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Gou S, Wu A, Luo Z. Integrins in cancer stem cells. Front Cell Dev Biol 2024; 12:1434378. [PMID: 39239559 PMCID: PMC11375753 DOI: 10.3389/fcell.2024.1434378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/12/2024] [Indexed: 09/07/2024] Open
Abstract
Integrins are a class of adhesion receptors on cell membranes, consisting of α and β subunits. By binding to the extracellular matrix, integrins activate intracellular signaling pathways, participating in every step of cancer initiation and progression. Tumor stem cells possess self-renewal and self-differentiation abilities, along with strong tumorigenic potential. In this review, we discussed the role of integrins in cancer, with a focus on their impact on tumor stem cells and tumor stemness. This will aid in targeting tumor stem cells as a therapeutic approach, leading to the exploration of novel cancer treatment strategies.
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Affiliation(s)
- Siqi Gou
- The Second Affiliated Hospital, Department of urology, Hengyang Medical School, University of South China, Hengyang, China
| | - Anqi Wu
- The Second Affiliated Hospital, Department of Clinical Research Center, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhigang Luo
- The Second Affiliated Hospital, Department of urology, Hengyang Medical School, University of South China, Hengyang, China
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Faraldo MM, Romagnoli M, Wallon L, Dubus P, Deugnier MA, Fre S. Alpha-6 integrin deletion delays the formation of Brca1/p53-deficient basal-like breast tumors by restricting luminal progenitor cell expansion. Breast Cancer Res 2024; 26:91. [PMID: 38835038 PMCID: PMC11151721 DOI: 10.1186/s13058-024-01851-4] [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: 12/19/2023] [Accepted: 05/28/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND The aberrant amplification of mammary luminal progenitors is at the origin of basal-like breast cancers associated with BRCA1 mutations. Integrins mediate cell-matrix adhesion and transmit mechanical and chemical signals that drive epithelial stem cell functions and regulate tumor progression, metastatic reactivation, and resistance to targeted therapies. Consistently, we have recently shown that laminin-binding integrins are essential for the expansion and differentiation of mammary luminal progenitors in physiological conditions. As over-expression of the laminin-binding α6 integrin (Itgα6) is associated with poor prognosis and reduced survival in breast cancer, we here investigate the role of Itgα6 in mammary tumorigenesis. METHODS We used Blg-Cre; Brca1F/F; Trp53F/F mice, a model that phenocopies human basal-like breast cancer with BRCA1 mutations. We generated mutant mice proficient or deficient in Itgα6 expression and followed tumor formation. Mammary tumors and pretumoral tissues were characterized by immunohistochemistry, flow cytometry, RT-qPCR, Western blotting and organoid cultures. Clonogenicity of luminal progenitors from preneoplastic glands was studied in 3D Matrigel cultures. RESULTS We show that Itga6 deletion favors activation of p16 cell cycle inhibitor in the preneoplastic tissue. Subsequently, the amplification of luminal progenitors, the cell of origin of Brca1-deficient tumors, is restrained in Itgα6-deficient gland. In addition, the partial EMT program operating in Brca1/p53-deficient epithelium is attenuated in the absence of Itgα6. As a consequence of these events, mammary tumor formation is delayed in Itgα6-deficient mice. After tumor formation, the lack of Itgα6 does not affect tumor growth but rather alters their differentiation, resulting in reduced expression of basal cell markers. CONCLUSIONS Our data indicate that Itgα6 has a pro-tumorigenic role in Blg-Cre; Brca1F/F; Trp53F/F mice developing basal-like mammary tumors. In particular, we reveal that Itgα6 is required for the luminal progenitor expansion and the aberrant partial EMT program that precedes the formation of BRCA1 deficient tumors.
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Affiliation(s)
- Marisa M Faraldo
- Laboratory of Genetics and Developmental Biology, Institut Curie, INSERM U934, CNRS UMR3215, PSL Research University, 75248, Paris, France.
| | - Mathilde Romagnoli
- Laboratory of Cell Biology and Cancer, CNRS UMR144, Institut Curie, PSL Research University, 75248, Paris, France
- Institut de Recherches Internationales Servier, 91190, Gif Sur Yvette, France
| | - Loane Wallon
- Laboratory of Genetics and Developmental Biology, Institut Curie, INSERM U934, CNRS UMR3215, PSL Research University, 75248, Paris, France
- Alacris Theranostics GmbH, 12489, Berlin, Germany
| | - Pierre Dubus
- Department of Histology and Pathology, Centre Hospitalier Universitaire de Bordeaux, 33000, Bordeaux, France
- BRIC U1312, INSERM, Bordeaux Institute of Oncology, Université de Bordeaux, 33000, Bordeaux, France
| | - Marie-Ange Deugnier
- Laboratory of Cell Biology and Cancer, CNRS UMR144, Institut Curie, PSL Research University, 75248, Paris, France
| | - Silvia Fre
- Laboratory of Genetics and Developmental Biology, Institut Curie, INSERM U934, CNRS UMR3215, PSL Research University, 75248, Paris, France.
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Fan C, Xiong F, Zhang S, Gong Z, Liao Q, Li G, Guo C, Xiong W, Huang H, Zeng Z. Role of adhesion molecules in cancer and targeted therapy. SCIENCE CHINA. LIFE SCIENCES 2024; 67:940-957. [PMID: 38212458 DOI: 10.1007/s11427-023-2417-3] [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: 06/08/2023] [Accepted: 07/17/2023] [Indexed: 01/13/2024]
Abstract
Adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interactions and transmit mechanical and chemical signals among them. Various mechanisms deregulate adhesion molecules in cancer, enabling tumor cells to proliferate without restraint, invade through tissue boundaries, escape from immune surveillance, and survive in the tumor microenvironment. Recent studies have revealed that adhesion molecules also drive angiogenesis, reshape metabolism, and are involved in stem cell self-renewal. In this review, we summarize the functions and mechanisms of adhesion molecules in cancer and the tumor microenvironment, as well as the therapeutic strategies targeting adhesion molecules. These studies have implications for furthering our understanding of adhesion molecules in cancer and providing a paradigm for exploring novel therapeutic approaches.
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Affiliation(s)
- Chunmei Fan
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Fang Xiong
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, 410078, China
| | - Shanshan Zhang
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, 410078, China
| | - Zhaojian Gong
- Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China
| | - Can Guo
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China
| | - He Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, China.
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China.
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Kwon MJ. Role of epithelial splicing regulatory protein 1 in cancer progression. Cancer Cell Int 2023; 23:331. [PMID: 38110955 PMCID: PMC10729575 DOI: 10.1186/s12935-023-03180-6] [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: 10/29/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023] Open
Abstract
As aberrant alternative splicing by either dysregulation or mutations of splicing factors contributes to cancer initiation and progression, splicing factors are emerging as potential therapeutic targets for cancer therapy. Therefore, pharmacological modulators targeting splicing factors have been under development. Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific splicing factor, whose downregulation is associated with epithelial-mesenchymal transition (EMT) by regulating alternative splicing of multiple genes, such as CD44, CTNND1, ENAH, and FGFR2. Consistent with the downregulation of ESRP1 during EMT, it has been initially revealed that high ESRP1 expression is associated with favorable prognosis and ESRP1 plays a tumor-suppressive role in cancer progression. However, ESRP1 has been found to promote cancer progression in some cancers, such as breast and ovarian cancers, indicating that it plays a dual role in cancer progression depending on the type of cancer. Furthermore, recent studies have reported that ESRP1 affects tumor growth by regulating the metabolism of tumor cells or immune cell infiltration in the tumor microenvironment, suggesting the novel roles of ESRP1 in addition to EMT. ESRP1 expression was also associated with response to anticancer drugs. This review describes current understanding of the roles and mechanisms of ESRP1 in cancer progression, and further discusses the emerging novel roles of ESRP1 in cancer and recent attempts to target splicing factors for cancer therapy.
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Affiliation(s)
- Mi Jeong Kwon
- Vessel-Organ Interaction Research Center (MRC), College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea.
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Mukhopadhyay D, Goel HL, Xiong C, Goel S, Kumar A, Li R, Zhu LJ, Clark JL, Brehm MA, Mercurio AM. The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing. Cell Rep 2023; 42:113347. [PMID: 37910503 PMCID: PMC10872598 DOI: 10.1016/j.celrep.2023.113347] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 09/06/2023] [Accepted: 10/10/2023] [Indexed: 11/03/2023] Open
Abstract
Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast cancer stem cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate integrin α6 mRNA splicing. Specifically, TRPC6-mediated calcium entry represses the epithelial splicing factor ESRP1 (epithelial splicing regulatory protein 1), which enables expression of the integrin α6B splice variant. TRPC6 and α6B function in tandem to facilitate stemness and persistence by activating TAZ and, consequently, repressing Myc. Therapeutic inhibition of TRPC6 sensitizes triple-negative breast cancer (TNBC) cells and tumors to chemotherapy by targeting the splicing of α6 integrin mRNA and inducing Myc. These data reveal a Ca2+-dependent mechanism of chemotherapy-induced persistence, which is amenable to therapy, that involves integrin mRNA splicing.
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Affiliation(s)
- Dimpi Mukhopadhyay
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Hira Lal Goel
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Choua Xiong
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Shivam Goel
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Ayush Kumar
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Rui Li
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Lihua Julie Zhu
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Jennifer L Clark
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Michael A Brehm
- Department of Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Arthur M Mercurio
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
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Khademi R, Malekzadeh H, Bahrami S, Saki N, Khademi R, Villa-Diaz LG. Regulation and Functions of α6-Integrin (CD49f) in Cancer Biology. Cancers (Basel) 2023; 15:3466. [PMID: 37444576 DOI: 10.3390/cancers15133466] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Over the past decades, our knowledge of integrins has evolved from being understood as simple cell surface adhesion molecules to receptors that have a complex range of intracellular and extracellular functions, such as delivering chemical and mechanical signals to cells. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Dysregulation of integrin signaling is a major factor in the development and progression of many tumors. Many reviews have covered the broader integrin family in molecular and cellular studies and its roles in diseases. Nevertheless, further understanding of the mechanisms specific to an individual subunit of different heterodimers is more useful. Thus, we describe the current understanding of and exploratory investigations on the α6-integrin subunit (CD49f, VLA6; encoded by the gene itga6) in normal and cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnosis biomarker, are discussed. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. In addition, exosomal ITGA6 also implies metastatic organotropism. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel prognostic or diagnostic marker and useful therapeutic target for better clinical outcomes.
