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1
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Go RE, Seong SM, Choi Y, Choi KC. A Fungicide, Fludioxonil, Formed the Polyploid Giant Cancer Cells and Induced Metastasis and Stemness in MDA-MB-231 Triple-Negative Breast Cancer Cells. Int J Mol Sci 2024; 25:9024. [PMID: 39201710 PMCID: PMC11354328 DOI: 10.3390/ijms25169024] [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: 06/29/2024] [Revised: 08/04/2024] [Accepted: 08/14/2024] [Indexed: 09/03/2024] Open
Abstract
Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10-5 M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial-mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells.
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Affiliation(s)
| | | | | | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea; (R.-E.G.); (S.-M.S.); (Y.C.)
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2
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Liu P, Wang L, Yu H. Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation. Front Cell Dev Biol 2024; 12:1410637. [PMID: 39055650 PMCID: PMC11269155 DOI: 10.3389/fcell.2024.1410637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 06/17/2024] [Indexed: 07/27/2024] Open
Abstract
Polyploid giant cancer cells (PGCCs) are characterized by the presence of either a single enlarged nucleus or multiple nuclei and are closely associated with tumor progression and treatment resistance. These cells contribute significantly to cellular heterogeneity and can arise from various stressors, including radiation, chemotherapy, hypoxia, and environmental factors. The formation of PGCCs can occur through mechanisms such as endoreplication, cell fusion, cytokinesis failure, mitotic slippage, or cell cannibalism. Notably, PGCCs exhibit traits similar to cancer stem cells (CSCs) and generate highly invasive progeny through asymmetric division. The presence of PGCCs and their progeny is pivotal in conferring resistance to chemotherapy and radiation, as well as facilitating tumor recurrence and metastasis. This review provides a comprehensive analysis of the origins, potential formation mechanisms, stressors, unique characteristics, and regulatory pathways of PGCCs, alongside therapeutic strategies targeting these cells. The objective is to enhance the understanding of PGCC initiation and progression, offering novel insights into tumor biology.
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Affiliation(s)
- Pan Liu
- Laboratory of Basic Medicine, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
- Beifang Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lili Wang
- Laboratory of Basic Medicine, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Huiying Yu
- Laboratory of Basic Medicine, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
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3
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Zheng M, Tian S, Zhou X, Yan M, Zhou M, Yu Y, Zhang Y, Wang X, Li N, Ren L, Zhang S. MITF regulates the subcellular location of HIF1α through SUMOylation to promote the invasion and metastasis of daughter cells derived from polyploid giant cancer cells. Oncol Rep 2024; 51:63. [PMID: 38456491 PMCID: PMC10940875 DOI: 10.3892/or.2024.8722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 01/23/2024] [Indexed: 03/09/2024] Open
Abstract
High concentrations of cobalt chloride (CoCl2) can induce the formation of polyploid giant cancer cells (PGCCs) in various tumors, which can produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric division. To study the role of hypoxia‑inducible factor (HIF) 1α in the formation of PGCCs, colon cancer cell lines Hct116 and LoVo were used as experimental subjects. Western blotting, nuclear and cytoplasmic protein extraction and immunocytochemical experiments were used to compare the changes in the expression and subcellular localization of HIF1α, microphthalmia‑associated transcription factor (MITF), protein inhibitor of activated STAT protein 4 (PIAS4) and von Hippel‑Lindau disease tumor suppressor (VHL) after treatment with CoCl2. The SUMOylation of HIFα was verified by co‑immunoprecipitation assay. After inhibiting HIF1α SUMOylation, the changes in proliferation, migration and invasion abilities of Hct116 and LoVo were compared by plate colony formation, wound healing and Transwell migration and invasion. In addition, lysine sites that led to SUMOylation of HIF1α were identified through site mutation experiments. The results showed that CoCl2 can induce the formation of PGCCs with the expression level of HIF1α higher in treated cells than in control cells. HIF1α was primarily located in the cytoplasm of control cell. Following CoCl2 treatment, the subcellular localization of HIF1α was primarily in the nuclei of PGCCs with daughter cells (PDCs). After treatment with SUMOylation inhibitors, the nuclear HIF1α expression in PDCs decreased. Furthermore, their proliferation, migration and invasion abilities also decreased. After inhibiting the expression of MITF, the expression of HIF1α decreased. MITF can regulate HIF1α SUMOylation. Expression and subcellular localization of VHL and HIF1α did not change following PIAS4 knockdown. SUMOylation of HIF1α occurs at the amino acid sites K391 and K477 in PDCs. After mutation of the two sites, nuclear expression of HIF1α in PDCs was reduced, along with a significant reduction in the proliferation, migration and invasion abilities. In conclusion, the post‑translation modification regulated the subcellular location of HIF1α and the nuclear expression of HIF1α promoted the proliferation, migration and invasion abilities of PDCs. MITF could regulate the transcription and protein levels of HIF1α and participate in the regulation of HIF1α SUMOylation.
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Affiliation(s)
- Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Shifeng Tian
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Xinyue Zhou
- Graduate School, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Man Yan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
| | - Mingming Zhou
- Graduate School, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Yongjun Yu
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Yue Zhang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
| | - Xiaorui Wang
- Graduate School, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Na Li
- Graduate School, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Li Ren
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institution and Hospital, Tianjin 300090, P.R. China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, P.R. China
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4
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Jiao Y, Yu Y, Zheng M, Yan M, Wang J, Zhang Y, Zhang S. Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis. Clin Transl Med 2024; 14:e1567. [PMID: 38362620 PMCID: PMC10870057 DOI: 10.1002/ctm2.1567] [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: 10/26/2023] [Revised: 01/11/2024] [Accepted: 01/16/2024] [Indexed: 02/17/2024] Open
Abstract
Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.
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Affiliation(s)
- Yuqi Jiao
- School of Integrative MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Yongjun Yu
- Department of PathologyTianjin Union Medical CenterTianjinChina
| | - Minying Zheng
- Department of PathologyTianjin Union Medical CenterNankai UniversityTianjinChina
| | - Man Yan
- School of Integrative MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Jiangping Wang
- School of Integrative MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Yue Zhang
- School of Integrative MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Shiwu Zhang
- Department of PathologyTianjin Union Medical CenterTianjinChina
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Zhou M, Ma Y, Chiang CC, Rock EC, Butler SC, Anne R, Yatsenko S, Gong Y, Chen YC. Single-cell morphological and transcriptome analysis unveil inhibitors of polyploid giant breast cancer cells in vitro. Commun Biol 2023; 6:1301. [PMID: 38129519 PMCID: PMC10739852 DOI: 10.1038/s42003-023-05674-5] [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: 06/06/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023] Open
Abstract
Considerable evidence suggests that breast cancer therapeutic resistance and relapse can be driven by polyploid giant cancer cells (PGCCs). The number of PGCCs increases with the stages of disease and therapeutic stress. Given the importance of PGCCs, it remains challenging to eradicate them. To discover effective anti-PGCC compounds, there is an unmet need to rapidly distinguish compounds that kill non-PGCCs, PGCCs, or both. Here, we establish a single-cell morphological analysis pipeline with a high throughput and great precision to characterize dynamics of individual cells. In this manner, we screen a library to identify promising compounds that inhibit all cancer cells or only PGCCs (e.g., regulators of HDAC, proteasome, and ferroptosis). Additionally, we perform scRNA-Seq to reveal altered cell cycle, metabolism, and ferroptosis sensitivity in breast PGCCs. The combination of single-cell morphological and molecular investigation reveals promising anti-PGCC strategies for breast cancer treatment and other malignancies.
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Affiliation(s)
- Mengli Zhou
- UPMC Hillman Cancer Center, University of Pittsburgh, 5115 Centre Ave, Pittsburgh, PA, 15232, USA
- Department of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Avenue, Pittsburgh, PA, 15260, USA
- Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yushu Ma
- UPMC Hillman Cancer Center, University of Pittsburgh, 5115 Centre Ave, Pittsburgh, PA, 15232, USA
- Department of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Avenue, Pittsburgh, PA, 15260, USA
| | - Chun-Cheng Chiang
- UPMC Hillman Cancer Center, University of Pittsburgh, 5115 Centre Ave, Pittsburgh, PA, 15232, USA
- Department of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Avenue, Pittsburgh, PA, 15260, USA
| | - Edwin C Rock
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, 3700 O'Hara Street, Pittsburgh, PA, 15260, USA
| | - Samuel Charles Butler
- UPMC Hillman Cancer Center, University of Pittsburgh, 5115 Centre Ave, Pittsburgh, PA, 15232, USA
| | - Rajiv Anne
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, 3700 O'Hara Street, Pittsburgh, PA, 15260, USA
| | - Svetlana Yatsenko
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA
- Magee Womens Research Institute, Pittsburgh, PA, USA
| | - Yinan Gong
- UPMC Hillman Cancer Center, University of Pittsburgh, 5115 Centre Ave, Pittsburgh, PA, 15232, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
| | - Yu-Chih Chen
- UPMC Hillman Cancer Center, University of Pittsburgh, 5115 Centre Ave, Pittsburgh, PA, 15232, USA.
- Department of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Avenue, Pittsburgh, PA, 15260, USA.
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, 3700 O'Hara Street, Pittsburgh, PA, 15260, USA.
- CMU-Pitt Ph.D. Program in Computational Biology, University of Pittsburgh, 3420 Forbes Avenue, Pittsburgh, PA, 15260, USA.
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6
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El Baba R, Haidar Ahmad S, Monnien F, Mansar R, Bibeau F, Herbein G. Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells. Oncogene 2023; 42:3047-3061. [PMID: 37634008 PMCID: PMC10555822 DOI: 10.1038/s41388-023-02813-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/10/2023] [Accepted: 08/15/2023] [Indexed: 08/28/2023]
Abstract
Human cytomegalovirus (HCMV) infection has been implicated in epithelial ovarian cancer (OC). Polyploidy giant cancer cells (PGCCs) have been observed in high-grade serous ovarian carcinoma (HGSOC); they possess cancer stem cell-like characteristics and give rise to progeny cells expressing epithelial-mesenchymal transition (EMT) markers. EZH2 plays a potential oncogenic role, correlating with high proliferative index and tumor grade in OC. Herein, we present the experimental evidence for HCMV as a reprogramming vector that elicited human ovarian epithelial cells (OECs) transformation leading to the generation of "CMV-transformed Ovarian cells" (CTO). The infection with the two high-risk clinical strains, namely HCMV-DB and BL provoked a distinct cellular and molecular mechanisms in infected OECs. EZH2 upregulation and cellular proliferation were curtailed by using EZH2 inhibitors. The HGSOC biopsies were characterized by an elevated EZH2 expression, possessing a strong positive correlation between the aforementioned marker and HCMV. From HGSOC biopsies, we isolated three HCMV clinical strains that transformed OECs generating CTO cells which displayed proliferative potentials in addition to EZH2 upregulation and PGCCs generation; these features were reduced upon EZH2 inhibition. High-risk HCMV strains transformed OECs confirming an HCMV-induced epithelial ovarian cancer model and highlighting EZH2 tumorigenic properties. Our findings might be highly relevant in the pathophysiology of ovarian tumors thereby nominating new targeted therapeutics.
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Affiliation(s)
- Ranim El Baba
- Department of Pathogens & Inflammation-EPILAB Laboratory EA4266, University of Franche-Comté, Besançon, France
| | - Sandy Haidar Ahmad
- Department of Pathogens & Inflammation-EPILAB Laboratory EA4266, University of Franche-Comté, Besançon, France
| | | | - Racha Mansar
- Department of Pathology, CHU Besançon, Besançon, France
| | | | - Georges Herbein
- Department of Pathogens & Inflammation-EPILAB Laboratory EA4266, University of Franche-Comté, Besançon, France.
