|
1
|
Conte M, Tomaciello M, De Feo MS, Frantellizzi V, Marampon F, De Cristofaro F, De Vincentis G, Filippi L. The Tight Relationship Between the Tumoral Microenvironment and Radium-223. Biomedicines 2025; 13:456. [PMID: 40002869 PMCID: PMC11853176 DOI: 10.3390/biomedicines13020456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/04/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Radium-223 (223Ra) was the first radioactive isotope approved for treating castration-resistant prostate cancer (CRPC) with symptomatic bone metastases without visceral metastatic disease. To better understand the action of 223Ra, its role in the tumor microenvironment represents a crucial aspect. A literature search was conducted using the PubMed/MEDLINE database and studies regarding the relationship between 223Ra and the tumoral microenvironment were considered. The tumoral microenvironment is a complex setting in which complex interactions between cells and molecules occur. Radium-223, as an alpha-emitter, induces double-stranded DNA breaks; to potentiate this effect, it could be used in patients with genetic instability but also in combination with therapies which inhibit DNA repair, modulate the immune response, or control tumor growth. In conclusion, a few studies have taken into consideration the tumoral microenvironment in association with 223Ra. However, its understanding is a priority to better comprehend how to effectively exploit 223Ra and its action mechanism.
Collapse
Affiliation(s)
- Miriam Conte
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Miriam Tomaciello
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Maria Silvia De Feo
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Viviana Frantellizzi
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Francesco Marampon
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Flaminia De Cristofaro
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Giuseppe De Vincentis
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Luca Filippi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
| |
Collapse
|
|
2
|
Ibrahim N, Alsadi N, Yasavoli-Sharahi H, Shahbazi R, Hebbo MJ, Kambli D, Balcells F, Matar C. Berberine Inhibits Breast Cancer Stem Cell Development and Decreases Inflammation: Involvement of miRNAs and IL-6. Curr Dev Nutr 2025; 9:104532. [PMID: 39896297 PMCID: PMC11786844 DOI: 10.1016/j.cdnut.2024.104532] [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: 10/27/2024] [Revised: 12/04/2024] [Accepted: 12/12/2024] [Indexed: 02/04/2025] Open
Abstract
Background Breast cancer (BC) is a health concern worldwide and is often accompanied by depressive symptoms in patients. In BC, elevated interleukin-6 (IL-6) levels contribute to an inflammatory signature linked to cancer stem cell (CSC) stemness and depressive behaviors. Bioactive food components, such as berberine (BBR), have preventative effects against BC by targeting CSCs. Objectives This study aimed to investigate the effects of BBR on breast CSC proliferation, on levels of specific micro (mi)RNAs and IL-6 in vitro and in vivo, and in alleviating depressive-like behaviors in mice with BC. Methods Mammosphere formation assays were conducted by treating murine 4T1 and human MDA-MB-231 BC cell lines with BBR. qPCR analysis of miRNAs miR-let-7c and miR-34a-5p was performed on 4T1 CSCs exposed to BBR. BBR was administered orally to female BALB/c, followed by injection with mammary carcinoma cells to induce BC. Behavioral tests were conducted to assess depressive-like behaviors. Tumor tissues were collected for ex vivo mammosphere assays, miRNA expression analysis, and IL-6 detection by ELISA. Serum was also collected for IL-6 analysis. Results BBR treatment inhibited mammosphere formation and proliferation of CSCs derived from 4T1 and MDA-MB-231 cell lines. Quantification of mammosphere formation showed a significant decrease in both cell lines at 75 μM BBR (4T1: P < 0.001; MDA-MB-231: P < 0.0001). BBR upregulated the expression of miRNAs miR-let-7c and miR-34a in both cell lines, with miR-34a showing a significant increase (P < 0.001) and let-7c showing a significant increase (P < 0.05) in expression. In vivo, oral administration of BBR reduced mammosphere formation in breast tumor tissues (P < 0.0001) and elevated expression of miR-145 and miR-34a, with both showing significant upregulation (P < 0.0001), indicating its potential tumor-suppressive effects. BBR treatment resulted in a significant decrease in serum IL-6 levels (P < 0.05), suggesting anti-inflammatory properties, while the IL-6 in tumor tissue did not show significant changes (P > 0.05). However, no significant differences were observed in depressive-like behaviors between control and treatment groups. Conclusions BBR may have the potential to be used as an "Epi-Natural Compound" to prevent cancer by reducing inflammation and affecting epigenetics.
Collapse
Affiliation(s)
- Nour Ibrahim
- Nutritional Sciences Department, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada
| | - Nawal Alsadi
- Cellular and Molecular in Medicine Department, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Hamed Yasavoli-Sharahi
- Cellular and Molecular in Medicine Department, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Roghayeh Shahbazi
- Cellular and Molecular in Medicine Department, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Mary Joe Hebbo
- Nutritional Sciences Department, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada
| | - Darshan Kambli
- Cellular and Molecular in Medicine Department, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Florencia Balcells
- Cellular and Molecular in Medicine Department, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Chantal Matar
- Nutritional Sciences Department, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada
- Cellular and Molecular in Medicine Department, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| |
Collapse
|
|
3
|
Ray P, Sedigh A, Confeld M, Alhalhooly L, Iduoku K, Casanola-Martin GM, Pham-The H, Rasulev B, Choi Y, Yang Z, Mallik S, Quadir M. Design and evaluation of nanoscale materials with programmed responsivity towards epigenetic enzymes. J Mater Chem B 2024; 12:9905-9920. [PMID: 39021201 DOI: 10.1039/d4tb00514g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing 'intelligent' encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly(acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles. The hydrodynamic diameters of particles were typically withing the range of 108-190 nm, depending on degree of acetylation of the hydrophobic block. However, their stability is compromised upon exposure to HDACs, depending on enzyme concentration and exposure time. Our investigation, utilizing HDAC8 as the model enzyme, revealed that the primary mechanism behind disassembly involves a decrease in amphiphilicity within the block copolymer due to the deacetylation of lysine residues within the particles' hydrophobic domains. To elucidate the response mechanism, we encapsulated a fluorescent dye within these nanoparticles. Upon incubation with HDAC, the nanoparticle structure collapsed, leading to controlled release of the dye over time. Notably, this release was not triggered by denatured HDAC8, other proteolytic enzymes like trypsin, or the co-presence of HDAC8 and its inhibitor. We also demonstrated the biocompatibility and cellular effects of these materials in the context of drug delivery in different types of anticancer cell lines, such as MIA PaCa-2, PANC-1, cancer like stem cells (CSCs), and non-cancerous HPNE cells. We observed that the release of a model drug (such as a STAT3 pathway inhibitor, Napabucasin) can be loaded into these nanoparticles, with >90% of the dosage can be released over 3 h under the influence of HDAC8 enzyme in a controlled fashion. Further, we conducted a comprehensive computational study to unveil the possible interaction mechanism between enzymes and particles. By drawing parallels to the mechanism of naturally occurring histone proteins, this research represents a pioneering step toward developing functional materials capable of harnessing the activity of epigenetic enzymes such as HDACs.
Collapse
Affiliation(s)
- Priyanka Ray
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| | - Abbas Sedigh
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA
| | - Matthew Confeld
- Deapartment of Physics, North Dakota State University, Fargo, ND 58102, USA
| | - Lina Alhalhooly
- Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58102, USA
| | - Kweeni Iduoku
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| | - Gerardo M Casanola-Martin
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| | - Hai Pham-The
- University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 10000, Vietnam
| | - Bakhtiyor Rasulev
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| | - Yongki Choi
- Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58102, USA
| | - Zhongyu Yang
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA
| | - Mohiuddin Quadir
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| |
Collapse
|
|
4
|
Chen B, Liu J. Advances in ovarian tumor stem cells and therapy. Cell Biochem Biophys 2024; 82:1871-1892. [PMID: 38955927 DOI: 10.1007/s12013-024-01385-8] [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] [Accepted: 06/21/2024] [Indexed: 07/04/2024]
Abstract
Ovarian cancer is considered the most lethal among all gynecological malignancies due to its early metastatic dissemination, extensive spread, and malignant ascites. The current standard of care for advanced ovarian cancer involves a combination of cytoreductive surgery and chemotherapy utilizing platinum-based and taxane-based agents. Although initial treatment yields clinical remission in 70-80% of patients, the majority eventually develop treatment resistance and tumor recurrence. A growing body of evidence indicates the existence of cancer stem cells within diverse solid tumors, including ovarian cancer, which function as a subpopulation to propel tumor growth and disease advancement by means of drug resistance, recurrence, and metastasis. The presence of ovarian cancer stem cells is widely considered to be a significant contributor to the unfavorable clinical outcomes observed in patients with ovarian cancer, as they play a crucial role in mediating chemotherapy resistance, recurrence, and metastasis. Ovarian cancer stem cells possess the capacity to reassemble within the entirety of the tumor following conventional treatment, thereby instigating the recurrence of ovarian cancer and inducing resistance to treatment. Consequently, the creation of therapeutic approaches aimed at eliminating ovarian cancer stem cells holds great potential for the management of ovarian cancer. These cells are regarded as one of the most auspicious targets and mechanisms for the treatment of ovarian cancer. There is a pressing need for a comprehensive comprehension of the fundamental mechanisms of ovarian cancer's recurrence, metastasis, and drug resistance, alongside the development of effective strategies to overcome chemoresistance, metastasis, and recurrence. The implementation of cancer stem cell therapies may potentially augment the tumor cells' sensitivity to existing chemotherapy protocols, thereby mitigating the risks of tumor metastasis and recurrence, and ultimately improving the survival rates of ovarian cancer patients.
Collapse
Affiliation(s)
- Biqing Chen
- Harbin Medical University, Harbin, Heilongjiang, China.
| | - Jiaqi Liu
- Jilin University, Changchun, Jilin Province, China
| |
Collapse
|
|
5
|
Aria H, Azizi M, Nazem S, Mansoori B, Darbeheshti F, Niazmand A, Daraei A, Mansoori Y. Competing endogenous RNAs regulatory crosstalk networks: The messages from the RNA world to signaling pathways directing cancer stem cell development. Heliyon 2024; 10:e35208. [PMID: 39170516 PMCID: PMC11337742 DOI: 10.1016/j.heliyon.2024.e35208] [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: 02/10/2024] [Revised: 07/08/2024] [Accepted: 07/24/2024] [Indexed: 08/23/2024] Open
Abstract
Cancer stem cells (CSCs) are one of the cell types that account for cancer heterogeneity. The cancer cells arrest in G0 and generate non-CSC progeny through self-renewal and pluripotency, resulting in tumor recurrence, metastasis, and resistance to chemotherapy. They can stimulate tumor relapse and re-grow a metastatic tumor. So, CSCs is a promising target for eradicating tumors, and developing an anti-CSCs therapy has been considered. In recent years competing endogenous RNA (ceRNA) has emerged as a significant class of post-transcriptional regulators that affect gene expression via competition for microRNA (miRNA) binding. Furthermore, aberrant ceRNA expression is associated with tumor progression. Recent findings show that ceRNA network can cause tumor progression through the effect on CSCs. To overcome therapeutic resistance due to CSCs, we need to improve our current understanding of the mechanisms by which ceRNAs are implicated in CSC-related relapse. Thus, this review was designed to discuss the role of ceRNAs in CSCs' function. Targeting ceRNAs may open the path for new cancer therapeutic targets and can be used in clinical research.
