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Lu Y, Huang Y, Zhu C, Li Z, Zhang B, Sheng H, Li H, Liu X, Xu Z, Wen Y, Zhang J, Zhang L. Cancer brain metastasis: molecular mechanisms and therapeutic strategies. MOLECULAR BIOMEDICINE 2025; 6:12. [PMID: 39998776 PMCID: PMC11861501 DOI: 10.1186/s43556-025-00251-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 01/06/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Brain metastases (BMs) are the most common intracranial tumors in adults and the major cause of cancer-related morbidity and mortality. The occurrence of BMs varies according to the type of primary tumors with most frequence in lung cancer, melanoma and breast cancer. Among of them, lung cancer has been reported to have a higher risk of BMs than other types of cancers with 40 ~ 50% of such patients will develop BMs during the course of disease. BMs lead to many neurological complications and result in a poor quality of life and short life span. Although the treatment strategies were improved for brain tumors in the past decades, the prognosis of BMs patients is grim. Poorly understanding of the molecular and cellular characteristics of BMs and the complicated interaction with brain microenvironment are the major reasons for the dismal prognosis of BM patients. Recent studies have enhanced understanding of the mechanisms of BMs. The newly identified potential therapeutic targets and the advanced therapeutic strategies have brought light for a better cure of BMs. In this review, we summarized the mechanisms of BMs during the metastatic course, the molecular and cellular landscapes of BMs, and the advances of novel drug delivery systems for overcoming the obstruction of blood-brain barrier (BBB). We further discussed the challenges of the emerging therapeutic strategies, such as synergistic approach of combining targeted therapy with immunotherapy, which will provide vital clues for realizing the precise and personalized medicine for BM patients in the future.
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Affiliation(s)
- Yu Lu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yunhang Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chenyan Zhu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhidan Li
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Bin Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hui Sheng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Haotai Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xixi Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhongwen Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Wen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Zhang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Liguo Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Brem S. Vagus nerve stimulation: Novel concept for the treatment of glioblastoma and solid cancers by cytokine (interleukin-6) reduction, attenuating the SASP, enhancing tumor immunity. Brain Behav Immun Health 2024; 42:100859. [PMID: 39512605 PMCID: PMC11541944 DOI: 10.1016/j.bbih.2024.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/31/2024] [Accepted: 09/07/2024] [Indexed: 11/15/2024] Open
Abstract
Immuno-oncology, specifically immune checkpoint inhibitors (ICIs), has revolutionized cancer care with dramatic, long-term responses and increased survival, including patients with metastatic cancer to the brain. Glioblastomas, and other primary brain tumors, are refractory to ICIs as monotherapy or in combination with standard therapy. The tumor microenvironment (TME) poses multiple biological hurdles: blood-brain barrier, immune suppression, heterogeneity, and tumor infiltration. Genomic analysis of the senescence-associated secretory phenotype (SASP) and preclinical models of glioma suggest that an exciting approach would entail reprogramming of the glioma microenvironment, attenuating the pro-inflammatory, pro-tumorigenic cytokines of the SASP, especially interleukin-6 (IL-6). A testable hypothesis now proposed is to modulate the immune system by harnessing the body's 'inflammatory reflex' to reduce cytokines. Vagus nerve stimulation can activate T cell immunity by the cholinergic, α7nicotinic acetylcholine receptor agonist (α7nAchR), and suppress IL-6 systemically, as well as other pro-inflammatory cytokines of the SASP, interleukin -1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). The hypothesis predicts that electrical activation of the vagus nerve, with cytokine reduction, in combination with ICIs, would convert an immune resistant ("cold") tumor to an immune responsive ("hot") tumor, and halt glioma progression. The hypothesis also envisions cancer as an immune "dysautonomia" whereby a therapeutic intervention, vagus nerve stimulation (VNS), resets the systemic and local cytokine levels. A prospective, randomized, phase II clinical trial, to confirm the hypothesis, is a logical, exigent, next step. Cytokine reduction by VNS could also be useful for other forms of human cancer, e.g., breast, colorectal, head and neck, lung, melanoma, ovarian, pancreatic, and prostate cancer, as the emerging field of "cancer neuroscience" shows a role for neural regulation of multiple tumor types. Because IL-6, and companion pro-inflammatory cytokines, participate in the initiation, progression, spread and recurrence of cancer, minimally invasive VNS could be employed to suppress glioma or cancer progression, while also mitigating depression and/or seizures, thereby enhancing quality of life. The current hypothesis reimagines glioma pathophysiology as a dysautonomia with the therapeutic objective to reset the autonomic nervous system and form an immune responsive state to halt tumor progression and prevent recurrence. VNS, as a novel method to control cancer, can be administered with ICIs, standard therapy, or in clinical trials, combined with emerging immunotherapy: dendritic cell, mRNA, or chimeric antigen receptor (CAR) T cell vaccines.
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Affiliation(s)
- Steven Brem
- University of Pennsylvania, Department of Neurosurgery, Perelman Center for Advanced Medicine, 15-141, 3400 Civic Center Blvd., Philadelphia, PA, 19104, United States
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, 19104, United States
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Pote MS, Singh D, M. A A, Suchita J, Gacche RN. Cancer metastases: Tailoring the targets. Heliyon 2024; 10:e35369. [PMID: 39170575 PMCID: PMC11336595 DOI: 10.1016/j.heliyon.2024.e35369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 07/26/2024] [Indexed: 08/23/2024] Open
Abstract
Metastasis is an intricate and formidable pathophysiological process encompassing the dissemination of cancer cells from the primary tumour body to distant organs. It stands as a profound and devastating phenomenon that constitutes the primary driver of cancer-related mortality. Despite great strides of advancements in cancer research and treatment, tailored anti-metastasis therapies are either lacking or have shown limited success, necessitating a deeper understanding of the intrinsic elements driving cancer invasiveness. This comprehensive review presents a contemporary elucidation of pivotal facets within the realm of cancer metastasis, commencing with the intricate processes of homing and invasion. The process of angiogenesis, which supports tumour growth and metastasis, is addressed, along with the pre-metastatic niche, wherein the primary tumour prepares for a favorable microenvironment at distant sites for subsequent metastatic colonization. The landscape of metastasis-related genetic and epigenetic mechanisms, involvement of metastasis genes and metastasis suppressor genes, and microRNAs (miRNA) are also discussed. Furthermore, immune modulators' impact on metastasis and their potential as therapeutic targets are addressed. The interplay between cancer cells and the immune system, including immune evasion mechanisms employed by metastatic cells, is discussed, highlighting the importance of targeting immune modulation in arresting metastatic progression. Finally, this review presents promising treatment opportunities derived from the insights gained into the mechanisms of metastasis. Identifying novel therapeutic targets and developing innovative strategies to disrupt the metastatic cascade holds excellent potential for improving patient outcomes and ultimately reducing cancer-related mortality.
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Affiliation(s)
| | | | | | | | - Rajesh N. Gacche
- Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India
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Stalin J, Coquoz O, Jeitziner Marcone R, Jemelin S, Desboeufs N, Delorenzi M, Blot-Chabaud M, Imhof BA, Ruegg C. Targeting of the NOX1/ADAM17 Enzymatic Complex Regulates Soluble MCAM-Dependent Pro-Tumorigenic Activity in Colorectal Cancer. Biomedicines 2023; 11:3185. [PMID: 38137406 PMCID: PMC10740863 DOI: 10.3390/biomedicines11123185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/16/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
The melanoma cell adhesion molecule, shed from endothelial and cancer cells, is a soluble growth factor that induces tumor angiogenesis and growth. However, the molecular mechanism accounting for its generation in a tumor context is still unclear. To investigate this mechanism, we performed in vitro experiments with endothelial/cancer cells, gene expression analyses on datasets from human colorectal tumor samples, and applied pharmacological methods in vitro/in vivo with mouse and human colorectal cancer cells. We found that soluble MCAM generation is governed by ADAM17 proteolytic activity and NOX1-regulating ADAM17 expression. The treatment of colorectal tumor-bearing mice with pharmacologic NOX1 inhibitors or tumor growth in NOX1-deficient mice reduced the blood concentration of soluble MCAM and abrogated the anti-tumor effects of anti-soluble MCAM antibodies while ADAM17 pharmacologic inhibitors reduced tumor growth and angiogenesis in vivo. Especially, the expression of MCAM, NOX1, and ADAM17 was more prominent in the angiogenic, colorectal cancer-consensus molecular subtype 4 where high MCAM expression correlated with angiogenic and lymphangiogenic markers. Finally, we demonstrated that soluble MCAM also acts as a lymphangiogenic factor in vitro. These results identify a role for NOX1/ADAM17 in soluble MCAM generation, with potential clinical therapeutic relevance to the aggressive, angiogenic CMS4 colorectal cancer subtype.
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Affiliation(s)
- Jimmy Stalin
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (S.J.); (B.A.I.)
- Department of Oncology, Microbiology, and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700 Fribourg, Switzerland; (O.C.); (N.D.); (C.R.)
- C2VN, Inserm 1263, Inra 1260, UFR Pharmacie, Aix-Marseille University, 27 Bd J. Moulin, 13005 Marseille, France;
| | - Oriana Coquoz
- Department of Oncology, Microbiology, and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700 Fribourg, Switzerland; (O.C.); (N.D.); (C.R.)
| | - Rachel Jeitziner Marcone
- Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; (R.J.M.); (M.D.)
| | - Stephane Jemelin
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (S.J.); (B.A.I.)
| | - Nina Desboeufs
- Department of Oncology, Microbiology, and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700 Fribourg, Switzerland; (O.C.); (N.D.); (C.R.)
| | - Mauro Delorenzi
- Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; (R.J.M.); (M.D.)
| | - Marcel Blot-Chabaud
- C2VN, Inserm 1263, Inra 1260, UFR Pharmacie, Aix-Marseille University, 27 Bd J. Moulin, 13005 Marseille, France;
| | - Beat A. Imhof
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (S.J.); (B.A.I.)
| | - Curzio Ruegg
- Department of Oncology, Microbiology, and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700 Fribourg, Switzerland; (O.C.); (N.D.); (C.R.)