- Department of Virology, CHU Besançon, Besançon, France.
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7
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Jemaà M, Daams R, Charfi S, Mertens F, Huber SM, Massoumi R. Tetraploidization Increases the Motility and Invasiveness of Cancer Cells. Int J Mol Sci 2023; 24:13926. [PMID: 37762227 PMCID: PMC10531202 DOI: 10.3390/ijms241813926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Polyploidy and metastasis are associated with a low probability of disease-free survival in cancer patients. Polyploid cells are known to facilitate tumorigenesis. However, few data associate polyploidization with metastasis. Here, by generating and using diploid (2n) and tetraploid (4n) clones from malignant fibrous histiocytoma (MFH) and colon carcinoma (RKO), we demonstrate the migration and invasion advantage of tetraploid cells in vitro using several assays, including the wound healing, the OrisTM two-dimensional cell migration, single-cell migration tracking by video microscopy, the Boyden chamber, and the xCELLigence RTCA real-time cell migration. Motility advantage was observed despite tetraploid cell proliferation weakness. We could also demonstrate preferential metastatic potential in vivo for the tetraploid clone using the tail vein injection in mice and tracking metastatic tumors in the lung. Using the Mitelman Database of Chromosome Aberrations in Cancer, we found an accumulation of polyploid karyotypes in metastatic tumors compared to primary ones. This work reveals the clinical relevance of the polyploid subpopulation and the strategic need to highlight polyploidy in preclinical studies as a therapeutic target for metastasis.
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Affiliation(s)
- Mohamed Jemaà
- Department of Laboratory Medicine, Translational Cancer Research, Faculty of Medicine, Lund University, 22381 Lund, Sweden;
- Human Genetics Laboratory (LR99ES10), Faculty of Medicine of Tunis (FMT), Tunis El Manar University, Tunis 1006, Tunisia
- Department of Biology, Faculty of Science of Tunis, Tunis El Manar University, Tunis 2092, Tunisia
| | - Renee Daams
- Department of Laboratory Medicine, Translational Cancer Research, Faculty of Medicine, Lund University, 22381 Lund, Sweden;
| | - Slim Charfi
- Department of Pathology, Habib Bourguiba Hospital, Sfax University, Sfax 3029, Tunisia;
| | - Fredrik Mertens
- Department of Laboratory Medicine, Division of Clinical Genetics Lund University, 22381 Lund, Sweden;
| | - Stephan M. Huber
- Department of Radiation Oncology, University Hospital of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany;
| | - Ramin Massoumi
- Department of Laboratory Medicine, Translational Cancer Research, Faculty of Medicine, Lund University, 22381 Lund, Sweden;
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Zheng M, Chen L, Fu J, Yang X, Chen S, Fu W, Li Y, Zhang S. Cdc42 Regulates the Expression of Cytoskeleton and Microtubule Network Proteins to Promote Invasion and Metastasis of Progeny Cells Derived from CoCl 2-induced Polyploid Giant Cancer Cells. J Cancer 2023; 14:1920-1934. [PMID: 37476197 PMCID: PMC10355212 DOI: 10.7150/jca.85032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/10/2023] [Indexed: 07/22/2023] Open
Abstract
Purpose: Our previous studies have shown that CoCl2 can induce the formation of polyploid giant cancer cells (PGCCs) and PGCCs could produce progeny cells via asymmetric division. In this study, the molecular mechanism by which PGCCs generate progeny cells with high invasion and migration abilities was explored. Methods: In this study, PGCCs induced by CoCl2 produced progeny cells via asymmetric division, which was observed dynamically using laser scanning confocal microscopy. Cell cycle in LoVo and Hct116 before and after CoCl2 treatment was analyzed by flow cytometry. Cell function experiments, co-immunoprecipitation, mass spectrometry analysis, ML141 treatment, western blotting, and siRNA transfection experiments were used to demonstrate that Cdc42/PAK1 was involved in the regulation of cytoskeleton expression. The proliferation, migration, and invasion abilities of PGCCs and progeny cells were compared in PGCCs and progeny cells with and without inhibiting the expression of Cdc42 and PAK1. Results: G2/M phase arrest appeared in CoCl2-treated LoVo and Hct116 cells. After CoCl2 treatment, an increased expression of Cdc42 and PAK1 led to a decrease in the expression of stathmin and an increase in the expression of phosphorylated stathmin, which is located in the nucleus of PGCCs and progeny cells. PTPN14 negatively regulates the expression of PAK1 and p38MAPK. Low levels of PTPN14 expression, a downstream regulatory protein of stathmin, endows progeny tumor cells generated by PGCCs with the ability to invade and metastasize. The expression of PKA1α, cathepsin B, and D increased in CoCl2-treated cells compared with that in the control cells, associated with the infiltration and migration of PGCCs with their progeny cells. Conclusion: CoCl2-induced overexpression of Cdc42 plays a critical role in increasing the infiltration and migration abilities of PGCCs and progeny cells by regulating cytoskeleton protein expression.
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Affiliation(s)
- Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, P.R. China
- State Key Laboratory of Medicinal Chemical Biology, NanKai University, Tianjin, 300071, P.R. China
| | - Lankai Chen
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, P.R. China
| | - Junjie Fu
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, P.R. China
| | - Xiaohui Yang
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, P.R. China
| | - Shuo Chen
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, P.R. China
| | - Wenzheng Fu
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, P.R. China
| | - Yuwei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, P.R. China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, P.R. China
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9
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Mallin MM, Kim N, Choudhury MI, Lee SJ, An SS, Sun SX, Konstantopoulos K, Pienta KJ, Amend SR. Cells in the polyaneuploid cancer cell (PACC) state have increased metastatic potential. Clin Exp Metastasis 2023:10.1007/s10585-023-10216-8. [PMID: 37326720 DOI: 10.1007/s10585-023-10216-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 06/02/2023] [Indexed: 06/17/2023]
Abstract
Although metastasis is the leading cause of cancer deaths, it is quite rare at the cellular level. Only a rare subset of cancer cells (~ 1 in 1.5 billion) can complete the entire metastatic cascade: invasion, intravasation, survival in the circulation, extravasation, and colonization (i.e. are metastasis competent). We propose that cells engaging a Polyaneuploid Cancer Cell (PACC) phenotype are metastasis competent. Cells in the PACC state are enlarged, endocycling (i.e. non-dividing) cells with increased genomic content that form in response to stress. Single-cell tracking using time lapse microscopy reveals that PACC state cells have increased motility. Additionally, cells in the PACC state exhibit increased capacity for environment-sensing and directional migration in chemotactic environments, predicting successful invasion. Magnetic Twisting Cytometry and Atomic Force Microscopy reveal that cells in the PACC state display hyper-elastic properties like increased peripheral deformability and maintained peri-nuclear cortical integrity that predict successful intravasation and extravasation. Furthermore, four orthogonal methods reveal that cells in the PACC state have increased expression of vimentin, a hyper-elastic biomolecule known to modulate biomechanical properties and induce mesenchymal-like motility. Taken together, these data indicate that cells in the PACC state have increased metastatic potential and are worthy of further in vivo analysis.
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Affiliation(s)
- Mikaela M Mallin
- Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA.
| | - Nicholas Kim
- Rutgers Institute for Translational Medicine and Science, New Brunswick, NJ, USA
| | | | - Se Jong Lee
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Steven S An
- Rutgers Institute for Translational Medicine and Science, New Brunswick, NJ, USA
| | - Sean X Sun
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | | | - Kenneth J Pienta
- Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA
| | - Sarah R Amend
- Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA
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10
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Casotti MC, Meira DD, Zetum ASS, de Araújo BC, da Silva DRC, dos Santos EDVW, Garcia FM, de Paula F, Santana GM, Louro LS, Alves LNR, Braga RFR, Trabach RSDR, Bernardes SS, Louro TES, Chiela ECF, Lenz G, de Carvalho EF, Louro ID. Computational Biology Helps Understand How Polyploid Giant Cancer Cells Drive Tumor Success. Genes (Basel) 2023; 14:801. [PMID: 37107559 PMCID: PMC10137723 DOI: 10.3390/genes14040801] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/17/2023] [Accepted: 03/20/2023] [Indexed: 03/29/2023] Open
Abstract
Precision and organization govern the cell cycle, ensuring normal proliferation. However, some cells may undergo abnormal cell divisions (neosis) or variations of mitotic cycles (endopolyploidy). Consequently, the formation of polyploid giant cancer cells (PGCCs), critical for tumor survival, resistance, and immortalization, can occur. Newly formed cells end up accessing numerous multicellular and unicellular programs that enable metastasis, drug resistance, tumor recurrence, and self-renewal or diverse clone formation. An integrative literature review was carried out, searching articles in several sites, including: PUBMED, NCBI-PMC, and Google Academic, published in English, indexed in referenced databases and without a publication time filter, but prioritizing articles from the last 3 years, to answer the following questions: (i) "What is the current knowledge about polyploidy in tumors?"; (ii) "What are the applications of computational studies for the understanding of cancer polyploidy?"; and (iii) "How do PGCCs contribute to tumorigenesis?"
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Affiliation(s)
- Matheus Correia Casotti
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Débora Dummer Meira
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Aléxia Stefani Siqueira Zetum
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Bruno Cancian de Araújo
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Danielle Ribeiro Campos da Silva
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | | | - Fernanda Mariano Garcia
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Flávia de Paula
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Gabriel Mendonça Santana
- Centro de Ciências da Saúde, Curso de Medicina, Universidade Federal do Espírito Santo (UFES), Vitória 29090-040, Brazil
| | - Luana Santos Louro
- Centro de Ciências da Saúde, Curso de Medicina, Universidade Federal do Espírito Santo (UFES), Vitória 29090-040, Brazil
| | - Lyvia Neves Rebello Alves
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Raquel Furlani Rocon Braga
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Raquel Silva dos Reis Trabach
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
| | - Sara Santos Bernardes
- Departamento de Patologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte 31270-901, Brazil
| | - Thomas Erik Santos Louro
- Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (EMESCAM), Vitória 29027-502, Brazil
| | - Eduardo Cremonese Filippi Chiela
- Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Brazil
- Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Brazil
- Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil
| | - Guido Lenz
- Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil
- Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91501-970, Brazil
| | - Elizeu Fagundes de Carvalho
- Instituto de Biologia Roberto Alcântara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro 20551-030, Brazil
| | - Iúri Drumond Louro
- Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil; (M.C.C.)
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11
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Tessmann JW, Rocha MR, Morgado-Díaz JA. Mechanisms of radioresistance and the underlying signaling pathways in colorectal cancer cells. J Cell Biochem 2023; 124:31-45. [PMID: 36565460 DOI: 10.1002/jcb.30361] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 11/23/2022] [Accepted: 12/13/2022] [Indexed: 12/25/2022]
Abstract
Radiotherapy is one of the most common modalities for the treatment of a wide range of tumors, including colorectal cancer (CRC); however, radioresistance of cancer cells remains a major limitation for this treatment. Following radiotherapy, the activities of various cellular mechanisms and cell signaling pathways are altered, resulting in the development of radioresistance, which leads to therapeutic failure and poor prognosis in patients with cancer. Furthermore, even though several inhibitors have been developed to target tumor resistance, these molecules can induce side effects in nontumor cells due to low specificity and efficiency. However, the role of these mechanisms in CRC has not been extensively studied. This review discusses recent studies regarding the relationship between radioresistance and the alterations in a series of cellular mechanisms and cell signaling pathways that lead to therapeutic failure and tumor recurrence. Our review also presents recent advances in the in vitro/in vivo study models aimed at investigating the radioresistance mechanism in CRC. Furthermore, it provides a relevant biochemical basis in theory, which can be useful to improve radiotherapy sensitivity and prolong patient survival.