Collapse
Affiliation(s)
- Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahdieh Azizi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shima Nazem
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnam Mansoori
- Pediatrics Department, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzaneh Darbeheshti
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abdolreza Daraei
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Yaser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran
| |
Collapse
|
|
6
|
Romaniuk-Drapała A, Totoń E, Taube M, Idzik M, Rubiś B, Lisiak N. Breast Cancer Stem Cells and Tumor Heterogeneity: Characteristics and Therapeutic Strategies. Cancers (Basel) 2024; 16:2481. [PMID: 39001543 PMCID: PMC11240630 DOI: 10.3390/cancers16132481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/27/2024] [Accepted: 07/05/2024] [Indexed: 07/16/2024] Open
Abstract
Breast cancer is one of the most frequently detected malignancies worldwide. It is responsible for more than 15% of all death cases caused by cancer in women. Breast cancer is a heterogeneous disease representing various histological types, molecular characteristics, and clinical profiles. However, all breast cancers are organized in a hierarchy of heterogeneous cell populations, with a small proportion of cancer stem cells (breast cancer stem cells (BCSCs)) playing a putative role in cancer progression, and they are responsible for therapeutic failure. In different molecular subtypes of breast cancer, they present different characteristics, with specific marker profiles, prognoses, and treatments. Recent efforts have focused on tackling the Wnt, Notch, Hedgehog, PI3K/Akt/mTOR, and HER2 signaling pathways. Developing diagnostics and therapeutic strategies enables more efficient elimination of the tumor mass together with the stem cell population. Thus, the knowledge about appropriate therapeutic methods targeting both "normal" breast cancer cells and breast cancer stem cell subpopulations is crucial for success in cancer elimination.
Collapse
Affiliation(s)
- Aleksandra Romaniuk-Drapała
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Ewa Totoń
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Magdalena Taube
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Malgorzata Idzik
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Błażej Rubiś
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| | - Natalia Lisiak
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, Rokietnicka Str. 3, 60-806 Poznan, Poland
| |
Collapse
|
|
7
|
Zhang X, Yu D, Tang P, Chen F. Insights into the role of mitophagy in lung cancer: current evidence and perspectives. Front Pharmacol 2024; 15:1420643. [PMID: 38962310 PMCID: PMC11220236 DOI: 10.3389/fphar.2024.1420643] [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: 04/20/2024] [Accepted: 06/04/2024] [Indexed: 07/05/2024] Open
Abstract
Lung cancer, recognized globally as a leading cause of malignancy-associated morbidity and mortality, is marked by its high prevalence and lethality, garnering extensive attention within the medical community. Mitophagy is a critical cellular process that plays a crucial role in regulating metabolism and ensuring quality control within cells. Its relevance to lung cancer has garnered significant attention among researchers and scientists. Mitophagy's involvement in lung cancer encompasses its initiation, progression, metastatic dissemination and treatment. The regulatory landscape of mitophagy is complex, involving numerous signaling proteins and pathways that may exhibit aberrant alterations or mutations within the tumor environment. In the field of treatment, the regulation of mitophagy is considered key to determining cancer chemotherapy, radiation therapy, other treatment options, and drug resistance. Contemporary investigations are directed towards harnessing mitophagy modulators, both inhibitors and activators, in therapeutic strategies, with an emphasis on achieving specificity to minimize collateral damage to healthy cellular populations. Furthermore, molecular constituents and pathways affiliated with mitophagy, serving as potential biomarkers, offer promising avenues for enhancing diagnostic accuracy, prognostic assessment, and prediction of therapeutic responses in lung cancer. Future endeavors will also involve investigating the impact of mitophagy on the composition and function of immune cells within the tumor microenvironment, aiming to enhance our understanding of how mitophagy modulates the immune response to lung cancer. This review aims to comprehensively overview recent advancements about the role of mitophagy in the tumor genesis, progenesis and metastasis, and the impact of mitophagy on the treatment of lung cancer. We also discussed the future research direction of mitophagy in the field of lung cancer.
Collapse
Affiliation(s)
- Xin Zhang
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Dongzhi Yu
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Peng Tang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fengshou Chen
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| |
Collapse
|
|
8
|
Yu M, Qin K, Fan J, Zhao G, Zhao P, Zeng W, Chen C, Wang A, Wang Y, Zhong J, Zhu Y, Wagstaff W, Haydon RC, Luu HH, Ho S, Lee MJ, Strelzow J, Reid RR, He TC. The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities. Genes Dis 2024; 11:101026. [PMID: 38292186 PMCID: PMC10825312 DOI: 10.1016/j.gendis.2023.04.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/18/2023] [Accepted: 04/12/2023] [Indexed: 02/01/2024] Open
Abstract
The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
Collapse
Affiliation(s)
- Michael Yu
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Kevin Qin
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Piao Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Jiamin Zhong
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yi Zhu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopaedic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Sherwin Ho
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael J. Lee
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jason Strelzow
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| |
Collapse
|
|
9
|
Martinez P, Baghli I, Gourjon G, Seyfried TN. Mitochondrial-Stem Cell Connection: Providing Additional Explanations for Understanding Cancer. Metabolites 2024; 14:229. [PMID: 38668357 PMCID: PMC11051897 DOI: 10.3390/metabo14040229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 03/29/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
The cancer paradigm is generally based on the somatic mutation model, asserting that cancer is a disease of genetic origin. The mitochondrial-stem cell connection (MSCC) proposes that tumorigenesis may result from an alteration of the mitochondria, specifically a chronic oxidative phosphorylation (OxPhos) insufficiency in stem cells, which forms cancer stem cells (CSCs) and leads to malignancy. Reviewed evidence suggests that the MSCC could provide a comprehensive understanding of all the different stages of cancer. The metabolism of cancer cells is altered (OxPhos insufficiency) and must be compensated by using the glycolysis and the glutaminolysis pathways, which are essential to their growth. The altered mitochondria regulate the tumor microenvironment, which is also necessary for cancer evolution. Therefore, the MSCC could help improve our understanding of tumorigenesis, metastases, the efficiency of standard treatments, and relapses.
Collapse
Affiliation(s)
- Pierrick Martinez
- Scientific and Osteopathic Research Department, Institut de Formation en Ostéopathie du Grand Avignon, 84140 Montfavet, France;
| | - Ilyes Baghli
- International Society for Orthomolecular Medicine, Toronto, ON M4B 3M9, Canada;
| | - Géraud Gourjon
- Scientific and Osteopathic Research Department, Institut de Formation en Ostéopathie du Grand Avignon, 84140 Montfavet, France;
| | | |
Collapse
|
|
10
|
Ray SK, Mukherjee S. Breast cancer stem cells as novel biomarkers. Clin Chim Acta 2024; 557:117855. [PMID: 38453050 DOI: 10.1016/j.cca.2024.117855] [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: 01/31/2024] [Revised: 03/02/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024]
Abstract
Breast cancer is the most common cancer and the leading cause of mortality worldwide. Despite advancements in detection and treatment, it remains a major cause of cancer-related deaths in women. Breast cancer stem cells (BCSCs) are a crucial group of cells responsible for carcinogenesis, metastasis, medication resistance, and tumor recurrence. Identifying and understanding their molecular pathways is essential for developing effective breast cancer therapy. BCSCs are responsible for tumor genesis, development, metastasis, treatment resistance, and recurrence. Biomarkers are essential tools for identifying high-risk patients, improving diagnostic accuracy, developing follow-up programs, assessing treatment susceptibility, and predicting prognostic outcomes. Stem cell intervention therapy can provide specialized tools for precision therapy. Biomarker analysis in cancer patients is crucial to identify cells associated with disease progression and post-therapeutic relapse. However, negative post-therapeutic impacts can enhance cancer stemness by boosting BCSCs plasticity phenotypes, activating stemness pathways in non-BCSCs, and promoting senescence escape, leading to tumor relapse and metastasis. Despite the advancements in precision medicine, challenges persist in identifying stem cell markers, limiting the number of eligible patients for treatment. The diversity of biomedical research hinders the development of individualization-based preventative, monitoring, and treatment strategies, especially in oncology. Integrating and interpreting clinical and scientific data remains challenging. The development of stem cell-related indicators could significantly improve disease precision, enabling stem cell-targeted therapy and personalized treatment plans, although BCSCs are promising for breast cancer treatment optimization, serving as biomarkers for current therapy modalities. This summary discusses recent advancements in breast cancer stem cell research, including biomarkers, identification methods, molecular mechanisms, and tools for studying their biological origin and lineage development for precision medicine.
Collapse
Affiliation(s)
- Suman Kumar Ray
- Independent Researcher, Bhopal, Madhya Pradesh 462020, India
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh 462020, India.
| |
Collapse
|
|
11
|
Ray P, Sedigh A, Confeld M, Alhalhooly L, Iduoku K, Casanola-Martin GM, Pham-The H, Rasulev B, Choi Y, Yang Z, Mallik S, Quadir M. Design and Evaluation of Nanoscale Materials with Programmed Responsivity towards Epigenetic Enzymes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.26.585429. [PMID: 38586020 PMCID: PMC10996597 DOI: 10.1101/2024.03.26.585429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing 'intelligent' encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly (acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles. However, their stability is compromised upon exposure to HDACs, depending on enzyme concentration and exposure time. Our investigation, utilizing HDAC8 as the model enzyme, revealed that the primary mechanism behind disassembly involves a decrease in amphiphilicity within the block copolymer due to the deacetylation of lysine residues within the particles' hydrophobic domains. To elucidate the response mechanism, we encapsulated a fluorescent dye within these nanoparticles. Upon incubation with HDAC, the nanoparticle structure collapsed, leading to controlled release of the dye over time. Notably, this release was not triggered by denatured HDAC8, other proteolytic enzymes like trypsin, or the co-presence of HDAC8 and its inhibitor. We further demonstrated the biocompatibility and cellular effects of these materials and conducted a comprehensive computational study to unveil the possible interaction mechanism between enzymes and particles. By drawing parallels to the mechanism of naturally occurring histone proteins, this research represents a pioneering step toward developing functional materials capable of harnessing the activity of epigenetic enzymes such as HDACs.
Collapse
|
|
12
|
Scodellaro C, Pina RR, Ferreira FC, Sanjuan-Alberte P, Fernandes TG. Unlocking the Potential of Stem Cell Microenvironments In Vitro. Bioengineering (Basel) 2024; 11:289. [PMID: 38534563 DOI: 10.3390/bioengineering11030289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/07/2024] [Accepted: 03/16/2024] [Indexed: 03/28/2024] Open
Abstract
The field of regenerative medicine has recently witnessed groundbreaking advancements that hold immense promise for treating a wide range of diseases and injuries. At the forefront of this revolutionary progress are stem cells. Stem cells typically reside in specialized environments in vivo, known as microenvironments or niches, which play critical roles in regulating stem cell behavior and determining their fate. Therefore, understanding the complex microenvironments that surround stem cells is crucial for advancing treatment options in regenerative medicine and tissue engineering applications. Several research articles have made significant contributions to this field by exploring the interactions between stem cells and their surrounding niches, investigating the influence of biomechanical and biochemical cues, and developing innovative strategies for tissue regeneration. This review highlights the key findings and contributions of these studies, shedding light on the diverse applications that may arise from the understanding of stem cell microenvironments, thus harnessing the power of these microenvironments to transform the landscape of medicine and offer new avenues for regenerative therapies.
Collapse
Affiliation(s)
- Chiara Scodellaro
- Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
| | - Raquel R Pina
- Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
| | - Frederico Castelo Ferreira
- Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
| | - Paola Sanjuan-Alberte
- Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
| | - Tiago G Fernandes
- Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
| |
Collapse
|
|
13
|
Dhanyamraju PK. Drug resistance mechanisms in cancers: Execution of pro-survival strategies. J Biomed Res 2024; 38:95-121. [PMID: 38413011 PMCID: PMC11001593 DOI: 10.7555/jbr.37.20230248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/21/2023] [Accepted: 12/07/2023] [Indexed: 02/29/2024] Open
Abstract
One of the quintessential challenges in cancer treatment is drug resistance. Several mechanisms of drug resistance have been described to date, and new modes of drug resistance continue to be discovered. The phenomenon of cancer drug resistance is now widespread, with approximately 90% of cancer-related deaths associated with drug resistance. Despite significant advances in the drug discovery process, the emergence of innate and acquired mechanisms of drug resistance has impeded the progress in cancer therapy. Therefore, understanding the mechanisms of drug resistance and the various pathways involved is integral to treatment modalities. In the present review, I discuss the different mechanisms of drug resistance in cancer cells, including DNA damage repair, epithelial to mesenchymal transition, inhibition of cell death, alteration of drug targets, inactivation of drugs, deregulation of cellular energetics, immune evasion, tumor-promoting inflammation, genome instability, and other contributing epigenetic factors. Furthermore, I highlight available treatment options and conclude with future directions.