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Affiliation(s)
- Rahele Khademi
- Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (Immuno_TACT), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
| | - Hossein Malekzadeh
- Department of Oral Medicine, Faculty of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Sara Bahrami
- Resident of Restorative Dentistry, Qazvin University of Medical Sciences, Qazvin 3419759811, Iran
| | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Reyhane Khademi
- Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (Immuno_TACT), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Laboratory Sciences, School of Para-Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Luis G Villa-Diaz
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
- Department of Bioengineering, Oakland University, Rochester, MI 48309, USA
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Modvig S, Jeyakumar J, Marquart HV, Christensen C. Integrins and the Metastasis-like Dissemination of Acute Lymphoblastic Leukemia to the Central Nervous System. Cancers (Basel) 2023; 15:cancers15092504. [PMID: 37173970 PMCID: PMC10177281 DOI: 10.3390/cancers15092504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/23/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Acute lymphoblastic leukemia (ALL) disseminates with high prevalence to the central nervous system (CNS) in a process resembling aspects of the CNS surveillance of normal immune cells as well as aspects of brain metastasis from solid cancers. Importantly, inside the CNS, the ALL blasts are typically confined within the cerebrospinal fluid (CSF)-filled cavities of the subarachnoid space, which they use as a sanctuary protected from both chemotherapy and immune cells. At present, high cumulative doses of intrathecal chemotherapy are administered to patients, but this is associated with neurotoxicity and CNS relapse still occurs. Thus, it is imperative to identify markers and novel therapy targets specific to CNS ALL. Integrins represent a family of adhesion molecules involved in cell-cell and cell-matrix interactions, implicated in the adhesion and migration of metastatic cancer cells, normal immune cells, and leukemic blasts. The ability of integrins to also facilitate cell-adhesion mediated drug resistance, combined with recent discoveries of integrin-dependent routes of leukemic cells into the CNS, have sparked a renewed interest in integrins as markers and therapeutic targets in CNS leukemia. Here, we review the roles of integrins in CNS surveillance by normal lymphocytes, dissemination to the CNS by ALL cells, and brain metastasis from solid cancers. Furthermore, we discuss whether ALL dissemination to the CNS abides by known hallmarks of metastasis, and the potential roles of integrins in this context.
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Affiliation(s)
- Signe Modvig
- Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Jenani Jeyakumar
- Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
| | - Hanne Vibeke Marquart
- Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Claus Christensen
- Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
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Araki M, Noguchi S, Kubo Y, Yasuda A, Koh M, Otsuka H, Yokosuka M, Soeta S. Expression of type VI collagen α3 chain in canine mammary carcinomas. Res Vet Sci 2023; 159:171-182. [PMID: 37148736 DOI: 10.1016/j.rvsc.2023.04.010] [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: 08/05/2022] [Revised: 03/06/2023] [Accepted: 04/13/2023] [Indexed: 05/08/2023]
Abstract
This study aimed to investigate the expression of type VI collagen α3 chain (COL6a3) in neoplastic cells of canine mammary gland carcinomas (CMGCs) using immunohistochemistry (IHC) and to evaluate the association between COL6a3 expression and tumor histological features, histological grades, and the differentiation status of neoplastic epithelial cells. COL6a3 expression in carcinoma cells was significantly associated with histologically low malignancy and low mitotic indices. In addition, COL6a3+ carcinoma cells were more frequently detected in simple carcinomas (tubular and tubulopapillary types) than in solid carcinomas. These findings indicate that reduced expression of COL6a3 in carcinoma cells contributes to the malignant phenotype in CMGCs. We also showed that COL6a3 expression in the carcinoma cells was more frequently detected in CK19+/CD49f + and/or CK19+/CK5+ tumors. In addition, COL6a3+/CK19+/CD49f + and COL6a3+/CK19+/CK5+ tumors consisted of CK19+/CD49f + and CK19+/CD49f- cells, and CK19+/CK5+ and CK19+/CK5- cells, respectively. Most of these tumors more frequently expressed GATA3, but not Notch1. These results indicate that COL6a3 is expressed in CMGCs containing both luminal progenitor-like and mature luminal-like cells and showing differentiation ability into mature luminal cells. It is possible that COL6 may be involved in the differentiation of luminal progenitor-like carcinoma cells into mature luminal-like carcinoma cells in CMGCs, which may suppresses the development of malignant phenotypes in CMGCs.
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Affiliation(s)
- Mami Araki
- Laboratory of Veterinary Anatomy, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, 1-7-1, Kyonan-cho, Musashino-shi, Tokyo, Japan
| | - Syunya Noguchi
- Department of Molecular Medicine and Anatomy, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, Japan
| | - Yoshiaki Kubo
- Veterinary Medical Teaching Hospital, Attached Facility, Nippon Veterinary and Life Science University, 1-7-1, Kyonan-cho, Musashino-shi, Tokyo, Japan
| | - Akiko Yasuda
- Veterinary Medical Teaching Hospital, Attached Facility, Nippon Veterinary and Life Science University, 1-7-1, Kyonan-cho, Musashino-shi, Tokyo, Japan
| | - Miki Koh
- Laboratory of Veterinary Anatomy, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, 1-7-1, Kyonan-cho, Musashino-shi, Tokyo, Japan
| | - Hirotada Otsuka
- Laboratory of Veterinary Anatomy, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, 1-7-1, Kyonan-cho, Musashino-shi, Tokyo, Japan
| | - Makoto Yokosuka
- Laboratory of Comparative and Behavioral Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, 1-7-1, Kyonan-cho, Musashino-shi, Tokyo, Japan
| | - Satoshi Soeta
- Laboratory of Veterinary Anatomy, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, 1-7-1, Kyonan-cho, Musashino-shi, Tokyo, Japan.
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Wu B, Shi X, Jiang M, Liu H. Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment. Mol Cancer 2023; 22:38. [PMID: 36810098 PMCID: PMC9942413 DOI: 10.1186/s12943-023-01748-4] [Citation(s) in RCA: 84] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Ongoing research has revealed that the existence of cancer stem cells (CSCs) is one of the biggest obstacles in the current cancer therapy. CSCs make an influential function in tumor progression, recurrence and chemoresistance due to their typical stemness characteristics. CSCs are preferentially distributed in niches, and those niche sites exhibit characteristics typical of the tumor microenvironment (TME). The complex interactions between CSCs and TME illustrate these synergistic effects. The phenotypic heterogeneity within CSCs and the spatial interactions with the surrounding tumor microenvironment led to increased therapeutic challenges. CSCs interact with immune cells to protect themselves against immune clearance by exploiting the immunosuppressive function of multiple immune checkpoint molecules. CSCs also can protect themselves against immune surveillance by excreting extracellular vesicles (EVs), growth factors, metabolites and cytokines into the TME, thereby modulating the composition of the TME. Therefore, these interactions are also being considered for the therapeutic development of anti-tumor agents. We discuss here the immune molecular mechanisms of CSCs and comprehensively review the interplay between CSCs and the immune system. Thus, studies on this topic seem to provide novel ideas for reinvigorating therapeutic approaches to cancer.
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Affiliation(s)
- Bo Wu
- grid.459742.90000 0004 1798 5889Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
| | - Xiang Shi
- grid.459742.90000 0004 1798 5889Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
| | - Meixi Jiang
- grid.412644.10000 0004 5909 0696Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032 China
| | - Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
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Araki M, Noguchi S, Kubo Y, Yasuda A, Koh M, Otsuka H, Yokosuka M, Soeta S. Expression of receptor-type tumour endothelial marker 8 in carcinoma cells showing luminal progenitor-like phenotypes in canine mammary gland carcinomas. J Comp Pathol 2023; 200:35-45. [PMID: 36641985 DOI: 10.1016/j.jcpa.2022.12.001] [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: 07/13/2022] [Revised: 09/05/2022] [Accepted: 11/05/2022] [Indexed: 01/15/2023]
Abstract
This study aimed to investigate the expression of receptor-type tumour endothelial marker 8 (TEM8RT) in canine mammary gland carcinomas (CMGCs) using immunohistochemistry and to evaluate the association between carcinoma cell TEM8RT expression and tumour histological features, histological grades and the differentiation status of neoplastic epithelial cells. TEM8RT expression was more frequently detected in simple carcinomas (tubular and tubulopapillary) than in solid carcinomas, and it was significantly correlated with histological grade Ⅰ tumours and a low mitotic index. Additionally, TEM8RT+ carcinoma cells were more frequently found in CMGCs showing luminal progenitor-like phenotypes, such as Notch1+, CK19+/CK5+/CD49f+ and CK19+/CK5-/CD49f+. Double-labelling immunofluorescence detection techniques confirmed that most TEM8RT+ carcinoma cells expressed CD49f, Notch1 and CK19. However, TEM8RT immunoreactivity was not found in carcinoma cells expressing GATA3, which upregulates mature luminal cell differentiation. Furthermore, TEM8RT+ carcinoma cells were detected in a few CMGCs showing basal/stem cell-like phenotypes such as CK19-/CK5+/CD49f+ and CK19-/CK5+/CD49f-. These findings indicate that TEM8RT is expressed in luminal progenitor-like carcinoma cells in CMGCs. Since TEM8 enhances self-renewal in human mammary stem/progenitor cells, it also may be involved in maintenance of luminal progenitor-like carcinoma cells, resulting in prevention of their transition to basal/stem cell-like carcinoma cells and development of less malignant CMGCs. Therefore, TEM8RT may be useful for indicating prognostic outcomes and identifying the possible ontogeny of carcinoma cells in mammary gland tumours.
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Affiliation(s)
- Mami Araki
- Laboratory of Veterinary Anatomy, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Syunya Noguchi
- Department of Molecular Medicine and Anatomy, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan
| | - Yoshiaki Kubo
- Veterinary Medical Teaching Hospital, Attached Facility, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Akiko Yasuda
- Veterinary Medical Teaching Hospital, Attached Facility, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Miki Koh
- Laboratory of Veterinary Anatomy, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Hirotada Otsuka
- Laboratory of Veterinary Anatomy, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Makoto Yokosuka
- Laboratory of Comparative and Behavioral Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Satoshi Soeta
- Laboratory of Veterinary Anatomy, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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Tripathi G, Tripathi A, Johnson J, Kashyap MK. Role of RNA Splicing in Regulation of Cancer Stem Cell. Curr Stem Cell Res Ther 2023; 18:3-6. [PMID: 34875992 DOI: 10.2174/1574888x16666211207103628] [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: 09/04/2021] [Revised: 09/16/2021] [Accepted: 10/01/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Greesham Tripathi
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon (Manesar), Haryana 122413, India
| | - Avantika Tripathi
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon (Manesar), Haryana 122413, India
| | - Joel Johnson
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon (Manesar), Haryana 122413, India
| | - Manoj Kumar Kashyap
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon (Manesar), Haryana 122413, India
- Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Bajhol, Solan, Himachal Pradesh 173229, India
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12
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Nallasamy P, Nimmakayala RK, Parte S, Are AC, Batra SK, Ponnusamy MP. Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis. Mol Cancer 2022; 21:225. [PMID: 36550571 PMCID: PMC9773588 DOI: 10.1186/s12943-022-01682-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 11/16/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of cancer cells. The correlation between TME and CSCs remains an enigma in understanding the events of metastasis and therapy resistance in cancer biology. Recent evidence suggests that TME dictates the CSCs maintenance to arbitrate cancer progression and metastasis. The immune, inflammatory, endothelial, adipocyte, and fibroblast cells in the TME release growth factors, cytokines, chemokines, microRNAs, and exosomes that provide cues for the gain and maintenance of CSC features. These intricate cross-talks are fueled to evolve into aggressive, invasive, migratory phenotypes for cancer development. In this review, we have abridged the recent developments in the role of the TME factors in CSC maintenance and how these events influence the transition of tumor progression to further translate into metastasis and therapy resistance in cancer.