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Puente-Cobacho B, Varela-López A, Quiles JL, Vera-Ramirez L. Involvement of redox signalling in tumour cell dormancy and metastasis. Cancer Metastasis Rev 2023; 42:49-85. [PMID: 36701089 PMCID: PMC10014738 DOI: 10.1007/s10555-022-10077-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 12/27/2022] [Indexed: 01/27/2023]
Abstract
Decades of research on oncogene-driven carcinogenesis and gene-expression regulatory networks only started to unveil the complexity of tumour cellular and molecular biology. This knowledge has been successfully implemented in the clinical practice to treat primary tumours. In contrast, much less progress has been made in the development of new therapies against metastasis, which are the main cause of cancer-related deaths. More recently, the role of epigenetic and microenviromental factors has been shown to play a key role in tumour progression. Free radicals are known to communicate the intracellular and extracellular compartments, acting as second messengers and exerting a decisive modulatory effect on tumour cell signalling. Depending on the cellular and molecular context, as well as the intracellular concentration of free radicals and the activation status of the antioxidant system of the cell, the signalling equilibrium can be tilted either towards tumour cell survival and progression or cell death. In this regard, recent advances in tumour cell biology and metastasis indicate that redox signalling is at the base of many cell-intrinsic and microenvironmental mechanisms that control disseminated tumour cell fate and metastasis. In this manuscript, we will review the current knowledge about redox signalling along the different phases of the metastatic cascade, including tumour cell dormancy, making emphasis on metabolism and the establishment of supportive microenvironmental connections, from a redox perspective.
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Affiliation(s)
- Beatriz Puente-Cobacho
- Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology, Pfizer-University of Granada and Andalusian Regional Government, PTS, Granada, Spain
| | - Alfonso Varela-López
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain
| | - José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain
| | - Laura Vera-Ramirez
- Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology, Pfizer-University of Granada and Andalusian Regional Government, PTS, Granada, Spain. .,Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain.
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Abstract
Gene therapy is a powerful biological tool that is reshaping therapeutic landscapes for several diseases. Researchers are using both non-viral and viral-based gene therapy methods with success in the lab and the clinic. In the cancer biology field, gene therapies are expanding treatment options and the possibility of favorable outcomes for patients. While cellular immunotherapies and oncolytic virotherapies have paved the way in cancer treatments based on genetic engineering, recombinant adeno-associated virus (rAAV), a viral-based module, is also emerging as a potential cancer therapeutic through its malleability, specificity, and broad application to common as well as rare tumor types, tumor microenvironments, and metastatic disease. A wide range of AAV serotypes, promoters, and transgenes have been successful at reducing tumor growth and burden in preclinical studies, suggesting more groundbreaking advances using rAAVs in cancer are on the horizon.
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Affiliation(s)
- Patrick L. Mulcrone
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
- Department of Pediatrics, Indiana University, Indianapolis, IN 46202, USA
| | - Roland W. Herzog
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
| | - Weidong Xiao
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
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Roy R, Yang J, Shimura T, Merritt L, Alluin J, Man E, Daisy C, Aldakhlallah R, Dillon D, Pories S, Chodosh LA, Moses MA. Escape from breast tumor dormancy: The convergence of obesity and menopause. Proc Natl Acad Sci U S A 2022; 119:e2204758119. [PMID: 36191215 PMCID: PMC9564105 DOI: 10.1073/pnas.2204758119] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 08/25/2022] [Indexed: 11/18/2022] Open
Abstract
Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.
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Affiliation(s)
- Roopali Roy
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
- Department of Surgery, Harvard Medical School and Boston Children’s Hospital, Boston, MA 02115
| | - Jiang Yang
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
- Department of Surgery, Harvard Medical School and Boston Children’s Hospital, Boston, MA 02115
| | - Takaya Shimura
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
- Department of Surgery, Harvard Medical School and Boston Children’s Hospital, Boston, MA 02115
| | - Lauren Merritt
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
| | - Justine Alluin
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
| | - Emily Man
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
| | - Cassandra Daisy
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
| | - Rama Aldakhlallah
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
| | - Deborah Dillon
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115
| | - Susan Pories
- Hoffman Breast Center, Mount Auburn Hospital, Cambridge, MA 02138
- Department of Surgery, Harvard Medical School, Boston, MA 02115
| | - Lewis A. Chodosh
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Marsha A. Moses
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115
- Department of Surgery, Harvard Medical School and Boston Children’s Hospital, Boston, MA 02115
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8
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La Mendola D, Trincavelli ML, Martini C. Angiogenesis in Disease. Int J Mol Sci 2022; 23:ijms231810962. [PMID: 36142885 PMCID: PMC9503835 DOI: 10.3390/ijms231810962] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
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González-Moles MÁ, Warnakulasuriya S, López-Ansio M, Ramos-García P. Hallmarks of Cancer Applied to Oral and Oropharyngeal Carcinogenesis: A Scoping Review of the Evidence Gaps Found in Published Systematic Reviews. Cancers (Basel) 2022; 14:3834. [PMID: 35954497 PMCID: PMC9367256 DOI: 10.3390/cancers14153834] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 02/07/2023] Open
Abstract
In 2000 and 2011, Hanahan and Weinberg published two papers in which they defined the characteristics that cells must fulfil in order to be considered neoplastic cells in all types of tumours that affect humans, which the authors called "hallmarks of cancer". These papers have represented a milestone in our understanding of the biology of many types of cancers and have made it possible to reach high levels of scientific evidence in relation to the prognostic impact that these hallmarks have on different tumour types. However, to date, there is no study that globally analyses evidence-based knowledge on the importance of these hallmarks in oral and oropharyngeal squamous cell carcinomas. For this reason, we set out to conduct this scoping review of systematic reviews with the aim of detecting evidence gaps in relation to the relevance of the cancer hallmarks proposed by Hanahan and Weinberg in oral and oropharyngeal cancer, and oral potentially malignant disorders, and to point out future lines of research in this field.
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Affiliation(s)
- Miguel Ángel González-Moles
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Saman Warnakulasuriya
- Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
- WHO Collaborating for Oral Cancer, King’s College London, London SE1 9RT, UK
| | - María López-Ansio
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Pablo Ramos-García
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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Farino Reyes CJ, Slater JH. Tuning Hydrogel Adhesivity and Degradability to Model the Influence of Premetastatic Niche Matrix Properties on Breast Cancer Dormancy and Reactivation. Adv Biol (Weinh) 2022; 6:e2200012. [PMID: 35277951 PMCID: PMC9090988 DOI: 10.1002/adbi.202200012] [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: 02/27/2022] [Revised: 01/01/2000] [Indexed: 01/27/2023]
Abstract
Dormant, disseminated tumor cells (DTCs) can persist for decades in secondary tissues before being reactivated to form tumors. The properties of the premetastatic niche can influence the DTC phenotype. To better understand how matrix properties of premetastatic niches influence DTC behavior, three hydrogel formulations are implemented to model a permissive niche and two nonpermissive niches. Poly(ethylene glycol) (PEG)-based hydrogels with varying adhesivity ([RGDS]) and degradability ([N-vinyl pyrrolidinone]) are implemented to mimic a permissive niche with high adhesivity and degradability and two nonpermissive niches, one with moderate adhesivity and degradability and one with no adhesivity and high degradability. The influence of matrix properties on estrogen receptor positive (ER+ ) breast cancer cells (MCF7s) is determined via a multimetric analysis. MCF7s cultured in the permissive niche adopted a growth state, while those in the nonpermissive niche with reduced adhesivity and degradability underwent tumor mass dormancy. Complete removal of adhesivity while maintaining high degradability induced single cell dormancy. The ability to mimic reactivation of dormant cells through a dynamic increase in [RGDS] is also demonstrated. This platform provides the capability of inducing growth, dormancy, and reactivation of ER+ breast cancer and can be useful in understanding how premetastatic niche properties influence cancer cell fate.
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Affiliation(s)
- Cindy J. Farino Reyes
- Department of Biomedical Engineering University of Delaware 590 Avenue 1743, Biomedical Engineering Newark DE 19713 USA
| | - John H. Slater
- Department of Biomedical Engineering University of Delaware 590 Avenue 1743, Biomedical Engineering Newark DE 19713 USA
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11
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Kronemberger GS, Miranda GASC, Tavares RSN, Montenegro B, Kopke ÚDA, Baptista LS. Recapitulating Tumorigenesis in vitro: Opportunities and Challenges of 3D Bioprinting. Front Bioeng Biotechnol 2021; 9:682498. [PMID: 34239860 PMCID: PMC8258101 DOI: 10.3389/fbioe.2021.682498] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is considered one of the most predominant diseases in the world and one of the principal causes of mortality per year. The cellular and molecular mechanisms involved in the development and establishment of solid tumors can be defined as tumorigenesis. Recent technological advances in the 3D cell culture field have enabled the recapitulation of tumorigenesis in vitro, including the complexity of stromal microenvironment. The establishment of these 3D solid tumor models has a crucial role in personalized medicine and drug discovery. Recently, spheroids and organoids are being largely explored as 3D solid tumor models for recreating tumorigenesis in vitro. In spheroids, the solid tumor can be recreated from cancer cells, cancer stem cells, stromal and immune cell lineages. Organoids must be derived from tumor biopsies, including cancer and cancer stem cells. Both models are considered as a suitable model for drug assessment and high-throughput screening. The main advantages of 3D bioprinting are its ability to engineer complex and controllable 3D tissue models in a higher resolution. Although 3D bioprinting represents a promising technology, main challenges need to be addressed to improve the results in cancer research. The aim of this review is to explore (1) the principal cell components and extracellular matrix composition of solid tumor microenvironment; (2) the recapitulation of tumorigenesis in vitro using spheroids and organoids as 3D culture models; and (3) the opportunities, challenges, and applications of 3D bioprinting in this area.