Collapse
Affiliation(s)
- Pavan Kumar Dhanyamraju
- Fels Cancer Institute of Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| |
Collapse
|
|
14
|
Sojka C, Sloan SA. Gliomas: a reflection of temporal gliogenic principles. Commun Biol 2024; 7:156. [PMID: 38321118 PMCID: PMC10847444 DOI: 10.1038/s42003-024-05833-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/18/2024] [Indexed: 02/08/2024] Open
Abstract
The hijacking of early developmental programs is a canonical feature of gliomas where neoplastic cells resemble neurodevelopmental lineages and possess mechanisms of stem cell resilience. Given these parallels, uncovering how and when in developmental time gliomagenesis intersects with normal trajectories can greatly inform our understanding of tumor biology. Here, we review how elapsing time impacts the developmental principles of astrocyte (AS) and oligodendrocyte (OL) lineages, and how these same temporal programs are replicated, distorted, or circumvented in pathological settings such as gliomas. Additionally, we discuss how normal gliogenic processes can inform our understanding of the temporal progression of gliomagenesis, including when in developmental time gliomas originate, thrive, and can be pushed towards upon therapeutic coercion.
Collapse
Affiliation(s)
- Caitlin Sojka
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Steven A Sloan
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
- Emory Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
| |
Collapse
|
|
15
|
Amato R, Lucchesi M, Marracci S, Filippi L, Dal Monte M. β-Adrenoceptors in Cancer: Old Players and New Perspectives. Handb Exp Pharmacol 2024; 285:665-688. [PMID: 37982890 DOI: 10.1007/164_2023_701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
Distress, or negative stress, is known to considerably increase the incidence of several diseases, including cancer. There is indeed evidence from pre-clinical models that distress causes a catecholaminergic overdrive that, mainly through the activation of β-adrenoceptors (β-ARs), results in cancer cell growth and cancer progression. In addition, clinical studies have evidenced a role of negative stress in cancer progression. Moreover, plenty of data demonstrates that β-blockers have positive effects in reducing the pro-tumorigenic activity of catecholamines, correlating with better outcomes in some type of cancers as evidenced by several clinical trials. Among β-ARs, β2-AR seems to be the main β-AR subtype involved in tumor development and progression. However, there are data indicating that also β1-AR and β3-AR may be involved in certain tumors. In this chapter, we will review current knowledge on the role of the three β-AR isoforms in carcinogenesis as well as in cancer growth and progression, with particular emphasis on recent studies that are opening new avenues in the use of β-ARs as therapeutic targets in treating tumors.
Collapse
MESH Headings
- Humans
- Neoplasms/metabolism
- Neoplasms/drug therapy
- Neoplasms/pathology
- Animals
- Receptors, Adrenergic, beta-3/metabolism
- Adrenergic beta-Antagonists/therapeutic use
- Adrenergic beta-Antagonists/pharmacology
- Receptors, Adrenergic, beta-2/metabolism
- Receptors, Adrenergic, beta-2/drug effects
- Receptors, Adrenergic, beta/metabolism
- Receptors, Adrenergic, beta/physiology
- Receptors, Adrenergic, beta-1/metabolism
- Signal Transduction
- Disease Progression
Collapse
Affiliation(s)
- Rosario Amato
- Department of Biology, University of Pisa, Pisa, Italy
| | | | | | - Luca Filippi
- Department of Clinical and Experimental Medicine, Neonatology and Neonatal Intensive Care Unit, University of Pisa, Pisa, Italy
| | | |
Collapse
|
|
16
|
Liu Y, Wang H. Biomarkers and targeted therapy for cancer stem cells. Trends Pharmacol Sci 2024; 45:56-66. [PMID: 38071088 PMCID: PMC10842814 DOI: 10.1016/j.tips.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/16/2023] [Accepted: 11/16/2023] [Indexed: 01/07/2024]
Abstract
Cancer stem cells (CSCs) are a small subpopulation of cancer cells with capabilities of self-renewal, differentiation, and tumorigenicity, and play a critical role in driving tumor heterogeneity that evolves insensitivity to therapeutics. For these reasons, extensive efforts have been made to identify and target CSCs to potentially improve the antitumor efficacy of therapeutics. While progress has been made to uncover certain CSC-associated biomarkers, the identification of CSC-specific markers, especially the targetable ones, remains a significant challenge. Here we provide an overview of the unique signaling and metabolic pathways of CSCs, summarize existing CSC biomarkers and CSC-targeted therapies, and discuss strategies to further differentiate CSCs from non-stem cancer cells and healthy cells for the development of enhanced CSC-targeted therapies.
Collapse
Affiliation(s)
- Yusheng Liu
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Hua Wang
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Cancer Center at Illinois (CCIL), Urbana, IL 61801, USA; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carle College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| |
Collapse
|
|
17
|
Terrinoni A, Micheloni G, Moretti V, Caporali S, Bernardini S, Minieri M, Pieri M, Giaroni C, Acquati F, Costantino L, Ferrara F, Valli R, Porta G. OTX Genes in Adult Tissues. Int J Mol Sci 2023; 24:16962. [PMID: 38069286 PMCID: PMC10707059 DOI: 10.3390/ijms242316962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/22/2023] [Accepted: 11/25/2023] [Indexed: 12/18/2023] Open
Abstract
OTX homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. Recently, their expression has also been reported in adult physiological and pathological tissues, including retina, mammary and pituitary glands, sinonasal mucosa, in several types of cancer, and in response to inflammatory, ischemic, and hypoxic stimuli. Reactivation of OTX genes in adult tissues supports the notion of the evolutionary amplification of functions of genes by varying their temporal expression, with the selection of homeobox genes from the "toolbox" to drive or contribute to different processes at different stages of life. OTX involvement in pathologies points toward these genes as potential diagnostic and/or prognostic markers as well as possible therapeutic targets.
Collapse
Affiliation(s)
- Alessandro Terrinoni
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Giovanni Micheloni
- Genomic Medicine Research Center, Department of Medicine and Surgery, University of Insubria, Via JH Dunant 5, 21100 Varese, Italy
| | - Vittoria Moretti
- Genomic Medicine Research Center, Department of Medicine and Surgery, University of Insubria, Via JH Dunant 5, 21100 Varese, Italy
| | - Sabrina Caporali
- Department of Industrial Engineering, University of Rome Tor Vergata, Via del Politecnico 1, 00133 Rome, Italy
| | - Sergio Bernardini
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Marilena Minieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Massimo Pieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Cristina Giaroni
- Department of Medicina e Innovazione Tecnologica, University of Insubria, Via JH Dunant 5, 21100 Varese, Italy
| | - Francesco Acquati
- Genomic Medicine Research Center, Department of Medicine and Surgery, University of Insubria, Via JH Dunant 5, 21100 Varese, Italy
- Department of Biotechnology and Life Science, University of Insubria, Via JH Dunant 3, 21100 Varese, Italy
| | - Lucy Costantino
- Department of Molecular Genetics, Centro Diagnostico Italiano, Via Saint Bon 20, 20147 Milano, Italy
| | - Fulvio Ferrara
- Department of Molecular Genetics, Centro Diagnostico Italiano, Via Saint Bon 20, 20147 Milano, Italy
| | - Roberto Valli
- Genomic Medicine Research Center, Department of Medicine and Surgery, University of Insubria, Via JH Dunant 5, 21100 Varese, Italy
| | - Giovanni Porta
- Genomic Medicine Research Center, Department of Medicine and Surgery, University of Insubria, Via JH Dunant 5, 21100 Varese, Italy
| |
Collapse
|
|
18
|
Ei ZZ, Racha S, Yokoya M, Hotta D, Zou H, Chanvorachote P. Simplified Synthesis of Renieramycin T Derivatives to Target Cancer Stem Cells via β-Catenin Proteasomal Degradation in Human Lung Cancer. Mar Drugs 2023; 21:627. [PMID: 38132948 PMCID: PMC10744608 DOI: 10.3390/md21120627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023] Open
Abstract
Cancer stem cells (CSCs) found within cancer tissue play a pivotal role in its resistance to therapy and its potential to metastasize, contributing to elevated mortality rates among patients. Significant strides in understanding the molecular foundations of CSCs have led to preclinical investigations and clinical trials focused on CSC regulator β-catenin signaling targeted interventions in malignancies. As part of the ongoing advancements in marine-organism-derived compound development, it was observed that among the six analogs of Renieramycin T (RT), a potential lead alkaloid from the blue sponge Xestospongia sp., the compound DH_32, displayed the most robust anti-cancer activity in lung cancer A549, H23, and H292 cells. In various lung cancer cell lines, DH_32 exhibited the highest efficacy, with IC50 values of 4.06 ± 0.24 μM, 2.07 ± 0.11 μM, and 1.46 ± 0.06 μM in A549, H23, and H292 cells, respectively. In contrast, parental RT compounds had IC50 values of 5.76 ± 0.23 μM, 2.93 ± 0.07 μM, and 1.52 ± 0.05 μM in the same order. Furthermore, at a dosage of 25 nM, DH_32 showed a stronger ability to inhibit colony formation compared to the lead compound, RT. DH_32 was capable of inducing apoptosis in lung cancer cells, as demonstrated by increased PARP cleavage and reduced levels of the proapoptotic protein Bcl2. Our discovery confirms that DH_32 treatment of lung cancer cells led to a reduced level of CD133, which is associated with the suppression of stem-cell-related transcription factors like OCT4. Moreover, DH_32 significantly suppressed the ability of tumor spheroids to form compared to the original RT compound. Additionally, DH_32 inhibited CSCs by promoting the degradation of β-catenin through ubiquitin-proteasomal pathways. In computational molecular docking, a high-affinity interaction was observed between DH_32 (grid score = -35.559 kcal/mol) and β-catenin, indicating a stronger binding interaction compared to the reference compound R9Q (grid score = -29.044 kcal/mol). In summary, DH_32, a newly developed derivative of the right-half analog of RT, effectively inhibited the initiation of lung cancer spheroids and the self-renewal of lung cancer cells through the upstream process of β-catenin ubiquitin-proteasomal degradation.
Collapse
Affiliation(s)
- Zin Zin Ei
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (Z.Z.E.); (S.R.)
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Satapat Racha
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (Z.Z.E.); (S.R.)
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Interdisciplinary Program in Pharmacology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
| | - Masashi Yokoya
- Department of Pharmaceutical Chemistry, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan; (M.Y.); (D.H.)
| | - Daiki Hotta
- Department of Pharmaceutical Chemistry, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan; (M.Y.); (D.H.)
| | - Hongbin Zou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (Z.Z.E.); (S.R.)
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| |
Collapse
|
|
19
|
Gowda BHJ, Ahmed MG, Alshehri SA, Wahab S, Vora LK, Singh Thakur RR, Kesharwani P. The cubosome-based nanoplatforms in cancer therapy: Seeking new paradigms for cancer theranostics. ENVIRONMENTAL RESEARCH 2023; 237:116894. [PMID: 37586450 DOI: 10.1016/j.envres.2023.116894] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/10/2023] [Accepted: 08/13/2023] [Indexed: 08/18/2023]
Abstract
Lyotropic liquid crystals are self-assembled, non-lamellar, and mesophase nanostructured materials that have garnered significant attention as drug carriers. Cubosomes, a subtype of lyotropic liquid crystalline nanoparticles, possess three-dimensional structures that display bicontinuous cubic liquid-crystalline patterns. These patterns are formed through the self-organization of unsaturated monoglycerides (amphphilic lipids such as glyceryl monooleate or phytantriol), followed by stabilization using steric polymers (poloxamers). Owing to their bicontinuous structure and steric polymer-based stabilization, cubosomes have been demonstrated to possess greater entrapment efficiency for hydrophobic drugs compared to liposomes, while also exhibiting high stability. In the past decade, there has been significant interest in cubosomes due to their ability to deliver therapeutic and contrast agents for cancer treatment and imaging with minimal side effects, establishing them as a safe and effective approach. Concerning these advantages, the present review elaborates on the general aspects, composition, and preparation techniques of cubosomes, followed by explanations of their mechanisms of drug loading and release patterns. Furthermore, the review provides meticulous discussions on the use of cubosomes in the treatment and imaging of various types of cancer, culminating in the enumeration of patents related to cubosome-based drug delivery systems.