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Affiliation(s)
- Josiane W Tessmann
- Cellular and Molecular Oncobiology Program, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
| | - Murilo R Rocha
- Cellular and Molecular Oncobiology Program, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
| | - Jose A Morgado-Díaz
- Cellular and Molecular Oncobiology Program, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
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12
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CCR3 blockage elicits polyploidization associated with the signatures of epithelial-mesenchymal transition in carcinoma cell lines. Cancer Gene Ther 2023; 30:137-148. [PMID: 36123391 DOI: 10.1038/s41417-022-00532-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/12/2022] [Accepted: 09/02/2022] [Indexed: 01/19/2023]
Abstract
Malignant features such as the acquisition of metastatic ability, stemness of cells, and therapeutic resistance of cancer cells are associated with epithelial-mesenchymal transition (EMT) accompanied by changes in motility and morphology. Recent reports implicated that the formation of polyploid giant cancer cells (PGCCs) in human malignancy correlated with the EMT processes. Chemokines are often involved in the regulation of cancer cell migration into tissues, and various types of human cancers exhibit enhanced expression of chemokine receptors, which could augment intrinsic potentials such as invasive activity, proliferating ability, and survival capacity in cancer cells. Nevertheless, the contribution of CCR3 in malignant cancer cells is controversial because it is a well-known primal receptor for the migration of eosinophils, one of the cells of the innate immune system. Here, we explored the blockage of chemokine receptor CCR3 in carcinoma cell lines and found that inhibition of CCR3 induced the formation of polyploid giant cells and stabilization of β-catenin via the PI3K/Akt/GSK-3β signaling pathway, which are processes associated with EMT. As a result of CCR3 inhibition, converted cells acquired enhanced mobile and proliferation abilities. In summary, these data indicate that modulation of the CCR3/PI3K/Akt/GSK-3β signaling pathway regulates polyploidization associated with the EMT processes.
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13
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Zhou X, Zhou M, Zheng M, Tian S, Yang X, Ning Y, Li Y, Zhang S. Polyploid giant cancer cells and cancer progression. Front Cell Dev Biol 2022; 10:1017588. [PMID: 36274852 PMCID: PMC9581214 DOI: 10.3389/fcell.2022.1017588] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/21/2022] [Indexed: 12/02/2022] Open
Abstract
Polyploid giant cancer cells (PGCCs) are an important feature of cellular atypia, the detailed mechanisms of their formation and function remain unclear. PGCCs were previously thought to be derived from repeated mitosis/cytokinesis failure, with no intrinsic ability to proliferate and divide. However, recently, PGCCs have been confirmed to have cancer stem cell (CSC)-like characteristics, and generate progeny cells through asymmetric division, which express epithelial-mesenchymal transition-related markers to promote invasion and migration. The formation of PGCCs can be attributed to multiple stimulating factors, including hypoxia, chemotherapeutic reagents, and radiation, can induce the formation of PGCCs, by regulating the cell cycle and cell fusion-related protein expression. The properties of CSCs suggest that PGCCs can be induced to differentiate into non-tumor cells, and produce erythrocytes composed of embryonic hemoglobin, which have a high affinity for oxygen, and thereby allow PGCCs survival from the severe hypoxia. The number of PGCCs is associated with metastasis, chemoradiotherapy resistance, and recurrence of malignant tumors. Targeting relevant proteins or signaling pathways related with the formation and transdifferentiation of adipose tissue and cartilage in PGCCs may provide new strategies for solid tumor therapy.
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Affiliation(s)
- Xinyue Zhou
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Mingming Zhou
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Shifeng Tian
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Xiaohui Yang
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Yidi Ning
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Yuwei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
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14
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Fu F, Chen L, Yang X, Fan L, Zhang M, Chen S, Zheng M, Gao M, Zhang S. PLK4 is a key molecule in the formation of PGCCs and promotes invasion and migration of progeny cells derived from PGCCs. J Cancer 2022; 13:2954-2969. [PMID: 35912011 PMCID: PMC9330457 DOI: 10.7150/jca.74211] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/09/2022] [Indexed: 11/08/2022] Open
Abstract
Purpose: Cancer stem cells (CSCs) are the evil source of tumor metastasis and recurrence. Polyploid giant cancer cells (PGCCs) that exhibit the characteristics of CSCs produced daughter cells via asymmetric division. The molecular mechanisms of daughter cells derived from PGCCs with high migration, invasion, and proliferation abilities in colorectal cancer (CRC) are explored in this paper based on the bioinformatics analysis. Materials and Methods: We characterized the expression of CSC-related genes in CRCs by analyzing the mRNAsi of The Cancer Genome Atlas and survival time. Weighted gene co-expression network analysis was performed to identify the modules of the hub and key genes. The migration, invasion, and proliferation abilities of cells, the expression of epithelial-mesenchymal transition (EMT)-related proteins and polo-like kinase 4 (PLK4) were compared in LoVo and Hct116 cells with and without bufalin treatment. In addition, the expression and subcellular location of cell division cycle 25C (CDC25C) in cells before and after PLK4 knockdown were assessed. Results: Eight hub genes were screened out and positively association with mRNAsi in CRCs based on bioinformatic analysis. Among them, checkpoint Kinase-1 (CHEK1), budding uninhibited by benzimidazoles 1 Homolog Beta (BUB1B) and PLK4 were closely associated with the prognosis of CRC patients. Bufalin could induce the formation of PGCCs in LoVo and Hct116 cell lines. PLK4 was overexpressed in PGCCs with progeny cells and progeny cells derived from PGCCs had strong migration and invasion abilities by expressing epithelial-mesenchymal transition (EMT)-related proteins. PLK4 could interact with CDC25C and promote CDC25C phosphorylation which was associated with the formation of PGCCs. Decreasing CDC25C expression in both LoVo and Hct116 PGCCs with progeny cells, while levels of pCDC25C-ser216 and pCDC25C-ser198 were increased in LoVo and decreased in Hct116 PGCCs with progeny cells. pCDC25C-ser216 located in the cytoplasm and pCDC25C-ser198 located in the nucleus in cells after bufalin treatment. Furthermore, expression of CDC25C, pCDC25C-ser216, and pCDC25C-ser198 was downregulated after PLK4 knockdown. Furthermore, the expression level of PLK4 was associated with differentiated degree, and lymph node metastasis in human CRC tissues. Conclusion: PLK4 contributes to the formation of PGCCs by regulating the expression of CDC25C and is associated with the expression and subcellular location of CDC25C, pCDC25C-ser216 and pCDC25C-ser198.
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Affiliation(s)
- Fangmei Fu
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, P.R. China
| | - Lankai Chen
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, P.R. China
| | - Xiaohui Yang
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, P.R. China
| | - Linlin Fan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, P.R. China
| | - Mingqing Zhang
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, P.R. China
| | - Shuo Chen
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, P.R. China
| | - Ming Gao
- Department of Thyroid Surgery, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, P.R. China
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15
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Nehme Z, Pasquereau S, Haidar Ahmad S, El Baba R, Herbein G. Polyploid giant cancer cells, EZH2 and Myc upregulation in mammary epithelial cells infected with high-risk human cytomegalovirus. EBioMedicine 2022; 80:104056. [PMID: 35596973 PMCID: PMC9121245 DOI: 10.1016/j.ebiom.2022.104056] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 02/08/2023] Open
Abstract
Background Human cytomegalovirus (HCMV) infection has been actively implicated in complex neoplastic processes. Beyond oncomodulation, the molecular mechanisms that might underlie HCMV-induced oncogenesis are being extensively studied. Polycomb repressive complex 2 (PRC2) proteins, in particular enhancer of zeste homolog 2 (EZH2) are associated with cancer progression. Nevertheless, little is known about EZH2 activation in the context of HCMV infection and breast oncogenesis. Methods Herein, we identified EZH2 as a downstream target for HCMV-induced Myc upregulation upon acute and chronic infection with high-risk strains using a human mammary epithelial model. Findings We detected polyploidy and CMV-transformed HMECs (CTH) cells harboring HCMV and dynamically undergoing the giant cells cycle. Acquisition of embryonic stemness markers positively correlated with EZH2 and Myc expression. EZH2 inhibitors curtail sustained CTH cells’ malignant phenotype. Besides harboring polyploid giant cancer cells (PGCCs), tumorigenic breast biopsies were characterized by an enhanced EZH2 and Myc expression, with a strong positive correlation between EZH2 and Myc expression, and between PGCC count and EZH2/Myc expression in the presence of HCMV. Further, we isolated two HCMV strains from EZH2HighMycHigh basal-like tumors which replicate in MRC5 cells and transform HMECs toward CTH cells after acute infection. Interpretation Our data establish a potential link between HCMV-induced Myc activation, the subsequent EZH2 upregulation, and polyploidy induction. These data support the proposed tumorigenesis properties of EZH2/Myc, and allow the isolation of two oncogenic HCMV strains from EZH2HighMycHigh basal breast tumors while identifying EZH2 as a potential therapeutic target in the management of breast cancer, particularly upon HCMV infection. Funding This work was supported by grants from the University of Franche-Comté (UFC) (CR3300), the Région Franche-Comté (2021-Y-08292 and 2021-Y-08290) and the Ligue contre le Cancer (CR3304) to Georges Herbein. Zeina Nehme is a recipient of a doctoral scholarship from the municipality of Habbouch. Sandy Haidar Ahmad is recipient of a doctoral scholarship from Lebanese municipality. Ranim El Baba is a recipient of a doctoral scholarship from Hariri foundation for sustainable human development.
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Affiliation(s)
- Zeina Nehme
- Department Pathogens and Inflammation-EPILAB, EA4266, Université de Franche-Comté, Université Bourgogne Franche-Comté (UBFC), 16 route de Gray, Besançon F-25030, France
| | - Sébastien Pasquereau
- Department Pathogens and Inflammation-EPILAB, EA4266, Université de Franche-Comté, Université Bourgogne Franche-Comté (UBFC), 16 route de Gray, Besançon F-25030, France
| | - Sandy Haidar Ahmad
- Department Pathogens and Inflammation-EPILAB, EA4266, Université de Franche-Comté, Université Bourgogne Franche-Comté (UBFC), 16 route de Gray, Besançon F-25030, France
| | - Ranim El Baba
- Department Pathogens and Inflammation-EPILAB, EA4266, Université de Franche-Comté, Université Bourgogne Franche-Comté (UBFC), 16 route de Gray, Besançon F-25030, France
| | - Georges Herbein
- Department Pathogens and Inflammation-EPILAB, EA4266, Université de Franche-Comté, Université Bourgogne Franche-Comté (UBFC), 16 route de Gray, Besançon F-25030, France; Department of Virology, CHU Besançon, Besançon, France.