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Affiliation(s)
- Palanisamy Nallasamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Seema Parte
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Abhirup C Are
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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13
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Quereda C, Pastor À, Martín-Nieto J. Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis. Cancer Cell Int 2022; 22:395. [PMID: 36494657 PMCID: PMC9733019 DOI: 10.1186/s12935-022-02812-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
Dystroglycan (DG) is a glycoprotein composed of two subunits that remain non-covalently bound at the plasma membrane: α-DG, which is extracellular and heavily O-mannosyl glycosylated, and β-DG, an integral transmembrane polypeptide. α-DG is involved in the maintenance of tissue integrity and function in the adult, providing an O-glycosylation-dependent link for cells to their extracellular matrix. β-DG in turn contacts the cytoskeleton via dystrophin and participates in a variety of pathways transmitting extracellular signals to the nucleus. Increasing evidence exists of a pivotal role of DG in the modulation of normal cellular proliferation. In this context, deficiencies in DG glycosylation levels, in particular those affecting the so-called matriglycan structure, have been found in an ample variety of human tumors and cancer-derived cell lines. This occurs together with an underexpression of the DAG1 mRNA and/or its α-DG (core) polypeptide product or, more frequently, with a downregulation of β-DG protein levels. These changes are in general accompanied in tumor cells by a low expression of genes involved in the last steps of the α-DG O-mannosyl glycosylation pathway, namely POMT1/2, POMGNT2, CRPPA, B4GAT1 and LARGE1/2. On the other hand, a series of other genes acting earlier in this pathway are overexpressed in tumor cells, namely DOLK, DPM1/2/3, POMGNT1, B3GALNT2, POMK and FKTN, hence exerting instead a pro-oncogenic role. Finally, downregulation of β-DG, altered β-DG processing and/or impaired β-DG nuclear levels are increasingly found in human tumors and cell lines. It follows that DG itself, particular genes/proteins involved in its glycosylation and/or their interactors in the cell could be useful as biomarkers of certain types of human cancer, and/or as molecular targets of new therapies addressing these neoplasms.
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Affiliation(s)
- Cristina Quereda
- grid.5268.90000 0001 2168 1800Departamento de Fisiología, Genética y Microbiología, Facultad de Ciencias, Universidad de Alicante, Campus Universitario San Vicente, P.O. Box 99, 03080 Alicante, Spain
| | - Àngels Pastor
- grid.5268.90000 0001 2168 1800Departamento de Fisiología, Genética y Microbiología, Facultad de Ciencias, Universidad de Alicante, Campus Universitario San Vicente, P.O. Box 99, 03080 Alicante, Spain
| | - José Martín-Nieto
- grid.5268.90000 0001 2168 1800Departamento de Fisiología, Genética y Microbiología, Facultad de Ciencias, Universidad de Alicante, Campus Universitario San Vicente, P.O. Box 99, 03080 Alicante, Spain ,grid.5268.90000 0001 2168 1800Instituto Multidisciplinar para el Estudio del Medio ‘Ramón Margalef’, Universidad de Alicante, 03080 Alicante, Spain
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14
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Fischer NG, Aparicio C. Junctional epithelium and hemidesmosomes: Tape and rivets for solving the "percutaneous device dilemma" in dental and other permanent implants. Bioact Mater 2022; 18:178-198. [PMID: 35387164 PMCID: PMC8961425 DOI: 10.1016/j.bioactmat.2022.03.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/14/2022] [Accepted: 03/12/2022] [Indexed: 02/06/2023] Open
Abstract
The percutaneous device dilemma describes etiological factors, centered around the disrupted epithelial tissue surrounding non-remodelable devices, that contribute to rampant percutaneous device infection. Natural percutaneous organs, in particular their extracellular matrix mediating the "device"/epithelium interface, serve as exquisite examples to inspire longer lasting long-term percutaneous device design. For example, the tooth's imperviousness to infection is mediated by the epithelium directly surrounding it, the junctional epithelium (JE). The hallmark feature of JE is formation of hemidesmosomes, cell/matrix adhesive structures that attach surrounding oral gingiva to the tooth's enamel through a basement membrane. Here, the authors survey the multifaceted functions of the JE, emphasizing the role of the matrix, with a particular focus on hemidesmosomes and their five main components. The authors highlight the known (and unknown) effects dental implant - as a model percutaneous device - placement has on JE regeneration and synthesize this information for application to other percutaneous devices. The authors conclude with a summary of bioengineering strategies aimed at solving the percutaneous device dilemma and invigorating greater collaboration between clinicians, bioengineers, and matrix biologists.
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Affiliation(s)
- Nicholas G. Fischer
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, MN, 55455, USA
| | - Conrado Aparicio
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, MN, 55455, USA
- Division of Basic Research, Faculty of Odontology, UIC Barcelona – Universitat Internacional de Catalunya, C/. Josep Trueta s/n, 08195, Sant Cugat del Valles, Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), C/. Baldiri Reixac 10-12, 08028, Barcelona, Spain
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15
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Underlying mechanisms of epithelial splicing regulatory proteins in cancer progression. J Mol Med (Berl) 2022; 100:1539-1556. [PMID: 36163376 DOI: 10.1007/s00109-022-02257-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/31/2022] [Accepted: 09/12/2022] [Indexed: 12/14/2022]
Abstract
Cancer is the second-leading disease-related cause of global mortality after cardiovascular disease. Despite significant advances in cancer therapeutic strategies, cancer remains one of the major obstacles to human life extension. Cancer pathogenesis is extremely complicated and not fully understood. Epithelial splicing regulatory proteins (ESRPs), including ESRP1 and ESRP2, belong to the heterogeneous nuclear ribonucleoprotein family of RNA-binding proteins and are crucial regulators of the alternative splicing of messenger RNAs (mRNAs). The expression and activity of ESRPs are modulated by various mechanisms, including post-translational modifications and non-coding RNAs. Although a growing body of evidence suggests that ESRP dysregulation is closely associated with cancer progression, the detailed mechanisms remain inconclusive. In this review, we summarize recent findings on the structures, functions, and regulatory mechanisms of ESRPs and focus on their underlying mechanisms in cancer progression. We also highlight the clinical implications of ESRPs as prognostic biomarkers and therapeutic targets in cancer treatment. The information reviewed herein could be extremely beneficial to the development of individualized therapeutic strategies for cancer patients.
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16
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Rix B, Maduro AH, Bridge KS, Grey W. Markers for human haematopoietic stem cells: The disconnect between an identification marker and its function. Front Physiol 2022; 13:1009160. [PMID: 36246104 PMCID: PMC9564379 DOI: 10.3389/fphys.2022.1009160] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
The haematopoietic system is a classical stem cell hierarchy that maintains all the blood cells in the body. Haematopoietic stem cells (HSCs) are rare, highly potent cells that reside at the apex of this hierarchy and are historically some of the most well studied stem cells in humans and laboratory models, with haematopoiesis being the original system to define functional cell types by cell surface markers. Whilst it is possible to isolate HSCs to near purity, we know very little about the functional activity of markers to purify HSCs. This review will focus on the historical efforts to purify HSCs in humans based on cell surface markers, their putative functions and recent advances in finding functional markers on HSCs.
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Affiliation(s)
| | | | | | - William Grey
- *Correspondence: Katherine S. Bridge, ; William Grey,
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17
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Zheng G, Bouamar H, Cserhati M, Zeballos CR, Mehta I, Zare H, Broome L, Hu R, Lai Z, Chen Y, Sharkey FE, Rani M, Halff GA, Cigarroa FG, Sun LZ. Integrin alpha 6 is upregulated and drives hepatocellular carcinoma progression through integrin α6β4 complex. Int J Cancer 2022; 151:930-943. [PMID: 35657344 PMCID: PMC9329238 DOI: 10.1002/ijc.34146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 12/24/2022]
Abstract
Integrin α6 (ITGA6) forms integrin receptors with either integrin β1 (ITGB1) or integrin β4 (ITGB4). How it functions to regulate hepatocellular carcinoma (HCC) progression is not well-elucidated. We found that ITGA6 RNA and protein expression levels are significantly elevated in human HCC tissues in comparison with paired adjacent nontumor tissues by RNA sequencing, RT-qPCR, Western blotting and immunofluorescence staining. Stable knockdown of ITGA6 with different ITGA6 shRNA expression lentivectors significantly inhibited proliferation, migration and anchorage-independent growth of HCC cell lines in vitro, and xenograft tumor growth in vivo. The inhibition of anchorage-dependent and -independent growth of HCC cell lines was also confirmed with anti-ITGA6 antibody. ITGA6 knockdown was shown to induce cell-cycle arrest at G0/G1 phase. Immunoprecipitation assay revealed apparent interaction of ITGA6 with ITGB4, but not ITGB1. Expression studies showed that ITGA6 positively regulates the expression of ITGB4 with no or negative regulation of ITGB1 expression. Finally, while high levels of ITGA6 and ITGB4 together were associated with significantly worse survival of HCC patients in TCGA data set, the association was not significant for high levels of ITGA6 and ITGB1. In conclusion, ITGA6 is upregulated in HCC tumors and has a malignant promoting role in HCC cells through integrin α6β4 complex. Thus, integrin α6β4 may be a therapeutic target for treating patients with HCC.
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Affiliation(s)
- Guixi Zheng
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, China
| | - Hakim Bouamar
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Matyas Cserhati
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Carla R. Zeballos
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Isha Mehta
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Habil Zare
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Larry Broome
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Ruolei Hu
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, TX
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX
| | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, TX
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, TX
| | - Francis E. Sharkey
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, TX
| | - Meenakshi Rani
- Transplant Center, University of Texas Health Science Center at San Antonio, TX
| | - Glenn A. Halff
- Transplant Center, University of Texas Health Science Center at San Antonio, TX
| | | | - Lu-Zhe Sun
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
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18
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Gahete MD, Herman-Sanchez N, Fuentes-Fayos AC, Lopez-Canovas JL, Luque RM. Dysregulation of splicing variants and spliceosome components in breast cancer. Endocr Relat Cancer 2022; 29:R123-R142. [PMID: 35728261 DOI: 10.1530/erc-22-0019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/16/2022] [Indexed: 12/26/2022]
Abstract
The dysregulation of the splicing process has emerged as a novel hallmark of metabolic and tumor pathologies. In breast cancer (BCa), which represents the most diagnosed cancer type among women worldwide, the generation and/or dysregulation of several oncogenic splicing variants have been described. This is the case of the splicing variants of HER2, ER, BRCA1, or the recently identified by our group, In1-ghrelin and SST5TMD4, which exhibit oncogenic roles, increasing the malignancy, poor prognosis, and resistance to treatment of BCa. This altered expression of oncogenic splicing variants has been closely linked with the dysregulation of the elements belonging to the macromolecular machinery that controls the splicing process (spliceosome components and the associated splicing factors). In this review, we compile the current knowledge demonstrating the altered expression of splicing variants and spliceosomal components in BCa, showing the existence of a growing body of evidence supporting the close implication of the alteration in the splicing process in mammary tumorigenesis.
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Affiliation(s)
- Manuel D Gahete
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
- Reina Sofía University Hospital, Córdoba, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
| | - Natalia Herman-Sanchez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
- Reina Sofía University Hospital, Córdoba, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
| | - Antonio C Fuentes-Fayos
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
- Reina Sofía University Hospital, Córdoba, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
| | - Juan L Lopez-Canovas
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
- Reina Sofía University Hospital, Córdoba, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
| | - Raúl M Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
- Reina Sofía University Hospital, Córdoba, Spain
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain
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19
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Choi SH, Kim JK, Chen CT, Wu C, Marco MR, Barriga FM, O’Rourke K, Pelossof R, Qu X, Chang Q, de Stanchina E, Shia J, Smith JJ, Sanchez-Vega F, Garcia-Aguilar J. KRAS Mutants Upregulate Integrin β4 to Promote Invasion and Metastasis in Colorectal Cancer. Mol Cancer Res 2022; 20:1305-1319. [PMID: 35394541 PMCID: PMC9357101 DOI: 10.1158/1541-7786.mcr-21-0994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/03/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023]
Abstract
KRAS mutation in colorectal cancer is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS-mutant colorectal cancer upregulates integrin α6β4 through ERK/MEK signaling. Knocking-out integrin β4 (ITGB4) specifically depleted the expression of integrin α6β4 and this resulted in a reduction in the invasion and migration ability of the cancer cells. We also observed a reduction in the number and area of lung metastatic foci in mice that were injected with ITGB4 knockout KRAS-mutant colorectal cancer cells compared with the mice injected with ITGB4 wild-type KRAS-mutant colorectal cancer cells, while no difference was observed in liver metastases. Inhibiting integrin α6β4 in KRAS-mutant colorectal cancer could be a potential therapeutic target to diminish the KRAS-invasive phenotype and associated pulmonary metastasis rate. IMPLICATIONS Knocking-out ITGB4, which is overexpressed in KRAS-mutant colorectal cancer and promotes tumor aggressiveness, diminishes local invasiveness and rates of pulmonary metastasis.