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Affiliation(s)
- Gabriela S. Kronemberger
- Nucleus of Multidisciplinary Research in Biology (Numpex-Bio), Federal University of Rio de Janeiro Xerém, Duque de Caxias, Brazil
- Laboratory of Tissue Bioengineering, National Institute of Metrology, Quality and Technology (Inmetro), Duque de Caxias, Brazil
- Post-graduation Program of Translational Biomedicine (Biotrans), Unigranrio, Duque de Caxias, Brazil
| | - Guilherme A. S. C. Miranda
- Nucleus of Multidisciplinary Research in Biology (Numpex-Bio), Federal University of Rio de Janeiro Xerém, Duque de Caxias, Brazil
- Laboratory of Tissue Bioengineering, National Institute of Metrology, Quality and Technology (Inmetro), Duque de Caxias, Brazil
- Post-graduation Program in Biotechnology, National Institute of Metrology, Quality and Technology (Inmetro), Duque de Caxias, Brazil
| | - Renata S. N. Tavares
- Laboratory of Tissue Bioengineering, National Institute of Metrology, Quality and Technology (Inmetro), Duque de Caxias, Brazil
| | - Bianca Montenegro
- Nucleus of Multidisciplinary Research in Biology (Numpex-Bio), Federal University of Rio de Janeiro Xerém, Duque de Caxias, Brazil
- Laboratory of Tissue Bioengineering, National Institute of Metrology, Quality and Technology (Inmetro), Duque de Caxias, Brazil
- Post-graduation Program of Translational Biomedicine (Biotrans), Unigranrio, Duque de Caxias, Brazil
| | - Úrsula de A. Kopke
- Nucleus of Multidisciplinary Research in Biology (Numpex-Bio), Federal University of Rio de Janeiro Xerém, Duque de Caxias, Brazil
- Laboratory of Tissue Bioengineering, National Institute of Metrology, Quality and Technology (Inmetro), Duque de Caxias, Brazil
| | - Leandra S. Baptista
- Nucleus of Multidisciplinary Research in Biology (Numpex-Bio), Federal University of Rio de Janeiro Xerém, Duque de Caxias, Brazil
- Laboratory of Tissue Bioengineering, National Institute of Metrology, Quality and Technology (Inmetro), Duque de Caxias, Brazil
- Post-graduation Program of Translational Biomedicine (Biotrans), Unigranrio, Duque de Caxias, Brazil
- Post-graduation Program in Biotechnology, National Institute of Metrology, Quality and Technology (Inmetro), Duque de Caxias, Brazil
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12
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Vandyck HHLD, Hillen LM, Bosisio FM, van den Oord J, zur Hausen A, Winnepenninckx V. Rethinking the biology of metastatic melanoma: a holistic approach. Cancer Metastasis Rev 2021; 40:603-624. [PMID: 33870460 PMCID: PMC8213587 DOI: 10.1007/s10555-021-09960-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/29/2021] [Indexed: 02/06/2023]
Abstract
Over the past decades, melanoma-related mortality has remained nearly stable. The main reason is treatment failure of metastatic disease and the inherently linked knowledge gap regarding metastasis formation. In order to elicit invasion, melanoma cells manipulate the tumor microenvironment, gain motility, and adhere to the extracellular matrix and cancer-associated fibroblasts. Melanoma cells thereby express different cell adhesion molecules like laminins, integrins, N-cadherin, and others. Epithelial-mesenchymal transition (EMT) is physiological during embryologic development, but reactivated during malignancy. Despite not being truly epithelial, neural crest-derived malignancies like melanoma share similar biological programs that enable tumorigenesis, invasion, and metastasis. This complex phenomenon is termed phenotype switching and is intertwined with oncometabolism as well as dormancy escape. Additionally, it has been shown that primary melanoma shed exosomes that create a favorable premetastatic niche in the microenvironment of secondary organs and lymph nodes. Although the growing body of literature describes the aforementioned concepts separately, an integrative holistic approach is missing. Using melanoma as a tumor model, this review will shed light on these complex biological principles in an attempt to clarify the mechanistic metastatic pathways that dictate tumor and patient fate.
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Affiliation(s)
- Hendrik HLD Vandyck
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Lisa M Hillen
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Francesca M Bosisio
- Laboratory of Translational Cell and Tissue Research (TCTR), Department of Pathology, KU Leuven and UZ Leuven, Leuven, Belgium
| | - Joost van den Oord
- Laboratory of Translational Cell and Tissue Research (TCTR), Department of Pathology, KU Leuven and UZ Leuven, Leuven, Belgium
| | - Axel zur Hausen
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Véronique Winnepenninckx
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202 AZ Maastricht, The Netherlands
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13
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Farino Reyes CJ, Pradhan S, Slater JH. The Influence of Ligand Density and Degradability on Hydrogel Induced Breast Cancer Dormancy and Reactivation. Adv Healthc Mater 2021; 10:e2002227. [PMID: 33929776 PMCID: PMC8555704 DOI: 10.1002/adhm.202002227] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/26/2021] [Indexed: 01/07/2023]
Abstract
The role of hydrogel properties in regulating the phenotype of triple negative metastatic breast cancer is investigated using four cell lines: the MDA-MB-231 parental line and three organotropic sublines BoM-1833 (bone-tropic), LM2-4175 (lung-tropic), and BrM2a-831 (brain-tropic). Each line is encapsulated and cultured for 15 days in three poly(ethylene glycol) (PEG)-based hydrogel formulations composed of proteolytically degradable PEG, integrin-ligating RGDS, and the non-degradable crosslinker N-vinyl pyrrolidone. Dormancy-associated metrics including viable cell density, proliferation, metabolism, apoptosis, chemoresistance, phosphorylated-ERK and -p38, and morphological characteristics are quantified. A multimetric classification approach is implemented to categorize each hydrogel-induced phenotype as: 1) growth, 2) balanced tumor dormancy, 3) balanced cellular dormancy, or 4) restricted survival, cellular dormancy. Hydrogels with high adhesivity and degradability promote growth. Hydrogels with no adhesivity, but high degradability, induce restricted survival, cellular dormancy in the parental line and balanced cellular dormancy in the organotropic lines. Hydrogels with reduced adhesivity and degradability induce balanced cellular dormancy in the parental and lung-tropic lines and balanced tumor mass dormancy in bone- and brain-tropic lines. The ability to induce escape from dormancy via dynamic incorporation of RGDS is also presented. These results demonstrate that ECM properties and organ-tropism synergistically regulate cancer cell phenotype and dormancy.
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Affiliation(s)
- Cindy J Farino Reyes
- Department of Biomedical Engineering, University of Delaware, 590 Avenue 1743, Biomedical Engineering, Newark, DE, 19713, USA
| | - Shantanu Pradhan
- Department of Biomedical Engineering, University of Delaware, 590 Avenue 1743, Biomedical Engineering, Newark, DE, 19713, USA
| | - John H Slater
- Department of Biomedical Engineering, University of Delaware, 590 Avenue 1743, Biomedical Engineering, Newark, DE, 19713, USA
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14
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Azimzade Y, Saberi AA, Gatenby RA. Superlinear growth reveals the Allee effect in tumors. Phys Rev E 2021; 103:042405. [PMID: 34005934 DOI: 10.1103/physreve.103.042405] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 03/16/2021] [Indexed: 12/17/2022]
Abstract
Integrating experimental data into ecological models plays a central role in understanding biological mechanisms that drive tumor progression where such knowledge can be used to develop new therapeutic strategies. While the current studies emphasize the role of competition among tumor cells, they fail to explain recently observed superlinear growth dynamics across human tumors. Here we study tumor growth dynamics by developing a model that incorporates evolutionary dynamics inside tumors with tumor-microenvironment interactions. Our results reveal that tumor cells' ability to manipulate the environment and induce angiogenesis drives superlinear growth-a process compatible with the Allee effect. In light of this understanding, our model suggests that, for high-risk tumors that have a higher growth rate, suppressing angiogenesis can be the appropriate therapeutic intervention.
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Affiliation(s)
- Youness Azimzade
- Department of Physics, University of Tehran, Tehran 14395-547, Iran
| | - Abbas Ali Saberi
- Department of Physics, University of Tehran, Tehran 14395-547, Iran and Institut für Theoretische Physik, Universitat zu Köln, Zülpicher Strasse 77, 50937 Köln, Germany
| | - Robert A Gatenby
- Cancer Biology and Evolution Program, Integrated Mathematical Oncology Department, and Diagnostic Imaging Department, Moffitt Cancer Center, Tampa, Florida 33612, USA
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15
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Mallone F, Sacchetti M, Lambiase A, Moramarco A. Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma. Cancers (Basel) 2020; 12:E2761. [PMID: 32992823 PMCID: PMC7600598 DOI: 10.3390/cancers12102761] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 09/14/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022] Open
Abstract
Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use.
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Affiliation(s)
| | | | - Alessandro Lambiase
- Department of Sense Organs, Sapienza University of Rome, 00161 Rome, Italy; (F.M.); (M.S.); (A.M.)
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16
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Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo. Proc Natl Acad Sci U S A 2020; 117:22910-22919. [PMID: 32859758 DOI: 10.1073/pnas.2009092117] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.
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17
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Farino CJ, Pradhan S, Slater JH. The Influence of Matrix-Induced Dormancy on Metastatic Breast Cancer Chemoresistance. ACS APPLIED BIO MATERIALS 2020; 3:5832-5844. [DOI: 10.1021/acsabm.0c00549] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Cindy J. Farino
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, Delaware 19716, United States
| | - Shantanu Pradhan
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, Delaware 19716, United States
| | - John H. Slater
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, Delaware 19716, United States
- Department of Material Science and Engineering, University of Delaware, 201 DuPont Hall, Newark, Delaware 19716, United States
- Delaware Biotechnology Institute, 15 Innovation Way, Newark, Delaware 19711, United States
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18
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Das SK, Maji S, Wechman SL, Bhoopathi P, Pradhan AK, Talukdar S, Sarkar D, Landry J, Guo C, Wang XY, Cavenee WK, Emdad L, Fisher PB. MDA-9/Syntenin (SDCBP): Novel gene and therapeutic target for cancer metastasis. Pharmacol Res 2020; 155:104695. [PMID: 32061839 PMCID: PMC7551653 DOI: 10.1016/j.phrs.2020.104695] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/12/2020] [Accepted: 02/12/2020] [Indexed: 02/06/2023]
Abstract
The primary cause of cancer-related death from solid tumors is metastasis. While unraveling the mechanisms of this complicated process continues, our ability to effectively target and treat it to decrease patient morbidity and mortality remains disappointing. Early detection of metastatic lesions and approaches to treat metastases (both pharmacological and genetic) are of prime importance to obstruct this process clinically. Metastasis is complex involving both genetic and epigenetic changes in the constantly evolving tumor cell. Moreover, many discrete steps have been identified in metastatic spread, including invasion, intravasation, angiogenesis, attachment at a distant site (secondary seeding), extravasation and micrometastasis and tumor dormancy development. Here, we provide an overview of the metastatic process and highlight a unique pro-metastatic gene, melanoma differentiation associated gene-9/Syntenin (MDA-9/Syntenin) also called syndecan binding protein (SDCBP), which is a major contributor to the majority of independent metastatic events. MDA-9 expression is elevated in a wide range of carcinomas and other cancers, including melanoma, glioblastoma multiforme and neuroblastoma, suggesting that it may provide an appropriate target to intervene in metastasis. Pre-clinical studies confirm that inhibiting MDA-9 either genetically or pharmacologically profoundly suppresses metastasis. An additional benefit to blocking MDA-9 in metastatic cells is sensitization of these cells to a second therapeutic agent, which converts anti-invasion effects to tumor cytocidal effects. Continued mechanistic and therapeutic insights hold promise to advance development of truly effective therapies for metastasis in the future.
