|
1
|
Aplin AC, Aghazadeh Y, Mohn OG, Hull-Meichle RL. Role of the Pancreatic Islet Microvasculature in Health and Disease. J Histochem Cytochem 2024; 72:711-728. [PMID: 39601198 PMCID: PMC11600425 DOI: 10.1369/00221554241299862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
The pancreatic islet vasculature comprises microvascular endothelial cells surrounded by mural cells (pericytes). Both cell types support the islet by providing (1) a conduit for delivery and exchange of nutrients and hormones; (2) paracrine signals and extracellular matrix (ECM) components that support islet development, architecture, and endocrine function; and (3) a barrier against inflammation and immune cell infiltration. In type 2 diabetes, the islet vasculature becomes inflamed, showing loss of endothelial cells, detachment, and/or trans-differentiation of pericytes, vessel dilation, and excessive ECM deposition. While most work to date has focused either on endothelial cells or pericytes in isolation, it is very likely that the interaction between these cell types and disruption of that interaction in diabetes are critically important. In fact, dissociation of pericytes from endothelial cells is an early, key feature of microvascular disease in multiple tissues/disease states. Moreover, in beta-cell replacement therapy, co-transplantation with microvessels versus endothelial cells alone is substantially more effective in improving survival and function of the transplanted cells. Ongoing studies, including characterization of islet vascular cell signatures, will aid in the identification of new therapeutic targets aimed at improving islet function and benefiting people living with all forms of diabetes.
Collapse
Affiliation(s)
- Alfred C. Aplin
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Yasaman Aghazadeh
- Institut de Recherches Cliniques de Montreal (IRCM), Department of Medicine, University of Montreal, and Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Olivia G. Mohn
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Rebecca L. Hull-Meichle
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington; and Alberta Diabetes Institute and Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
2
|
Seo S, Kim YA, Lee Y, Kim YJ, Kim BJ, An JH, Jin H, Do AR, Park K, Won S, Seo JH. Epigenetic link between Agent Orange exposure and type 2 diabetes in Korean veterans. Front Endocrinol (Lausanne) 2024; 15:1375459. [PMID: 39072272 PMCID: PMC11272593 DOI: 10.3389/fendo.2024.1375459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 06/24/2024] [Indexed: 07/30/2024] Open
Abstract
Conflicting findings have been reported regarding the association between Agent Orange (AO) exposure and type 2 diabetes. This study aimed to examine whether AO exposure is associated with the development of type 2 diabetes and to verify the causal relationship between AO exposure and type 2 diabetes by combining DNA methylation with DNA genotype analyses. An epigenome-wide association study and DNA genotype analyses of the blood of AO-exposed and AO-unexposed individuals with type 2 diabetes and that of healthy controls were performed. Methylation quantitative trait locus and Mendelian randomisation analyses were performed to evaluate the causal effect of AO-exposure-identified CpGs on type 2 diabetes. AO-exposed individuals with type 2 diabetes were associated with six hypermethylated CpG sites (cg20075319, cg21757266, cg05203217, cg20102280, cg26081717, and cg21878650) and one hypo-methylated CpG site (cg07553761). Methylation quantitative trait locus analysis showed the methylation levels of some CpG sites (cg20075319, cg20102280, and cg26081717) to be significantly different. Mendelian randomisation analysis showed that CpG sites that were differentially methylated in AO-exposed individuals were causally associated with type 2 diabetes; the reverse causal effect was not significant. These findings reflect the need for further epigenetic studies on the causal relationship between AO exposure and type 2 diabetes.
Collapse
Affiliation(s)
- Sujin Seo
- Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
| | - Ye An Kim
- Division of Endocrinology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Republic of Korea
| | - Young Lee
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea
| | - Young Jin Kim
- Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju-si, Republic of Korea
| | - Bong-Jo Kim
- Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju-si, Republic of Korea
| | - Jae Hoon An
- Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea
| | - Heejin Jin
- Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea
| | - Ah Ra Do
- Interdisciplinary Program of Bioinformatics, College of National Sciences, Seoul National University, Seoul, Republic of Korea
| | - Kyungtaek Park
- Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea
| | - Sungho Won
- Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
- Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea
- Interdisciplinary Program of Bioinformatics, College of National Sciences, Seoul National University, Seoul, Republic of Korea
| | - Je Hyun Seo
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea
| |
Collapse
|
|
3
|
De Palma M, Hanahan D. Milestones in tumor vascularization and its therapeutic targeting. NATURE CANCER 2024; 5:827-843. [PMID: 38918437 DOI: 10.1038/s43018-024-00780-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 04/22/2024] [Indexed: 06/27/2024]
Abstract
Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future.
Collapse
Affiliation(s)
- Michele De Palma
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
| | - Douglas Hanahan
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
| |
Collapse
|
|
4
|
Zhang X, Ma H, Gao Y, Liang Y, Du Y, Hao S, Ni T. The Tumor Microenvironment: Signal Transduction. Biomolecules 2024; 14:438. [PMID: 38672455 PMCID: PMC11048169 DOI: 10.3390/biom14040438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
In the challenging tumor microenvironment (TME), tumors coexist with diverse stromal cell types. During tumor progression and metastasis, a reciprocal interaction occurs between cancer cells and their environment. These interactions involve ongoing and evolving paracrine and proximal signaling. Intrinsic signal transduction in tumors drives processes such as malignant transformation, epithelial-mesenchymal transition, immune evasion, and tumor cell metastasis. In addition, cancer cells embedded in the tumor microenvironment undergo metabolic reprogramming. Their metabolites, serving as signaling molecules, engage in metabolic communication with diverse matrix components. These metabolites act as direct regulators of carcinogenic pathways, thereby activating signaling cascades that contribute to cancer progression. Hence, gaining insights into the intrinsic signal transduction of tumors and the signaling communication between tumor cells and various matrix components within the tumor microenvironment may reveal novel therapeutic targets. In this review, we initially examine the development of the tumor microenvironment. Subsequently, we delineate the oncogenic signaling pathways within tumor cells and elucidate the reciprocal communication between these pathways and the tumor microenvironment. Finally, we give an overview of the effect of signal transduction within the tumor microenvironment on tumor metabolism and tumor immunity.