Collapse
Affiliation(s)
- B H Jaswanth Gowda
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, Karnataka, India
| | - Mohammed Gulzar Ahmed
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, Karnataka, India
| | - Saad Ali Alshehri
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia
| | - Lalitkumar K Vora
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom
| | - Raghu Raj Singh Thakur
- School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India; Center for Global health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India.
| |
Collapse
|
|
20
|
Ibarra AMC, Aguiar EMG, Ferreira CBR, Siqueira JM, Corrêa L, Nunes FD, Franco ALDS, Cecatto RB, Hamblin MR, Rodrigues MFSD. Photodynamic therapy in cancer stem cells - state of the art. Lasers Med Sci 2023; 38:251. [PMID: 37919479 DOI: 10.1007/s10103-023-03911-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/14/2023] [Indexed: 11/04/2023]
Abstract
Despite significant efforts to control cancer progression and to improve oncology treatment outcomes, recurrence and tumor resistance are frequently observed in cancer patients. These problems are partly related to the presence of cancer stem cells (CSCs). Photodynamic therapy (PDT) has been developed as a therapeutic approach for solid tumors; however, it remains unclear how this therapy can affect CSCs. In this review, we focus on the effects of PDT on CSCs and the possible changes in the CSC population after PDT exposure. Tumor response to PDT varies according to the photosensitizer and light parameters employed, but most studies have reported the successful elimination of CSCs after PDT. However, some studies have reported that CSCs were more resistant to PDT than non-CSCs due to the increased efflux of photosensitizer molecules and the action of autophagy. Additionally, using different PDT approaches to target the CSCs resulted in increased sensitivity, reduction of sphere formation, invasiveness, stem cell phenotype, and improved response to chemotherapy. Lastly, although mainly limited to in vitro studies, PDT, combined with targeted therapies and/or chemotherapy, could successfully target CSCs in different solid tumors and promote the reduction of stemness, suggesting a promising therapeutic approach requiring evaluation in robust pre-clinical studies.
Collapse
Affiliation(s)
- Ana Melissa C Ibarra
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | | | - Cássia B R Ferreira
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | | | - Luciana Corrêa
- School of Dentistry, University of São Paulo - FOUSP, São Paulo, Brazil
| | - Fabio D Nunes
- School of Dentistry, University of São Paulo - FOUSP, São Paulo, Brazil
| | | | - Rebeca B Cecatto
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Johannesburg, South Africa
| | - Maria Fernanda S D Rodrigues
- Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University - UNINOVE, São Paulo, Brazil.
| |
Collapse
|
|
21
|
Li YR, Fang Y, Lyu Z, Zhu Y, Yang L. Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies. J Transl Med 2023; 21:686. [PMID: 37784157 PMCID: PMC10546755 DOI: 10.1186/s12967-023-04575-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 09/28/2023] [Indexed: 10/04/2023] Open
Abstract
Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between CSCs and the tumor microenvironment (TME) is observed, with the TME providing a supportive niche for CSC survival and self-renewal, while CSCs, in turn, influence the polarization and persistence of the TME, promoting an immunosuppressive state. Consequently, these interactions hinder the efficacy of current cancer therapies, necessitating the exploration of novel therapeutic approaches to modulate the TME and target CSCs. In this review, we highlight the intricate strategies employed by CSCs to evade immune surveillance and develop resistance to therapies. Furthermore, we examine the dynamic interplay between CSCs and the TME, shedding light on how this interaction impacts cancer progression. Moreover, we provide an overview of advanced therapeutic strategies that specifically target CSCs and the TME, which hold promise for future clinical and translational studies in cancer treatment.
Collapse
Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
| | - Ying Fang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Zibai Lyu
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Yichen Zhu
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
| |
Collapse
|
|
22
|
Pasqualetti F, Miniati M, Gonnelli A, Gadducci G, Giannini N, Palagini L, Mancino M, Fuentes T, Paiar F. Cancer Stem Cells and Glioblastoma: Time for Innovative Biomarkers of Radio-Resistance? BIOLOGY 2023; 12:1295. [PMID: 37887005 PMCID: PMC10604498 DOI: 10.3390/biology12101295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/22/2023] [Accepted: 09/23/2023] [Indexed: 10/28/2023]
Abstract
Despite countless papers in the field of radioresistance, researchers are still far from clearly understanding the mechanisms triggered in glioblastoma. Cancer stem cells (CSC) are important to the growth and spread of cancer, according to many studies. In addition, more recently, it has been suggested that CSCs have an impact on glioblastoma patients' prognosis, tumor aggressiveness, and treatment outcomes. In reviewing this new area of biology, we will provide a summary of the most recent research on CSCs and their role in the response to radio-chemotherapy in GB. In this review, we will examine the radiosensitivity of stem cells. Moreover, we summarize the current knowledge of the biomarkers of stemness and evaluate their potential function in the study of radiosensitivity.
Collapse
Affiliation(s)
- Francesco Pasqualetti
- Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56100 Pisa, Italy; (F.P.); (A.G.); (G.G.); (N.G.); (M.M.); (T.F.); (F.P.)
| | - Mario Miniati
- Department of Clinical and Experimental Medicine, University of Pisa, Italy, Via Roma 67, 56100 Pisa, Italy;
| | - Alessandra Gonnelli
- Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56100 Pisa, Italy; (F.P.); (A.G.); (G.G.); (N.G.); (M.M.); (T.F.); (F.P.)
| | - Giovanni Gadducci
- Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56100 Pisa, Italy; (F.P.); (A.G.); (G.G.); (N.G.); (M.M.); (T.F.); (F.P.)
| | - Noemi Giannini
- Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56100 Pisa, Italy; (F.P.); (A.G.); (G.G.); (N.G.); (M.M.); (T.F.); (F.P.)
| | - Laura Palagini
- Department of Clinical and Experimental Medicine, University of Pisa, Italy, Via Roma 67, 56100 Pisa, Italy;
| | - Maricia Mancino
- Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56100 Pisa, Italy; (F.P.); (A.G.); (G.G.); (N.G.); (M.M.); (T.F.); (F.P.)
| | - Taiusha Fuentes
- Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56100 Pisa, Italy; (F.P.); (A.G.); (G.G.); (N.G.); (M.M.); (T.F.); (F.P.)
| | - Fabiola Paiar
- Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56100 Pisa, Italy; (F.P.); (A.G.); (G.G.); (N.G.); (M.M.); (T.F.); (F.P.)
| |
Collapse
|
|
23
|
Srivastava N, Usmani SS, Subbarayan R, Saini R, Pandey PK. Hypoxia: syndicating triple negative breast cancer against various therapeutic regimens. Front Oncol 2023; 13:1199105. [PMID: 37492478 PMCID: PMC10363988 DOI: 10.3389/fonc.2023.1199105] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 06/05/2023] [Indexed: 07/27/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer (BC) for its high aggressiveness, heterogeneity, and hypoxic nature. Based on biological and clinical observations the TNBC related mortality is very high worldwide. Emerging studies have clearly demonstrated that hypoxia regulates the critical metabolic, developmental, and survival pathways in TNBC, which include glycolysis and angiogenesis. Alterations to these pathways accelerate the cancer stem cells (CSCs) enrichment and immune escape, which further lead to tumor invasion, migration, and metastasis. Beside this, hypoxia also manipulates the epigenetic plasticity and DNA damage response (DDR) to syndicate TNBC survival and its progression. Hypoxia fundamentally creates the low oxygen condition responsible for the alteration in Hypoxia-Inducible Factor-1alpha (HIF-1α) signaling within the tumor microenvironment, allowing tumors to survive and making them resistant to various therapies. Therefore, there is an urgent need for society to establish target-based therapies that overcome the resistance and limitations of the current treatment plan for TNBC. In this review article, we have thoroughly discussed the plausible significance of HIF-1α as a target in various therapeutic regimens such as chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapy, adjuvant therapy photodynamic therapy, adoptive cell therapy, combination therapies, antibody drug conjugates and cancer vaccines. Further, we also reviewed here the intrinsic mechanism and existing issues in targeting HIF-1α while improvising the current therapeutic strategies. This review highlights and discusses the future perspectives and the major alternatives to overcome TNBC resistance by targeting hypoxia-induced signaling.
Collapse
Affiliation(s)
- Nityanand Srivastava
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Salman Sadullah Usmani
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Rajasekaran Subbarayan
- Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Educations, Chennai, India
| | - Rashmi Saini
- Department of Zoology, Gargi College, University of Delhi, New Delhi, India
| | - Pranav Kumar Pandey
- Dr. R.P. Centre for Opthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
24
|
Zhang H, Du Y, Qi L, Xiao S, Braun FK, Kogiso M, Huang Y, Huang F, Abdallah A, Suarez M, Karthick S, Ahmed NM, Salsman VS, Baxter PA, Su JM, Brat DJ, Hellenbeck PL, Teo WY, Patel AJ, Li XN. Targeting GBM with an Oncolytic Picornavirus SVV-001 alone and in combination with fractionated Radiation in a Novel Panel of Orthotopic PDX models. J Transl Med 2023; 21:444. [PMID: 37415222 PMCID: PMC10324131 DOI: 10.1186/s12967-023-04237-w] [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: 03/07/2023] [Accepted: 05/30/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It's capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM. MATERIALS AND METHODS 23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 105 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 1011 viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage. RESULTS PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times. CONCLUSION A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo.
Collapse
Affiliation(s)
- Huiyuan Zhang
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yuchen Du
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
- Department of Pharmacology, School of Medicine, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Lin Qi
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Sophie Xiao
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
| | - Frank K Braun
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Mari Kogiso
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yulun Huang
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Neurosurgery, Dushou Lake Hospital, Soochow University Medical School, Suzhou, Jiangsu, China
| | - Frank Huang
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
| | - Aalaa Abdallah
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
| | - Milagros Suarez
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA
| | - Sekar Karthick
- Pediatric Brain Tumor Research Office, Cancer and Stem Cell Biology Program, SingHealth Duke-NUS Academic Medical Center, Humphrey Oei Institute of Cancer Research, National Cancer Center Singapore, Duke-NUS Medical School, 169610, Singapore, Singapore
| | | | | | - Patricia A Baxter
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jack M Su
- Texas Children's Cancer Center, Houston, TX, USA
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Daniel J Brat
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | | | - Wan-Yee Teo
- Texas Children's Cancer Center, Houston, TX, USA
- Pediatric Brain Tumor Research Office, Cancer and Stem Cell Biology Program, SingHealth Duke-NUS Academic Medical Center, Humphrey Oei Institute of Cancer Research, National Cancer Center Singapore, Duke-NUS Medical School, 169610, Singapore, Singapore
| | - Akash J Patel
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA.
- Dan Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
| | - Xiao-Nan Li
- Texas Children's Cancer Center, Houston, TX, USA.
- Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA.
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, 60611, USA.
- Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
| |
Collapse
|
|
25
|
Ayed K, Nabi L, Akrout R, Mrizak H, Gorrab A, Bacha D, Boussen H, Gati A. Obesity and cancer: focus on leptin. Mol Biol Rep 2023:10.1007/s11033-023-08525-y. [PMID: 37227675 DOI: 10.1007/s11033-023-08525-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 05/12/2023] [Indexed: 05/26/2023]
Abstract
Over the past decades, obesity has grown to epidemic proportions worldwide. It has been associated with an increased risk for different types of cancer. In addition, obesity has been associated with a poor prognosis, an increased risk of metastasis and mortality, and resistance to anti-cancer therapies. The pathophysiological mechanisms underlying the obesity-cancer connection have not yet been fully elucidated. However, this connection could result, at least in part, from the action of adipokines, whose levels are increased in obesity. Among these adipokines, evidence suggests leptin's critical role in linking obesity to cancer. In this review, we first summarize the current state of the literature regarding the implication of leptin in tumorigenic processes. Next, we focus on the effects of leptin on the anti-tumor immune response. Then, we discuss the influence of leptin on the efficiency of antineoplastic treatments and the development of tumor resistance. Finally, we highlight the use of leptin as a potential target for the prevention and treatment of cancer.