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Affiliation(s)
- Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
| | - Santanu Maji
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Stephen L Wechman
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Praveen Bhoopathi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Anjan K Pradhan
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Sarmistha Talukdar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Joseph Landry
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Chunqing Guo
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Webster K Cavenee
- Ludwig Institute for Cancer Research, University of California, San Diego, CA, USA
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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19
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Harihar S, Ray S, Narayanan S, Santhoshkumar A, Ly T, Welch DR. Role of the tumor microenvironment in regulating the anti-metastatic effect of KISS1. Clin Exp Metastasis 2020; 37:209-223. [PMID: 32088827 PMCID: PMC7339126 DOI: 10.1007/s10585-020-10030-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 02/19/2020] [Indexed: 12/29/2022]
Abstract
KISS1, a metastasis suppressor gene, has been shown to block metastasis without affecting primary tumor formation. Loss of KISS1 leads to invasion and metastasis in multiple cancers, which is the leading cause of cancer morbidity and mortality. The discovery of KISS1 has provided a ray of hope for early clinical diagnosis and for designing effective treatments targeting metastatic cancer. However, this goal requires greater holistic understanding of its mechanism of action. In this review, we go back into history and highlight some key developments, from the discovery of KISS1 to its role in regulating multiple physiological processes including cancer. We discuss key emerging roles for KISS1, specifically interactions with tissue microenvironment to promote dormancy and regulation of tumor cell metabolism, acknowledged as some of the key players in tumor progression and metastasis. We finally discuss strategies whereby KISS1 might be exploited clinically to treat metastasis.
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Affiliation(s)
- Sitaram Harihar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
| | - Srijit Ray
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Samyukta Narayanan
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Anirudh Santhoshkumar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Thuc Ly
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
- The University Kansas Cancer Center, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Danny R Welch
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
- The University Kansas Cancer Center, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
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20
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Mayhew V, Omokehinde T, Johnson RW. Tumor dormancy in bone. Cancer Rep (Hoboken) 2020; 3:e1156. [PMID: 32632400 PMCID: PMC7337256 DOI: 10.1002/cnr2.1156] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/10/2018] [Accepted: 01/04/2019] [Indexed: 12/20/2022] Open
Abstract
Background Bone marrow is a common site of metastasis for a number of tumor types, including breast, prostate, and lung cancer, but the mechanisms controlling tumor dormancy in bone are poorly understood. In breast cancer, while advances in drug development, screening practices, and surgical techniques have dramatically improved survival rates in recent decades, metastatic recurrence in the bone remains common and can develop years or decades after elimination of the primary tumor. Recent Findings It is now understood that tumor cells disseminate to distant metastatic sites at early stages of tumor progression, leaving cancer survivors at a high risk of recurrence. This review will discuss mechanisms of bone lesion development and current theories of how dormant cancer cells behave in bone, as well as a number of processes suspected to be involved in the maintenance of and exit from dormancy in the bone microenvironment. Conclusions The bone is a complex microenvironment with a multitude of cell types and processes. Many of these factors, including angiogenesis, immune surveillance, and hypoxia, are thought to regulate tumor cell entry and exit from dormancy in different bone marrow niches.
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Affiliation(s)
- Vera Mayhew
- Graduate Program in Cancer BiologyVanderbilt UniversityNashvilleTNUSA
- Vanderbilt Center for Bone Biology
| | - Tolu Omokehinde
- Graduate Program in Cancer BiologyVanderbilt UniversityNashvilleTNUSA
- Vanderbilt Center for Bone Biology
| | - Rachelle W. Johnson
- Vanderbilt Center for Bone Biology
- Department of Medicine, Division of Clinical PharmacologyVanderbilt University Medical CenterNashvilleTNUSA
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21
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Mátyási B, Farkas Z, Kopper L, Sebestyén A, Boissan M, Mehta A, Takács-Vellai K. The Function of NM23-H1/NME1 and Its Homologs in Major Processes Linked to Metastasis. Pathol Oncol Res 2020; 26:49-61. [PMID: 31993913 PMCID: PMC7109179 DOI: 10.1007/s12253-020-00797-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/14/2020] [Indexed: 12/12/2022]
Abstract
Metastasis suppressor genes (MSGs) inhibit different biological processes during metastatic progression without globally influencing development of the primary tumor. The first MSG, NM23 (non-metastatic clone 23, isoform H1) or now called NME1 (stands for non-metastatic) was identified some decades ago. Since then, ten human NM23 paralogs forming two groups have been discovered. Group I NM23 genes encode enzymes with evolutionarily highly conserved nucleoside diphosphate kinase (NDPK) activity. In this review we summarize how results from NDPKs in model organisms converged on human NM23 studies. Next, we examine the role of NM23-H1 and its homologs within the metastatic cascade, e.g. cell migration and invasion, proliferation and apoptosis. NM23-H1 homologs are well known inhibitors of cell migration. Drosophila studies revealed that AWD, the fly counterpart of NM23-H1 is a negative regulator of cell motility by modulating endocytosis of chemotactic receptors on the surface of migrating cells in cooperation with Shibire/Dynamin; this mechanism has been recently confirmed by human studies. NM23-H1 inhibits proliferation of tumor cells by phosphorylating the MAPK scaffold, kinase suppressor of Ras (KSR), resulting in suppression of MAPK signalling. This mechanism was also observed with the C. elegans homolog, NDK-1, albeit with an inverse effect on MAPK activation. Both NM23-H1 and NDK-1 promote apoptotic cell death. In addition, NDK-1, NM23-H1 and their mouse counterpart NM23-M1 were shown to promote phagocytosis in an evolutionarily conserved manner. In summary, inhibition of cell migration and proliferation, alongside actions in apoptosis and phagocytosis are all mechanisms through which NM23-H1 acts against metastatic progression.
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Affiliation(s)
- Barbara Mátyási
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter stny. 1/C, H-1117, Budapest, Hungary
| | - Zsolt Farkas
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter stny. 1/C, H-1117, Budapest, Hungary
| | - László Kopper
- Department of Pathology and Experimental Cancer Research, Semmelweis University, 1st, Budapest, Hungary
| | - Anna Sebestyén
- Department of Pathology and Experimental Cancer Research, Semmelweis University, 1st, Budapest, Hungary
| | - Mathieu Boissan
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012, Paris, France
- Service de Biochimie et Hormonologie, AP- HP, Hôpital Tenon, Paris, France
| | - Anil Mehta
- Division of Medical Sciences, Centre for CVS and Lung Biology, Ninewells Hospital Medical School, DD19SY, Dundee, UK
| | - Krisztina Takács-Vellai
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter stny. 1/C, H-1117, Budapest, Hungary.
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22
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Welch DR, Hurst DR. Defining the Hallmarks of Metastasis. Cancer Res 2019; 79:3011-3027. [PMID: 31053634 PMCID: PMC6571042 DOI: 10.1158/0008-5472.can-19-0458] [Citation(s) in RCA: 422] [Impact Index Per Article: 70.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/12/2019] [Accepted: 03/14/2019] [Indexed: 12/24/2022]
Abstract
Metastasis is the primary cause of cancer morbidity and mortality. The process involves a complex interplay between intrinsic tumor cell properties as well as interactions between cancer cells and multiple microenvironments. The outcome is the development of a nearby or distant discontiguous secondary mass. To successfully disseminate, metastatic cells acquire properties in addition to those necessary to become neoplastic. Heterogeneity in mechanisms involved, routes of dissemination, redundancy of molecular pathways that can be utilized, and the ability to piggyback on the actions of surrounding stromal cells makes defining the hallmarks of metastasis extraordinarily challenging. Nonetheless, this review identifies four distinguishing features that are required: motility and invasion, ability to modulate the secondary site or local microenvironments, plasticity, and ability to colonize secondary tissues. By defining these first principles of metastasis, we provide the means for focusing efforts on the aspects of metastasis that will improve patient outcomes.
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Affiliation(s)
- Danny R Welch
- Department of Cancer Biology and The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas.
| | - Douglas R Hurst
- Department of Pathology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
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23
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A potential function of RLIP76 in the ovarian corpus luteum. J Ovarian Res 2019; 12:34. [PMID: 30999946 PMCID: PMC6474048 DOI: 10.1186/s13048-019-0510-8] [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: 02/01/2019] [Accepted: 04/08/2019] [Indexed: 11/24/2022] Open
Abstract
Ral interacting protein of 76 kDa (RLIP76) is multifunctional protein localized and distributed in the plasma membrane, cytosol, and nucleus of the cell. In tumorigenesis, RLIP76 emerges as a common feature for the solid tumor growth. RLIP76 is ubiquitously expressed in various tissues including the ovary. Interestingly, the similar physiological events in obtaining an adequate supply of nutrient by gaining access to the host vascular system are required either for corpus luteum formation or tumor development. In addition, the identical angiogenesis modulators were found in neoplastic and normal ovaries. Our previous study involving RLIP76−/− mice implanted with melanoma or carcinoma cell conclusively demonstrated that RLIP76 is necessary for angiogenesis and neovascularization of primary solid tumors. RLIP76 plays an essential role in tumor angiogenesis through the regulation of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1). In certain previous studies, those pro-angiogenic factors were found significantly to be upregulated during the corpus luteum formation. To that, the following review will discuss the likelihood of RLIP76 role in ovarian corpus luteum.