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16
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Bowers RR, Andrade MF, Jones CM, White-Gilbertson S, Voelkel-Johnson C, Delaney JR. Autophagy modulating therapeutics inhibit ovarian cancer colony generation by polyploid giant cancer cells (PGCCs). BMC Cancer 2022; 22:410. [PMID: 35421971 PMCID: PMC9012005 DOI: 10.1186/s12885-022-09503-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/04/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Genomic instability and chemoresistance can arise in cancer due to a unique form of plasticity: that of polyploid giant cancer cells (PGCCs). These cells form under the stress of chemotherapy and have higher than diploid chromosome content. PGCCs are able to then repopulate tumors through an asymmetric daughter cell budding process. PGCCs have been observed in ovarian cancer histology, including the deadly and common form high-grade serous ovarian carcinoma (HGSC). We previously discovered that drugs which disrupt the cellular recycling process of autophagy are uniquely efficacious in pre-clinical HGSC models. While autophagy induction has been associated with PGCCs, it has never been previously investigated if autophagy modulation interacts with the PGCC life cycle and this form of tumor cell plasticity. METHODS CAOV3 and OVCAR3 ovarian cancer cell lines were treated with carboplatin or docetaxel to induce PGCC formation. Microscopy was used to characterize and quantify PGCCs formed by chemotherapy. Two clinically available drugs that inhibit autophagy, hydroxychloroquine and nelfinavir, and a clinically available activator of autophagy, rapamycin, were employed to test the effect of these autophagy modulators on PGCC induction and subsequent colony formation from PGCCs. Crystal violet-stained colony formation assays were used to quantify the tumor-repopulating stage of the PGCC life cycle. RESULTS Autophagy inhibitors did not prevent PGCC formation in OVCAR3 or CAOV3 cells. Rapamycin did not induce PGCC formation on its own nor did it exacerbate PGCC formation by chemotherapy. However, hydroxychloroquine prevented efficient colony formation in CAOV3 PGCCs induced by carboplatin (27% inhibition) or docetaxel (41% inhibition), as well as in OVCAR3 cells (95% and 77%, respectively). Nelfinavir similarly prevented colony formation in CAOV3 PGCCs induced by carboplatin (64% inhibition) or docetaxel (94% inhibition) as well as in OVCAR3 cells (89% and 80%, respectively). Rapamycin surprisingly also prevented PGCC colony outgrowth (52-84% inhibition). CONCLUSIONS While the autophagy previously observed to correlate with PGCC formation is unlikely necessary for PGCCs to form, autophagy modulating drugs severely impair the ability of HGSC PGCCs to form colonies. Clinical trials which utilize hydroxychloroquine, nelfinavir, and/or rapamycin after chemotherapy may be of future interest.
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Affiliation(s)
- Robert R Bowers
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Maya F Andrade
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Christian M Jones
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Shai White-Gilbertson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Christina Voelkel-Johnson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Joe R Delaney
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
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17
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Li Z, Zheng M, Zhang H, Yang X, Fan L, Fu F, Fu J, Niu R, Yan M, Zhang S. Arsenic Trioxide Promotes Tumor Progression by Inducing the Formation of PGCCs and Embryonic Hemoglobin in Colon Cancer Cells. Front Oncol 2021; 11:720814. [PMID: 34676163 PMCID: PMC8523995 DOI: 10.3389/fonc.2021.720814] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/17/2021] [Indexed: 12/24/2022] Open
Abstract
Arsenic trioxide (ATO) has been used to treat acute promyelocytic leukemia. However, it is not effective in treating solid tumors such as colorectal cancer. We have previously reported that polyploid giant cancer cells (PGCCs) exhibiting the characteristics of cancer stem cells can be generated by various inducers. In this study, ATO was used to induce the formation of PGCCs in LoVo and Hct116 colon cancer cell lines. The migration, invasion, and proliferation abilities of colon cancer cells with and without ATO treatment were assessed by wound-healing, transwell, and plate colony formation assays. The expression of epithelial to mesenchymal transition-related proteins and erythroid differentiation-related proteins in colon cancer cells was further evaluated by western blot and immunocytochemical assays. LoVo and Hct116 cells were transfected with a eukaryotic expression vector for green fluorescent protein (GFP), red fluorescent protein (RFP), H2B-GFP, and H2B-mCherry to study PGCCs formation via cell fusion. WB and ICC assays were performed to assess the expression of cell fusion-related proteins. MG132, small interfering RNA-glial cell missing 1 (GCM1), and chromatin immunoprecipitation-polymerase chain reaction assays were performed to study the role of GCM1/syncytin-1-mediated cell fusion. Clinically, the significance of cell fusion-related proteins and erythroid differentiation-related proteins expression in human colorectal cancer tissues was evaluated. Results of our study showed that ATO induced the formation of PGCCs, and the daughter cells derived from PGCCs gained a mesenchymal phenotype and exhibited strong migration, invasion, and proliferation abilities. PGCCs also produced embryonic hemoglobin-delta and -zeta with strong oxygen-binding ability and erythroid differentiation-related proteins after ATO treatment. In addition, cell fusion was observed during the formation of PGCCs, indicated by the presence of yellow fluorescence via the GCM1/syncytin-1 signaling pathway. Clinically, the expression of cell fusion-related and erythroid differentiation-related proteins gradually increased with the progression of human colorectal cancer tissues. In conclusion, ATO can promote tumor progression by inducing the formation of PGCCs via GCM1/syncytin-1-mediated cell fusion. PGCCs can produce daughter cells with high invasion and migration abilities and embryonic hemoglobin with strong oxygen binding ability, promoting survival of tumor cells in a hypoxic microenvironment.
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Affiliation(s)
- Zugui Li
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Hao Zhang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaohui Yang
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Linlin Fan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fangmei Fu
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Junjie Fu
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Rui Niu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Man Yan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
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18
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Kostecka LG, Pienta KJ, Amend SR. Lipid droplet evolution gives insight into polyaneuploid cancer cell lipid droplet functions. Med Oncol 2021; 38:133. [PMID: 34581907 PMCID: PMC8478749 DOI: 10.1007/s12032-021-01584-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 09/12/2021] [Indexed: 12/16/2022]
Abstract
Lipid droplets (LDs) are found throughout all phyla across the tree of life. Originating as pure energy stores in the most basic organisms, LDs have evolved to fill various roles as regulators of lipid metabolism, signaling, and trafficking. LDs have been noted in cancer cells and have shown to increase tumor aggressiveness and chemotherapy resistance. A certain transitory state of cancer cell, the polyaneuploid cancer cell (PACC), appears to have higher LD levels than the cancer cell from which they are derived. PACCs are postulated to be the mediators of metastasis and resistance in many different cancers. Utilizing the evolutionarily conserved roles of LDs to protect from cellular lipotoxicity allows PACCs to survive otherwise lethal stressors. By better understanding how LDs have evolved throughout different phyla we will identify opportunities to target LDs in PACCs to increase therapeutic efficiency in cancer cells.
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Affiliation(s)
- Laurie G Kostecka
- The Brady Urological Institute, Johns Hopkins School of Medicine, 600 N. Wolfe St., Marburg Building Room 113, Baltimore, MD, 21287, USA. .,Cellular and Molecular Medicine Program, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
| | - Kenneth J Pienta
- The Brady Urological Institute, Johns Hopkins School of Medicine, 600 N. Wolfe St., Marburg Building Room 113, Baltimore, MD, 21287, USA.,Cellular and Molecular Medicine Program, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Sarah R Amend
- The Brady Urological Institute, Johns Hopkins School of Medicine, 600 N. Wolfe St., Marburg Building Room 113, Baltimore, MD, 21287, USA.,Cellular and Molecular Medicine Program, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
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19
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Song Y, Zhao Y, Deng Z, Zhao R, Huang Q. Stress-Induced Polyploid Giant Cancer Cells: Unique Way of Formation and Non-Negligible Characteristics. Front Oncol 2021; 11:724781. [PMID: 34527590 PMCID: PMC8435787 DOI: 10.3389/fonc.2021.724781] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Polyploidy is a conserved mechanism in cell development and stress responses. Multiple stresses of treatment, including radiation and chemotherapy drugs, can induce the polyploidization of tumor cells. Through endoreplication or cell fusion, diploid tumor cells convert into giant tumor cells with single large nuclei or multiple small nucleuses. Some of the stress-induced colossal cells, which were previously thought to be senescent and have no ability to proliferate, can escape the fate of death by a special way. They can remain alive at least before producing progeny cells through asymmetric cell division, a depolyploidization way named neosis. Those large and danger cells are recognized as polyploid giant cancer cells (PGCCs). Such cells are under suspicion of being highly related to tumor recurrence and metastasis after treatment and can bring new targets for cancer therapy. However, differences in formation mechanisms between PGCCs and well-accepted polyploid cancer cells are largely unknown. In this review, the methods used in different studies to induce polyploid cells are summarized, and several mechanisms of polyploidization are demonstrated. Besides, we discuss some characteristics related to the poor prognosis caused by PGCCs in order to provide readers with a more comprehensive understanding of these huge cells.
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Affiliation(s)
- Yanwei Song
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yucui Zhao
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng Deng
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruyi Zhao
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Huang
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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20
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Thura M, Ye Z, Al-Aidaroos AQ, Xiong Q, Ong JY, Gupta A, Li J, Guo K, Ang KH, Zeng Q. PRL3 induces polypoid giant cancer cells eliminated by PRL3-zumab to reduce tumor relapse. Commun Biol 2021; 4:923. [PMID: 34326464 PMCID: PMC8322210 DOI: 10.1038/s42003-021-02449-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 07/13/2021] [Indexed: 12/18/2022] Open
Abstract
PRL3, a unique oncotarget, is specifically overexpressed in 80.6% of cancers. In 2003, we reported that PRL3 promotes cell migration, invasion, and metastasis. Herein, firstly, we show that PRL3 induces Polyploid Giant Cancer Cells (PGCCs) formation. PGCCs constitute stem cell-like pools to facilitate cell survival, chemo-resistance, and tumor relapse. The correlations between PRL3 overexpression and PGCCs attributes raised possibilities that PRL3 could be involved in PGCCs formation. Secondly, we show that PRL3+ PGCCs co-express the embryonic stem cell markers SOX2 and OCT4 and arise mainly due to incomplete cytokinesis despite extensive DNA damage. Thirdly, we reveal that PRL3+ PGCCs tolerate prolonged chemotherapy-induced genotoxic stress via suppression of the pro-apoptotic ATM DNA damage-signaling pathway. Fourthly, we demonstrated PRL3-zumab, a First-in-Class humanized antibody drug against PRL3 oncotarget, could reduce tumor relapse in 'tumor removal' animal model. Finally, we confirmed that PGCCs were enriched in relapse tumors versus primary tumors. PRL3-zumab has been approved for Phase 2 clinical trials in Singapore, US, and China to block all solid tumors. This study further showed PRL3-zumab could potentially serve an 'Adjuvant Immunotherapy' after tumor removal surgery to eliminate PRL3+ PGCC stem-like cells, preventing metastasis and relapse.
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Affiliation(s)
- Min Thura
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Zu Ye
- MD Anderson Cancer Centre, The University of Texas, Houston, TX, USA
| | - Abdul Qader Al-Aidaroos
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Qiancheng Xiong
- Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA
| | - Jun Yi Ong
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Abhishek Gupta
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Jie Li
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Ke Guo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Koon Hwee Ang
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Qi Zeng
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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21
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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22
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Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells. Proc Natl Acad Sci U S A 2021; 118:2020838118. [PMID: 33504594 PMCID: PMC7896294 DOI: 10.1073/pnas.2020838118] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.
