | - Charles M Roth
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, USA; Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, USA.
| |
Collapse
|
|
27
|
Davidson LA, Callaway ES, Kim E, Weeks BR, Fan YY, Allred CD, Chapkin RS. Targeted Deletion of p53 in Lgr5-Expressing Intestinal Stem Cells Promotes Colon Tumorigenesis in a Preclinical Model of Colitis-Associated Cancer. Cancer Res 2015; 75:5392-7. [PMID: 26631266 DOI: 10.1158/0008-5472.can-15-1706] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 10/02/2015] [Indexed: 02/07/2023]
Abstract
p53 has been shown to mediate cancer stem-like cell function by suppressing pluripotency and cellular dedifferentiation. However, there have been no studies to date that have addressed the specific effects of p53 loss in colonic adult stem cells. In this study, we investigated the consequences of conditionally ablating p53 in the highly relevant Lgr5(+) stem cell population on tumor initiation and progression in the colon. In a mouse model of carcinogen (AOM)-induced colon cancer, tamoxifen-inducible Lgr5-driven deletion of p53 reduced apoptosis and increased proliferation of crypt stem cells, but had no effect on tumor incidence or size. Conversely, in a mouse model of colitis-associated cancer, in which mice are exposed to AOM and the potent inflammation inducer DSS, stem cell-specific p53 deletion greatly enhanced tumor size and incidence in the colon. These novel findings suggest that the loss of p53 function in stem cells enables colonic tumor formation only when combined with DNA damage and chronic inflammation. Furthermore, we propose that stem cell targeting approaches are valuable for interrogating prevention and therapeutic strategies that aim to specifically eradicate genetically compromised stem cells.
Collapse
Affiliation(s)
- Laurie A Davidson
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
| | - Evelyn S Callaway
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
| | - Eunjoo Kim
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
| | - Brad R Weeks
- Department of Veterinary Pathobiology, College Station, Texas
| | - Yang-Yi Fan
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
| | - Clinton D Allred
- Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. Center for Translational Environmental Health Research, Texas A&M University, College Station, Texas
| | - Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. Center for Translational Environmental Health Research, Texas A&M University, College Station, Texas.
| |
Collapse
|
|
28
|
Zhang W, Yang H, Zhang Y, Lu Y, Zhou T, Li M, Wen Y, Lin X, Xiang R, Chen X. A biotherapy based on PSCs-in-3D spheroid-ameliorated biologics depletes in vivo cancer-sustaining stem cells. Oncotarget 2015; 6:40762-74. [PMID: 26512920 PMCID: PMC4747367 DOI: 10.18632/oncotarget.5691] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Accepted: 09/14/2015] [Indexed: 02/05/2023] Open
Abstract
CSCs are able to survive routine anticancer procedures and peripheral-immune attack. Here we develop and detail a framework of CSC elimination governed by 3D-biologics. Pluripotent cells-engineered 3D-biologics (PMSB) and control non-3D-biologics were prepared from placenta-based somatic stem cells (PSCs) and inoculated respectively into senile hosts bearing progressive mammary, lung, colon carcinomas and melanoma. We demonstrate that PMSB evokes in vivo central-immune microenvironment with subsequent re-expression of thymosin-α1 ~ β4 in thymic cortex-medulla borderline for rapid MHC-unrestricted renewal of γδT-dominated immunocompetence. The post-renewal γδT-subsets could accurately bind and drive CSCs into apoptosis. Finally, with central/peripheral integral microenvironment renewal and TERT/Wnt/β-catenin pathway blockade, the CSC-subsets are fully depleted, leading to substantial cure of diverse tumors by PMSB inoculation (P < 0.01), yet not by non-3D-biologics. Thus, our study may contribute to open up a new avenue for tumor remission via pluripotent cells-engineered 3D-biologics addressing quick renewal of central-thymus and peripheral immune-microenvironment.