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24
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A systematic review of contemporary management of oligometastatic prostate cancer: fighting a challenge or tilting at windmills? World J Urol 2019; 37:2343-2353. [PMID: 30706122 DOI: 10.1007/s00345-019-02652-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/22/2019] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Amongst the unanswered questions regarding prostate cancer (PCa), the optimal management of oligometastatic disease remains one of the major concerns of the scientific community. The very existence of this category is still subject to controversy. Aim of this systematic review is to summarize current available data on the most appropriate management of oligometastatic PCa. EVIDENCE ACQUISITION All relevant studies published in English up to November the 1st were identified through systematic searches in PubMed, EMBASE, Cochrane Library, CINAHL, Google Scholar and Ovid database. A search was performed including the combination of following words: (prostate cancer) and (metastatic) and [(oligo) or (PSMA) or (cytoreductive) or (stereotaxic radiotherapy) or (prostatectomy)]. 3335 articles were reviewed. After title screening and abstract reading, 118 papers were considered for full reading, leaving a total of 36 articles for the systematic review. EVIDENCE SYNTHESIS There is still no consensus on the definition of oligometastatic disease, nor on the imaging modalities used for its detection. While retrospective studies suggest an added benefit with the treatment the primitive tumor by cytoreductive prostatectomy (55% survival rate vs 21%, p < 0.001), prospective studies do not validate the same outcome. Nonetheless, most studies have reported a reduction in local complications after cytoreductive prostatectomy (< 10%) compared to the best systemic treatment (25-30%). Concerning radiotherapy, an overall survival benefit for patients with a low metastatic burden was found in STAMPEDE (HR 0.68, 95% CI 0.52-0.90; p = 0.007) and suggested in subgroup analysis of the HORRAD trial. Regarding the impact of metastases-directed therapy (MDT), the STOMP and ORIOLE trials suggested that metastatic disease control might improve androgen deprivation therapy-free survival (in STOMP: 21 vs 13 months for MDT vs standard of care). Nonetheless, the impact of MDT on long-term oncologic results remains unclear. Finally, oligometastatic disease appears to be a biologically different entity compared to high-burden metastatic disease. New findings on exosomes appear to make them intriguing biomarkers in the early phases of oligometastatic PCa. CONCLUSION Oligometastatic PCa is today a poorly understood disease. The implementation of new imaging techniques as whole-body MRI and PSMA PET/CT has increased exponentially the number of oligometastatic patients detected. Data of available trials suggest a benefit from cytoreductive prostatectomy to reduce local complication, though its impact on survival remains unknown. Radiotherapy may be beneficial for patients with low-burden metastatic PCa, while MDT may delay the need for androgen deprivation therapy. Results from ongoing trials data are eagerly awaited to draw reliable recommendations.
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Pradhan S, Sperduto JL, Farino CJ, Slater JH. Engineered In Vitro Models of Tumor Dormancy and Reactivation. J Biol Eng 2018; 12:37. [PMID: 30603045 PMCID: PMC6307145 DOI: 10.1186/s13036-018-0120-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 11/16/2018] [Indexed: 12/23/2022] Open
Abstract
Metastatic recurrence is a major hurdle to overcome for successful control of cancer-associated death. Residual tumor cells in the primary site, or disseminated tumor cells in secondary sites, can lie in a dormant state for long time periods, years to decades, before being reactivated into a proliferative growth state. The microenvironmental signals and biological mechanisms that mediate the fate of disseminated cancer cells with respect to cell death, single cell dormancy, tumor mass dormancy and metastatic growth, as well as the factors that induce reactivation, are discussed in this review. Emphasis is placed on engineered, in vitro, biomaterial-based approaches to model tumor dormancy and subsequent reactivation, with a focus on the roles of extracellular matrix, secondary cell types, biochemical signaling and drug treatment. A brief perspective of molecular targets and treatment approaches for dormant tumors is also presented. Advances in tissue-engineered platforms to induce, model, and monitor tumor dormancy and reactivation may provide much needed insight into the regulation of these processes and serve as drug discovery and testing platforms.
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Affiliation(s)
- Shantanu Pradhan
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, DE 19716 USA
| | - John L. Sperduto
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, DE 19716 USA
| | - Cindy J. Farino
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, DE 19716 USA
| | - John H. Slater
- Department of Biomedical Engineering, University of Delaware, 150 Academy Street, 161 Colburn Lab, Newark, DE 19716 USA
- Delaware Biotechnology Institute, 15 Innovation Way, Newark, DE 19711 USA
- Department of Materials Science and Engineering, University of Delaware, 201 DuPont Hall, Newark, DE 19716 USA
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26
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Wei HC. A mathematical model of tumour growth with Beddington-DeAngelis functional response: a case of cancer without disease. JOURNAL OF BIOLOGICAL DYNAMICS 2018; 12:194-210. [PMID: 29322865 DOI: 10.1080/17513758.2017.1418028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/11/2017] [Indexed: 06/07/2023]
Abstract
A previously published mathematical model, governing tumour growth with mixed immunotherapy and chemotherapy treatments, is modified and studied. The search time, which is assumed to be neglectable in the previously published model, is incorporated into the functional response for tumour-cell lysis by effector cells. The model exhibits bistability where a tumour-cell population threshold exists. A tumour with an initial cell population below the threshold can be controlled by the immune system and remains microscopic and asymptomatic called cancer without disease while that above the threshold grows to lethal size. Bifurcation analysis shows that (a) the chemotherapy-induced damage may cause a microscopic tumour, which would never grow to become lethal if untreated, to grow to lethal size, (b) applying chemotherapy alone requires a large dosage to be successful,
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Affiliation(s)
- Hsiu-Chuan Wei
- a Department of Applied Mathematics , Feng Chia University , TaiChung , Taiwan
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27
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Dillekås H, Straume O. The link between wound healing and escape from tumor dormancy. Surg Oncol 2018; 28:50-56. [PMID: 30851911 DOI: 10.1016/j.suronc.2018.11.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 11/08/2018] [Indexed: 12/19/2022]
Abstract
Tumor dormancy is considered one of the major unsolved questions in cancer biology. Understanding the mechanisms responsible for maintaining and interrupting dormancy would be a major step towards preventing overt metastatic disease. Increasing evidence points to tissue trauma and subsequent wound healing as contributing events in escape from dormancy. In this review, we outline relevant aspects of the wound healing process, and relate this to mechanisms of tumor dormancy and metastatic progression. In addition to important findings in epidemiological and experimental studies, more direct evidence of such a link has recently been presented. These results can have major implications for treatment and prevention of cancer.
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Affiliation(s)
- Hanna Dillekås
- Department of Clinical Science, University of Bergen, N5020, Bergen, Norway.
| | - Oddbjørn Straume
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, N5020, Bergen, Norway; Department of Oncology and Medical Physics, Haukeland University Hospital, N5021, Bergen, Norway.
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Ouhtit A, Rizeq B, Saleh HA, Rahman MM, Zayed H. Novel CD44-downstream signaling pathways mediating breast tumor invasion. Int J Biol Sci 2018; 14:1782-1790. [PMID: 30443182 PMCID: PMC6231220 DOI: 10.7150/ijbs.23586] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 02/04/2018] [Indexed: 01/06/2023] Open
Abstract
CD44, also known as homing cell adhesion molecule is a multi-structural cell molecule involved in cell-cell and cell-extracellular matrix communications. CD44 regulates a number of central signaling pathways, including PI3K/AKT, Rho GTPases and the Ras-MAPK pathways, but also acts as a growth/arrest sensor, and inhibitor of angiogenesis and invasion, in response to signals from the microenvironment. The function of CD44 has been very controversial since it acts as both, a suppressor and a promoter of tumor growth and progression. To address this discrepancy, we have previously established CD44-inducible system both in vitro and in vivo. Next, using microarray analysis, we have identified and validated Survivin, Cortactin and TGF-β2 as novel CD44-downstream target genes, and characterized their signaling pathways underpinning CD44-promoted breast cancer (BC) cell invasion. This report aims to update the literature by adding and discussing the impact of these novel three signaling pathways to better understand the CD44-signaling pathways involved in BC tumor cell invasion.
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Affiliation(s)
- Allal Ouhtit
- Department of Biological and Environmental Sciences, College of Arts & Sciences, Qatar University, Doha, Qatar
| | - Balsam Rizeq
- Department of Biological and Environmental Sciences, College of Arts & Sciences, Qatar University, Doha, Qatar.,Biomedical Research Center, Qatar University, Doha, Qatar
| | - Haissam Abou Saleh
- Department of Biological and Environmental Sciences, College of Arts & Sciences, Qatar University, Doha, Qatar
| | - Md Mizanur Rahman
- Department of Biological and Environmental Sciences, College of Arts & Sciences, Qatar University, Doha, Qatar
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar
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Natale G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data. Cancer Lett 2018; 432:28-37. [PMID: 29885517 DOI: 10.1016/j.canlet.2018.06.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 05/11/2018] [Accepted: 06/03/2018] [Indexed: 02/08/2023]
Abstract
Tumor dormancy is the ability of cancer cells to survive in a non-proliferating state. This condition can depend on three main mechanisms: cell cycle arrest (quiescence or cell dormancy), immunosurveillance (immunologic dormancy), or lack of functional blood vessels (angiogenic dormancy). In particular, under angiogenic dormancy, cancer cell proliferation is counterbalanced by apoptosis owing to poor vascularization, impeding tumor mass expansion beyond a microscopic size, with an asymptomatic and non-metastatic state. Tumor vasculogenic or non-angiogenic switch is essential to promote escape from tumor dormancy, leading to tumor mass proliferation and metastasis. In avascular lesions angiogenesis process results blocked from the equilibrium between pro- and anti-angiogenic factors, such as vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1), respectively. The angiogenic switch mainly depends on the disruption of this balance, in favor of pro-angiogenic factors, and on the recruitment of circulating endothelial progenitors (CEPs) that promote the formation of new blood vessels. Metronomic chemotherapy, the regular intake of doses able to sustain low but active concentrations of chemotherapeutic drugs during protracted time periods, is an encouraging therapeutic approach that has shown to upregulate anti-angiogenic factors such as TSP-1 and decline pro-angiogenic factors such as VEGF, suppressing the proangiogenic cells such as CEPs. In this perspective, metronomic chemotherapy may be one of the available therapeutic approaches capable to modulate favorably the angiogenic tumor dormancy, but further research is essential to better define this particular characteristic.
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Affiliation(s)
- Gianfranco Natale
- Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, and Museo di Anatomia Umana ''Filippo Civinini'', Università di Pisa, Pisa, Italy
| | - Guido Bocci
- Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Pisa, Italy.