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23
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Zhao Q, Zhang K, Li Z, Zhang H, Fu F, Fu J, Zheng M, Zhang S. High Migration and Invasion Ability of PGCCs and Their Daughter Cells Associated With the Nuclear Localization of S100A10 Modified by SUMOylation. Front Cell Dev Biol 2021; 9:696871. [PMID: 34336846 PMCID: PMC8322665 DOI: 10.3389/fcell.2021.696871] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 06/21/2021] [Indexed: 12/24/2022] Open
Abstract
Our previous studies have confirmed that cobalt chloride (CoCl2) or chemoradiotherapy could induce the formation of polyploid tumor giant cells (PGCCs). Polyploid giant cancer cells are a special subpopulation of cancer cells that contribute to solid tumor heterogeneity. The size of PGCC was at least three times larger than regular diploid cancer cells. PGCCs have the properties of cancer stem cells (CSCs) and can express CSC markers CD44 and CD133. Daughter cells derived from PGCCs have strong proliferation, infiltration and migration abilities. However, the detailed molecular mechanism of daughter cells expressing mesenchymal phenotype and displaying strong abilities of proliferation and migration is unclear. As a plasminogen receptor, S100A10 which is closely associated with the invasion and metastasis of malignant tumors, was highly expressed in PGCCs with their daughter cells. In this study, CoCl2 was used to induce the formation of PGCCs in LoVo and HCT116 CRC cells. Cell functional experiments, co-immunoprecipitation, MG132 and ginkgolic acid treatment, western blot, and ChIP-Seq were used to identify the mechanism of S100A10 nuclear location. The proliferation and migration abilities of PGCCs and their daughter cells decreased significantly after S100A10 knockdown. In the control cells, S100A10 was mainly ubiquitinated, while in PGCCs and daughter cells, S100A10 was mainly SUMOylated, which was associated with S100A10 nuclear location. After SUMO1 was inhibited, the nuclear S100A10 in PGCCs and daughter cells decreased, and their proliferation and migration abilities significantly decreased. ChIP-Seq combined with real-time fluorescent quantitative PCR showed that S100A10 regulated the expression of neutrophil defensin 3 (DEFA3), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), and rho guanine nucleotide exchange factor 18 (ARHGEF18), which were associated with actin dynamics and cytoskeleton remodeling. The expression of S100A10 in the nuclei and cytoplasm of rectal cancer after neoadjuvant chemoradiation (nCRT) and liver metastases increased compared with that in rectal cancer without nCRT. Taken together, the expression and nuclear localization of S100A10 modified by SUMOylation were associated with the high proliferation and migration of PGCCs and their daughter cells, and the differentiation, metastases, and relapse of CRCs by regulating the expression of ARHGEF18, PTPRN2, and DEFA3.
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Affiliation(s)
- Qi Zhao
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- Tianjin Medical University, Tianjin, China
| | - Kexin Zhang
- Graduate School, School of Medicine, Nankai University, Tianjin, China
| | - Zugui Li
- 3Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Zhang
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- 3Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fangmei Fu
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- 3Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Junjie Fu
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- Tianjin Medical University, Tianjin, China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, China
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24
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Kostecka LG, Pienta KJ, Amend SR. Polyaneuploid Cancer Cell Dormancy: Lessons From Evolutionary Phyla. Front Ecol Evol 2021. [DOI: 10.3389/fevo.2021.660755] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Dormancy is a key survival strategy in many organisms across the tree of life. Organisms that utilize some type of dormancy (hibernation, aestivation, brumation, diapause, and quiescence) are able to survive in habitats that would otherwise be uninhabitable. Induction into dormant states is typically caused by environmental stress. While organisms are dormant, their physical activity is minimal, and their metabolic rates are severely depressed (hypometabolism). These metabolic reductions allow for the conservation and distribution of energy while conditions in the environment are poor. When conditions are more favorable, the organisms are then able to come out of dormancy and reengage in their environment. Polyaneuploid cancer cells (PACCs), proposed mediators of cancer metastasis and resistance, access evolutionary programs and employ dormancy as a survival mechanism in response to stress. Quiescence, the type of dormancy observed in PACCs, allows these cells the ability to survive stressful conditions (e.g., hypoxia in the microenvironment, transiting the bloodstream during metastasis, and exposure to chemotherapy) by downregulating and altering metabolic function, but then increasing metabolic activities again once stress has passed. We can gain insights regarding the mechanisms underlying PACC dormancy by looking to the evolution of dormancy in different organisms.
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25
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Nezu K, Kakoi N, Tezuka F, Ota S. Successful treatment of metastatic bladder pleomorphic giant cell carcinoma with pembrolizumab. IJU Case Rep 2021; 4:200-203. [PMID: 34258526 PMCID: PMC8255290 DOI: 10.1002/iju5.12281] [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: 10/20/2020] [Revised: 02/25/2021] [Accepted: 03/03/2021] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Bladder pleomorphic giant cell carcinoma is a rare and aggressive malignancy with a poor prognosis. There are no reports of immune checkpoint inhibitors for bladder pleomorphic giant cell carcinoma to date. CASE PRESENTATION A 72-year-old man presented with gross hematuria due to multiple bladder cancers. Despite transurethral bladder resection and intravesical injection of Bacillus Calmette-Guérin, bladder cancer recurred. Nineteen months later, he underwent total cystectomy. Pathological examination revealed bladder giant cell carcinoma. Twenty-eight months later, pembrolizumab was administered due to para-aortic lymph node metastasis. Forty-four months later, the lymph node metastasis disappeared, and pembrolizumab administration was terminated. Fifty-eight months later, the patient has remained in remission at the time of writing. CONCLUSION Immune checkpoint inhibitors manifest a therapeutic potential in bladder pleomorphic giant cell carcinoma.
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Affiliation(s)
- Kunihisa Nezu
- Department ofUrologySendai Red Cross HospitalSendaiMiyagiJapan
| | - Narihiko Kakoi
- Department ofUrologySendai Red Cross HospitalSendaiMiyagiJapan
| | - Fumiaki Tezuka
- Department ofPathologySendai Red Cross HospitalSendaiMiyagiJapan
| | - Shozo Ota
- Department ofUrologySendai Red Cross HospitalSendaiMiyagiJapan
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26
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IR-Surviving NSCLC Cells Exhibit Different Patterns of Molecular and Cellular Reactions Relating to the Multifraction Irradiation Regimen and p53-Family Proteins Expression. Cancers (Basel) 2021; 13:cancers13112669. [PMID: 34071477 PMCID: PMC8198560 DOI: 10.3390/cancers13112669] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/06/2021] [Accepted: 05/25/2021] [Indexed: 01/09/2023] Open
Abstract
Simple Summary For the first time, we demonstrated that the significant decrease in p63/p73 expression together with the absence of functional p53 could underlie an increase in the fraction of polyploid cells, transformation rates, and the glycolytic NAD(P)H production in multifraction X-ray radiation exposure (MFR)-surviving cancer cells, providing conditions for radioresistance associated with epithelial–mesenchymal transition (EMT)-like process activation. During radiation therapy (RT), the treatment dose, fractionation, and dose limits for organs at risk (OARs) do not change between patients and are still prescribed mainly based on the Tumor, Node, Metastasis (TNM) stage, performance status, and comorbidities, taking no account of the tumor biology. Our data once again emphasize that non-small cell lung cancer (NSCLC) therapy approaches should become more personalized according to RT regimen, tumor histology, and molecular status of critical proteins. Abstract Radiotherapy is a primary treatment modality for patients with unresectable non-small cell lung cancer (NSCLC). Tumor heterogeneity still poses the central question of cancer radioresistance, whether the presence of a particular cell population inside a tumor undergoing a selective outgrowth during radio- and chemotherapy give rise to metastasis and tumor recurrence. In this study, we examined the impact of two different multifraction X-ray radiation exposure (MFR) regimens, fraction dose escalation (FDE) in the split course and the conventional hypofractionation (HF), on the phenotypic and molecular signatures of four MFR-surviving NSCLC cell sublines derived from parental A549 (p53 wild-type) and H1299 (p53-null) cells, namely A549FR/A549HR, H1299FR/H1299HR cells. We demonstrate that sublines surviving different MFR regimens in a total dose of 60 Gy significantly diverge in their molecular traits related to irradiation regimen and p53 status. The observed changes regarding radiosensitivity, transformation, proliferation, metabolic activity, partial epithelial-to-mesenchymal transition (EMT) program activation and 1D confined migratory behavior (wound healing). For the first time, we demonstrated that MFR exposure led to the significant decrease in the expression of p63 and p73, the p53-family members, in p53null cells, which correlated with the increase in cell polyploidy. We could not find significant differences in FRA1 expression between parental cells and their sublines that survived after any MFR regimen regardless of p53 status. In our study, the FDE regimen probably causes partial EMT program activation in MFR-survived NSCLC cells through either Vimentin upregulation in p53null or an aberrant N-cadherin upregulation in p53wt cells. The HF regimen likely less influences the EMT activation irrespectively of the p53 status of MFR-survived NSCLC cells. Our data highlight that both MFR regimens caused overall higher cell transformation of p53null H1299FR and H1299HR cells than their parental H1299 cells. Moreover, our results indicate that the FDE regimen raised the radioresistance and transformation of MFR-surviving NSCLC cells irrespectively of their p53 status, though the HF regimen demonstrated a similar effect on p53null NSCLC cells only. Our data once again emphasize that NSCLC therapy approaches should become more personalized according to radiation therapy (RT) regimen, tumor histology, and molecular status of critical proteins.
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27
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de Castro E Gloria H, Jesuíno Nogueira L, Bencke Grudzinski P, da Costa Ghignatti PV, Guecheva TN, Motta Leguisamo N, Saffi J. Olaparib-mediated enhancement of 5-fluorouracil cytotoxicity in mismatch repair deficient colorectal cancer cells. BMC Cancer 2021; 21:448. [PMID: 33888065 PMCID: PMC8063290 DOI: 10.1186/s12885-021-08188-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
Background The advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved. Methods Human colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed. Results Our results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities. Conclusion Our results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.
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Affiliation(s)
- Helena de Castro E Gloria
- Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Sarmento Leite st 245, Porto Alegre, RS, Brazil
| | - Laura Jesuíno Nogueira
- Cardiology Institute of Rio Grande do Sul/ University Foundation of Cardiology (ICFUC), Porto Alegre, RS, Brazil
| | - Patrícia Bencke Grudzinski
- Cardiology Institute of Rio Grande do Sul/ University Foundation of Cardiology (ICFUC), Porto Alegre, RS, Brazil
| | | | - Temenouga Nikolova Guecheva
- Cardiology Institute of Rio Grande do Sul/ University Foundation of Cardiology (ICFUC), Porto Alegre, RS, Brazil
| | - Natalia Motta Leguisamo
- Cardiology Institute of Rio Grande do Sul/ University Foundation of Cardiology (ICFUC), Porto Alegre, RS, Brazil
| | - Jenifer Saffi
- Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Sarmento Leite st 245, Porto Alegre, RS, Brazil.