Collapse
Affiliation(s)
- Wenhui Zhang
- National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Huanhuan Yang
- National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yanna Zhang
- National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yanan Lu
- National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Tianlin Zhou
- National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Meng Li
- National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yanjun Wen
- Department of Gynecology & Obstetrics, West China Hospital/Second Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Xiaojuan Lin
- Department of Gynecology & Obstetrics, West China Hospital/Second Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Rong Xiang
- Department of Immunology, Nankai University School of Medicine, Tianjin, People's Republic of China
| | - Xiancheng Chen
- National Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| |
Collapse
|
|
29
|
Deng Q, Tang DG. Androgen receptor and prostate cancer stem cells: biological mechanisms and clinical implications. Endocr Relat Cancer 2015; 22:T209-20. [PMID: 26285606 PMCID: PMC4646167 DOI: 10.1530/erc-15-0217] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/18/2015] [Indexed: 12/13/2022]
Abstract
Prostate cancer (PCa) contains phenotypically and functionally distinct cells, and this cellular heterogeneity poses clinical challenges as the distinct cell types likely respond differently to various therapies. Clonal evolution, driven by genetic instability, and intraclonal cancer cell diversification, driven by cancer stem cells (CSCs), together create tumor cell heterogeneity. In this review, we first discuss PCa stem cells (PCSCs) and heterogeneity of androgen receptor (AR) expression in primary, metastatic, and treatment-failed PCa. Based on literature reports and our own studies, we hypothesize that, whereas PCSCs in primary and untreated tumors and models are mainly AR(-), PCSCs in CRPCs could be either AR(+) or AR(-/lo). We illustrate the potential mechanisms AR(+) and AR(-) PCSCs may employ to propagate PCa at the population level, mediate therapy resistance, and metastasize. As a result, targeting AR alone may not achieve long-lasting therapeutic efficacy. Elucidating the roles of AR and PCSCs should provide important clues to designing novel personalized combinatorial therapeutic protocols targeting both AR(+) and AR(-) PCa cells.
Collapse
Affiliation(s)
- Qu Deng
- Department of Epigenetics and Molecular CarcinogenesisUniversity of Texas MD Anderson Cancer Center, Science Park, Park Road 1C, Smithville, Texas 78957, USAProgram in Molecular CarcinogenesisUniversity of Texas Graduate School of Biomedical Sciences, Houston, Texas, USACancer Stem Cell InstituteResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Epigenetics and Molecular CarcinogenesisUniversity of Texas MD Anderson Cancer Center, Science Park, Park Road 1C, Smithville, Texas 78957, USAProgram in Molecular CarcinogenesisUniversity of Texas Graduate School of Biomedical Sciences, Houston, Texas, USACancer Stem Cell InstituteResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Dean G Tang
- Department of Epigenetics and Molecular CarcinogenesisUniversity of Texas MD Anderson Cancer Center, Science Park, Park Road 1C, Smithville, Texas 78957, USAProgram in Molecular CarcinogenesisUniversity of Texas Graduate School of Biomedical Sciences, Houston, Texas, USACancer Stem Cell InstituteResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Epigenetics and Molecular CarcinogenesisUniversity of Texas MD Anderson Cancer Center, Science Park, Park Road 1C, Smithville, Texas 78957, USAProgram in Molecular CarcinogenesisUniversity of Texas Graduate School of Biomedical Sciences, Houston, Texas, USACancer Stem Cell InstituteResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Epigenetics and Molecular CarcinogenesisUniversity of Texas MD Anderson Cancer Center, Science Park, Park Road 1C, Smithville, Texas 78957, USAProgram in Molecular CarcinogenesisUniversity of Texas Graduate School of Biomedical Sciences, Houston, Texas, USACancer Stem Cell InstituteResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| |
Collapse
|
|
30
|
Yoshida GJ. Metabolic reprogramming: the emerging concept and associated therapeutic strategies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:111. [PMID: 26445347 PMCID: PMC4595070 DOI: 10.1186/s13046-015-0221-y] [Citation(s) in RCA: 487] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 09/11/2015] [Indexed: 12/15/2022]
Abstract
Tumor tissue is composed of cancer cells and surrounding stromal cells with diverse genetic/epigenetic backgrounds, a situation known as intra-tumoral heterogeneity. Cancer cells are surrounded by a totally different microenvironment than that of normal cells; consequently, tumor cells must exhibit rapidly adaptive responses to hypoxia and hypo-nutrient conditions. This phenomenon of changes of tumor cellular bioenergetics, called “metabolic reprogramming”, has been recognized as one of 10 hallmarks of cancer. Metabolic reprogramming is required for both malignant transformation and tumor development, including invasion and metastasis. Although the Warburg effect has been widely accepted as a common feature of metabolic reprogramming, accumulating evidence has revealed that tumor cells depend on mitochondrial metabolism as well as aerobic glycolysis. Remarkably, cancer-associated fibroblasts in tumor stroma tend to activate both glycolysis and autophagy in contrast to neighboring cancer cells, which leads to a reverse Warburg effect. Heterogeneity of monocarboxylate transporter expression reflects cellular metabolic heterogeneity with respect to the production and uptake of lactate. In tumor tissue, metabolic heterogeneity induces metabolic symbiosis, which is responsible for adaptation to drastic changes in the nutrient microenvironment resulting from chemotherapy. In addition, metabolic heterogeneity is responsible for the failure to induce the same therapeutic effect against cancer cells as a whole. In particular, cancer stem cells exhibit several biological features responsible for resistance to conventional anti-tumor therapies. Consequently, cancer stem cells tend to form minimal residual disease after chemotherapy and exhibit metastatic potential with additional metabolic reprogramming. This type of altered metabolic reprogramming leads to adaptive/acquired resistance to anti-tumor therapy. Collectively, complex and dynamic metabolic reprogramming should be regarded as a reflection of the “robustness” of tumor cells against unfavorable conditions. This review focuses on the concept of metabolic reprogramming in heterogeneous tumor tissue, and further emphasizes the importance of developing novel therapeutic strategies based on drug repositioning.