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The dosage-dependent effect exerted by the NM23-H1/H2 homolog NDK-1 on distal tip cell migration in C. elegans. J Transl Med 2018; 98:182-189. [PMID: 28920944 DOI: 10.1038/labinvest.2017.99] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 06/12/2017] [Accepted: 06/13/2017] [Indexed: 12/19/2022] Open
Abstract
Abnormal regulation of cell migration and altered rearrangement of the cytoskeleton are fundamental properties of metastatic cells. The first identified metastasis suppressor NM23-H1, which displays nucleoside-diphosphate kinase (NDPK) activity is involved in these processes. NM23-H1 inhibits the migratory and invasive potential of some cancer cells. Correspondingly, numerous invasive cancer cell lines (eg, breast, colon, oral, hepatocellular carcinoma, and melanoma) display low endogenous NM23 levels. In this review, we summarize mechanisms, which are linked to the anti-metastatic activity of NM23. In human cancer cell lines NM23-H1 was shown to regulate cytoskeleton dynamics through inactivation of Rho/Rac-type GTPases. The Drosophila melanogaster NM23 homolog abnormal wing disc (AWD) controls tracheal and border cell migration. The molecular function of AWD is well characterized in both processes as a GTP supplier of Shi/Dynamin whereby AWD regulates the level of chemotactic receptors on the surface of migrating cells through receptor internalization, by its endocytic function. Our group studied the role of the sole group I NDPK, NDK-1 in distal tip cell (DTC) migration in Caenorhabditis elegans. In the absence of NDK-1 the migration of DTCs is incomplete. A half dosage of NDPK as present in ndk-1 (+/-) heterozygotes results in extra turns and overshoots of migrating gonad arms. Conversely, an elevated NDPK level also leads to incomplete gonadal migration owing to a premature stop of DTCs in the third phase of migration, where NDK-1 acts. We propose that NDK-1 exerts a dosage-dependent effect on the migration of DTCs. Our data derived from DTC migration in C. elegans is consistent with data on AWD's function in Drosophila. The combined data suggest that NDPK enzymes control the availability of surface receptors to regulate cell-sensing cues during cell migration. The dosage of NDPKs may be a coupling factor in cell migration by modulating the efficiency of receptor recycling.
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31
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Oncogenic Epstein-Barr virus recruits Nm23-H1 to regulate chromatin modifiers. J Transl Med 2018; 98:258-268. [PMID: 29035376 PMCID: PMC6053075 DOI: 10.1038/labinvest.2017.112] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 08/03/2017] [Accepted: 08/16/2017] [Indexed: 12/17/2022] Open
Abstract
In cancer progression, metastasis is a major cause of poor survival of patients and can be targeted for therapeutic interventions. The first discovered metastatic-suppressor Nm23-H1 possesses nucleoside diphosphate kinase, histidine kinase, and DNase activity as a broad-spectrum enzyme. Recent advances in cancer metastasis have opened new ways for the development of therapeutic molecular approaches. In this review, we provide a summary of the current understanding of Nm23/NDPKs in the context of viral oncogenesis. We also focused on Nm23-H1-mediated cellular events with an emphasis on chromatin modifications. How Nm23-H1 modulates the activities of chromatin modifiers through interaction with Epstein-Barr virus-encoded oncogenic antigens and related crosstalks are discussed in the context of other oncogenic viruses. We also described the current understanding of the cellular and viral interactions of Nm23-H1 and their reference to transcription regulation and metastasis. Further, we summarized the recent therapeutic approaches targeting Nm23 and its potential links to pathways that can be exploited by oncogenic viruses.
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Temporal and regional distribution of initial recurrence site in completely resected N1-stage II lung adenocarcinoma: The effect of postoperative adjuvant chemotherapy. Lung Cancer 2018; 117:7-13. [PMID: 29496256 DOI: 10.1016/j.lungcan.2018.01.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 01/02/2018] [Accepted: 01/05/2018] [Indexed: 11/22/2022]
Abstract
OBJECTIVES Understanding the timing and pattern of cancer recurrence is essential to explain the causes of treatment failure. We investigated the recurrence pattern and rate over time in patients with completely resected N1-stage II lung adenocarcinoma. MATERIALS AND METHODS We retrospectively reviewed the medical records of 333 patients who underwent complete surgical resection for N1-stage II lung adenocarcinoma. RESULTS The median recurrence-free survival (RFS) was 38.8 months and the 5-year RFS rate was 39.6%. Left-sided tumors, large tumor size, and lymph node (LN) ratio higher than 0.15 were significantly correlated with a worse RFS, whereas female sex, direct LN involvement, and adjuvant chemotherapy were significantly correlated with a better RFS. Among the 182 patients who experienced recurrences, 46 (25.3%) had only loco-regional recurrences and 136 (74.7%) had distant metastases. The organs most commonly involved in initial recurrence were the lungs (n = 89, 48.9%), followed by bone (n = 41, 22.5%) and the brain (n = 38, 20.9%). The recurrence hazard curve for the entire study population demonstrated a similarly shaped and sized initial and second peak at 15 and 23 months, and a third smaller peak during the fourth year. The recurrence hazard curve of patients who received adjuvant chemotherapy exhibited a more delayed and smaller first peak than those who did not receive adjuvant chemotherapy. The patients treated with adjuvant chemotherapy had a lower rate of distant metastasis (p = 0.037); adjuvant chemotherapy had no effect on brain metastasis (p = 0.640). CONCLUSION In the present cohort, the hazard curves suggested that bone and brain recurrences exhibited an earlier first peak, while lung recurrences presented later. Adjuvant chemotherapy not only reduced the recurrence hazard but also delayed the recurrence and altered the pattern of recurrence. However, these results need to be confirmed in a prospective study.
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Mahecha AM, Wang H. The influence of vascular endothelial growth factor-A and matrix metalloproteinase-2 and -9 in angiogenesis, metastasis, and prognosis of endometrial cancer. Onco Targets Ther 2017; 10:4617-4624. [PMID: 29033580 PMCID: PMC5614795 DOI: 10.2147/ott.s132558] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Angiogenesis (the growth of new blood vessels) is essential in most of the body’s physiological processes, such as in the normal functioning of the endometrium during and after the menstrual cycle. Vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) are the mostly expressed angiogenic factors, especially, during the process of endometrial degeneration and remodeling. In carcinogenesis, tumor hypoxia-induced factors, through the process of “angiogenic switch”, stimulate the production of angiogenic factors, particularly VEGF and MMP. Subsequently, these angiogenic factors are associated with degradation, differentiation, proliferation, and migration of vascular endothelial cells, enhancing the formation of new blood vessels to supply the tumor with oxygen and nutrients. This process is equally significant for tumor development and metastasis. Hence, like in other cancers, the overexpression of MMP and VEGF in endometrial cancer (EC) seems to play a significant role in its tumorigenesis and metastasis. This research will discuss the influence of MMP and VEGF on angiogenesis, metastasis, and the prognosis of EC as well as the clinical importance of the factors in the diagnosis of EC.
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Affiliation(s)
- Anna M Mahecha
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hongbo Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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34
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Manjili MH. Tumor Dormancy and Relapse: From a Natural Byproduct of Evolution to a Disease State. Cancer Res 2017; 77:2564-2569. [PMID: 28507050 PMCID: PMC5459601 DOI: 10.1158/0008-5472.can-17-0068] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 02/22/2017] [Accepted: 03/10/2017] [Indexed: 12/24/2022]
Abstract
Species evolve by mutations and epigenetic changes acting on individuals in a population; tumors evolve by similar mechanisms at a cellular level in a tissue. This article reviews growing evidence about tumor dormancy and suggests that (i) cellular malignancy is a natural byproduct of evolutionary mechanisms, such as gene mutations and epigenetic modifications, which is manifested in the form of tumor dormancy in healthy individuals as well as in cancer survivors; (ii) cancer metastasis could be an early dissemination event that could occur during malignant dormancy even before primary cancer is clinically detectable; and (iii) chronic inflammation is a key factor in awakening dormant malignant cells at the primary site, leading to primary cancer development, and at distant sites, leading to advanced stage diseases. On the basis of this evidence, it is reasonable to propose that we are all cancer survivors rather than cancer-free individuals because of harboring dormant malignant cells in our organs. A better understanding of local and metastatic tumor dormancy could lead to novel cancer therapeutics for the prevention of cancer. Cancer Res; 77(10); 2564-9. ©2017 AACR.
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Affiliation(s)
- Masoud H Manjili
- Department of Microbiology & Immunology, VCU School of Medicine, Massey Cancer Center, Richmond, Virginia.
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35
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Sun X, Liu X. Cancer metastasis: enactment of the script for human reproductive drama. Cancer Cell Int 2017; 17:51. [PMID: 28469531 PMCID: PMC5414196 DOI: 10.1186/s12935-017-0421-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 04/24/2017] [Indexed: 12/14/2022] Open
Abstract
Based on compelling evidence from many biological disciplines, we put forth a hypothesis for cancer metastasis. In the hypothesis, the metastatic cascade is depicted as human reproduction in miniature. Illustrated in a reproductive light, the staggering resemblance of cancer metastasis to human reproduction becomes evident despite some ostensible dis-similarities. In parallel to the appearance of primordial germ cells during early embryogenesis, the cancer reproductive saga starts with the separation of metastasis initiating cells (MICs) from cancer initiating cells when the primary cancer is still in its infancy. Prime MICs embark on a journey to the host bone marrow where they undergo further development and regulation. Migrating MICs are guided by the same CXCR4/CYCL12 axis as used in the migration of primordial germ cells to the genital ridge. Like the ovary, the host bone marrow features immune privileges, coolness, hypoxia and acidity which are essential for stemness maintenance and regulation. Opportune activation of the MICs via fusion with bone marrow stem cells triggers a frenzy of cellular proliferation and sets them on the move again. This scenario is akin to oocyte fertilization in the Fallopian tube and its subsequent journey towards the decidum. Just as the human reproductive process is plagued with undesirable outcomes so is the cancer metastasis highly inefficient. The climax of the cancer metastatic drama (colonization) is reached when proliferating MIC clusters attempt to settle down on decidum-like premetastatic sites. Successfully colonized clusters blossom into overt macrometastases only after the execution of sophisticated immunomodulation, angiogenesis and vascular remodeling. Similarly, the implanted blastomere needs to orchestrate these feats before flourishing into a new life. What is more, the cancer reproductive drama seems to be directed by a primordial hypothalamus–pituitary–gonad axis. Pursuing this reproductive trail could lead to new frontiers and breakthroughs in cancer research and therapeutics.