Collapse
Affiliation(s)
- Khouloud Ayed
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Lamis Nabi
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Rym Akrout
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Hela Mrizak
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Amal Gorrab
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Dhouha Bacha
- Anatomopathology Department, Mongi Slim Hospital, Tunis, Tunisia
| | - Hamouda Boussen
- Medical Oncology Department, Salah Azaiez Institute, Faculty of Medicine of Tunis, University of Tunis El Manar, Ariana, Tunisia
| | - Asma Gati
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia.
| |
Collapse
|
|
26
|
Quinn CH, Beierle AM, Julson JR, Erwin ME, Alrefai H, Markert HR, Stewart JE, Hutchins SC, Bownes LV, Aye JM, Mroczek-Musulman E, Hicks PH, Yoon KJ, Willey CD, Beierle1 EA. Using 3D-bioprinted models to study pediatric neural crest-derived tumors. Int J Bioprint 2023; 9:723. [PMID: 37323483 PMCID: PMC10261178 DOI: 10.18063/ijb.723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/21/2023] [Indexed: 06/17/2023] Open
Abstract
The use of three-dimensional (3D) bioprinting has remained at the forefront of tissue engineering and has recently been employed for generating bioprinted solid tumors to be used as cancer models to test therapeutics. In pediatrics, neural crest-derived tumors are the most common type of extracranial solid tumors. There are only a few tumor-specific therapies that directly target these tumors, and the lack of new therapies remains detrimental to improving the outcomes for these patients. The absence of more efficacious therapies for pediatric solid tumors, in general, may be due to the inability of the currently employed preclinical models to recapitulate the solid tumor phenotype. In this study, we utilized 3D bioprinting to generate neural crest-derived solid tumors. The bioprinted tumors consisted of cells from established cell lines and patient-derived xenograft tumors mixed with a 6% gelatin/1% sodium alginate bioink. The viability and morphology of the bioprints were analyzed via bioluminescence and immunohisto chemistry, respectively. We compared the bioprints to traditional twodimensional (2D) cell culture under conditions such as hypoxia and therapeutics. We successfully produced viable neural crest-derived tumors that retained the histology and immunostaining characteristics of the original parent tumors. The bioprinted tumors propagated in culture and grew in orthotopic murine models. Furthermore, compared to cells grown in traditional 2D culture, the bioprinted tumors were resistant to hypoxia and chemotherapeutics, suggesting that the bioprints exhibited a phenotype that is consistent with that seen clinically in solid tumors, thus potentially making this model superior to traditional 2D culture for preclinical investigations. Future applications of this technology entail the potential to rapidly print pediatric solid tumors for use in high-throughput drug studies, expediting the identification of novel, individualized therapies.
Collapse
Affiliation(s)
- Colin H Quinn
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, 35205, USA
| | - Andee M Beierle
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, 35205, USA
| | - Janet R Julson
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, 35205, USA
| | - Michael E Erwin
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, 35205, USA
| | - Hasan Alrefai
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, 35205, USA
| | - Hooper R Markert
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, 35205, USA
| | - Jerry E Stewart
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, 35205, USA
| | - Sara Claire Hutchins
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Laura V Bownes
- Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, 35205, USA
| | - Jamie M Aye
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | | | - Patricia H Hicks
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Karina J Yoon
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Christopher D Willey
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, 35205, USA
| | | |
Collapse
|
|
27
|
Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy. Int J Mol Sci 2023; 24:ijms24065665. [PMID: 36982740 PMCID: PMC10055343 DOI: 10.3390/ijms24065665] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/12/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023] Open
Abstract
BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic development and in pathogenic conditions, including cancerogenesis. Glioblastoma is the most aggressive form of glioma, characterized by a very poor prognosis despite the application of a multimodal therapy. Recently, new insights are emerging about the glioblastoma cellular origin, leading to the hypothesis that several putative mechanisms occur during gliomagenesis. Interestingly, epigenome dysregulation associated with loss of cellular identity and functions are emerging as crucial features of glioblastoma pathogenesis. Therefore, the emerging roles of BET protein in glioblastoma onco-biology and the compelling demand for more effective therapeutic strategies suggest that BET family members could be promising targets for translational breakthroughs in glioblastoma treatment. Primarily, “Reprogramming Therapy”, which is aimed at reverting the malignant phenotype, is now considered a promising strategy for GBM therapy.
Collapse
|
|
28
|
Navas LE, Blanco-Alcaina E, Suarez-Martinez E, Verdugo-Sivianes EM, Espinosa-Sanchez A, Sanchez-Diaz L, Dominguez-Medina E, Fernandez-Rozadilla C, Carracedo A, Wu LE, Carnero A. NAD pool as an antitumor target against cancer stem cells in head and neck cancer. J Exp Clin Cancer Res 2023; 42:55. [PMID: 36864434 PMCID: PMC9983242 DOI: 10.1186/s13046-023-02631-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/25/2023] [Indexed: 03/04/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that affect different anatomical locations. Despite this heterogeneity, HNSCC treatment depends on the anatomical location, TNM stage and resectability of the tumor. Classical chemotherapy is based on platinum-derived drugs (cisplatin, carboplatin and oxaliplatin), taxanes (docetaxel, paclitaxel) and 5-fluorouracil1. Despite advances in HNSCC treatment, the rate of tumor recurrence and patient mortality remain high. Therefore, the search for new prognostic identifiers and treatments targeting therapy-resistant tumor cells is vital. Our work demonstrates that there are different subgroups with high phenotypic plasticity within the CSC population in HNSCC. CD10, CD184, and CD166 may identify some of these CSC subpopulations with NAMPT as a common metabolic gene for the resilient cells of these subpopulations. We observed that NAMPT reduction causes a decrease in tumorigenic and stemness properties, migration capacity and CSC phenotype through NAD pool depletion. However, NAMPT-inhibited cells can acquire resistance by activating the NAPRT enzyme of the Preiss-Handler pathway. We observed that coadministration of the NAMPT inhibitor with the NAPRT inhibitor cooperated inhibiting tumor growth. The use of an NAPRT inhibitor as an adjuvant improved NAMPT inhibitor efficacy and reduced the dose and toxicity of these inhibitors. Therefore, it seems that the reduction in the NAD pool could have efficacy in tumor therapy. This was confirmed by in vitro assays supplying the cells with products of inhibited enzymes (NA, NMN or NAD) and restoring their tumorigenic and stemness properties. In conclusion, the coinhibition of NAMPT and NAPRT improved the efficacy of antitumor treatment, indicating that the reduction in the NAD pool is important to prevent tumor growth.
Collapse
Affiliation(s)
- Lola E. Navas
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Elena Blanco-Alcaina
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Elisa Suarez-Martinez
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Eva M. Verdugo-Sivianes
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Asuncion Espinosa-Sanchez
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Sanchez-Diaz
- grid.9224.d0000 0001 2168 1229Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013 Seville, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Eduardo Dominguez-Medina
- grid.11794.3a0000000109410645BioFarma-USEF Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ceres Fernandez-Rozadilla
- grid.488911.d0000 0004 0408 4897Grupo de Medicina Xenómica (USC), Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain
| | - Angel Carracedo
- grid.488911.d0000 0004 0408 4897Grupo de Medicina Xenómica (USC), Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain ,grid.413448.e0000 0000 9314 1427CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Lindsay E. Wu
- grid.1005.40000 0004 4902 0432School of Medical Sciences, UNSW Sydney, Sydney, NSW Australia
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS)/HUVR/CSIC, Hospital Universitario Virgen del Rocío, Ed. IBIS, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avda. Manuel Siurot S/N, 41013, Seville, Spain. .,CIBER de Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
| |
Collapse
|
|
29
|
TRUONG NC, HUYNH NT, PHAM KD, PHAM PV. Roles of cancer stem cells in cancer immune surveillance. MINERVA BIOTECHNOLOGY AND BIOMOLECULAR RESEARCH 2023. [DOI: 10.23736/s2724-542x.23.02944-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
|
|
30
|
Saga R, Matsuya Y, Sato H, Hasegawa K, Obara H, Komai F, Yoshino H, Aoki M, Hosokawa Y. Translational study for stereotactic body radiotherapy against non-small cell lung cancer, including oligometastases, considering cancer stem-like cells enable predicting clinical outcome from in vitro data. Radiother Oncol 2023; 181:109444. [PMID: 37011969 DOI: 10.1016/j.radonc.2022.109444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/15/2022] [Accepted: 12/06/2022] [Indexed: 02/16/2023]
Abstract
BACKGROUND Curative effects of stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC) have been evaluated using various biophysical models. Because such model parameters are empirically determined based on clinical experience, there is a large gap between in vitro and clinical studies. In this study, considering the heterogeneous cell population, we performed a translational study to realize the possible linkage based on a modeling approach. METHODS We modeled cell-killing and tumor control probability (TCP) considering two populations: progeny and cancer stem-like cells. The model parameters were determined from in vitro survival data of A549 and EBC-1 cells. Based on the cellular parameters, we predicted TCP and compared it with the corresponding clinical data from 553 patients collected at Hirosaki University Hospital. RESULTS Using an all-in-one developed model, the so-called integrated microdosimetric-kinetic (IMK) model, we successfully reproduced both in vitro survival after acute irradiation and the 3-year TCP with various fractionation schemes (6-10 Gy per fraction). From the conventional prediction without considering cancer stem cells (CSCs), this study revealed that radioresistant CSCs play a key role in the linkage between in vitro and clinical outcomes. CONCLUSIONS This modeling study provides a possible generalized biophysical model that enables precise estimation of SBRT worldwide.
Collapse
Affiliation(s)
- Ryo Saga
- Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan.
| | - Yusuke Matsuya
- Nuclear Science and Engineering Center, Research Group for Radiation Transport Analysis, Japan Atomic Energy Agency, 2-4 Shirakata, Tokai, Ibaraki 319-1195, Japan; Faculty of Health Sciences, Hokkaido University, Kita-12 Nishi-5, Kita-ku, Sapporo, Hokkaido 060-0812, Japan
| | - Hikari Sato
- Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan
| | - Kazuki Hasegawa
- Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan
| | - Hideki Obara
- Division of Radiology, Hirosaki University Hospital, 53 Hon-cho, Hirosaki, Aomori 036-8563, Japan
| | - Fumio Komai
- Division of Radiology, Hirosaki University Hospital, 53 Hon-cho, Hirosaki, Aomori 036-8563, Japan
| | - Hironori Yoshino
- Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan
| | - Masahiko Aoki
- Department of Radiation Oncology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Yoichiro Hosokawa
- Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan
| |
Collapse
|
|
31
|
Eid RA, Alaa Edeen M, Shedid EM, Kamal ASS, Warda MM, Mamdouh F, Khedr SA, Soltan MA, Jeon HW, Zaki MSA, Kim B. Targeting Cancer Stem Cells as the Key Driver of Carcinogenesis and Therapeutic Resistance. Int J Mol Sci 2023; 24:ijms24021786. [PMID: 36675306 PMCID: PMC9861138 DOI: 10.3390/ijms24021786] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/08/2022] [Accepted: 12/09/2022] [Indexed: 01/18/2023] Open
Abstract
The emerging concept of cancer stem cells (CSCs) as the key driver behind carcinogenesis, progression, and diversity has displaced the prior model of a tumor composed of cells with similar subsequently acquired mutations and an equivalent capacity for renewal, invasion, and metastasis. This significant change has shifted the research focus toward targeting CSCs to eradicate cancer. CSCs may be characterized using cell surface markers. They are defined by their capacity to self-renew and differentiate, resist conventional therapies, and generate new tumors following repeated transplantation in xenografted mice. CSCs' functional capabilities are governed by various intracellular and extracellular variables such as pluripotency-related transcription factors, internal signaling pathways, and external stimuli. Numerous natural compounds and synthetic chemicals have been investigated for their ability to disrupt these regulatory components and inhibit stemness and terminal differentiation in CSCs, hence achieving clinical implications. However, no cancer treatment focuses on the biological consequences of these drugs on CSCs, and their functions have been established. This article provides a biomedical discussion of cancer at the time along with an overview of CSCs and their origin, features, characterization, isolation techniques, signaling pathways, and novel targeted therapeutic approaches. Additionally, we highlighted the factors endorsed as controlling or helping to promote stemness in CSCs. Our objective was to encourage future studies on these prospective treatments to develop a framework for their application as single or combined therapeutics to eradicate various forms of cancer.