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28
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Was H, Borkowska A, Olszewska A, Klemba A, Marciniak M, Synowiec A, Kieda C. Polyploidy formation in cancer cells: How a Trojan horse is born. Semin Cancer Biol 2021; 81:24-36. [PMID: 33727077 DOI: 10.1016/j.semcancer.2021.03.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/29/2021] [Accepted: 03/03/2021] [Indexed: 01/04/2023]
Abstract
Ploidy increase has been shown to occur in different type of tumors and participate in tumor initiation and resistance to the treatment. Polyploid giant cancer cells (PGCCs) are cells with multiple nuclei or a single giant nucleus containing multiple complete sets of chromosomes. The mechanism leading to formation of PGCCs may depend on: endoreplication, mitotic slippage, cytokinesis failure, cell fusion or cell cannibalism. Polyploidy formation might be triggered in response to various genotoxic stresses including: chemotherapeutics, radiation, hypoxia, oxidative stress or environmental factors like: air pollution, UV light or hyperthermia. A fundamental feature of polyploid cancer cells is the generation of progeny during the reversal of the polyploid state (depolyploidization) that may show high aggressiveness resulting in the formation of resistant disease and tumor recurrence. Therefore, we propose that modern anti-cancer therapies should be designed taking under consideration polyploidization/ depolyploidization processes, which confer the polyploidization a hidden potential similar to a Trojan horse delayed aggressiveness. Various mechanisms and stress factors leading to polyploidy formation in cancer cells are discussed in this review.
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Affiliation(s)
- Halina Was
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland.
| | - Agata Borkowska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; Postgraduate School of Molecular Medicine, Zwirki i Wigury 61 Street, Warsaw, Poland
| | - Aleksandra Olszewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; Postgraduate School of Molecular Medicine, Zwirki i Wigury 61 Street, Warsaw, Poland
| | - Aleksandra Klemba
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Banacha 2c Street, Warsaw, Poland
| | - Marta Marciniak
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
| | - Agnieszka Synowiec
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
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29
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Cancer cells employ an evolutionarily conserved polyploidization program to resist therapy. Semin Cancer Biol 2020; 81:145-159. [PMID: 33276091 DOI: 10.1016/j.semcancer.2020.11.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 12/24/2022]
Abstract
Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality.
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30
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Tan GF, Goh S, Lim AH, Liu W, Lee JY, Rajasegaran V, Sam XX, Tay TKY, Selvarajan S, Ng CCY, Teh BT, Chan JY. Bizarre giant cells in human angiosarcoma exhibit chemoresistance and contribute to poor survival outcomes. Cancer Sci 2020; 112:397-409. [PMID: 33164299 PMCID: PMC7780052 DOI: 10.1111/cas.14726] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/31/2020] [Accepted: 11/04/2020] [Indexed: 11/28/2022] Open
Abstract
Giant cells (GC) are a poorly understood subset of tumor cells that have been increasingly recognized as a potential contributor to tumor heterogeneity and treatment resistance. We aimed to characterize the biological and clinical significance of GC in angiosarcoma, an aggressive rare cancer of endothelial origin. Archival angiosarcoma samples were examined for the presence of GC and compared with clinicopathological as well as NanoString gene expression data. GC were examined in angiosarcoma cell lines MOLAS and ISOHAS using conventional and electron microscopy, single cell whole genome profiling, and other assays. In the cell lines, GC represented a rare population of mitotically active, non–senescent CD31+ cells, and shared similar genomic profiles with regular‐sized cells, consistent with a malignant endothelial phenotype. GC remained viable and persisted in culture following exposure to paclitaxel and doxorubicin. In patient samples, GC were present in 24 of 58 (41.4%) cases. GC was correlated with poorer responses to chemotherapy (25.0% vs 73.3%, P = 0.0213) and independently contributed to worse overall survival outcomes (hazard ratio 2.20, 95% confidence interval 1.17‐4.15, P = 0.0142). NanoString profiling revealed overexpression of genes, including COL11A1, STC1, and ERO1A, accompanied by upregulation of immune‐related metabolic stress and metastasis/matrix remodeling pathways in GC‐containing tumors. In conclusion, GC may contribute to chemoresistance and poor prognosis in angiosarcoma.
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Affiliation(s)
- Grace Fangmin Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore City, Singapore
| | - Shane Goh
- Integrated Genomics Platform, National Cancer Centre Singapore, Singapore City, Singapore
| | - Abner Herbert Lim
- Integrated Genomics Platform, National Cancer Centre Singapore, Singapore City, Singapore
| | - Wei Liu
- Integrated Genomics Platform, National Cancer Centre Singapore, Singapore City, Singapore
| | - Jing Yi Lee
- Integrated Genomics Platform, National Cancer Centre Singapore, Singapore City, Singapore
| | - Vikneswari Rajasegaran
- Integrated Genomics Platform, National Cancer Centre Singapore, Singapore City, Singapore
| | - Xin Xiu Sam
- Department of Anatomical Pathology, Singapore General Hospital, Singapore City, Singapore
| | - Timothy Kwang Yong Tay
- Department of Anatomical Pathology, Singapore General Hospital, Singapore City, Singapore
| | | | - Cedric Chuan-Young Ng
- Integrated Genomics Platform, National Cancer Centre Singapore, Singapore City, Singapore
| | - Bin Tean Teh
- Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore City, Singapore.,Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore City, Singapore.,Institute of Molecular and Cell Biology, Singapore City, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore.,Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore City, Singapore
| | - Jason Yongsheng Chan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore City, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore.,Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore City, Singapore
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31
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Tagal V, Roth MG. Loss of Aurora Kinase Signaling Allows Lung Cancer Cells to Adopt Endoreplication and Form Polyploid Giant Cancer Cells That Resist Antimitotic Drugs. Cancer Res 2020; 81:400-413. [PMID: 33172929 DOI: 10.1158/0008-5472.can-20-1693] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 09/10/2020] [Accepted: 11/05/2020] [Indexed: 11/16/2022]
Abstract
Polyploid giant cancer cells (PGCC) are common in tumors and have been associated with resistance to cancer therapy, tumor relapse, malignancy, immunosuppression, metastasis, cancer stem cell production, and modulation of the tumor microenvironment. However, the molecular mechanisms that cause these cells to form are not yet known. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases were inhibited together, lung cancer cells uniformly grew into multinucleated PGCCs. These cells adopted an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size. Consequently, such cells continued to safely grow in the presence of antimitotic agents. These PGCC re-entered the proliferative cell cycle and grew in cell number when treatment was terminated. Thus, PGCC formation might represent a fundamental cellular response to Aurora kinase inhibitors and contributes to therapy resistance or tumor relapse. SIGNIFICANCE: These findings provide a novel insight about how cancer cells respond to Aurora kinase inhibitors and identify a new mechanism responsible for resistance to these agents and other antimitotic drugs.
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Affiliation(s)
- Vural Tagal
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Michael G Roth
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.,Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
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32
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Cancer regeneration: Polyploid cells are the key drivers of tumor progression. Biochim Biophys Acta Rev Cancer 2020; 1874:188408. [PMID: 32827584 DOI: 10.1016/j.bbcan.2020.188408] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/16/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022]
Abstract
In spite of significant advancements of therapies for initial eradication of cancers, tumor relapse remains a major challenge. It is for a long time known that polyploid malignant cells are a main source of resistance against chemotherapy and irradiation. However, therapeutic approaches targeting these cells have not been appropriately pursued which could partly be due to the shortage of knowledge on the molecular biology of cell polyploidy. On the other hand, there is a rising trend to appreciate polyploid/ multinucleated cells as key players in tissue regeneration. In this review, we suggest an analogy between the functions of polyploid cells in normal and malignant tissues and discuss the idea that cell polyploidy is an evolutionary conserved source of tissue regeneration also exploited by cancers as a survival factor. In addition, polyploid cells are highlighted as a promising therapeutic target to overcome drug resistance and relapse.
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33
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Chen J, Niu N, Zhang J, Qi L, Shen W, Donkena KV, Feng Z, Liu J. Polyploid Giant Cancer Cells (PGCCs): The Evil Roots of Cancer. Curr Cancer Drug Targets 2020; 19:360-367. [PMID: 29968537 DOI: 10.2174/1568009618666180703154233] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 05/28/2018] [Accepted: 06/08/2018] [Indexed: 12/20/2022]
Abstract
Polyploidy is associated with increased cell size and is commonly found in a subset of adult organs and blastomere stage of the human embryo. The polyploidy is formed through endoreplication or cell fusion to support the specific need of development including earliest embryogenesis. Recent data demonstrated that Polyploid Giant Cancer Cells (PGCCs) may have acquired an activated early embryonic-like program in response to oncogenic and therapeutic stress to generate reprogrammed cancer cells for drug resistance and metastasis. Targeting PGCCs may open up new opportunities for cancer therapy.
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Affiliation(s)
- Junsong Chen
- Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, China.,Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Na Niu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jing Zhang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lisha Qi
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Pathology, Tianjin Cancer Institute and Hospital, Tianjin, China
| | - Weiwei Shen
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Krishna Vanaja Donkena
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Zhenqing Feng
- Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jinsong Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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34
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Hypoxic colorectal cancer cells promote metastasis of normoxic cancer cells depending on IL-8/p65 signaling pathway. Cell Death Dis 2020; 11:610. [PMID: 32737283 PMCID: PMC7395770 DOI: 10.1038/s41419-020-02797-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/14/2020] [Accepted: 07/14/2020] [Indexed: 12/17/2022]
Abstract
Tumor heterogeneity is an important feature of malignant tumors, and cell subpopulations may positively interact to facilitate tumor progression. Studies have shown that hypoxic cancer cells possess enhanced metastatic capacity. However, it is still unclear whether hypoxic cancer cells may promote the metastasis of normoxic cells, which have greater access to the blood circulation. When cocultured with hypoxic CRC cells or treated with hypoxic CRC cell-derived CM, normoxic CRC cells possessed increased metastatic capacity. Furthermore, hypoxic CRC cell-derived CM was enriched in interleukin 8. Hypoxic CRC cell-derived CM and recombinant human IL-8 both enhanced the metastatic capacity of normoxic cells by increasing the phosphorylation of p65 and then by inducing epithelial-mesenchymal transition. Knockdown of IL-8 in hypoxic CRC cells or the use of an anti-IL-8 antibody attenuated the CM- or rhIL-8-induced prometastatic capacity of normoxic CRC cells. Inhibition or knockdown of p65 abrogated IL-8-induced prometastatic effects. Most importantly, hypoxia-treated xenograft tumors enhanced the metastasis of normoxic CRC cells. Hypoxic CRC cell-derived IL-8 promotes the metastatic capacity of normoxic cells, and novel therapies targeting the positive interactions between hypoxic and normoxic cells should be developed.
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35
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Zhao F, Yang G, Feng M, Cao Z, Liu Y, Qiu J, You L, Zheng L, Zhang T, Zhao Y. Expression, function and clinical application of stanniocalcin-1 in cancer. J Cell Mol Med 2020; 24:7686-7696. [PMID: 32468698 PMCID: PMC7348177 DOI: 10.1111/jcmm.15348] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 10/10/2019] [Accepted: 10/19/2019] [Indexed: 12/13/2022] Open
Abstract
The glycoprotein stanniocalcin-1 functions as a regulatory endocrine hormone that maintains the balance of calcium and phosphorus in bony fish and as a paracrine/autocrine factor involved in many physiological/pathological processes in humans, including carcinogenesis. In this review, we provide an overview of (a) the possible mechanisms through which STC1 affects the malignant properties of cancer, (b) transcriptional and post-transcriptional regulation pathways of STC1 and (c) the potential clinical relevance of STC1 as a cancer biomarker and even a therapeutic target in the future. Exploring the role of STC1 in cancer development may provide a better understanding of the tumorigenesis process in humans and may facilitate finding an effective therapeutic method against cancer.