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Affiliation(s)
- Xichun Sun
- Department of Pathology and Laboratory Medicine, McGuire Holmes Veteran Affairs Medical Center, School of Medicine, Virginia Commonwealth University, 1201 Broad Rock Boulevard, Richmond, VA 23249 USA.,Department of Hepatobiliary Surgery, People's Hospital of Hunan Province, Hunan, China
| | - Xiwu Liu
- Department of Pathology and Laboratory Medicine, McGuire Holmes Veteran Affairs Medical Center, School of Medicine, Virginia Commonwealth University, 1201 Broad Rock Boulevard, Richmond, VA 23249 USA.,Department of Hepatobiliary Surgery, People's Hospital of Hunan Province, Hunan, China
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36
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Mechanisms governing metastatic dormancy in breast cancer. Semin Cancer Biol 2017; 44:72-82. [PMID: 28344165 DOI: 10.1016/j.semcancer.2017.03.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 03/17/2017] [Accepted: 03/21/2017] [Indexed: 02/07/2023]
Abstract
Breast cancer is a systemic disease characterized by early dissemination of tumor cells to distant organs. In this foreign environment, tumor cells may stay in a dormant state as single cells or as micrometastases for many years before growing out into a macrometastatic lesion. As metastasis is the primary cause for breast cancer-related death, it is important to understand the mechanisms underlying the maintenance of dormancy and dormancy escape to find druggable targets to eradicate metastatic tumor cells. Metastatic dormancy is regulated by complex interactions between tumor cells and the local microenvironment. In addition, cancer-directed immunity and systemic instigation play a crucial role.
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Wang C, Saji M, Justiniano SE, Yusof AM, Zhang X, Yu L, Fernández S, Wakely P, La Perle K, Nakanishi H, Pohlman N, Ringel MD. RCAN1-4 is a thyroid cancer growth and metastasis suppressor. JCI Insight 2017; 2:e90651. [PMID: 28289712 DOI: 10.1172/jci.insight.90651] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Metastasis suppressors are key regulators of tumor growth, invasion, and metastases. Loss of metastasis suppressors has been associated with aggressive tumor behaviors and metastatic progression. We previously showed that regulator of calcineurin 1, isoform 4 (RCAN1-4) was upregulated by the KiSS1 metastatic suppression pathway and could inhibit cell motility when overexpressed in cancer cells. To test the effects of endogenous RCAN1-4 loss on thyroid cancer in vivo, we developed RCAN1-4 knockdown stable cells. Subcutaneous xenograft models demonstrated that RCAN1-4 knockdown promotes tumor growth. Intravenous metastasis models demonstrated that RCAN1-4 loss promotes tumor metastases to the lungs and their subsequent growth. Finally, stable induction of RCAN1-4 expression reduced thyroid cancer cell growth and invasion. Microarray analysis predicted that nuclear factor, erythroid 2-like 3 (NFE2L3) was a pivotal downstream effector of RCAN1-4. NFE2L3 overexpression was shown to be necessary for RCAN1-4-mediated enhanced growth and invasiveness and NEF2L3 overexpression independently increased cell invasion. In human samples, NFE2L3 was overexpressed in TCGA thyroid cancer samples versus normal tissues and NFE2L3 overexpression was demonstrated in distant metastasis samples from thyroid cancer patients. In conclusion, we provide the first evidence to our knowledge that RCAN1-4 is a growth and metastasis suppressor in vivo and that it functions in part through NFE2L3.
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Affiliation(s)
- Chaojie Wang
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.,Ohio State Biochemistry Program
| | - Motoyasu Saji
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine
| | - Steven E Justiniano
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine
| | - Adlina Mohd Yusof
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine
| | - Xiaoli Zhang
- Center for Biostatistics, Department of Biomedical Informatics
| | - Lianbo Yu
- Center for Biostatistics, Department of Biomedical Informatics
| | | | | | - Krista La Perle
- Department of Veterinary Biosciences and Comparative Pathology and Mouse Phenotyping Shared Resource, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Hiroshi Nakanishi
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine
| | - Neal Pohlman
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine
| | - Matthew D Ringel
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.,Ohio State Biochemistry Program
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Tubeimoside-1 suppresses tumor angiogenesis by stimulation of proteasomal VEGFR2 and Tie2 degradation in a non-small cell lung cancer xenograft model. Oncotarget 2017; 7:5258-72. [PMID: 26701724 PMCID: PMC4868684 DOI: 10.18632/oncotarget.6676] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 12/07/2015] [Indexed: 12/29/2022] Open
Abstract
Tubeimoside-1 (TBMS1) is a potent anti-tumor phytochemical. Its functional and molecular mode of action, however, remains elusive so far. Since angiogenesis is essential for tumor progression and metastasis, we herein investigated the anti-angiogenic effects of the compound. In a non-small cell lung cancer (NSCLC) xenograft model we found that treatment of CD1 nu/nu mice with TBMS1 (5 mg/kg) significantly suppressed the growth and vascularization of NCI-H460 flank tumors. Moreover, TBMS1 dose-dependently reduced vascular sprouting in a rat aortic ring assay. In vitro, TBMS1 induced endothelial cell apoptosis without decreasing the viability of NSCLC tumor cells and inhibited the migration of endothelial cells by disturbing their actin filament organization. TBMS1 further stimulated the proteasomal degradation of vascular endothelial growth factor receptor-2 (VEGFR2) and Tie2 in endothelial cells, which down-regulated AKT/mTOR signaling. These findings indicate that TBMS1 represents a novel phytochemical for anti-angiogenic treatment of cancer and other angiogenesis-related diseases.
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Abstract
Tumor dormancy is one of the stages in tumor development without clinical symptoms. Tumor dormant cells may appear in early stages of tumor development, as well as in micrometastasis and minimal residual disease. The mechanism for the switch of dormant cells between quiescent and proliferative stages is still largely unknown. Potential mechanisms that may account for the transition between dormant tumor cells and proliferative cells include angiogenesis, immune response, cellular factors, and signaling pathways. The clinical and therapeutic importance of dormant cells requires further studies to provide therapeutic strategies for inhibition of metastasis and tumor recurrence.
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40
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Hu KL, Zhao H, Chang HM, Yu Y, Qiao J. Kisspeptin/Kisspeptin Receptor System in the Ovary. Front Endocrinol (Lausanne) 2017; 8:365. [PMID: 29354093 PMCID: PMC5758547 DOI: 10.3389/fendo.2017.00365] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 12/13/2017] [Indexed: 12/26/2022] Open
Abstract
Kisspeptins are a family of neuropeptides that are critical for initiating puberty and regulating ovulation in sexually mature females via the central control of the hypothalamic-pituitary-gonadal axis. Recent studies have shown that kisspeptin and its receptor kisspeptin receptor (KISS1R) are expressed in the mammalian ovary. Convincing evidence indicates that kisspeptins can activate a wide variety of signals via its binding to KISS1R. Experimental data gathered recently suggest a putative role of kisspeptin signaling in the direct control of ovarian function, including follicular development, oocyte maturation, steroidogenesis, and ovulation. Dysregulation or naturally occurring mutations of the kisspeptin/KISS1R system may negatively affect the ovarian function, leading to reproductive pathology or female infertility. A comprehensive understanding of the expression, actions, and underlying molecular mechanisms of this system in the human ovary is essential for novel approaches to therapeutic and diagnostic interventions in reproductive diseases and infertility.
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Affiliation(s)
- Kai-Lun Hu
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Hongcui Zhao
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- *Correspondence: Hongcui Zhao, ; Yang Yu,
| | - Hsun-Ming Chang
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Yang Yu
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- *Correspondence: Hongcui Zhao, ; Yang Yu,
| | - Jie Qiao
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
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41
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Blaschuk OW. N-cadherin antagonists as oncology therapeutics. Philos Trans R Soc Lond B Biol Sci 2015; 370:20140039. [PMID: 25533096 DOI: 10.1098/rstb.2014.0039] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The cell adhesion molecule (CAM), N-cadherin, has emerged as an important oncology therapeutic target. N-cadherin is a transmembrane glycoprotein mediating the formation and structural integrity of blood vessels. Its expression has also been documented in numerous types of poorly differentiated tumours. This CAM is involved in regulating the proliferation, survival, invasiveness and metastasis of cancer cells. Disruption of N-cadherin homophilic intercellular interactions using peptide or small molecule antagonists is a promising novel strategy for anti-cancer therapies. This review discusses: the discovery of N-cadherin, the mechanism by which N-cadherin promotes cell adhesion, the role of N-cadherin in blood vessel formation and maintenance, participation of N-cadherin in cancer progression, the different types of N-cadherin antagonists and the use of N-cadherin antagonists as anti-cancer drugs.
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Affiliation(s)
- Orest W Blaschuk
- Division of Urology, Department of Surgery, McGill University, Montreal, Quebec, Canada H3A 1A1
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42
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Friberg S, Nyström A. Cancer Metastases: Early Dissemination and Late Recurrences. CANCER GROWTH AND METASTASIS 2015; 8:43-9. [PMID: 26640389 PMCID: PMC4664198 DOI: 10.4137/cgm.s31244] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/01/2015] [Accepted: 09/03/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Metastatic cells from a primary tumor can occur before the primary cancer is detected. Metastatic cells can also remain in the patient for many years after removal of the primary tumor without proliferating. These dormant malignant cells can awaken and cause recurrent disease decades after the primary treatment. The purpose of this article is to review the clinical evidence for early dissemination and late recurrences in human malignant tumors. We used the following definitions: dormancy of cells may be defined as a nonproliferating state or an arrest in the cell cycle that results in a prolonged G0 phase. If one accepts the term "late metastases" to indicate a period exceeding 10 years from the removal of the primary tumor, then the two malignancies in which this occurs most frequently are cutaneous malignant melanoma (CMM) and renal cell carcinoma (RCC). METHODS PubMed, Web of Science, and Scopus were searched with the keywords "metastases," "early dissemination," "late recurrences," "inadvertently transmitted cancer," "tumor growth rate," "dormancy," "circulating tumor cells," and "transplantation of cancer." RESULTS Several case reports of early dissemination and late recurrences of various types of malignancies were found. Analyses of the growth rates of several malignant tumors in the original host indicated that the majority of cancers had metastasized years before they were detected. CMM, RCC, and malignant glioblastoma were the three most common malignancies resulting from an organ transplantation. CMM and RCC were also the two most common malignancies that showed dormancy. In several cases of transplanted CMM and RCC, the donor did not have any known malignancy or had had the malignancy removed so long ago that the donor was regarded as cured. CONCLUSION (1) Metastases can frequently exist prior to the detection of the primary tumor. (2) Metastatic cells may reside in organs in the original host that are not usually the site of detectable secondary tumors, for example, the kidneys and heart. (3) Metastatic cells remain dormant for decades after the primary tumor has been removed. (4) Dormancy might be reversible and lead to late recurrences.