Collapse
Affiliation(s)
- Refaat A. Eid
- Pathology Department, College of Medicine, King Khalid University, Abha P.O. Box 62529, Saudi Arabia
| | - Muhammad Alaa Edeen
- Cell Biology, Histology & Genetics Division, Biology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
- Correspondence: (M.A.E.); (B.K.)
| | - Eslam M. Shedid
- Biotechnology Division, Zoology Department, Faculty of Science, Benha University, Al Qalyubia Governorate, Banha 13511, Egypt
| | - Al Shaimaa S. Kamal
- Biotechnology Department, Faculty of Agriculture, Benha University, Al Qalyubia Governorate, Banha 13511, Egypt
| | - Mona M. Warda
- Biotechnology Division, Zoology Department, Faculty of Science, Benha University, Al Qalyubia Governorate, Banha 13511, Egypt
| | - Farag Mamdouh
- Biotechnology Division, Zoology Department, Faculty of Science, Benha University, Al Qalyubia Governorate, Banha 13511, Egypt
| | - Sohila A. Khedr
- Industrial Biotechnology Department, Faculty of Science, Tanta University, Tanta 31733, Egypt
| | - Mohamed A. Soltan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Sinai University, Ismailia 41611, Egypt
| | - Hee Won Jeon
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Mohamed Samir A. Zaki
- Anatomy Department, College of Medicine, King Khalid University, Abha P.O. Box 62529, Saudi Arabia
- Department of Histology and Cell Biology, College of Medicine, Zagazig University, Zagazig 31527, Egypt
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Correspondence: (M.A.E.); (B.K.)
| |
Collapse
|
|
32
|
Marcu LG, Moghaddasi L, Bezak E. Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells. Int J Mol Sci 2023; 24:ijms24021524. [PMID: 36675033 PMCID: PMC9864237 DOI: 10.3390/ijms24021524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/29/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Cancer stem cells are known to play a key role in tumour development, proliferation, and metastases. Their unique properties confer resistance to therapy, often leading to treatment failure. It is believed that research into the identification, targeting, and eradication of these cells can revolutionise oncological treatment. Based on the principle that what cannot be seen, cannot be targeted, a primary step in cancer management is the identification of these cells. The current review aims to encompass the state-of-the-art functional imaging techniques that enable the identification of cancer stem cells via various pathways and mechanisms. The paper presents in vivo molecular techniques that are currently available or await clinical implementation. Challenges and future prospects are highlighted to open new research avenues in cancer stem cell imaging.
Collapse
Affiliation(s)
- Loredana G. Marcu
- Faculty of Informatics and Science, University of Oradea, 1 Universitatii Str., 410087 Oradea, Romania
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
- Correspondence:
| | - Leyla Moghaddasi
- Northern Sydney Cancer Centre, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
- School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
| | - Eva Bezak
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
- School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
| |
Collapse
|
|
33
|
Czerwinska P, Mackiewicz AA. Bromodomain (BrD) Family Members as Regulators of Cancer Stemness-A Comprehensive Review. Int J Mol Sci 2023; 24:995. [PMID: 36674511 PMCID: PMC9861003 DOI: 10.3390/ijms24020995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/30/2022] [Accepted: 12/31/2022] [Indexed: 01/06/2023] Open
Abstract
Epigenetic mechanisms involving DNA methylation and chromatin modifications have emerged as critical facilitators of cancer heterogeneity, substantially affecting cancer development and progression, modulating cell phenotypes, and enhancing or inhibiting cancer cell malignant properties. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins are essential to maintaining the cancer stem cell (CSC)-like state. With increased tumor-initiating capacities and self-renewal potential, CSCs promote tumor growth, provide therapy resistance, spread tumors, and facilitate tumor relapse after treatment. In this review, we characterized the epigenetic mechanisms that regulate the acquisition and maintenance of cancer stemness concerning selected epigenetic factors belonging to the Bromodomain (BrD) family of proteins. An increasing number of BrD proteins reinforce cancer stemness, supporting the maintenance of the cancer stem cell population in vitro and in vivo via the utilization of distinct mechanisms. As bromodomain possesses high druggable potential, specific BrD proteins might become novel therapeutic targets in cancers exhibiting de-differentiated tumor characteristics.
Collapse
Affiliation(s)
- Patrycja Czerwinska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Andrzej Adam Mackiewicz
- Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| |
Collapse
|
|
34
|
Verma AH, Haldavnekar R, Venkatakrishnan K, Tan B. Dual-Purpose 3D-Silica Nanostructure Matrix for Rapid Epigenetic Reprogramming of Tumor Cell to Cancer Stem Cell Spheroid. SMALL METHODS 2023; 7:e2200798. [PMID: 36424183 DOI: 10.1002/smtd.202200798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/14/2022] [Indexed: 06/16/2023]
Abstract
Cancer stem cells (CSCs), a rare subpopulation responsible for tumorigenesis and therapeutic resistance, are difficult to characterize and isolate. Conventional method of growing CSCs takes up to 2-8 weeks inhibiting the rate of research. Therefore, rapid reprogramming (RR) of tumor cells into CSCs is crucial to accelerate the stem cell oncology research. The current RR techniques cannot be utilized for CSC RR due to many limitations posed due to isolation requirements resulting in loss of vital data. Hence, a technique that can induce CSC RR without the need for isolation procedures is needed. Here, fabrication of a 3D-silica nanostructured extracellular matrix for RR and in situ monitoring is reported. The RR is tested using three preclinical cancer models. The 3D matrix and a zeta potential study confirm an intense material-cellular interaction resulting in the enhanced expressions of surface and epigenetic biomarkers. Cancer cells require only 3-day period to form CSC spheroids with 3D-silica extracellular matrix. Real-time single-cell monitoring of the methylene blue-induced photodynamic demonstrates the dual functionality. To the authors' knowledge, this is the first study to demonstrate a CSC epigenetic reprogramming using nanostructures. These findings may pave the path for accelerating the stem cell research in oncology.
Collapse
Affiliation(s)
- Anish Hiresha Verma
- Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, ON, M5B 1W8, Canada
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada
- Nano-Bio Interface facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada
| | - Rupa Haldavnekar
- Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, ON, M5B 1W8, Canada
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada
- Nano-Bio Interface facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada
| | - Krishnan Venkatakrishnan
- Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, ON, M5B 1W8, Canada
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada
- Nano-Bio Interface facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada
| | - Bo Tan
- Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, ON, M5B 1W8, Canada
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- Nano-Bio Interface facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada
- Nano-characterization Laboratory, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada
| |
Collapse
|
|
35
|
Mukherjee AG, Wanjari UR, Gopalakrishnan AV, Bradu P, Sukumar A, Patil M, Renu K, Dey A, Vellingiri B, George A, Ganesan R. Implications of cancer stem cells in diabetes and pancreatic cancer. Life Sci 2022; 312:121211. [PMID: 36414089 DOI: 10.1016/j.lfs.2022.121211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022]
Abstract
This review provides a detailed study of pancreatic cancer (PC) and the implication of different types of cancers concerning diabetes. The combination of anti-diabetic drugs with other anti-cancer drugs and phytochemicals can help prevent and treat this disease. PC cancer stem cells (CSCs) and how they migrate and develop into malignant tumors are discussed. A detailed explanation of the different mechanisms of diabetes development, which can enhance the pancreatic CSCs' proliferation by increasing the IGF factor levels, epigenetic modifications, DNA damage, and the influence of lifestyle factors like obesity, and inflammation, has been discussed. It also explains how cancer due to diabetes is associated with high mortality rates. One of the well-known diabetic drugs, metformin, can be combined with other anti-cancer drugs and prevent the development of PC and has been taken as one of the prime focus in this review. Overall, this paper provides insight into the relationship between diabetes and PC and the methods that can be employed to diagnose this disease at an earlier stage successfully.
Collapse
Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
| | - Pragya Bradu
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Aarthi Sukumar
- Department of Integrative Biology, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Megha Patil
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, Tamil Nadu, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, West Bengal, 700073, India
| | - Balachandar Vellingiri
- Stem cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda - 151401, Punjab, India
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, 680005, Kerala, India
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, 24252, Republic of Korea
| |
Collapse
|
|
36
|
Shim JK, Choi S, Yoon SJ, Choi RJ, Park J, Lee EH, Cho HJ, Lee S, Teo WY, Moon JH, Kim HS, Kim EH, Cheong JH, Chang JH, Yook JI, Kang SG. Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres. Cancer Cell Int 2022; 22:309. [PMID: 36221088 PMCID: PMC9552483 DOI: 10.1186/s12935-022-02731-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 09/22/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. Methods The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. Results GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. Conclusion ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02731-7.
Collapse
Affiliation(s)
- Jin-Kyoung Shim
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.,Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Seonah Choi
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Seon-Jin Yoon
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.,Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Ran Joo Choi
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.,Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Junseong Park
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.,Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.,Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, 03722, Republic of Korea
| | - Eun Hee Lee
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.,Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Hye Joung Cho
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.,Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Suji Lee
- Department of Medical Science, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Wan-Yee Teo
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, 169857, Singapore.,Institute of Molecular and Cell Biology, A*STAR, Singapore, 169857, Singapore
| | - Ju Hyung Moon
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Hyun Sil Kim
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - Eui Hyun Kim
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.,Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Jong Hee Chang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Jong In Yook
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - Seok-Gu Kang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. .,Brain Tumor Translational Research Laboratory, Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. .,Departments of Medical Science, Yonsei University Graduate School, Seoul, 03722, Republic of Korea.
| |
Collapse
|
|
37
|
Xiao X, Chen H, Yang L, Xie G, Shimuzu R, Murai A. Concise review: Cancer cell reprogramming and therapeutic implications. Transl Oncol 2022; 24:101503. [PMID: 35933935 PMCID: PMC9364012 DOI: 10.1016/j.tranon.2022.101503] [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: 06/29/2022] [Revised: 07/22/2022] [Accepted: 07/28/2022] [Indexed: 11/18/2022] Open
Abstract
The cancer stem cell (CSC) act as tumor initiating cells. Reprogramming technology can convert cells into CSCs. Metabolic reprogramming is critical for CSCs. MiRNA can mediate cancer cell reprogramming as emerging alternatives. The cancer stem cell (CSC) hypothesis postulates that cancer originates from the malignant transformation of stem cells and is considered to apply to a variety of cancers. Additionally, cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. Further, microRNAs (miRNAs) are found to be involved in acquisition of stem cell-like properties, regulation and reprogramming of cancer cells during cancer progression through its post-transcriptional-regulatory activity. In this concise review, we aim to integrate the current knowledge and recent advances to elucidate the mechanisms involved in the regulation of cell reprogramming and highlights the potential therapeutic implications for the future.