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Affiliation(s)
- Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengyu Feng
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhe Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yueze Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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36
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White-Gilbertson S, Voelkel-Johnson C. Giants and monsters: Unexpected characters in the story of cancer recurrence. Adv Cancer Res 2020; 148:201-232. [PMID: 32723564 DOI: 10.1016/bs.acr.2020.03.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Polyploid giant cancer cells (PGCC) constitute a dangerous subpopulation of cancer cells and are a driving force in cancer recurrence. These unique cells arise from diploid tumor cells in response to stress encountered in the tumor microenvironment or during cancer therapy. PGCC are greatly dedifferentiated, acquire pluripotency, and are able to replicate through a form of asymmetric division called neosis, which results in new populations that are themselves able to differentiate into new cell types or to re-establish tumors. Progeny tend to be more genetically unstable than the founding population due to the dysregulation required to transition through a PGCC state. Therefore, cancers that escape stressors through this mechanism tend to re-emerge with a more aggressive phenotype that is therapy resistant. This review focuses on the clinical significance of PGCC, the need for standardized nomenclature and molecular markers, as well as possible avenues to develop therapies aimed at PGCC and the process of neosis. The biology underlying the development of PGCC including cell cycle checkpoint dysregulation, stress responses, dedifferentiation, stemness and epithelial-mesenchymal transition is discussed.
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Affiliation(s)
- Shai White-Gilbertson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Christina Voelkel-Johnson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States.
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37
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Fei F, Liu K, Li C, Du J, Wei Z, Li B, Li Y, Zhang Y, Zhang S. Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer. Front Oncol 2020; 10:182. [PMID: 32154176 PMCID: PMC7047322 DOI: 10.3389/fonc.2020.00182] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/03/2020] [Indexed: 01/09/2023] Open
Abstract
Recently, an increasing number of evidences have shown that polyploid giant cancer cells (PGCCs) could generate daughter cells with a strong migration and invasion ability, which have been implicated in cancer recurrence and metastasis. However, the underlying molecular mechanisms of PGCCs with their daughter cells remain largely unclear. In vitro and in vivo experiments combined with 222 cases of human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4-related proteins regulating the invasion and metastasis of PGCCs with their daughter cells. PGCCs with their daughter cells had high migration, invasion, and proliferation abilities compared to control cells; these were significantly inhibited after S100A4 knockdown. The high expression of cathepsin B, cyclin B1, TRIM21, and Annexin A2 were significantly downregulated after S100A4 knockdown, while the overexpression of S100A4, cathepsin B, cyclin B1, and S100A10 were significantly downregulated after TRIM21 knockdown in PGCCs with their daughter cells. The tumorigenic and metastatic ability of PGCCs with their daughter cells in vivo was significantly stronger compared to the untreated cells, which was significantly decreased after S100A4 knockdown. Moreover, the expression of S100A4-related proteins was positively correlated with the malignancy degree of human CRC, and maintained a high level in lymph node metastasis. S100A4 and TRIM21 may regulate each other to affect the expression and subcellular localization of cyclin B1, and participate in regulating the structure and function of Annexin A2/S100A10 complex, affecting downstream cathepsin B, resulting in the invasion and metastasis of PGCCs with their daughter cells. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs with their daughter cells via cytoskeletal constructions with S100A4.
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Affiliation(s)
- Fei Fei
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Kai Liu
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Chunyuan Li
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Jiaxing Du
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhen Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Bo Li
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuwei Li
- Departments of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Yi Zhang
- Departments of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
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38
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Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance. Cells 2020; 9:cells9020428. [PMID: 32059478 PMCID: PMC7072371 DOI: 10.3390/cells9020428] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/27/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) contributes to tumor progression, cancer cell invasion, and therapy resistance. EMT is regulated by transcription factors such as the protein products of the SNAI gene family, which inhibits the expression of epithelial genes. Several signaling pathways, such as TGF-beta1, IL-6, Akt, and Erk1/2, trigger EMT responses. Besides regulatory transcription factors, RNA molecules without protein translation, micro RNAs, and long non-coding RNAs also assist in the initialization of the EMT gene cluster. A challenging novel aspect of EMT research is the investigation of the interplay between tumor microenvironments and EMT. Several microenvironmental factors, including fibroblasts and myofibroblasts, as well as inflammatory, immune, and endothelial cells, induce EMT in tumor cells. EMT tumor cells change their adverse microenvironment into a tumor friendly neighborhood, loaded with stromal regulatory T cells, exhausted CD8+ T cells, and M2 (protumor) macrophages. Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use.
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39
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Identification and Characterization of a New Platinum-Induced TP53 Mutation in MDAH Ovarian Cancer Cells. Cells 2019; 9:cells9010036. [PMID: 31877751 PMCID: PMC7016977 DOI: 10.3390/cells9010036] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/18/2019] [Accepted: 12/19/2019] [Indexed: 12/26/2022] Open
Abstract
Platinum-based chemotherapy is the therapy of choice for epithelial ovarian cancer (EOC). Acquired resistance to platinum (PT) is a frequent event that leads to disease progression and predicts poor prognosis. To understand possible mechanisms underlying acquired PT-resistance, we have recently generated and characterized three PT-resistant isogenic EOC cell lines. Here, we more deeply characterize several PT-resistant clones derived from MDAH-2774 cells. We show that, in these cells, the increased PT resistance was accompanied by the presence of a subpopulation of multinucleated giant cells. This phenotype was likely due to an altered progression through the M phase of the cell cycle and accompanied by the deregulated expression of genes involved in M phase progression known to be target of mutant TP53. Interestingly, we found that PT-resistant MDAH cells acquired in the TP53 gene a novel secondary mutation (i.e., S185G) that accompanied the R273H typical of MDAH cells. The double p53S185G/R273H mutant increases the resistance to PT in a TP53 null EOC cellular model. Overall, we show how the selective pressure of PT is able to induce additional mutation in an already mutant TP53 gene in EOC and how this event could contribute to the acquisition of novel cellular phenotypes.
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40
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Amend SR, Torga G, Lin KC, Kostecka LG, de Marzo A, Austin RH, Pienta KJ. Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance. Prostate 2019; 79:1489-1497. [PMID: 31376205 PMCID: PMC6706309 DOI: 10.1002/pros.23877] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 06/17/2019] [Indexed: 12/19/2022]
Abstract
Cancer led to the deaths of more than 9 million people worldwide in 2018, and most of these deaths were due to metastatic tumor burden. While in most cases, we still do not know why cancer is lethal, we know that a total tumor burden of 1 kg-equivalent to one trillion cells-is not compatible with life. While localized disease is curable through surgical removal or radiation, once cancer has spread, it is largely incurable. The inability to cure metastatic cancer lies, at least in part, to the fact that cancer is resistant to all known compounds and anticancer drugs. The source of this resistance remains undefined. In fact, the vast majority of metastatic cancers are resistant to all currently available anticancer therapies, including chemotherapy, hormone therapy, immunotherapy, and systemic radiation. Thus, despite decades-even centuries-of research, metastatic cancer remains lethal and incurable. We present historical and contemporary evidence that the key actuators of this process-of tumorigenesis, metastasis, and therapy resistance-are polyploid giant cancer cells.
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Affiliation(s)
- Sarah R. Amend
- Department of Urology, Johns Hopkins University School of Medicine
| | - Gonzalo Torga
- Department of Urology, Johns Hopkins University School of Medicine
| | | | - Laurie G. Kostecka
- Department of Urology, Johns Hopkins University School of Medicine
- Cellular and Molecular Medicine Program, Johns Hopkins University
| | - Angelo de Marzo
- Depatment of Pathology, Johns Hopkins University School of Medicine
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41
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Fei F, Zhang M, Li B, Zhao L, Wang H, Liu L, Li Y, Ding P, Gu Y, Zhang X, Jiang T, Zhu S, Zhang S. Formation of Polyploid Giant Cancer Cells Involves in the Prognostic Value of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer. JOURNAL OF ONCOLOGY 2019; 2019:2316436. [PMID: 31558902 PMCID: PMC6735173 DOI: 10.1155/2019/2316436] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/09/2019] [Accepted: 07/30/2019] [Indexed: 12/24/2022]
Abstract
We previously reported that polyploid giant cancer cells (PGCCs) exhibit cancer stem cell properties and can generate daughter cells with the epithelial-mesenchymal transition phenotype. This study investigated the role of PGCC formation in the prognostic value of neoadjuvant chemoradiation therapy (nCRT) in locally advanced rectal cancer (LARC). The morphological characteristics were observed in patients with LARC after nCRT. Colorectal cancer cell lines were treated with irradiation or chemotherapeutic drugs, and the metastasis-related proteins were detected. 304 nCRT cases and 301 paired non-nCRT cases were collected for analysis. More PGCCs and morphologic characteristics related to invasion and metastasis appeared in tumor tissue after nCRT. Irradiation or chemicals could induce the formation of PGCCs with daughter cells exhibiting strong migratory, invasive, and proliferation abilities. In patients after nCRT, pathologic complete remission, partial remission, stable disease, and progressive disease were observed in 29 (9.54%), 125 (41.12%), 138 (45.39%), and 12 (3.95%) patients, respectively. Mucinous adenocarcinomas (MCs) occurred more frequently in nCRT than in non-nCRT patients (χ 2 = 29.352, P=0.001), and the prognosis in MC patients was worse than that in non-MC patients (χ 2 = 24.617, P=0.001). The difference in survival time had statistical significance for 60 days (χ 2 = 5.357, P=0.021) and 70 days (χ 2 = 18.830, P=0.001) rest interval time. On multivariable analysis, 60 days rest interval, Duke's stage, and recurrence and/or distant metastasis remained significant predictors of survival. In conclusion, irradiation or chemicals induce the formation of PGCCs and PGCCs produce daughter cells with strong migration and invasion abilities after a long incubation period. Appropriate rest interval (incubation period) is very important for patients with LARC who will receive nCRT.
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Affiliation(s)
- Fei Fei
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, China
- Nankai University School of Medicine, Nankai University, Tianjin 300071, China
| | - Mingqing Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Bo Li
- Departments of Radiology, Tianjin Union Medical Center, Tianjin, China
| | - Lizhong Zhao
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, China
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute, Tianjin, China
| | - Hui Wang
- Departments of Radiology, Tianjin Union Medical Center, Tianjin, China
| | - Lina Liu
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, China
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute, Tianjin, China
| | - Yuwei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Po Ding
- Departments of Emergency, Tianjin Union Medical Center, Tianjin, China
| | - Yanjun Gu
- Department of Pathology, Affiliated Hospital of Logistic University of People's Armed Police Force, Tianjin 300071, China
| | - Xipeng Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Tao Jiang
- Department of General Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Siwei Zhu
- Tianjin Union Medical Center, Tianjin 300121, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, China
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42
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Wang X, Zheng M, Fei F, Li C, Du J, Liu K, Li Y, Zhang S. EMT-related protein expression in polyploid giant cancer cells and their daughter cells with different passages after triptolide treatment. Med Oncol 2019; 36:82. [PMID: 31407170 DOI: 10.1007/s12032-019-1303-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 08/04/2019] [Indexed: 02/08/2023]
Abstract
Our previous work has demonstrated that paclitaxel can induce the formation of polyploid giant cancer cells (PGCCs) and inhibit tumor growth by reprogramming ovarian cancer epithelial cells to a benign fibroblastic state via epithelial-mesenchymal transition. Here, triptolide (TPL) was used to treat the breast and ovarian cancer lines. The morphologic characteristics and EMT-related protein expression were studied in different generation of cancer cells after TPL treatment. When BT-549 and HEY cells reached 80-90% confluence, TPL was added to BT-549 for 48 h and HEY for 9 h at a concentration of 40 ng/ml. Scattered PGCCs survived from TPL treatment and generated daughter cells, and then were cultured in medium without TPL for at least ten generation. Western blot analysis and immunocytochemical staining were performed to detect the expression levels and subcellular location of EMT-related proteins in control cells and different generation of TPL-induced PGCCs with daughter cells. Furthermore, wound-healing, transwell, cell counting kit-8, and MTT assay were used to compare the alternation of migration, invasion, and proliferation among control cells and different generation of TPL-induced PGCCs with daughter cells. Scattered PGCCs survived from the treatment of TPL and produced small-sized daughter cells 20-30 days after treatment. Compared to the control cells, the first generation of TPL-induced PGCCs with their daughter cells differentially expressed EMT-related proteins including fibronectin, E-cadherin, vimentin, and Twist, and had lower migration, invasion, and proliferation abilities. The abilities of migration, invasion, and proliferation of TPL-induced PGCCs with their daughter cells gradually enhanced as the passages increasing, and markedly exceeded the control cells in the tenth generation. TPL-induced PGCCs with their daughter cells gradually obtain the abilities of invasion and metastasis in vitro as the number of passage increasing, which can be used to mimick the cancer cells subjected to anti-cancer drugs in vivo and may provide some new insights to explore the mechanism of cancer invasion, metastasis and relapse after chemotherapy.