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Affiliation(s)
- Seo-Hyun Choi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jin K. Kim
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chin-Tung Chen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chao Wu
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael R. Marco
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Francisco M. Barriga
- Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin O’Rourke
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA,Department of Medicine, Weill-Cornell Medical College, New York, NY, USA
| | - Raphael Pelossof
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xuan Qu
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Qing Chang
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elisa de Stanchina
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - J. Joshua Smith
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Francisco Sanchez-Vega
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA,Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julio Garcia-Aguilar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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20
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Kumar VE, Nambiar R, De Souza C, Nguyen A, Chien J, Lam KS. Targeting Epigenetic Modifiers of Tumor Plasticity and Cancer Stem Cell Behavior. Cells 2022; 11:cells11091403. [PMID: 35563709 PMCID: PMC9102449 DOI: 10.3390/cells11091403] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/11/2022] [Accepted: 04/15/2022] [Indexed: 02/01/2023] Open
Abstract
Tumor heterogeneity poses one of the greatest challenges to a successful treatment of cancer. Tumor cell populations consist of different subpopulations that have distinct phenotypic and genotypic profiles. Such variability poses a challenge in successfully targeting all tumor subpopulations at the same time. Relapse after treatment has been previously explained using the cancer stem cell model and the clonal evolution model. Cancer stem cells are an important subpopulation of tumor cells that regulate tumor plasticity and determine therapeutic resistance. Tumor plasticity is controlled by genetic and epigenetic changes of crucial genes involved in cancer cell survival, growth and metastasis. Targeting epigenetic modulators associated with cancer stem cell survival can unlock a promising therapeutic approach in completely eradicating cancer. Here, we review various factors governing epigenetic dysregulation of cancer stem cells ranging from the role of epigenetic mediators such as histone and DNA methyltransferases, histone deacetylases, histone methyltransferases to various signaling pathways associated with cancer stem cell regulation. We also discuss current treatment regimens targeting these factors and other promising inhibitors in clinical trials.
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Affiliation(s)
- Vigneshwari Easwar Kumar
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
| | - Roshni Nambiar
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
| | - Cristabelle De Souza
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
- Department of Stem Cell Research and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Audrey Nguyen
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
| | - Jeremy Chien
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
- Department of Obstetrics and Gynecology, UC Davis Medical Center, Sacramento, CA 95817, USA
- Correspondence:
| | - Kit S. Lam
- Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA 95817, USA; (V.E.K.); (R.N.); (C.D.S.); (A.N.); (K.S.L.)
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21
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Bergonzini C, Kroese K, Zweemer AJM, Danen EHJ. Targeting Integrins for Cancer Therapy - Disappointments and Opportunities. Front Cell Dev Biol 2022; 10:863850. [PMID: 35356286 PMCID: PMC8959606 DOI: 10.3389/fcell.2022.863850] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 02/16/2022] [Indexed: 12/29/2022] Open
Abstract
Integrins mediate adhesive interactions between cells and their environment, including neighboring cells and extracellular matrix (ECM). These heterodimeric transmembrane receptors bind extracellular ligands with their globular head domains and connect to the cytoskeleton through multi-protein interactions at their cytoplasmic tails. Integrin containing cell–matrix adhesions are dynamic force-responsive protein complexes that allow bidirectional mechanical coupling of cells with their environment. This allows cells to sense and modulate tissue mechanics and regulates intracellular signaling impacting on cell faith, survival, proliferation, and differentiation programs. Dysregulation of these functions has been extensively reported in cancer and associated with tumor growth, invasion, angiogenesis, metastasis, and therapy resistance. This central role in multiple hallmarks of cancer and their localization on the cell surface makes integrins attractive targets for cancer therapy. However, despite a wealth of highly encouraging preclinical data, targeting integrin adhesion complexes in clinical trials has thus far failed to meet expectations. Contributing factors to therapeutic failure are 1) variable integrin expression, 2) redundancy in integrin function, 3) distinct roles of integrins at various disease stages, and 4) sequestering of therapeutics by integrin-containing tumor-derived extracellular vesicles. Despite disappointing clinical results, new promising approaches are being investigated that highlight the potential of integrins as targets or prognostic biomarkers. Improvement of therapeutic delivery at the tumor site via integrin binding ligands is emerging as another successful approach that may enhance both efficacy and safety of conventional therapeutics. In this review we provide an overview of recent encouraging preclinical findings, we discuss the apparent disagreement between preclinical and clinical results, and we consider new opportunities to exploit the potential of integrin adhesion complexes as targets for cancer therapy.
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22
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Conde I, Ribeiro AS, Paredes J. Breast Cancer Stem Cell Membrane Biomarkers: Therapy Targeting and Clinical Implications. Cells 2022; 11:934. [PMID: 35326385 PMCID: PMC8946706 DOI: 10.3390/cells11060934] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most common malignancy affecting women worldwide. Importantly, there have been significant improvements in prevention, early diagnosis, and treatment options, which resulted in a significant decrease in breast cancer mortality rates. Nevertheless, the high rates of incidence combined with therapy resistance result in cancer relapse and metastasis, which still contributes to unacceptably high mortality of breast cancer patients. In this context, a small subpopulation of highly tumourigenic cancer cells within the tumour bulk, commonly designated as breast cancer stem cells (BCSCs), have been suggested as key elements in therapy resistance, which are responsible for breast cancer relapses and distant metastasis. Thus, improvements in BCSC-targeting therapies are crucial to tackling the metastatic progression and might allow therapy resistance to be overcome. However, the design of effective and specific BCSC-targeting therapies has been challenging since there is a lack of specific biomarkers for BCSCs, and the most common clinical approaches are designed for commonly altered BCSCs signalling pathways. Therefore, the search for a new class of BCSC biomarkers, such as the expression of membrane proteins with cancer stem cell potential, is an area of clinical relevance, once membrane proteins are accessible on the cell surface and easily recognized by specific antibodies. Here, we discuss the significance of BCSC membrane biomarkers as potential prognostic and therapeutic targets, reviewing the CSC-targeting therapies under clinical trials for breast cancer.
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Affiliation(s)
- Inês Conde
- i3S, Institute of Investigation and Innovation in Health, 4200-135 Porto, Portugal; (I.C.); (A.S.R.)
- Ipatimup, Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Ana Sofia Ribeiro
- i3S, Institute of Investigation and Innovation in Health, 4200-135 Porto, Portugal; (I.C.); (A.S.R.)
- Ipatimup, Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Joana Paredes
- i3S, Institute of Investigation and Innovation in Health, 4200-135 Porto, Portugal; (I.C.); (A.S.R.)
- Ipatimup, Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
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23
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Paul R, Dorsey JF, Fan Y. Cell plasticity, senescence, and quiescence in cancer stem cells: Biological and therapeutic implications. Pharmacol Ther 2022; 231:107985. [PMID: 34480963 PMCID: PMC8844041 DOI: 10.1016/j.pharmthera.2021.107985] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/06/2021] [Accepted: 08/18/2021] [Indexed: 01/10/2023]
Abstract
Cancer stem cells (CSCs) are a distinct population of cells within tumors with capabilities of self-renewal and tumorigenicity. CSCs play a pivotal role in cancer progression, metastasis, and relapse and tumor resistance to cytotoxic therapy. Emerging scientific evidence indicates that CSCs adopt several mechanisms, driven by cellular plasticity, senescence and quiescence, to maintain their self-renewal capability and to resist tumor microenvironmental stress and treatments. These pose major hindrances for CSC-targeting anti-cancer therapies: cell plasticity maintains stemness in CSCs and renders tumor cells to acquire stem-like phenotypes, contributing to tumor heterogeneity and CSC generation; cellular senescence induces genetic reprogramming and stemness activation, leading to CSC-mediated tumor progression and metastasis; cell quienscence facilitates CSC to overcome their intrinsic vulnerabilities and therapeutic stress, inducing tumor relapse and therapy resistance. These mechanisms are subjected to spatiotemporal regulation by hypoxia, CSC niche, and extracellular matrix in the tumor microenvironment. Here we integrate the recent advances and current knowledge to elucidate the mechanisms involved in the regulation of plasticity, senescence and quiescence of CSCs and the potential therapeutic implications for the future.
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Affiliation(s)
- Ritama Paul
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA 19104
| | - Jay F. Dorsey
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA 19104
| | - Yi Fan
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
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24
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Lyu J, Cheng C. Regulation of Alternative Splicing during Epithelial-Mesenchymal Transition. Cells Tissues Organs 2022; 211:238-251. [PMID: 34348273 PMCID: PMC8741878 DOI: 10.1159/000518249] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/28/2021] [Indexed: 01/03/2023] Open
Abstract
Alternative splicing is an essential mechanism of gene regulation, giving rise to remarkable protein diversity in higher eukaryotes. Epithelial-mesenchymal transition (EMT) is a developmental process that plays an essential role in metazoan embryogenesis. Recent studies have revealed that alternative splicing serves as a fundamental layer of regulation that governs cells to undergo EMT. In this review, we summarize recent findings on the functional impact of alternative splicing in EMT and EMT-associated activities. We then discuss the regulatory mechanisms that control alternative splicing changes during EMT.
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Affiliation(s)
- Jingyi Lyu
- Lester and Sue Smith Breast Center, Department of Molecular
& Human Genetics, Department of Molecular & Cellular Biology, Baylor College
of Medicine, Houston, TX 77030, USA,Integrative Molecular and Biomedical Sciences Graduate
Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chonghui Cheng
- Lester and Sue Smith Breast Center, Department of Molecular
& Human Genetics, Department of Molecular & Cellular Biology, Baylor College
of Medicine, Houston, TX 77030, USA,Integrative Molecular and Biomedical Sciences Graduate
Program, Baylor College of Medicine, Houston, TX 77030, USA.,To whom correspondence should be addressed:
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25
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Xiong J, Yan L, Zou C, Wang K, Chen M, Xu B, Zhou Z, Zhang D. Integrins regulate stemness in solid tumor: an emerging therapeutic target. J Hematol Oncol 2021; 14:177. [PMID: 34715893 PMCID: PMC8555177 DOI: 10.1186/s13045-021-01192-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/14/2021] [Indexed: 02/08/2023] Open
Abstract
Integrins are the adhesion molecules and transmembrane receptors that consist of α and β subunits. After binding to extracellular matrix components, integrins trigger intracellular signaling and regulate a wide spectrum of cellular functions, including cell survival, proliferation, differentiation and migration. Since the pattern of integrins expression is a key determinant of cell behavior in response to microenvironmental cues, deregulation of integrins caused by various mechanisms has been causally linked to cancer development and progression in several solid tumor types. In this review, we discuss the integrin signalosome with a highlight of a few key pro-oncogenic pathways elicited by integrins, and uncover the mutational and transcriptomic landscape of integrin-encoding genes across human cancers. In addition, we focus on the integrin-mediated control of cancer stem cell and tumor stemness in general, such as tumor initiation, epithelial plasticity, organotropic metastasis and drug resistance. With insights into how integrins contribute to the stem-like functions, we now gain better understanding of the integrin signalosome, which will greatly assist novel therapeutic development and more precise clinical decisions.