Collapse
Affiliation(s)
- Xue Xiao
- Laboratory Department of xingouqiao Street Community Health Service Center, Qingshan District, Wuhan City, Hubei Province, China
| | - Hua Chen
- Laboratory Department of community health service station, Wuhan Engineering University, Wuhan City, Hubei Province, China
| | - Lili Yang
- Laboratory Department of xingouqiao Street Community Health Service Center, Qingshan District, Wuhan City, Hubei Province, China
| | - Guoping Xie
- Laboratory of the second staff hospital of Wuhan Iron and steel (Group) Company, Wuhan City, Hubei Province, China
| | - Risa Shimuzu
- Department of medicine and molecular science, Gunma University, Maebeshi, Japan
| | - Akiko Murai
- Department of Gynecology Oncology, University of Chicago, , 5841 South Maryland Ave, Chicago, IL 60637, USA.
| |
Collapse
|
|
38
|
Monzer A, Wakimian K, Ballout F, Al Bitar S, Yehya A, Kanso M, Saheb N, Tawil A, Doughan S, Hussein M, Mukherji D, Faraj W, Gali-Muhtasib H, Abou-Kheir W. Novel therapeutic diiminoquinone exhibits anticancer effects on human colorectal cancer cells in two-dimensional and three-dimensional in vitro models. World J Gastroenterol 2022; 28:4787-4811. [PMID: 36156922 PMCID: PMC9476858 DOI: 10.3748/wjg.v28.i33.4787] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/24/2022] [Accepted: 08/05/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second leading cause of cancer-related mortality. Cancer stem cells (CSCs) in CRC, which are spared by many chemotherapeutics, have tumorigenic capacity and are believed to be the reason behind cancer relapse. So far, there have been no effective drugs to target colon CSCs. Diiminoquinone (DIQ) has shown promising effects on targeting colon cancer. However, there is limited research on the effects of DIQ on eradicating CSCs in CRC.
AIM To investigate the anticancer potential of DIQ on colon CSCs in two-dimensional (2D) and three-dimensional (3D) models using colonospheres and patient-derived organoids.
METHODS Various 2D methods have been used to assess the effect and the mechanism of DIQ on HCT116 and HT29 cell lines including cell proliferation and viability assays, migration and invasion assays, immunofluorescence staining, and flow cytometry. The potency of DIQ was also assessed in 3D culture using the sphere formation assay and colon cancer patient-derived organoid model.
RESULTS Our results showed that DIQ significantly inhibited cell proliferation, migration, and invasion in HCT116 and HT29 cell lines. DIQ treatment induced apoptosis along with an accumulation of HCT116 and HT29 cancer cells in the sub-G1 region and an increase in reactive oxygen species in both CRC cell lines. DIQ reduced sphere-forming and self-renewal ability of colon cancer HCT116 and HT29 stem/progenitor cells at sub-toxic doses of 1 μmol/L. Mechanistically, DIQ targets CSCs by downregulating the main components of stem cell-related -catenin, AKT, and ERK oncogenic signaling pathways. Potently, DIQ displayed a highly significant decrease in both the count and the size of the organoids derived from colon cancer patients as compared to control and 5-fluorouracil conditions.
CONCLUSION This study is the first documentation of the molecular mechanism of the novel anticancer therapeutic DIQ via targeting CSC, a promising compound that needs further investigation.
Collapse
Affiliation(s)
- Alissar Monzer
- Department of Biology, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Kevork Wakimian
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Farah Ballout
- Department of Biology, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Samar Al Bitar
- Department of Biology, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Amani Yehya
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Mariam Kanso
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Nour Saheb
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Ayman Tawil
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Samer Doughan
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Maher Hussein
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Deborah Mukherji
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Walid Faraj
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Hala Gali-Muhtasib
- Department of Biology and Center for Drug Discovery, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| |
Collapse
|
|
39
|
Navas LE, Carnero A. Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer. Cells 2022; 11:cells11172627. [PMID: 36078035 PMCID: PMC9454445 DOI: 10.3390/cells11172627] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/25/2022] [Accepted: 08/16/2022] [Indexed: 11/22/2022] Open
Abstract
NAD+ is an important metabolite in cell homeostasis that acts as an essential cofactor in oxidation–reduction (redox) reactions in various energy production processes, such as the Krebs cycle, fatty acid oxidation, glycolysis and serine biosynthesis. Furthermore, high NAD+ levels are required since they also participate in many other nonredox molecular processes, such as DNA repair, posttranslational modifications, cell signalling, senescence, inflammatory responses and apoptosis. In these nonredox reactions, NAD+ is an ADP-ribose donor for enzymes such as sirtuins (SIRTs), poly-(ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADPRs). Therefore, to meet both redox and nonredox NAD+ demands, tumour cells must maintain high NAD+ levels, enhancing their synthesis mainly through the salvage pathway. NAMPT, the rate-limiting enzyme of this pathway, has been identified as an oncogene in some cancer types. Thus, NAMPT has been proposed as a suitable target for cancer therapy. NAMPT inhibition causes the depletion of NAD+ content in the cell, leading to the inhibition of ATP synthesis. This effect can cause a decrease in tumour cell proliferation and cell death, mainly by apoptosis. Therefore, in recent years, many specific inhibitors of NAMPT have been developed, and some of them are currently in clinical trials. Here we review the NAD metabolism as a cancer therapy target.
Collapse
Affiliation(s)
- Lola E. Navas
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, 41013 Sevilla, Spain
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, 41013 Sevilla, Spain
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence:
| |
Collapse
|
|
40
|
Muylaert C, Van Hemelrijck LA, Maes A, De Veirman K, Menu E, Vanderkerken K, De Bruyne E. Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity? Front Oncol 2022; 12:979569. [PMID: 36059621 PMCID: PMC9434119 DOI: 10.3389/fonc.2022.979569] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 07/22/2022] [Indexed: 11/30/2022] Open
Abstract
Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called ‘epimutations’ have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies.
Collapse
|
|
41
|
Escudero Mendez L, Srinivasan M, Hamouda RK, Ambedkar B, Arzoun H, Sahib I, Fondeur J, Mohammed L. Evaluation of CD44+/CD24- and Aldehyde Dehydrogenase Enzyme Markers in Cancer Stem Cells as Prognostic Indicators for Triple-Negative Breast Cancer. Cureus 2022; 14:e28056. [PMID: 36120232 PMCID: PMC9476834 DOI: 10.7759/cureus.28056] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 08/16/2022] [Indexed: 11/10/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has been extensively studied not just for its aggressive behavior but also to understand its complex molecular nature. This type of heterogeneous tumor shows no expression of estrogen receptor (ER) or progesterone receptor (PR) and does not express the HER2 gene, and often these tumors are high grade with distinct histological groups. The basal-like subtype is most commonly related to the TNBC type of neoplasms; it can be further classified according to Lehmann and Burstein expert’s criteria. TNBC is related to breast stem cell markers such as CD44+/CD24- and high levels of enzyme aldehyde dehydrogenase (ALDH), which have been shown to possess stem cell features that are involved in differentiation, vascular invasion, tumorigenesis, and metastatic potential. CD44+/CD24- and high levels of ALDH have significance as markers as well as indicators of poor prognosis in TNBC. The databases used in this review are PMC, PubMed, and Google Scholar.
Collapse
|
|
42
|
Liu B, Zhang G, Cui S, Du G. Upregulation of KIF11 in TP53 Mutant Glioma Promotes Tumor Stemness and Drug Resistance. Cell Mol Neurobiol 2022; 42:1477-1485. [PMID: 33491154 PMCID: PMC11421707 DOI: 10.1007/s10571-020-01038-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/31/2020] [Indexed: 12/21/2022]
Abstract
Glioma is the most common type of primary brain malignancy with high morbidity and mortality, but little is known about its pathological mechanisms. Kinesin family member 11 (KIF11) is a key driver of malignancy in glioblastoma, a grade IV glioma, but its involvement in glioma chemoresistance remains to be determined. We accessed the TCGA open datasets, collected glioma tumor tissue samples, and analyzed the expression of KIF11 in glioma patients. Meanwhile, the correlation between KIF11 and survival outcomes was determined by the Kaplan-Meier analysis. The role of KIF11 in glioma tumor cell function was assessed in an in vitro knockdown and overexpressing system. Here, we found that KIF11 was upregulated in glioma tumors and negatively correlated with overall survival outcomes via analyzing the open datasets. KIF11 was negatively correlated with TP53 expression. Furthermore, KIF11 promoted the stemness in glioma cells, accompanied by increased cell proliferation and chemoresistance. Mechanistically, we found that KIF11 promoted cell cycle progression via upregulating cyclin expression.
Collapse
Affiliation(s)
- Bin Liu
- Department of Neurosurgery Six, Cangzhou Central Hospital, Xinhua West Road, Cangzhou, 061000, Hebei, China.
| | - Gang Zhang
- Department of Neurosurgery Six, Cangzhou Central Hospital, Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Shukun Cui
- Department of Neurosurgery Six, Cangzhou Central Hospital, Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Guoliang Du
- Department of Neurosurgery Six, Cangzhou Central Hospital, Xinhua West Road, Cangzhou, 061000, Hebei, China
| |
Collapse
|
|
43
|
Ubiquitin-Specific Protease 6 n-Terminal-like Protein (USP6NL) and the Epidermal Growth Factor Receptor (EGFR) Signaling Axis Regulates Ubiquitin-Mediated DNA Repair and Temozolomide-Resistance in Glioblastoma. Biomedicines 2022; 10:biomedicines10071531. [PMID: 35884836 PMCID: PMC9312792 DOI: 10.3390/biomedicines10071531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant glioma, with a 30–60% epidermal growth factor receptor (EGFR) mutation. This mutation is associated with unrestricted cell growth and increases the possibility of cancer invasion. Patients with EGFR-mutated GBM often develop resistance to the available treatment modalities and higher recurrence rates. The drug resistance observed is associated with multiple genetic or epigenetic factors. The ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) is a GTPase-activating protein that functions as a deubiquitinating enzyme and regulates endocytosis and signal transduction. It is highly expressed in many cancer types and may promote the growth and proliferation of cancer cells. We hypothesized that USP6NL affects GBM chemoresistance and tumorigenesis, and that its inhibition may be a novel therapeutic strategy for GBM treatment. The USP6NL level, together with EGFR expression in human GBM tissue samples and cell lines associated with therapy resistance, tumor growth, and cancer invasion, were investigated. Its pivotal roles and potential mechanism in modulating tumor growth, and the key mechanism associated with therapy resistance of GBM cells, were studied, both in vitro and in vivo. Herein, we found that deubiquitinase USP6NL and growth factor receptor EGFR were strongly associated with the oncogenicity and resistance of GBM, both in vitro and in vivo, toward temozolomide, as evidenced by enhanced migration, invasion, and acquisition of a highly invasive and drug-resistant phenotype by the GBM cells. Furthermore, abrogation of USP6NL reversed the properties of GBM cells and resensitized them toward temozolomide by enhancing autophagy and reducing the DNA damage repair response. Our results provide novel insights into the probable mechanism through which USP6NL/EGFR signaling might suppress the anticancer therapeutic response, induce cancer invasiveness, and facilitate reduced sensitivity to temozolomide treatment in GBM in an autolysosome-dependent manner. Therefore, controlling the USP6NL may offer an alternative, but efficient, therapeutic strategy for targeting and eradicating otherwise resistant and recurrent phenotypes of aggressive GBM cells.
Collapse
|
|
44
|
Boccellato C, Rehm M. Glioblastoma, from disease understanding towards optimal cell-based in vitro models. Cell Oncol (Dordr) 2022; 45:527-541. [PMID: 35763242 PMCID: PMC9424171 DOI: 10.1007/s13402-022-00684-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2022] [Indexed: 11/24/2022] Open
Abstract
Abstract
Background
Glioblastoma (GBM) patients are notoriously difficult to treat and ultimately all succumb to disease. This unfortunate scenario motivates research into better characterizing and understanding this disease, and into developing novel research tools by which potential novel therapeutics and treatment options initially can be evaluated pre-clinically. Here, we provide a concise overview of glioblastoma epidemiology, disease classification, the challenges faced in the treatment of glioblastoma and current novel treatment strategies. From this, we lead into a description and assessment of advanced cell-based models that aim to narrow the gap between pre-clinical and clinical studies. Such invitro models are required to deliver reliable and meaningful data for the development and pre-validation of novel therapeutics and treatments.
Conclusions
The toolbox for GBM cell-based models has expanded substantially, with the possibility of 3D printing tumour tissues and thereby replicating invivo tissue architectures now looming on the horizon. A comparison of experimental cell-based model systems and techniques highlights advantages and drawbacks of the various tools available, based on which cell-based models and experimental approaches best suited to address a diversity of research questions in the glioblastoma research field can be selected.