Collapse
Affiliation(s)
- Go J Yoshida
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan. .,Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
| |
Collapse
|
|
31
|
Zhang W, Meng Y, Liu N, Wen XF, Yang T. Insights into Chemoresistance of Prostate Cancer. Int J Biol Sci 2015; 11:1160-70. [PMID: 26327810 PMCID: PMC4551752 DOI: 10.7150/ijbs.11439] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Accepted: 06/29/2015] [Indexed: 12/17/2022] Open
Abstract
Prostate cancer (PCa) remains the most prevalent malignancy among males in the western world. Though hormonal therapies through chemical or surgical castration have been proposed many years ago, heretofore, such mainstay for the treatment on advanced PCa has not fundamentally changed. These therapeutic responses are temporary and most cases will eventually undergo PCa recurrence and metastasis, or even progress to castration-resistant prostate cancer (CRPC) due to persistent development of drug resistance. Prostate cancer stem cells (PCSCs) are a small population of cells, which possess unlimited self-renewal capacities, and can regenerate tumorigenic progenies, and play an essential role in PCa therapy resistance, metastasis and recurrence. Nowadays advanced progresses have been made in understanding of PCSC properties, roles of androgen receptor signaling and ATP-binding cassette sub-family G member 2 (ABCG2), as well as roles of genomic non-coding microRNAs and key signaling pathways, which have led to the development of novel therapies which are active against chemoresistant PCa and CRPC. Based on these progresses, this review is dedicated to address mechanisms underlying PCa chemoresistance, unveil crosstalks among pivotal signaling pathways, explore novel biotherapeutic agents, and elaborate functional properties and specific roles of chemoresistant PCSCs, which may act as a promising target for novel therapies against chemoresistant PCa.
Collapse
Affiliation(s)
- Wei Zhang
- 1. Department of Pharmacology, School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Yan Meng
- 2. Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Na Liu
- 3. Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiao-Fei Wen
- 4. Department of Urology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Tao Yang
- 2. Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| |
Collapse
|
|
32
|
Kast RE, Karpel-Massler G, Halatsch ME. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget 2015; 5:8052-82. [PMID: 25211298 PMCID: PMC4226667 DOI: 10.18632/oncotarget.2408] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs--aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.
Collapse
Affiliation(s)
| | - Georg Karpel-Massler
- University of Ulm, Department of Neurosurgery, Albert-Einstein-Allee 23, Ulm, Germany
| | - Marc-Eric Halatsch
- University of Ulm, Department of Neurosurgery, Albert-Einstein-Allee 23, Ulm, Germany
| |
Collapse
|
|
33
|
Abstract
This review discusses quantitative modeling studies of stem and non-stem cancer cell interactions and the fraction of cancer stem cells.
Collapse
Affiliation(s)
- Heiko Enderling
- Department of Integrated Mathematical Oncology
- H. Lee Moffitt Cancer Center & Research Institute
- Tampa
- USA
| |
Collapse
|
|
34
|
Le JM, Squarize CH, Castilho RM. Histone modifications: Targeting head and neck cancer stem cells. World J Stem Cells 2014; 6:511-525. [PMID: 25426249 PMCID: PMC4178252 DOI: 10.4252/wjsc.v6.i5.511] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 09/10/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor improvement in the last three decades. Despite new surgical techniques and chemotherapy protocols, tumor resistance to chemotherapy remains a significant challenge for HNSCC patients. Numerous mechanisms underlie chemoresistance, including genetic and epigenetic alterations in cancer cells that may be acquired during treatment and activation of mitogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer-of activated B cell, that cause reduced apoptosis. In addition to dysfunctional molecular signaling, emerging evidence reveals involvement of cancer stem cells (CSCs) in tumor development and in tumor resistance to chemotherapy and radiotherapy. These observations have sparked interest in understanding the mechanisms involved in the control of CSC function and fate. Post-translational modifications of histones dynamically influence gene expression independent of alterations to the DNA sequence. Recent findings from our group have shown that pharmacological induction of post-translational modifications of tumor histones dynamically modulates CSC plasticity. These findings suggest that a better understanding of the biology of CSCs in response to epigenetic switches and pharmacological inhibitors of histone function may directly translate to the development of a mechanism-based strategy to disrupt CSCs. In this review, we present and discuss current knowledge on epigenetic modifications of HNSCC and CSC response to DNA methylation and histone modifications. In addition, we discuss chromatin modifications and their role in tumor resistance to therapy.