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Affiliation(s)
- Jiangling Xiong
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Lianlian Yan
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Cheng Zou
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Kai Wang
- Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Mengjie Chen
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Bin Xu
- Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, Jiangsu Province, China.
| | - Zhipeng Zhou
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei Province, China.
| | - Dingxiao Zhang
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China. .,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China.
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26
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Ebrahimie E, Rahimirad S, Tahsili M, Mohammadi-Dehcheshmeh M. Alternative RNA splicing in stem cells and cancer stem cells: Importance of transcript-based expression analysis. World J Stem Cells 2021; 13:1394-1416. [PMID: 34786151 PMCID: PMC8567453 DOI: 10.4252/wjsc.v13.i10.1394] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/21/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
Alternative ribonucleic acid (RNA) splicing can lead to the assembly of different protein isoforms with distinctive functions. The outcome of alternative splicing (AS) can result in a complete loss of function or the acquisition of new functions. There is a gap in knowledge of abnormal RNA splice variants promoting cancer stem cells (CSCs), and their prospective contribution in cancer progression. AS directly regulates the self-renewal features of stem cells (SCs) and stem-like cancer cells. Notably, octamer-binding transcription factor 4A spliced variant of octamer-binding transcription factor 4 contributes to maintaining stemness properties in both SCs and CSCs. The epithelial to mesenchymal transition pathway regulates the AS events in CSCs to maintain stemness. The alternative spliced variants of CSCs markers, including cluster of differentiation 44, aldehyde dehydrogenase, and doublecortin-like kinase, α6β1 integrin, have pivotal roles in increasing self-renewal properties and maintaining the pluripotency of CSCs. Various splicing analysis tools are considered in this study. LeafCutter software can be considered as the best tool for differential splicing analysis and identification of the type of splicing events. Additionally, LeafCutter can be used for efficient mapping splicing quantitative trait loci. Altogether, the accumulating evidence re-enforces the fact that gene and protein expression need to be investigated in parallel with alternative splice variants.
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Affiliation(s)
- Esmaeil Ebrahimie
- School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide 5005, South Australia, Australia
- La Trobe Genomics Research Platform, School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Melbourne 3086, Australia
- School of Biosciences, The University of Melbourne, Melbourne 3010, Australia,
| | - Samira Rahimirad
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran 1497716316, Iran
- Division of Urology, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal H4A 3J1, Quebec, Canada
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27
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Te Molder L, de Pereda JM, Sonnenberg A. Regulation of hemidesmosome dynamics and cell signaling by integrin α6β4. J Cell Sci 2021; 134:272177. [PMID: 34523678 DOI: 10.1242/jcs.259004] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Hemidesmosomes (HDs) are specialized multiprotein complexes that connect the keratin cytoskeleton of epithelial cells to the extracellular matrix (ECM). In the skin, these complexes provide stable adhesion of basal keratinocytes to the underlying basement membrane. Integrin α6β4 is a receptor for laminins and plays a vital role in mediating cell adhesion by initiating the assembly of HDs. In addition, α6β4 has been implicated in signal transduction events that regulate diverse cellular processes, including proliferation and survival. In this Review, we detail the role of α6β4 in HD assembly and beyond, and we discuss the molecular mechanisms that regulate its function.
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Affiliation(s)
- Lisa Te Molder
- Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Jose M de Pereda
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Arnoud Sonnenberg
- Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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28
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Parker KA, Gooding AJ, Valadkhan S, Schiemann WP. lncRNA BORG:TRIM28 Complexes Drive Metastatic Progression by Inducing α6 Integrin/CD49f Expression in Breast Cancer Stem Cells. Mol Cancer Res 2021; 19:2068-2080. [PMID: 34497119 DOI: 10.1158/1541-7786.mcr-21-0137] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 07/22/2021] [Accepted: 08/27/2021] [Indexed: 11/16/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with its aggressive phenotype being attributed to chemotherapy resistance, metastatic dissemination, and rapid disease recurrence. Breast cancer stem cells (BCSC) are significant contributors to tumor initiation, as well as to the acquisition of aggressive tumorigenic phenotypes, namely due to their ability to self-replicate and to produce heterogeneous differentiated tumor cells. To elucidate the underlying mechanisms that drive BCSC tumorigenicity in TNBC, we identified the long noncoding RNA (lncRNA) B MP/ O P- R esponsive G ene (BORG) as an enhancer of BCSC phenotypes. Indeed, we found BORG expression to: (i) correlate with stem cell markers Nanog, Aldh1a3, and Itga6 (α6 integrin/CD49f); (ii) enhance stem cell phenotypes in murine and human TNBC cells, and (iii) promote TNBC tumor initiation in mice. Mechanistically, BORG promoted BCSC phenotypes through its ability to interact physically with the E3 SUMO ligase TRIM28. Moreover, TRIM28 binding was observed in the promoter region of Itga6, whose genetic inactivation prevented BORG:TRIM28 complexes from: (i) inducing BCSC self-renewal and expansion in vitro, and (ii) eliciting BCSC metastatic outgrowth in the lungs of mice. Collectively, these findings implicate BORG:TRIM28 complexes as novel drivers of BCSC phenotypes in developing and progressing TNBCs. IMPLICATIONS: This work establishes the lncRNA BORG as a driver of BCSC phenotypes and the aggressive behaviors of TNBCs, events critically dependent upon the formation of BORG:TRIM28 complexes and expression of α6 integrin.
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Affiliation(s)
- Kimberly A Parker
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio
| | - Alex J Gooding
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Saba Valadkhan
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio
| | - William P Schiemann
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
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29
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Stanzani E, Pedrosa L, Bourmeau G, Anezo O, Noguera-Castells A, Esteve-Codina A, Passoni L, Matteoli M, de la Iglesia N, Seano G, Martínez-Soler F, Tortosa A. Dual Role of Integrin Alpha-6 in Glioblastoma: Supporting Stemness in Proneural Stem-Like Cells While Inducing Radioresistance in Mesenchymal Stem-Like Cells. Cancers (Basel) 2021; 13:cancers13123055. [PMID: 34205341 PMCID: PMC8235627 DOI: 10.3390/cancers13123055] [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: 04/19/2021] [Revised: 06/10/2021] [Accepted: 06/12/2021] [Indexed: 11/23/2022] Open
Abstract
Simple Summary Glioblastoma stem-like cells (GSCs) are responsible for most of the malignant characteristics of glioblastoma, including therapeutic resistance, tumour recurrence, and tumour cellular heterogeneity. Therefore, increased understanding of the mechanisms regulating GSCs aggressiveness may help to improve patients’ outcomes. Here, we investigated the role of integrin a6 in controlling stemness and resistance to radiotherapy across proneural and mesenchymal molecular subtypes. We observed that integrin a6 had a clear role in stemness maintenance in proneural but not in mesenchymal GSCs. In addition, we proved a crucial role of integrin a6 in supporting mesenchymal GSCs resistance to ionizing radiation. Finally, we highlighted that integrin a6 may control different stem-associated features in GSCs, depending on the molecular subtype. The inhibition of integrin a6 limits stem-like malignant characteristics in both GSCs subtypes and thus may potentially control tumour relapse following conventional treatment. Abstract Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms that drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore essential. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq, and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that used in the clinical setting, mesenchymal GSCs were dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes.
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Affiliation(s)
- Elisabetta Stanzani
- Apoptosis and Cancer Unit, Department of Physiological Sciences, IDIBELL, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08907 L’Hospitalet del Llobregat, Spain;
- Correspondence: or (E.S.); (A.T.)
| | - Leire Pedrosa
- Haematology and Oncology Unit, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (L.P.); (N.d.l.I.)
| | - Guillaume Bourmeau
- Tumor Microenvironment Lab., Institut Curie, Université PSL, Université Paris-Saclay, CNRS UMR3347, Inserm U1021, Signalisation Radiobiologie et Cancer, 91400 Orsay, France; (G.B.); (O.A.); (G.S.)
| | - Oceane Anezo
- Tumor Microenvironment Lab., Institut Curie, Université PSL, Université Paris-Saclay, CNRS UMR3347, Inserm U1021, Signalisation Radiobiologie et Cancer, 91400 Orsay, France; (G.B.); (O.A.); (G.S.)
| | - Aleix Noguera-Castells
- Laboratory of Molecular and Translational Oncology, Departament of Medicine, CELLEX Biomedical Research Centre, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08036 Barcelona, Spain;
| | - Anna Esteve-Codina
- Functional Genomics, Centre for Genomic Regulation (CNAG-CRG), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain;
- Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain
| | - Lorena Passoni
- Laboratory of Pharmacology and Brain Pathology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy;
| | - Michela Matteoli
- CNR Institute of Neuroscience, c/o Humanitas, 20089 Rozzano, Italy;
| | - Núria de la Iglesia
- Haematology and Oncology Unit, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (L.P.); (N.d.l.I.)
| | - Giorgio Seano
- Tumor Microenvironment Lab., Institut Curie, Université PSL, Université Paris-Saclay, CNRS UMR3347, Inserm U1021, Signalisation Radiobiologie et Cancer, 91400 Orsay, France; (G.B.); (O.A.); (G.S.)
| | - Fina Martínez-Soler
- Apoptosis and Cancer Unit, Department of Physiological Sciences, IDIBELL, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08907 L’Hospitalet del Llobregat, Spain;
- Department of Basic Nursing, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08907 L’Hospitalet del Llobregat, Spain
| | - Avelina Tortosa
- Apoptosis and Cancer Unit, Department of Physiological Sciences, IDIBELL, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08907 L’Hospitalet del Llobregat, Spain;
- Department of Basic Nursing, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08907 L’Hospitalet del Llobregat, Spain
- Correspondence: or (E.S.); (A.T.)
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30
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Mosca L, Ilari A, Fazi F, Assaraf YG, Colotti G. Taxanes in cancer treatment: Activity, chemoresistance and its overcoming. Drug Resist Updat 2021; 54:100742. [PMID: 33429249 DOI: 10.1016/j.drup.2020.100742] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
Since 1984, when paclitaxel was approved by the FDA for the treatment of advanced ovarian carcinoma, taxanes have been widely used as microtubule-targeting antitumor agents. However, their historic classification as antimitotics does not describe all their functions. Indeed, taxanes act in a complex manner, altering multiple cellular oncogenic processes including mitosis, angiogenesis, apoptosis, inflammatory response, and ROS production. On the one hand, identification of the diverse effects of taxanes on oncogenic signaling pathways provides opportunities to apply these cytotoxic drugs in a more rational manner. On the other hand, this may facilitate the development of novel treatment modalities to surmount anticancer drug resistance. In the latter respect, chemoresistance remains a major impediment which limits the efficacy of antitumor chemotherapy. Taxanes have shown impact on key molecular mechanisms including disruption of mitotic spindle, mitosis slippage and inhibition of angiogenesis. Furthermore, there is an emerging contribution of cellular processes including autophagy, oxidative stress, epigenetic alterations and microRNAs deregulation to the acquisition of taxane resistance. Hence, these two lines of findings are currently promoting a more rational and efficacious taxane application as well as development of novel molecular strategies to enhance the efficacy of taxane-based cancer treatment while overcoming drug resistance. This review provides a general and comprehensive picture on the use of taxanes in cancer treatment. In particular, we describe the history of application of taxanes in anticancer therapeutics, the synthesis of the different drugs belonging to this class of cytotoxic compounds, their features and the differences between them. We further dissect the molecular mechanisms of action of taxanes and the molecular basis underlying the onset of taxane resistance. We further delineate the possible modalities to overcome chemoresistance to taxanes, such as increasing drug solubility, delivery and pharmacokinetics, overcoming microtubule alterations or mitotic slippage, inhibiting drug efflux pumps or drug metabolism, targeting redox metabolism, immune response, and other cellular functions.