Collapse
Affiliation(s)
- Chiara Boccellato
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
- Stuttgart Research Center Systems Biology, University of Stuttgart, 70569, Stuttgart, Germany.
| |
Collapse
|
|
45
|
Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting. Stem Cells Int 2022; 2022:9653244. [PMID: 35800881 PMCID: PMC9256444 DOI: 10.1155/2022/9653244] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 06/07/2022] [Indexed: 12/22/2022] Open
Abstract
Cancer is characterized by an abnormal growth of the cells in an uncontrolled manner. These cells have the potential to invade and can eventually turn into malignancy, leading to highly fatal forms of tumor. Small subpopulations of cancer cells that are long-lived with the potential of excessive self-renewal and tumor formation are called cancer stem cells (CSCs) or cancer-initiating cells or tumor stem cells. CSCs can be found in tissues, such as breast, brain, lung, liver, ovary, and testis; however, their origin is still a matter of debate. These cells can differentiate and possess self-renewal capacity maintained by numerous intracellular signal transduction pathways, such as the Wnt/β-catenin signaling, Notch signaling, transforming growth factor-β signaling, and Hedgehog signaling. They can also contribute to numerous malignancies and are an important reason for tumor recurrence and metastasis because they are resistant to the known therapeutic strategies that mainly target the bulk of the tumor cells. This review contains collected and compiled information after analyzing published works of the last three decades. The goal was to gather information of recent breakthroughs related to CSCs, strategies to target CSCs' niche (e.g., nanotechnology with tumor biology), and their signaling pathways for cancer therapy. Moreover, the role of metformin, an antidiabetic drug, acting as a chemotherapeutic agent on CSCs by inhibiting cellular transformation and its selective killing is also addressed.
Collapse
|
|
46
|
Montazer M, Taghehchian N, Mojarrad M, Moghbeli M. Role of microRNAs in regulation of WNT signaling pathway in urothelial and prostate cancers. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00315-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Urothelial cancer (UC) and prostate cancer (PCa) are the most common cancers among men with a high ratio of mortality in advanced-stages. The higher risk of these malignancies among men can be associated with higher carcinogens exposure. Molecular pathology of UC and PCa is related to the specific mutations and aberrations in some signaling pathways. WNT signaling is a highly regulated pathway that has a pivotal role during urothelial and prostate development and homeostasis. This pathway also plays a vital role in adult stem cell niches to maintain a balance between stemness and differentiation. Deregulation of the WNT pathway is frequently correlated with tumor progression and metastasis in urothelial and prostate tumors. Therefore, regulatory factors of WNT pathways are being investigated as diagnostic or prognostic markers and novel therapeutic targets during urothelial and prostate tumorigenesis. MicroRNAs (miRNAs) have a pivotal role in WNT signaling regulation in which there are interactions between miRNAs and WNT signaling pathway during tumor progression. Since, the miRNAs are sensitive, specific, and noninvasive, they can be introduced as efficient biomarkers of tumor progression.
Main body
In present review, we have summarized all of the miRNAs that have been involved in regulation of WNT signaling pathway in urothelial and prostate cancers.
Conclusions
It was observed that miRNAs were mainly involved in regulation of WNT signaling in bladder cancer cells through targeting the WNT ligands and cytoplasmic WNT components such as WNT5A, WNT7A, CTNNB1, GSK3β, and AXIN. Whereas, miRNAs were mainly involved in regulation of WNT signaling in prostate tumor cells via targeting the cytoplasmic WNT components and WNT related transcription factors such as CTNNB1, GSK3β, AXIN, TCF7, and LEF1. MiRNAs mainly functioned as tumor suppressors in bladder and prostate cancers through the WNT signaling inhibition. This review paves the way of introducing a noninvasive diagnostic panel of WNT related miRNAs in urothelial and prostate tumors.
Collapse
|
|
47
|
Nascimento-Filho CHV, Glinos AT, Jang Y, Goloni-Bertollo EM, Castilho RM, Squarize CH. From Tissue Physoxia to Cancer Hypoxia, Cost-Effective Methods to Study Tissue-Specific O 2 Levels in Cellular Biology. Int J Mol Sci 2022; 23:ijms23105633. [PMID: 35628446 PMCID: PMC9144419 DOI: 10.3390/ijms23105633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 05/06/2022] [Accepted: 05/13/2022] [Indexed: 12/10/2022] Open
Abstract
The human body is endowed with an extraordinary ability to maintain different oxygen levels in various tissues and organs. The maintenance of physiological levels of oxygen is known as physoxia. The development of hypoxic conditions plays an important role in the biology of several pathologies, including cancer. In vitro studies using normal and neoplastic cells require that culture conditions be carried out under appropriate oxygen levels, either physoxic or hypoxic conditions. Such requirements are difficult to widely implement in laboratory practice, mainly due to the high costs of specialized equipment. In this work, we present and characterize a cost-effective method to culture cells under a range of oxygen levels using deoxidizing pouches. Our results show that physoxic and hypoxic levels using deoxidizing absorbers can be achieved either by implementing a gradual change in oxygen levels or by a regimen of acute depletion of oxygen. This approach triggers the activation of an epithelial-mesenchymal transition in cancer cells while stimulating the expression of HIF-1α. Culturing cancer cells with deoxidizing agent pouches revealed PI3K oncogenic pathway exacerbations compared to tumor cells growing under atmospheric levels of oxygen. Similar to the PI3K signaling disturbance, we also observed augmented oxidative stress and superoxide levels and increased cell cycle arrest. Most interestingly, the culture of cancer cells under hypoxia resulted in the accumulation of cancer stem cells in a time-dependent manner. Overall, we present an attractive, cost-effective method of culturing cells under appropriate physoxic or hypoxic conditions that is easily implementable in any wet laboratory equipped with cell culture tools.
Collapse
Affiliation(s)
- Carlos H. V. Nascimento-Filho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA; (C.H.V.N.-F.); (A.T.G.); (Y.J.); (C.H.S.)
| | - Alexandra T. Glinos
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA; (C.H.V.N.-F.); (A.T.G.); (Y.J.); (C.H.S.)
| | - Yeejin Jang
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA; (C.H.V.N.-F.); (A.T.G.); (Y.J.); (C.H.S.)
| | - Eny M. Goloni-Bertollo
- Genetics and Molecular Biology Research Unit (UPGEM), Department of Molecular Biology, School of Medicine of São José do Rio Preto, São José do Rio Preto 15090-000, SP, Brazil;
| | - Rogerio M. Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA; (C.H.V.N.-F.); (A.T.G.); (Y.J.); (C.H.S.)
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109-0944, USA
- Correspondence:
| | - Cristiane H. Squarize
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA; (C.H.V.N.-F.); (A.T.G.); (Y.J.); (C.H.S.)
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109-0944, USA
| |
Collapse
|
|
48
|
Sun M, Chen X, Yang Z. Single cell mass spectrometry studies reveal metabolomic features and potential mechanisms of drug-resistant cancer cell lines. Anal Chim Acta 2022; 1206:339761. [PMID: 35473873 PMCID: PMC9046687 DOI: 10.1016/j.aca.2022.339761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 12/28/2022]
Abstract
Irinotecan (Iri) is a key drug to treat metastatic colorectal cancer, but its clinical activity is often limited by de novo and acquired drug resistance. Studying the underlying mechanisms of drug resistance is necessary for developing novel therapeutic strategies. In this study, we used both regular and irinotecan-resistant (Iri-resistant) colorectal cell lines as models, and performed single cell mass spectrometry (SCMS) metabolomics studies combined with analyses from cytotoxicity assay, western blot, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), and reactive oxygen species (ROS). Our SCMS results indicate that Iri-resistant cancer cells possess higher levels of unsaturated lipids compared with the regular cancer cells. In addition, multiple protein biomarkers and their corresponding mRNAs of colon cancer stem cells are overexpressed in Iri-resistance cells. Particularly, stearoyl-CoA desaturase 1 (SCD1) is upregulated with the development of drug resistance in Iri-resistant cells, whereas inhibiting the activity of SCD1 efficiently increase their sensitivity to Iri treatment. In addition, we demonstrated that SCD1 directly regulates the expression of ALDH1A1, which contributes to the cancer stemness and ROS level in Iri-resistant cell lines.
Collapse
|
|
49
|
Saito S, Ku CC, Wuputra K, Pan JB, Lin CS, Lin YC, Wu DC, Yokoyama KK. Biomarkers of Cancer Stem Cells for Experimental Research and Clinical Application. J Pers Med 2022; 12:715. [PMID: 35629138 PMCID: PMC9147761 DOI: 10.3390/jpm12050715] [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: 03/03/2022] [Revised: 04/22/2022] [Accepted: 04/27/2022] [Indexed: 12/12/2022] Open
Abstract
The use of biomarkers in cancer diagnosis, therapy, and prognosis has been highly effective over several decades. Studies of biomarkers in cancer patients pre- and post-treatment and during cancer progression have helped identify cancer stem cells (CSCs) and their related microenvironments. These analyses are critical for the therapeutic application of drugs and the efficient targeting and prevention of cancer progression, as well as the investigation of the mechanism of the cancer development. Biomarkers that characterize CSCs have thus been identified and correlated to diagnosis, therapy, and prognosis. However, CSCs demonstrate elevated levels of plasticity, which alters their functional phenotype and appearance by interacting with their microenvironments, in response to chemotherapy and radiotherapeutics. In turn, these changes induce different metabolic adaptations of CSCs. This article provides a review of the most frequently used CSCs and stem cell markers.
Collapse
Affiliation(s)
- Shigeo Saito
- Saito Laboratory of Cell Technology, Yaita 329-1571, Japan
- Horus Co., Ltd., Nakano, Tokyo 164-0001, Japan
| | - Chia-Chen Ku
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Kenly Wuputra
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Jia-Bin Pan
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Chang-Shen Lin
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
| | - Ying-Chu Lin
- School of Dentistry, Department of Dentistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Deng-Chyang Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Kazunari K. Yokoyama
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| |
Collapse
|
|
50
|
Carmona-Carmona CA, Dalla Pozza E, Ambrosini G, Errico A, Dando I. Divergent Roles of Mitochondria Dynamics in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14092155. [PMID: 35565283 PMCID: PMC9105422 DOI: 10.3390/cancers14092155] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma is one of the most lethal neoplasia due to the lack of early diagnostic markers and effective therapies. The study of metabolic alterations of PDAC is of crucial importance since it would open the way to the discovery of new potential therapies. Mitochondria represent key organelles that regulate energy metabolism, and they remodel their structure by undergoing modifications by fusing with other mitochondria or dividing to generate smaller ones. The alterations of mitochondria arrangement may influence the metabolism of PDAC cells, thus supporting the proliferative needs of cancer. Shedding light on this topic regarding cancer and, more specifically, PDAC may help identify new potential strategies that hit cancer cells at their “core,” i.e., mitochondria. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors; it is often diagnosed at an advanced stage and is hardly treatable. These issues are strictly linked to the absence of early diagnostic markers and the low efficacy of treatment approaches. Recently, the study of the metabolic alterations in cancer cells has opened the way to important findings that can be exploited to generate new potential therapies. Within this scenario, mitochondria represent important organelles within which many essential functions are necessary for cell survival, including some key reactions involved in energy metabolism. These organelles remodel their shape by dividing or fusing themselves in response to cellular needs or stimuli. Interestingly, many authors have shown that mitochondrial dynamic equilibrium is altered in many different tumor types. However, up to now, it is not clear whether PDAC cells preferentially take advantage of fusion or fission processes since some studies reported a wide range of different results. This review described the role of both mitochondria arrangement processes, i.e., fusion and fission events, in PDAC, showing that a preference for mitochondria fragmentation could sustain tumor needs. In addition, we also highlight the importance of considering the metabolic arrangement and mitochondria assessment of cancer stem cells, which represent the most aggressive tumor cell type that has been shown to have distinctive metabolic features to that of differentiated tumor cells.
Collapse
Affiliation(s)
| | | | | | | | - Ilaria Dando
- Correspondence: (C.A.C.-C.); (I.D.); Tel.: +39-045-802-7174 (C.A.C.-C.); +39-045-802-7169 (I.D.)
| |
Collapse
|