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Affiliation(s)
- Sten Friberg
- Swedish Medical Nanoscience Centre, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Andreas Nyström
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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43
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In vivo quantification of cochlin in glaucomatous DBA/2J mice using optical coherence tomography. Sci Rep 2015; 5:11092. [PMID: 26047051 PMCID: PMC4457137 DOI: 10.1038/srep11092] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 04/28/2015] [Indexed: 11/24/2022] Open
Abstract
The expression of cochlin in the trabecular meshwork (TM) precedes the clinical
glaucoma symptoms in DBA/2J mice. The ability to quantify cochlin in the local
tissue (TM) offers potential diagnostic and prognostic values. We present two
(spectroscopic and magnetomotive) optical coherence tomography (OCT) approaches for
in vivo cochlin quantification in a periodic manner. The cochlin-antibody
OCT signal remains stable for up to 24 hours as seen at
3.5 hours after injection allowing for repeated quantification in the
living mouse eyes.
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44
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Morales M, Arenas EJ, Urosevic J, Guiu M, Fernández E, Planet E, Fenwick RB, Fernández-Ruiz S, Salvatella X, Reverter D, Carracedo A, Massagué J, Gomis RR. RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation. EMBO Mol Med 2015; 6:865-81. [PMID: 24867881 PMCID: PMC4119352 DOI: 10.15252/emmm.201303675] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme.
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Affiliation(s)
- Mònica Morales
- Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
| | - Enrique J Arenas
- Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
| | - Jelena Urosevic
- Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
| | - Marc Guiu
- Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
| | - Esther Fernández
- Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
| | - Evarist Planet
- Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
| | - Robert Bryn Fenwick
- Joint BSC-IRB Research Programme in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
| | | | - Xavier Salvatella
- Joint BSC-IRB Research Programme in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - David Reverter
- Departament de Bioquímica i de Biologia Molecular, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Arkaitz Carracedo
- CIC bioGUNE Bizkaia Tecnology park, Derio, Spain Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain Ikerbasque Basque Foundation for Science, Bilbao, Spain
| | - Joan Massagué
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Roger R Gomis
- Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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45
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Wikman H, Westphal L, Schmid F, Pollari S, Kropidlowski J, Sielaff-Frimpong B, Glatzel M, Matschke J, Westphal M, Iljin K, Huhtala H, Terracciano L, Kallioniemi A, Sauter G, Müller V, Witzel I, Lamszus K, Kemming D, Pantel K. Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients. Oncotarget 2015; 5:3076-87. [PMID: 24833255 PMCID: PMC4102793 DOI: 10.18632/oncotarget.1832] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Breast cancer brain metastases (BCBM) are detected with increasing incidence. In order to detect potential genes involved in BCBM, we first screened for genes down-regulated by methylation in cell lines with site-specific metastatic ability. The expression of five genes, CADM1, SPARC, RECK, TNFAIP3 and CXCL14, which were also found down-regulated in gene expression profiling analyses of BCBM tissue samples, was verified by qRT-PCR in a larger patient cohort. CADM1 was chosen for further down-stream analyses. A higher incidence of CADM1 methylation, correlating with lower expression levels, was found in BCBM as compared to primary BC. Loss of CADM1 protein expression was detected most commonly among BCBM samples as well as among primary tumors with subsequent brain relapse. The prognostic role of CADM1 expression was finally verified in four large independent breast cancer cohorts (n=2136). Loss of CADM1 protein expression was associated with disease stage, lymph node status, and tumor size in primary BC. Furthermore, all analyses revealed a significant association between loss of CADM1 and shorter survival. In multivariate analyses, survival was significantly shorter among patients with CADM1-negative tumors. Loss of CADM1 expression is an independent prognostic factor especially associated with the development of brain metastases in breast cancer patients.
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Affiliation(s)
- Harriet Wikman
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Popescu NC, Goodison S. Deleted in liver cancer-1 (DLC1): an emerging metastasis suppressor gene. Mol Diagn Ther 2015; 18:293-302. [PMID: 24519699 DOI: 10.1007/s40291-014-0086-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
While significant progress continues to be made in the early detection and therapeutic management of primary tumors, the incidence of metastatic disease remains the major cause of mortality. Accordingly, the development of novel effective therapies that can ameliorate dissemination and secondary tumor growth are a clinical priority. The identification of genetic and functional alterations in cancer cells that affect factors implicated in the metastatic process is critical for designing preventive and therapeutic strategies. Evidence implicating the protein deleted in liver cancer-1 (DLC1), a Rho GTPase activator, in metastasis has accumulated to a point where DLC1 may be considered as a metastasis suppressor gene. This review presents evidence supporting an anti-metastatic role for DLC1 in several human cancers and discusses the mechanisms contributing to its inhibitory effects. In addition, promising opportunities for therapeutic interventions based on DLC1 function and downstream pathways involved in the metastatic process are considered.
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Affiliation(s)
- Nicholas C Popescu
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, Building 37, Room 4140, 37 Convent Dr., MSC 4262, Bethesda, MD, 20892-4262, USA,
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47
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Wu YY, V. Nguyen A, Wu XX, Loh M, Vu M, Zou Y, Liu Q, Guo P, Wang Y, Montgomery LL, Orlofsky A, Rand JH, Lin EY. Antiphospholipid Antibodies Promote Tissue Factor–Dependent Angiogenic Switch and Tumor Progression. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:3359-75. [DOI: 10.1016/j.ajpath.2014.07.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 07/22/2014] [Accepted: 07/29/2014] [Indexed: 12/30/2022]
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48
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Lim EK, Kim T, Paik S, Haam S, Huh YM, Lee K. Nanomaterials for Theranostics: Recent Advances and Future Challenges. Chem Rev 2014; 115:327-94. [DOI: 10.1021/cr300213b] [Citation(s) in RCA: 916] [Impact Index Per Article: 83.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Eun-Kyung Lim
- Department
of Radiology, Yonsei University, Seoul 120-752, Korea
- BioNanotechnology
Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea
| | - Taekhoon Kim
- Department
of Chemistry, Korea University, Seoul 136-701, Korea
- Electronic
Materials Laboratory, Samsung Advanced Institute of Technology, Mt. 14-1,
Nongseo-Ri, Giheung-Eup, Yongin-Si, Gyeonggi-Do 449-712, Korea
| | - Soonmyung Paik
- Severance
Biomedical Research Institute, Yonsei University College of Medicine, Seoul 120-749, Korea
- Division
of Pathology, NSABP Foundation, Pittsburgh, Pennsylvania 15212, United States
| | - Seungjoo Haam
- Department
of Chemical and Biomolecular Engineering, Yonsei University, Seoul 120-749, Korea
| | - Yong-Min Huh
- Department
of Radiology, Yonsei University, Seoul 120-752, Korea
| | - Kwangyeol Lee
- Department
of Chemistry, Korea University, Seoul 136-701, Korea
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49
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Aoun F, Peltier A, van Velthoven R. A comprehensive review of contemporary role of local treatment of the primary tumor and/or the metastases in metastatic prostate cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:501213. [PMID: 25485280 PMCID: PMC4251412 DOI: 10.1155/2014/501213] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 09/09/2014] [Indexed: 01/09/2023]
Abstract
To provide an overview of the currently available literature regarding local control of primary tumor and oligometastases in metastatic prostate cancer and salvage lymph node dissection of clinical lymph node relapse after curative treatment of prostate cancer. Evidence Acquisition. A systematic literature search was conducted in 2014 to identify abstracts, original articles, review articles, research articles, and editorials relevant to the local control in metastatic prostate cancer. Evidence Synthesis. Local control of primary tumor in metastatic prostate cancer remains experimental with low level of evidence. The concept is supported by a growing body of genetic and molecular research as well as analogy with other cancers. There is only one retrospective observational population based study showing prolonged survival. To eradicate oligometastases, several options exist with excellent local control rates. Stereotactic body radiotherapy is safe, well tolerated, and efficacious treatment for lymph node and bone lesions. Both biochemical and clinical progression are slowed down with a median time to initiate ADT of 2 years. Salvage lymph node dissection is feasible in patients with clinical lymph node relapse after local curable treatment. Conclusion. Despite encouraging oncologic midterm results, a complete cure remains elusive in metastatic prostate cancer patients. Further advances in imaging are crucial in order to rapidly evolve beyond the proof of concept.
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Affiliation(s)
- Fouad Aoun
- Department of Urology, Jules Bordet Institute, 1 Héger-Bordet Street, 1000 Brussels, Belgium
- Université Libre de Bruxelles, 50 Franklin Roosevelt Avenue, 1050 Brussels, Belgium
| | - Alexandre Peltier
- Department of Urology, Jules Bordet Institute, 1 Héger-Bordet Street, 1000 Brussels, Belgium
- Université Libre de Bruxelles, 50 Franklin Roosevelt Avenue, 1050 Brussels, Belgium
| | - Roland van Velthoven
- Department of Urology, Jules Bordet Institute, 1 Héger-Bordet Street, 1000 Brussels, Belgium
- Université Libre de Bruxelles, 50 Franklin Roosevelt Avenue, 1050 Brussels, Belgium
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50
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Viger L, Denis F, Rosalie M, Letellier C. A cancer model for the angiogenic switch. J Theor Biol 2014; 360:21-33. [DOI: 10.1016/j.jtbi.2014.06.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 06/04/2014] [Accepted: 06/17/2014] [Indexed: 11/28/2022]
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