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Affiliation(s)
- Luciana Mosca
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Andrea Ilari
- Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
| | - Francesco Fazi
- Dept. Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology and Medical Embryology, Sapienza University, Via A. Scarpa 14-16, 00161 Rome, Italy
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Gianni Colotti
- Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
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31
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Mavingire N, Campbell P, Wooten J, Aja J, Davis MB, Loaiza-Perez A, Brantley E. Cancer stem cells: Culprits in endocrine resistance and racial disparities in breast cancer outcomes. Cancer Lett 2020; 500:64-74. [PMID: 33309858 DOI: 10.1016/j.canlet.2020.12.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/24/2020] [Accepted: 12/05/2020] [Indexed: 12/18/2022]
Abstract
Breast cancer stem cells (BCSCs) promote endocrine therapy (ET) resistance, also known as endocrine resistance in hormone receptor (HR) positive breast cancer. Endocrine resistance occurs via mechanisms that are not yet fully understood. In vitro, in vivo and clinical data suggest that signaling cascades such as Notch, hypoxia inducible factor (HIF), and integrin/Akt promote BCSC-mediated endocrine resistance. Once HR positive breast cancer patients relapse on ET, targeted therapy agents such as cyclin dependent kinase inhibitors are frequently implemented, though secondary resistance remains a threat. Here, we discuss Notch, HIF, and integrin/Akt pathway regulation of BCSC activity and potential strategies to target these pathways to counteract endocrine resistance. We also discuss a plausible link between elevated BCSC-regulatory gene levels and reduced survival observed among African American women with basal-like breast cancer which lacks HR expression. Should future studies reveal a similar link for patients with luminal breast cancer, then the use of agents that impede BCSC activity could prove highly effective in improving clinical outcomes among African American breast cancer patients.
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Affiliation(s)
- Nicole Mavingire
- Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA, USA.
| | - Petreena Campbell
- Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA, USA.
| | - Jonathan Wooten
- Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA, USA; Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, USA.
| | - Joyce Aja
- National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City, Philippines.
| | - Melissa B Davis
- Department of Surgery, Weill Cornell Medicine-New York Presbyterian Hospital Network, New York, NY, USA.
| | - Andrea Loaiza-Perez
- Facultad de Medicina, Instituto de Oncología Ángel H. Roffo (IOAHR), Universidad de Buenos Aires, Área Investigación, Av. San Martin, 5481, C1417 DTB Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
| | - Eileen Brantley
- Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA, USA; Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, USA; Department of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA, USA.
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32
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Geng Y, Amante JJ, Goel HL, Zhang X, Walker MR, Luther DC, Mercurio AM, Rotello VM. Differentiation of Cancer Stem Cells through Nanoparticle Surface Engineering. ACS NANO 2020; 14:15276-15285. [PMID: 33164505 PMCID: PMC10566532 DOI: 10.1021/acsnano.0c05589] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Cancer stem cells (CSCs) are a crucial therapeutic target because of their role in resistance to chemo- and radiation therapy, metastasis, and tumor recurrence. Differentiation therapy presents a potential strategy for "defanging" CSCs. To date, only a limited number of small-molecule and nanomaterial-based differentiating agents have been identified. We report here the integrated use of nanoparticle engineering and hypothesis-free sensing to identify nanoparticles capable of efficient differentiation of CSCs into non-CSC phenotypes. Using this strategy, we identified a nanoparticle that induces CSC differentiation by increasing intracellular reactive oxygen species levels. Importantly, this unreported phenotype is more susceptible to drug treatment than either CSCs or non-CSCs, demonstrating a potentially powerful strategy for anticancer therapeutics.
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Affiliation(s)
- Yingying Geng
- Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003, United States
- Department of Chemistry, University of Massachusetts, Amherst, MA 01003, United States
| | - John J. Amante
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States
| | - Hira L. Goel
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States
| | - Xianzhi Zhang
- Department of Chemistry, University of Massachusetts, Amherst, MA 01003, United States
| | - Melanie R. Walker
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States
| | - David C. Luther
- Department of Chemistry, University of Massachusetts, Amherst, MA 01003, United States
| | - Arthur M. Mercurio
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States
| | - Vincent M. Rotello
- Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003, United States
- Department of Chemistry, University of Massachusetts, Amherst, MA 01003, United States
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Seachrist DD, Hannigan MM, Ingles NN, Webb BM, Weber-Bonk KL, Yu P, Bebek G, Singh S, Sizemore ST, Varadan V, Licatalosi DD, Keri RA. The transcriptional repressor BCL11A promotes breast cancer metastasis. J Biol Chem 2020; 295:11707-11719. [PMID: 32576660 PMCID: PMC7450125 DOI: 10.1074/jbc.ra120.014018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/17/2020] [Indexed: 01/14/2023] Open
Abstract
The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Here, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-α6 (ITGA6), which is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing of ITGA6 Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.
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Affiliation(s)
- Darcie D Seachrist
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
| | - Molly M Hannigan
- Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, Ohio, USA
| | - Natasha N Ingles
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Bryan M Webb
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
| | - Kristen L Weber-Bonk
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Peng Yu
- Department of Electrical and Computer Engineering and TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, Texas, USA
| | - Gurkan Bebek
- Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA
| | - Salendra Singh
- Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Steven T Sizemore
- Department of Radiation Oncology, The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio, USA
| | - Vinay Varadan
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
- Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Donny D Licatalosi
- Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, Ohio, USA
| | - Ruth A Keri
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
- Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA
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Ray D, Yun YC, Idris M, Cheng S, Boot A, Iain TBH, Rozen SG, Tan P, Epstein DM. A tumor-associated splice-isoform of MAP2K7 drives dedifferentiation in MBNL1-low cancers via JNK activation. Proc Natl Acad Sci U S A 2020; 117:16391-16400. [PMID: 32601196 PMCID: PMC7368273 DOI: 10.1073/pnas.2002499117] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Master splicing regulator MBNL1 shapes large transcriptomic changes that drive cellular differentiation during development. Here we demonstrate that MBNL1 is a suppressor of tumor dedifferentiation. We surveyed MBNL1 expression in matched tumor/normal pairs across The Cancer Genome Atlas and found that MBNL1 was down-regulated in several common cancers. Down-regulation of MBNL1 predicted poor overall survival in breast, lung, and stomach adenocarcinomas and increased relapse and distant metastasis in triple-negative breast cancer. Down-regulation of MBNL1 led to increased tumorigenic and stem/progenitor-like properties in vitro and in vivo. A discrete set of alternative splicing events (ASEs) are shared between MBNL1-low cancers and embryonic stem cells including a MAP2K7∆exon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversing MAP2K7∆exon2-driven tumor dedifferentiation in MBNL1-low cancer cells. Our work elucidates an alternative-splicing mechanism that drives tumor dedifferentiation and identifies biomarkers that predict enhanced susceptibility to JNK inhibition.
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Affiliation(s)
- Debleena Ray
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore;
| | - Yu Chye Yun
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore
| | - Muhammad Idris
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore
| | - Shanshan Cheng
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore
- Centre for Computational Biology, Duke-NUS Medical School, 165897 Singapore, Singapore
| | - Arnoud Boot
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore
- Centre for Computational Biology, Duke-NUS Medical School, 165897 Singapore, Singapore
| | - Tan Bee Huat Iain
- Division of Medical Oncology, National Cancer Centre, 169610 Singapore, Singapore
| | - Steven G Rozen
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore
- Centre for Computational Biology, Duke-NUS Medical School, 165897 Singapore, Singapore
| | - Patrick Tan
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore
| | - David M Epstein
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore;
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Farina AR, Cappabianca L, Sebastiano M, Zelli V, Guadagni S, Mackay AR. Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer. J Exp Clin Cancer Res 2020; 39:110. [PMID: 32536347 PMCID: PMC7294618 DOI: 10.1186/s13046-020-01616-9] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/03/2020] [Indexed: 12/16/2022] Open
Abstract
Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic re-programming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease. The impressive number of hypoxia-induced alternative spliced protein isoforms that characterize tumour progression, classifies hypoxia-induced alternative splicing as the 11th hallmark of cancer, and offers a fertile source of potential diagnostic/prognostic markers and therapeutic targets.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Lucia Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Stefano Guadagni
- Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100 L’Aquila, Italy
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Velázquez-Quesada I, Ruiz-Moreno AJ, Casique-Aguirre D, Aguirre-Alvarado C, Cortés-Mendoza F, de la Fuente-Granada M, García-Pérez C, Pérez-Tapia SM, González-Arenas A, Segura-Cabrera A, Velasco-Velázquez MA. Pranlukast Antagonizes CD49f and Reduces Stemness in Triple-Negative Breast Cancer Cells. Drug Des Devel Ther 2020; 14:1799-1811. [PMID: 32494122 PMCID: PMC7229803 DOI: 10.2147/dddt.s247730] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 03/10/2020] [Indexed: 01/16/2023] Open
Abstract
INTRODUCTION Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. MATERIALS AND METHODS We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clinically tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. RESULTS Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces conformational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transactivation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. CONCLUSION Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients.
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Affiliation(s)
- Inés Velázquez-Quesada
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Research and Development in Bioprocess Unit, National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Angel J Ruiz-Moreno
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Graduate Program in Biomedical Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Department of Drug Design, Graduate School of Science and Engineering, University of Groningen (RUG), Groningen, The Netherlands
| | - Diana Casique-Aguirre
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Charmina Aguirre-Alvarado
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Fabiola Cortés-Mendoza
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Graduate Program in Biochemical Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Marisol de la Fuente-Granada
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Carlos García-Pérez
- Center for Genomic Biotechnology, Instituto Politécnico Nacional, Reynosa, Tamaulipas, Mexico
| | - Sonia M Pérez-Tapia
- Research and Development in Bioprocess Unit, National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City, Mexico
- National Laboratory for Specialized Services of Investigation, Development and Innovation (I+D+i) for Pharma Chemicals and Biotechnological Products, LANSEIDI-FarBiotec-CONACyT, Mexico City, Mexico
| | - Aliesha González-Arenas
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Aldo Segura-Cabrera
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
| | - Marco A Velasco-Velázquez
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Peripherical Unit for Research in Translational Biomedicine, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Beaulieu JF. Integrin α6β4 in Colorectal Cancer: Expression, Regulation, Functional Alterations and Use as a Biomarker. Cancers (Basel) 2019; 12:41. [PMID: 31877793 PMCID: PMC7016599 DOI: 10.3390/cancers12010041] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 12/17/2019] [Accepted: 12/19/2019] [Indexed: 12/27/2022] Open
Abstract
Integrin α6β4 is one of the main laminin receptors and is primarily expressed by epithelial cells as an active component of hemidesmosomes. In this article, after a brief summary about integrins in the gut epithelium in general, I review the knowledge and clinical potential of this receptor in human colorectal cancer (CRC) cells. Most CRC cells overexpress both α6 and β4 subunits, in situ in primary tumours as well as in established CRC cell lines. The mechanisms that lead to overexpression have not yet been elucidated but clearly involve specific transcription factors such as MYC. From a functional point of view, one key element affecting CRC cell behaviour is the relocalization of α6β4 to the actin cytoskeleton, favouring a more migratory and anoikis-resistant phenotype. Another major element is its expression under various molecular forms that have the distinct ability to interact with ligands (α6β4 ± ctd) or to promote pro- or anti-proliferative properties (α6Aβ4 vs. α6Bβ4). The integrin α6β4 is thus involved in most steps susceptible to participation with CRC progression. The potential clinical significance of this integrin has begun to be investigated and recent studies have shown that ITGA6 and ITGB4 can be useful biomarkers for CRC early detection in a non-invasive assay and as a prognostic factor, respectively.