Collapse
|
|
35
|
Pors K, Moreb JS. Aldehyde dehydrogenases in cancer: an opportunity for biomarker and drug development? Drug Discov Today 2014; 19:1953-63. [PMID: 25256776 DOI: 10.1016/j.drudis.2014.09.009] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 08/31/2014] [Accepted: 09/15/2014] [Indexed: 02/07/2023]
Abstract
Aldehyde dehydrogenases (ALDHs) belong to a superfamily of 19 isozymes that are known to participate in many physiologically important biosynthetic processes including detoxification of specific endogenous and exogenous aldehyde substrates. The high expression levels of an emerging number of ALDHs in various cancer tissues suggest that these enzymes have pivotal roles in cancer cell survival and progression. Mapping out the heterogeneity of tumours and their cancer stem cell (CSC) component will be key to successful design of strategies involving therapeutics that are targeted against specific ALDH isozymes. This review summarises recent progress in ALDH-focused cancer research and discovery of small-molecule-based inhibitors.
Collapse
Affiliation(s)
- Klaus Pors
- Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK.
| | - Jan S Moreb
- Hematological Malignancies, PO Box 100278, Gainesville, FL 32610-0277, USA.
| |
Collapse
|
|
36
|
From sprouting angiogenesis to erythrocytes generation by cancer stem cells: evolving concepts in tumor microcirculation. BIOMED RESEARCH INTERNATIONAL 2014; 2014:986768. [PMID: 25162040 PMCID: PMC4138761 DOI: 10.1155/2014/986768] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 07/13/2014] [Accepted: 07/14/2014] [Indexed: 01/26/2023]
Abstract
Angiogenesis is essential for tumor growth and metastasis. Over the last decades, a substantial progress has been achieved in defining different patterns of tumor microcirculation. Sprouting angiogenesis, the oldest model of microcirculation, is the de novo vessel formation from preexisting blood vessels. Vessel splitting and hijacking, also known, respectively, as intussusception and cooption, are alternative models that account for tumor resistance to antiangiogenic therapy. In addition to remodeling the microenvironment, the tumor cell can undergo intrinsic changes and survive hypoxic conditions by acquiring stem cell properties. In line with the concept of pluripotency, tumor cells can form vascular mimicry structures creating their own microcirculation despite a latent vessel growth. The recent identification of the polyploid giant cancer cells and tumor-derived erythrocytes is the most innovative survival mechanism in hypoxia and provides a potential target for more effective therapies.
Collapse
|
|
37
|
Suguro M, Yoshida N, Umino A, Kato H, Tagawa H, Nakagawa M, Fukuhara N, Karnan S, Takeuchi I, Hocking TD, Arita K, Karube K, Tsuzuki S, Nakamura S, Kinoshita T, Seto M. Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis. Cancer Sci 2014; 105:897-904. [PMID: 24815991 PMCID: PMC4317909 DOI: 10.1111/cas.12442] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 05/01/2014] [Accepted: 05/06/2014] [Indexed: 11/30/2022] Open
Abstract
Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T-cell lymphoma/leukemia, peripheral T-cell lymphoma, not otherwise specified, and mantle cell lymphoma. Our analysis was extended to other types of lymphoma including marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma. To determine the presence of clonal heterogeneity, 332 cases were examined using array comparative genomic hybridization analysis. Results showed that incidence of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Survival analysis revealed that mantle cell lymphoma and diffuse large B-cell lymphoma with clonal heterogeneity showed significantly poorer prognosis, and that clonal heterogeneity was confirmed as an independent predictor of poor prognosis for both types of lymphoma. Interestingly, 8q24.1 (MYC) gain, 9p21.3 (CDKN2A/2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were recurrent genomic lesions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that alterations of these genes may play a role in clonal heterogeneity.
Collapse
Affiliation(s)
- Miyuki Suguro
- Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
|