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Affiliation(s)
- Xinlu Wang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, People's Republic of China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, People's Republic of China
| | - Fei Fei
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, People's Republic of China
| | - Chunyuan Li
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, People's Republic of China
| | - Jiaxing Du
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, People's Republic of China
- Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People's Republic of China
| | - Kai Liu
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, People's Republic of China
- Graduate School of Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Yuwei Li
- Departments of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, People's Republic of China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, People's Republic of China.
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43
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Fei F, Li C, Cao Y, Liu K, Du J, Gu Y, Wang X, Li Y, Zhang S. CK7 expression associates with the location, differentiation, lymph node metastasis, and the Dukes' stage of primary colorectal cancers. J Cancer 2019; 10:2510-2519. [PMID: 31258757 PMCID: PMC6584339 DOI: 10.7150/jca.29397] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 04/13/2019] [Indexed: 02/07/2023] Open
Abstract
Purpose: Most colorectal cancers (CRCs) show positive immunohistochemical (IHC) staining for CK20 and negative staining for CK7. However, in clinical settings, some CRCs show positive IHC staining for CK7, and the clinicopathological significance of this needs to be studied. This study investigated the clinicopathological significance of CK7 positivity in CRCs. Materials and Methods: A total of 178 patients with CRC were used to study the clinicopathological significance of CK7 positivity. Western blotting and immunocytochemical (ICC) staining were used to compare the expression levels of CK7 before and after CoCl2 treatment. Results: CK7 expression was associated with the location, differentiation, lymph node metastasis, and the Dukes' stage of CRCs. CK7 positive cells were mainly distributed at the edge of cancer nests, at the invasion front, as single stromal polyploid giant cancer cells (PGCCs), in tumor buds, in intravascular tumor emboli, and in a micropapillary pattern. Results of ICC staining showed that CK7 expression was almost negative in LoVo and HCT116 before CoCl2 treatment. After CoCl2 treatment, the PGCCs and their daughter cells of LoVo and HCT116 yielded positive results in CK7 ICC staining. Results of western blotting also confirmed that there was higher CK7 expression in LoVo and HCT116 after CoCl2 treatment than in the control. Conclusion: CRC cells expressing CK7 may have strong invasive and metastatic abilities. Some metastasis-related morphological characteristics in CRCs including the invasion front, micropapillary pattern, tumor emboli, and single stromal PGCCs associated with CK7 positive expression.
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Affiliation(s)
- Fei Fei
- Nankai University School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Chunyuan Li
- Nankai University School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Yuan Cao
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Kai Liu
- Tianjin Medical University, Tianjin, P.R. China
| | - Jiaxing Du
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Yanjun Gu
- Department of pathology, Affiliated Hospital of Logistic University of People's Armed Police Force, Tianjin, P.R. China
| | - Xinlu Wang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Yuwei Li
- Departments of colorectal surgery, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Shiwu Zhang
- Nankai University School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
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Fei F, Qu J, Liu K, Li C, Wang X, Li Y, Zhang S. The subcellular location of cyclin B1 and CDC25 associated with the formation of polyploid giant cancer cells and their clinicopathological significance. J Transl Med 2019; 99:483-498. [PMID: 30487595 DOI: 10.1038/s41374-018-0157-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 09/05/2018] [Accepted: 10/04/2018] [Indexed: 12/14/2022] Open
Abstract
Polyploid giant cancer cells (PGCCs) are key contributors to cancer heterogeneity, and the formation of PGCCs is associated with changes in the expression of cell-cycle-related proteins. This study investigated the intracellular localization and expression level of multiple cell-cycle-related proteins in PGCCs derived from BT-549 and HEY cells. In addition, the formation of PGCCs and the clinicopathological significance of cell-cycle-related proteins in human breast and ovarian cancer were examined. The expression levels of cell-cycle-related proteins, including cyclin B1, CDC25B, CDC25C, and other cell cycle phosphoproteins, including Chk2, and Aurora-A kinase, were determined using immunostaining and western blotting both in vitro and in vivo. Migration, invasion, and proliferation in control cells, cyclin B1 knockdown cells and their PGCCs following CoCl2 treatment were compared. In addition, human breast and ovarian cancer samples were collected to determine the correlation of number of PGCCs, expression of cell-cycle-related proteins, and tumor pathologic grade and metastasis. Our results confirm that cyclin B1 was localized in the cytoplasm of PGCCs and in the nuclei of their budding daughter cells. The phosphorylated proteins Chk2 and Aurora-A kinase regulated the expression and subcellular localization of cyclin B1, CDC25B, and CDC25C. The rate of positive cytoplasmic staining of cyclin B1 and positive nuclear staining of both CDC25B and CDC25C increased with increase in tumor grade and lymph node metastasis. Cell-cycle-related proteins, including cyclin B1, CDC25B, and CDC25C play an important role in regulating the formation of PGCCs. The inhibition of cyclinB1 and CoCl2 treatment significantly promoted cell proliferation, invasion, and migration abilities. The subcellular localization of these cell-cycle-related proteins was regulated by other cell cycle phosphoproteins, and was associated with pathologic grade and metastasis of tumors in cases of human breast and ovarian cancer.
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Affiliation(s)
- Fei Fei
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, China
- Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Jie Qu
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, China
- Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Kai Liu
- Tianjin Medical University, Tianjin, 300070, China
| | - Chunyuan Li
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, China
- Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Xinlu Wang
- Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuwei Li
- Departments of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Shiwu Zhang
- Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121, China.
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Lin KC, Torga G, Sun Y, Axelrod R, Pienta KJ, Sturm JC, Austin RH. The role of heterogeneous environment and docetaxel gradient in the emergence of polyploid, mesenchymal and resistant prostate cancer cells. Clin Exp Metastasis 2019; 36:97-108. [PMID: 30810874 DOI: 10.1007/s10585-019-09958-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 02/19/2019] [Indexed: 12/01/2022]
Abstract
The ability of a population of PC3 prostate epithelial cancer cells to become resistant to docetaxel therapy and progress to a mesenchymal state remains a fundamental problem. The progression towards resistance is difficult to directly study in heterogeneous ecological environments such as tumors. In this work, we use a micro-fabricated "evolution accelerator" environment to create a complex heterogeneous yet controllable in-vitro environment with a spatially-varying drug concentration. With such a structure we observe the rapid emergence of a surprisingly large number of polyploid giant cancer cells (PGCCs) in regions of very high drug concentration, which does not occur in conventional cell culture of uniform concentration. This emergence of PGCCs in a high drug environment is due to migration of diploid epithelial cells from regions of low drug concentration, where they proliferate, to regions of high drug concentration, where they rapidly convert to PGCCs. Such a mechanism can only occur in spatially-varying rather than homogeneous environments. Further, PGCCs exhibit increased expression of the mesenchymal marker ZEB1 in the same high-drug regions where they are formed, suggesting the possible induction of an epithelial to mesenchymal transition (EMT) in these cells. This is consistent with prior work suggesting the PGCC cells are mediators of resistance in response to chemotherapeutic stress. Taken together, this work shows the key role of spatial heterogeneity and the migration of proliferative diploid cells to form PGCCs as a survival strategy for the cancer population, with implications for new therapies.
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Affiliation(s)
| | | | - Yusha Sun
- Princeton University, Princeton, NJ, USA
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46
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Clinical characteristics and preliminary morphological observation of 47 cases of primary anorectal malignant melanomas. Melanoma Res 2018; 28:592-599. [DOI: 10.1097/cmr.0000000000000491] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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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.
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Affiliation(s)
- Jinsong Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4095, United States.
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Abstract
The zinc metalloproteinase, PAPP-A, enhances local insulin-like growth factor (IGF) action through cleavage of inhibitory IGF-binding proteins, thereby increasing IGF available for IGF receptor-mediated cell proliferation, migration and survival. In many tumors, enhanced IGF receptor signaling is associated with tumor growth, invasion and metastasis. We will first discuss PAPP-A structure and function, and post-translational inhibitors of PAPP-A expression or proteolytic activity. We will then review the evidence supporting an important role for PAPP-A in many cancers, including breast, ovarian and lung cancer, and Ewing sarcoma.
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Affiliation(s)
- Cheryl A Conover
- From the Division of Endocrinology Mayo ClinicRochester, Minnesota, USA
| | - Claus Oxvig
- Department of Molecular Biology and GeneticsAarhus University, Aarhus, Denmark
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Shu Z, Row S, Deng WM. Endoreplication: The Good, the Bad, and the Ugly. Trends Cell Biol 2018; 28:465-474. [PMID: 29567370 DOI: 10.1016/j.tcb.2018.02.006] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 02/08/2018] [Accepted: 02/15/2018] [Indexed: 01/08/2023]
Abstract
To battle adverse internal and external conditions and maintain homeostasis, diploid organisms employ various cellular processes, such as proliferation and apoptosis. In some tissues, an alternative mechanism, endoreplication, is employed toward similar goals. Endoreplication is an evolutionarily conserved cell cycle program during which cells replicate their genomes without division, resulting in polyploid cells. Importantly, endoreplication is reported to be indispensable for normal development and organ formation across various organisms, from fungi to humans. In recent years, more attention has been drawn to delineating its connections to wound healing and tumorigenesis. In this Review, we discuss mechanisms of endoreplication and polyploidization, their essential and positive roles in normal development and tissue homeostasis, and the relationship between polyploidy and cancer.
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Affiliation(s)
- Zhiqiang Shu
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Sarayu Row
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Wu-Min Deng
- Department of Biological Science, Florida State University, Tallahassee, FL, USA.
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50
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Modelling Cooperative Tumorigenesis in Drosophila. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4258387. [PMID: 29693007 PMCID: PMC5859872 DOI: 10.1155/2018/4258387] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 01/21/2018] [Indexed: 12/13/2022]
Abstract
The development of human metastatic cancer is a multistep process, involving the acquisition of several genetic mutations, tumour heterogeneity, and interactions with the surrounding microenvironment. Due to the complexity of cancer development in mammals, simpler model organisms, such as the vinegar fly, Drosophila melanogaster, are being utilized to provide novel insights into the molecular mechanisms involved. In this review, we highlight recent advances in modelling tumorigenesis using the Drosophila model, focusing on the cooperation of oncogenes or tumour suppressors, and the interaction of mutant cells with the surrounding tissue in epithelial tumour initiation and progression.
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