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Affiliation(s)
- Jean-François Beaulieu
- Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; ; Tel.: +1-819-821-8000 (ext. 75269)
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
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38
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Bigoni-Ordóñez GD, Czarnowski D, Parsons T, Madlambayan GJ, Villa-Diaz LG. Integrin α6 (CD49f), The Microenvironment and Cancer Stem Cells. Curr Stem Cell Res Ther 2019; 14:428-436. [PMID: 30280675 DOI: 10.2174/1574888x13666181002151330] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 08/20/2018] [Accepted: 09/02/2018] [Indexed: 12/16/2022]
Abstract
Cancer is a highly prevalent and potentially terminal disease that affects millions of individuals worldwide. Here, we review the literature exploring the intricacies of stem cells bearing tumorigenic characteristics and collect evidence demonstrating the importance of integrin α6 (ITGA6, also known as CD49f) in cancer stem cell (CSC) activity. ITGA6 is commonly used to identify CSC populations in various tissues and plays an important role sustaining the self-renewal of CSCs by interconnecting them with the tumorigenic microenvironment.
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Affiliation(s)
- Gabriele D Bigoni-Ordóñez
- Division de Investigacion Basica, Instituto Nacional de Cancerologia, Secretaria de Salud, Mexico City, Mexico.,Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, UNAM, Mexico City, Mexico
| | - Daniel Czarnowski
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Tyler Parsons
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Gerard J Madlambayan
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Luis G Villa-Diaz
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
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Alvarado-Ortiz E, Sarabia-Sánchez MÁ, García-Carrancá A. Molecular Mechanisms Underlying the Functions of Cellular Markers Associated with the Phenotype of Cancer Stem Cells. Curr Stem Cell Res Ther 2019; 14:405-420. [PMID: 30147013 DOI: 10.2174/1574888x13666180821154752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/18/2018] [Accepted: 08/13/2018] [Indexed: 12/19/2022]
Abstract
Cancer Stem Cells (CSC) generally constitute a minor cellular population within tumors that exhibits some capacities of normal Stem Cells (SC). The existence of CSC, able to self-renew and differentiate, influences central aspects of tumor biology, in part because they can continue tumor growth, give rise to metastasis, and acquire drug and radioresistance, which open new avenues for therapeutics. It is well known that SC constantly interacts with their niche, which includes mesenchymal cells, extracellular ligands, and the Extra Cellular Matrix (ECM). These interactions regularly lead to homeostasis and maintenance of SC characteristics. However, the exact participation of each of these components for CSC maintenance is not clear, as they appear to be context- or cell-specific. In the recent past, surface cellular markers have been fundamental molecular tools for identifying CSC and distinguishing them from other tumor cells. Importantly, some of these cellular markers have been shown to possess functional roles that affect central aspects of CSC. Likewise, some of these markers can participate in regulating the interaction of CSC with their niche, particularly the ECM. We focused this review on the molecular mechanisms of surface cellular markers commonly employed to identify CSC, highlighting the signaling pathways and mechanisms involved in CSC-ECM interactions, through each of the cellular markers commonly used in the study of CSC, such as CD44, CD133, CD49f, CD24, CXCR4, and LGR5. Their presence does not necessarily implicate them in CSC biology.
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Affiliation(s)
- Eduardo Alvarado-Ortiz
- Programa de Maestría y Doctorado en Ciencias Biológicas, Facultad de Ciencias, Universidad Nacional Autónoma de México, México City, México.,Laboratory of Virus and Cancer, Unidad de Investigacion Biomedica en Cáncer, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico & Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Secretaria de Salud, Ciudad de Mexico, Mexico
| | - Miguel Á Sarabia-Sánchez
- Laboratory of Virus and Cancer, Unidad de Investigacion Biomedica en Cáncer, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico & Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Secretaria de Salud, Ciudad de Mexico, Mexico.,Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México, , México City, México
| | - Alejandro García-Carrancá
- Laboratory of Virus and Cancer, Unidad de Investigacion Biomedica en Cáncer, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico & Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Secretaria de Salud, Ciudad de Mexico, Mexico
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40
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Day BW, Lathia JD, Bruce ZC, D'Souza RCJ, Baumgartner U, Ensbey KS, Lim YC, Stringer BW, Akgül S, Offenhäuser C, Li Y, Jamieson PR, Smith FM, Jurd CLR, Robertson T, Inglis PL, Lwin Z, Jeffree RL, Johns TG, Bhat KPL, Rich JN, Campbell KP, Boyd AW. The dystroglycan receptor maintains glioma stem cells in the vascular niche. Acta Neuropathol 2019; 138:1033-1052. [PMID: 31463571 PMCID: PMC6851226 DOI: 10.1007/s00401-019-02069-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023]
Abstract
Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the perivascular niche. Glycosylated αDG is highly expressed and functional on the most aggressive mesenchymal-like (MES-like) GBM tumour compartment. Furthermore, we found that DG acts to maintain an MES-like state via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation in MES-like GBM, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor, not only as a structural element, but also as a critical factor promoting MES-like GBM and the maintenance of GSCs residing in the perivascular niche.
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Affiliation(s)
- Bryan W Day
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
- Faculty of Health, Queensland University of Technology, Brisbane, 4059, Australia.
- Faculty of Medicine, The University of Queensland, Brisbane, 4072, Australia.
| | - Justin D Lathia
- Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
| | - Zara C Bruce
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Rochelle C J D'Souza
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Ulrich Baumgartner
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Kathleen S Ensbey
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Yi Chieh Lim
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Brett W Stringer
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Seçkin Akgül
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Carolin Offenhäuser
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Yuchen Li
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Paul R Jamieson
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Fiona M Smith
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Courtney L R Jurd
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Thomas Robertson
- Royal Brisbane and Women's Hospital, Brisbane, QLD, 4006, Australia
| | - Po-Ling Inglis
- Royal Brisbane and Women's Hospital, Brisbane, QLD, 4006, Australia
| | - Zarnie Lwin
- Royal Brisbane and Women's Hospital, Brisbane, QLD, 4006, Australia
| | | | | | - Krishna P L Bhat
- Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jeremy N Rich
- Medicine Department, University of California, La Jolla, San Diego, CA, 92093-0021, USA
| | - Kevin P Campbell
- Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, Howard Hughes Medical Institute, University of Iowa, Iowa City, IA, 52242, USA
- Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, Howard Hughes Medical Institute, University of Iowa, Iowa City, IA, 52242, USA
| | - Andrew W Boyd
- Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, 4072, Australia
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Alveolar progenitor cells in the mammary gland are dependent on the β4 integrin. Dev Biol 2019; 457:13-19. [PMID: 31586558 DOI: 10.1016/j.ydbio.2019.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/18/2019] [Accepted: 10/01/2019] [Indexed: 01/13/2023]
Abstract
Understanding how progenitor cell function is regulated in the mammary gland is an important developmental problem that has significant implications for breast cancer. Although it had been assumed that the expression the α6β4 integrin (β4) is restricted to the basal lineage, we report that alveolar progenitor cells in the mouse mammary gland also express this integrin based on analysis of single cell RNA-Seq data. Subsequent experiments using a mouse mammary epithelial cell line (NMuMG) confirmed this finding and revealed that β4 is essential for maintaining progenitor function as assessed by serial passage mammosphere assays. These data were substantiated by analyzing the alveolar progenitor population isolated from nulliparous mouse mammary glands. Based on the finding that the alveolar progenitor cells express Whey Acidic Protein (WAP), WAP-Cre mice were crossed with itgβ4flox/flox mice to generate conditional knock-out of β4 in alveolar progenitor cells. These itgβ4flox/floxWAP-Cre+ mice exhibited significant defects in alveologenesis and milk production during pregnancy compared to itgβ4flox/floxWAP-Cre- mice, establishing a novel role for the β4 integrin in alveolar progenitor function and alveologenesis.
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Tanaka S, Senda N, Iida A, Sehara-Fujisawa A, Ishii T, Sato F, Toi M, Itou J. In silico analysis-based identification of the target residue of integrin α6 for metastasis inhibition of basal-like breast cancer. Genes Cells 2019; 24:596-607. [PMID: 31295752 DOI: 10.1111/gtc.12714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 07/04/2019] [Accepted: 07/08/2019] [Indexed: 01/24/2023]
Abstract
Metastasis causes death in breast cancer patients. To inhibit breast cancer metastasis, we focused on integrin α6, a membrane protein that contributes to cell migration and metastasis. According to in silico analysis, we identified Asp-358 as an integrin α6-specific vertebrate-conserved residue and consequently as a potential therapeutic target. Because Asp-358 is located on the surface of the β propeller domain that interacts with other molecules for integrin α6 function, we hypothesized that a peptide with the sequence around Asp-358 competitively inhibits integrin α6 complex formation. We treated basal-like breast cancer cells with the peptide and observed reductions in cell migration and metastasis. The result of the immunoprecipitation assay showed that the peptide inhibited integrin α6 complex formation. Our immunofluorescence for phosphorylated paxillin, a marker of integrin-regulated focal adhesion, showed that the peptide reduced the number of focal adhesions. These results indicate that the peptide inhibits integrin α6 function. This study identified the functional residue of integrin α6 and designed the inhibitory peptide. For breast cancer patients, metastasis inhibition therapy may be developed in the future based on this study.
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Affiliation(s)
- Sunao Tanaka
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Noriko Senda
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsuo Iida
- Department of Regeneration Science and Engineering, Institute of Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - Atsuko Sehara-Fujisawa
- Department of Regeneration Science and Engineering, Institute of Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - Tomoko Ishii
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Fumiaki Sato
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Breast Surgery, Kansai Electric Power Hospital and Kansai Electric Power Medical Research Institute, Osaka, Japan
| | - Masakazu Toi
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Junji Itou
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Elaimy AL, Wang M, Sheel A, Brown CW, Walker MR, Amante JJ, Xue W, Chan A, Baer CE, Goel HL, Mercurio AM. Real-time imaging of integrin β4 dynamics using a reporter cell line generated by Crispr/Cas9 genome editing. J Cell Sci 2019; 132:jcs.231241. [PMID: 31262785 DOI: 10.1242/jcs.231241] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 06/22/2019] [Indexed: 12/27/2022] Open
Abstract
The ability to monitor changes in the expression and localization of integrins is essential for understanding their contribution to development, tissue homeostasis and disease. Here, we pioneered the use of Crispr/Cas9 genome editing to tag an allele of the β4 subunit of the α6β4 integrin. A tdTomato tag was inserted with a linker at the C-terminus of integrin β4 in mouse mammary epithelial cells. Cells harboring this tagged allele were similar to wild-type cells with respect to integrin β4 surface expression, association with the α6 subunit, adhesion to laminin and consequent signaling. These integrin β4 reporter cells were transformed with YAP (also known as YAP1), which enabled us to obtain novel insight into integrin β4 dynamics in response to a migratory stimulus (scratch wound) by live-cell video microscopy. An increase in integrin β4 expression in cells proximal to the wound edge was evident, and a population of integrin β4-expressing cells that exhibited unusually rapid migration was identified. These findings could shed insight into integrin β4 dynamics during invasion and metastasis. Moreover, these integrin β4 reporter cells should facilitate studies on the contribution of this integrin to mammary gland biology and cancer.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Ameer L Elaimy
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA.,Medical Scientist Training Program, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Mengdie Wang
- Medical Scientist Training Program, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Ankur Sheel
- Medical Scientist Training Program, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA.,RNA Therapeutics Institute, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Caitlin W Brown
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Melanie R Walker
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - John J Amante
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Wen Xue
- RNA Therapeutics Institute, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Amanda Chan
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Christina E Baer
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA.,Sanderson Center for Optical Examination, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Hira Lal Goel
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
| | - Arthur M Mercurio
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA
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Qiu Y, Wang L, Zhong X, Li L, Chen F, Xiao L, Liu F, Fu B, Zheng H, Ye F, Bu H. A multiple breast cancer stem cell model to predict recurrence of T 1-3, N 0 breast cancer. BMC Cancer 2019; 19:729. [PMID: 31340763 PMCID: PMC6657050 DOI: 10.1186/s12885-019-5941-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 04/23/2019] [Indexed: 02/05/2023] Open
Abstract
Background Local or distant relapse is the key event for the overall survival of early-stage breast cancer after initial surgery. A small subset of breast cancer cells, which share similar properties with normal stem cells, has been proven to resist to clinical therapy contributing to recurrence. Methods In this study, we aimed to develop a prognostic model to predict recurrence based on the prevalence of breast cancer stem cells (BCSCs) in breast cancer. Immunohistochemistry and dual-immunohistochemistry were performed to quantify the stem cells of the breast cancer patients. The performance of Cox proportional hazard regression model was assessed using the holdout methods, where the dataset was randomly split into two exclusive sets (70% training and 30% testing sets). Additionally, we performed bootstrapping to overcome a possible biased error estimate and obtain confidence intervals (CI). Results Four groups of BCSCs (ALDH1A3, CD44+/CD24−, integrin alpha 6 (ITGA6), and protein C receptor (PROCR)) were identified as associated with relapse-free survival (RFS). The correlated biomarkers were integrated as a prognostic panel to calculate a relapse risk score (RRS) and to classify the patients into different risk groups (high-risk or low-risk). According to RRS, 67.81 and 32.19% of patients were categorized into low-risk and high-risk groups respectively. The relapse rate at 5 years in the low-risk group (2.67, 95% CI: 0.72–4.63%) by Kaplan-Meier method was significantly lower than that of the high-risk group (19.30, 95% CI: 12.34–26.27%) (p < 0.001). In the multiple Cox model, the RRS was proven to be a powerful classifier independent of age at diagnosis or tumour size (p < 0.001). In addition, we found that high RRS score ER-positive patients do not benefit from hormonal therapy treatment (RFS, p = 0.860). Conclusion The RRS model can be applied to predict the relapse risk in early stage breast cancer. As such, high RRS score ER-positive patients do not benefit from hormonal therapy treatment. Electronic supplementary material The online version of this article (10.1186/s12885-019-5941-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yan Qiu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China.,Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, China.,Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Liya Wang
- Big Data Research Center, School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaorong Zhong
- Laboratory of Molecular Diagnosis of Cancer & Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Fei Chen
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Xiao
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Fangyu Liu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Bo Fu
- Big Data Research Center, School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Hong Zheng
- Laboratory of Molecular Diagnosis of Cancer & Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Feng Ye
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China. .,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China. .,Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Bu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China.,Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, China.,Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
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45
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Are Integrins Still Practicable Targets for Anti-Cancer Therapy? Cancers (Basel) 2019; 11:cancers11070978. [PMID: 31336983 PMCID: PMC6678560 DOI: 10.3390/cancers11070978] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 06/27/2019] [Accepted: 07/09/2019] [Indexed: 01/01/2023] Open
Abstract
Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells. In spite of compelling preclinical results demonstrating that the inhibition of integrin αVβ3/αVβ5 and α5β1 has therapeutic potential, clinical trials with integrin inhibitors targeting those integrins have repeatedly failed to demonstrate therapeutic benefits in cancer patients. Here, we review emerging integrin functions and their proposed contribution to tumor progression, discuss preclinical evidence of therapeutic significance, revisit clinical trial results, and consider alternative approaches for their therapeutic targeting in oncology, including targeting integrins in the other cells of the tumor microenvironment, e.g., cancer-associated fibroblasts and immune/inflammatory cells. We conclude that integrins remain a valid target for cancer therapy; however, agents with better pharmacological properties, alternative models for their preclinical evaluation, and innovative combination strategies for clinical testing (e.g., together with immuno-oncology agents) are needed.
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Elaimy AL, Amante JJ, Zhu LJ, Wang M, Walmsley CS, FitzGerald TJ, Goel HL, Mercurio AM. The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression. Proc Natl Acad Sci U S A 2019; 116:14174-14180. [PMID: 31235595 PMCID: PMC6628806 DOI: 10.1073/pnas.1821194116] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF-NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF-NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF-NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ-TEAD transcriptional target. We also discovered that VEGF-NRP2-YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF-NRP2 or YAP/TAZ. These findings reveal roles for VEGF-NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF-NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.
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Affiliation(s)
- Ameer L Elaimy
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
- Medical Scientist Training Program, University of Massachusetts Medical School, Worcester, MA 01605
| | - John J Amante
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Lihua Julie Zhu
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
- Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
- Department of Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Mengdie Wang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Charlotte S Walmsley
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Thomas J FitzGerald
- Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Hira Lal Goel
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Arthur M Mercurio
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
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47
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DiPersio CM, Van De Water L. Integrin Regulation of CAF Differentiation and Function. Cancers (Basel) 2019; 11:cancers11050715. [PMID: 31137641 PMCID: PMC6563118 DOI: 10.3390/cancers11050715] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/14/2019] [Accepted: 05/21/2019] [Indexed: 02/07/2023] Open
Abstract
Extensive remodeling of the extracellular matrix, together with paracrine communication between tumor cells and stromal cells, contribute to an “activated” tumor microenvironment that supports malignant growth and progression. These stromal cells include inflammatory cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Integrins are expressed on all tumor and stromal cell types where they regulate both cell adhesion and bidirectional signal transduction across the cell membrane. In this capacity, integrins control pro-tumorigenic cell autonomous functions such as growth and survival, as well as paracrine crosstalk between tumor cells and stromal cells. The myofibroblast-like properties of cancer-associated fibroblasts (CAFs), such as robust contractility and extracellular matrix (ECM) deposition, allow them to generate both chemical and mechanical signals that support invasive tumor growth. In this review, we discuss the roles of integrins in regulating the ability of CAFs to generate and respond to extracellular cues in the tumor microenvironment. Since functions of specific integrins in CAFs are only beginning to emerge, we take advantage of a more extensive literature on how integrins regulate wound myofibroblast differentiation and function, as some of these integrin functions are likely to extrapolate to CAFs within the tumor microenvironment. In addition, we discuss the roles that integrins play in controlling paracrine signals that emanate from epithelial/tumor cells to stimulate fibroblasts/CAFs.
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48
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Qiryaqoz Z, Timilsina S, Czarnowski D, Krebsbach PH, Villa‐Diaz LG. Identification of biomarkers indicative of functional skeletal stem cells. Orthod Craniofac Res 2019; 22 Suppl 1:192-198. [DOI: 10.1111/ocr.12260] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 12/04/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Zeena Qiryaqoz
- Department of Biological SciencesOakland University Rochester Michigan
| | - Suraj Timilsina
- Department of Biological SciencesOakland University Rochester Michigan
| | - Daniel Czarnowski
- Department of Biological SciencesOakland University Rochester Michigan
| | - Paul H. Krebsbach
- School of DentistryUniversity of California, Los Angeles Los Angeles California
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Valencia-González HA, Ruíz G, Ortiz-Sánchez E, García-Carrancá A. Cancer Stem Cells from Tumor Cell Lines Activate the DNA Damage Response Pathway after Ionizing Radiation More Efficiently Than Noncancer Stem Cells. Stem Cells Int 2019; 2019:7038953. [PMID: 31073313 PMCID: PMC6470433 DOI: 10.1155/2019/7038953] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/29/2018] [Accepted: 12/24/2018] [Indexed: 02/07/2023] Open
Abstract
Recently, a subpopulation of tumor cells, called cancer stem cells (CSC), has been characterized, and these have emerged as a major topic in cancer research. CSC are proposed to repair DNA damage more efficiently than the rest of tumor cells, resisting chemotherapy or radiotherapy and causing clinical recurrence and metastasis. We aimed to determine the molecular basis of radioresistance and first compared the response to ionizing radiation (IR) between cancer stem cell-enriched cultures grown as spheres and conventional tumor cell line cultures grown as monolayer, from HeLa and MCF-7 cancer cell lines. To verify that our sphere cultures were enriched in CSC, we evaluated the double staining of CD49f and ALDH activity for HeLa cells by flow cytometry. We then evaluated whether differences could exist in sensor elements in the DNA damage response pathway among these cultures. We found that CSC cultures showed less sensitivity to radiation than conventional tumor cell line cultures. We observed a higher baseline expression of activated response sensor proteins of DNA damage, such as ATM, H2A.X, and PARP1, in untreated CSC cultures. These findings provide the first evidence, to our knowledge, that DNA damage response sensor proteins are present and preferentially activated in CSC, as opposed to the bulk of cells in monolayer cultures. Likewise, they provide the basis for biological differences in response to IR between CSC and other tumor cell populations. Understanding the DNA damage response pathway may provide therapeutic targets to sensitize CSC to cytotoxic therapies to improve current cancer treatments.
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Affiliation(s)
- Heriberto Abraham Valencia-González
- Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico
| | - Graciela Ruíz
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico
| | - Elizabeth Ortiz-Sánchez
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico
| | - Alejandro García-Carrancá
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico
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50
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Cooper J, Giancotti FG. Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell 2019; 35:347-367. [PMID: 30889378 PMCID: PMC6684107 DOI: 10.1016/j.ccell.2019.01.007] [Citation(s) in RCA: 600] [Impact Index Per Article: 100.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 10/10/2018] [Accepted: 01/14/2019] [Indexed: 12/16/2022]
Abstract
Integrins mediate cell adhesion and transmit mechanical and chemical signals to the cell interior. Various mechanisms deregulate integrin signaling in cancer, empowering tumor cells with the ability to proliferate without restraint, to invade through tissue boundaries, and to survive in foreign microenvironments. Recent studies have revealed that integrin signaling drives multiple stem cell functions, including tumor initiation, epithelial plasticity, metastatic reactivation, and resistance to oncogene- and immune-targeted therapies. Here, we discuss the mechanisms leading to the deregulation of integrin signaling in cancer and its various consequences. We place emphasis on novel functions, determinants of context dependency, and mechanism-based therapeutic opportunities.
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Affiliation(s)
- Jonathan Cooper
- Department of Translational Oncology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Filippo G Giancotti
- Department of Cancer Biology and David H. Koch Center for Applied Research of Genitourinary Cancers, UT MD Anderson Cancer Center, Houston, TX 77054, USA.
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