Collapse
Affiliation(s)
- Xianhong Zhang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China; (X.Z.); (Y.G.); (Y.L.); (Y.D.)
| | - Haijun Ma
- Key Laboratory of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, China;
| | - Yue Gao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China; (X.Z.); (Y.G.); (Y.L.); (Y.D.)
| | - Yabing Liang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China; (X.Z.); (Y.G.); (Y.L.); (Y.D.)
| | - Yitian Du
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China; (X.Z.); (Y.G.); (Y.L.); (Y.D.)
| | - Shuailin Hao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China; (X.Z.); (Y.G.); (Y.L.); (Y.D.)
| | - Ting Ni
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China; (X.Z.); (Y.G.); (Y.L.); (Y.D.)
| |
Collapse
|
|
5
|
Andriolo LG, Cammisotto V, Spagnoli A, Alunni Fegatelli D, Chicone M, Di Rienzo G, Dell’Anna V, Lobreglio G, Serio G, Pignatelli P. Overview of angiogenesis and oxidative stress in cancer. World J Meta-Anal 2023; 11:253-265. [DOI: 10.13105/wjma.v11.i6.253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/07/2023] [Accepted: 07/10/2023] [Indexed: 09/13/2023] Open
Abstract
Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions. Therefore, they promote angiogenesis through the same neovascularization pathway used physiologically. Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress; the latter being one of the most powerful stimuli of angiogenesis. As a result of altered tumor metabolism due to hypoxia, acidosis occurs. The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers. The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers, ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies. In particular, in the treatment of patients with similar clinical tumor phenotypes but different prognoses, the new biomarkers could be useful. Moreover, they may lead to a better understanding of the mechanisms underlying drug resistance. Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells, which require a high vascular supply.
Collapse
Affiliation(s)
- Luigi Gaetano Andriolo
- Department of General and Specialistic Surgery Paride Stefanini, Policlinico Umberto I, University of Rome Sapienza, Rome 06100, Italy
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
| | - Alessandra Spagnoli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Danilo Alunni Fegatelli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Michele Chicone
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Gaetano Di Rienzo
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | | | - Giambattista Lobreglio
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Giovanni Serio
- Pathological Anatomy Unit, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
| |
Collapse
|
|
6
|
Mosalem O, Sonbol MB, Halfdanarson TR, Starr JS. Tyrosine Kinase Inhibitors and Immunotherapy Updates in Neuroendocrine Neoplasms. Best Pract Res Clin Endocrinol Metab 2023; 37:101796. [PMID: 37414652 DOI: 10.1016/j.beem.2023.101796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/08/2023]
Abstract
Neuroendocrine tumors (NETs) represent a heterogeneous group of malignancies that arise from neuroendocrine cells dispersed throughout the organs/tissues of the body. Treatment of advanced/metastatic disease varies depending on tumor origin and grade. Somatostatin analogs (SSA) have been the mainstay first-line treatment in the advanced/metastatic setting for tumor control and managing hormonal syndromes. Treatments beyond SSAs have expanded to include everolimus (mTOR inhibitor), tyrosine kinase inhibitors (TKI) (e.g., sunitinib), and peptide receptor radionuclide therapy (PRRT) with the choice of therapy to some extent dictated by the anatomic origin of the NETs. This review will focus on emerging systemic treatments for advanced/metastatic NETs, particularly TKIs, and immunotherapy.
Collapse
Affiliation(s)
- Osama Mosalem
- Division of Hematology and Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA.
| | | | | | - Jason S Starr
- Division of Hematology and Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA.
| |
Collapse
|
|
7
|
de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023; 41:374-403. [PMID: 36917948 DOI: 10.1016/j.ccell.2023.02.016] [Citation(s) in RCA: 1392] [Impact Index Per Article: 696.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/28/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023]
Abstract
Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. The cellular composition and functional state of the TME can differ extensively depending on the organ in which the tumor arises, the intrinsic features of cancer cells, the tumor stage, and patient characteristics. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments.
Collapse
Affiliation(s)
- Karin E de Visser
- Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
| | - Johanna A Joyce
- Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, 1011 Lausanne, Switzerland; Agora Cancer Center Lausanne, and Swiss Cancer Center Léman, 1011 Lausanne, Switzerland.
| |
Collapse
|
|
8
|
Gaspar TB, Lopes JM, Soares P, Vinagre J. An update on genetically engineered mouse models of pancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2022; 29:R191-R208. [PMID: 36197786 DOI: 10.1530/erc-22-0166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/29/2022] [Indexed: 11/09/2022]
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are rare and clinically challenging entities. At the molecular level, PanNENs' genetic profile is well characterized, but there is limited knowledge regarding the contribution of the newly identified genes to tumor initiation and progression. Genetically engineered mouse models (GEMMs) are the most versatile tool for studying the plethora of genetic variations influencing PanNENs' etiopathogenesis and behavior over time. In this review, we present the state of the art of the most relevant PanNEN GEMMs available and correlate their findings with the human neoplasms' counterparts. We discuss the historic GEMMs as the most used and with higher translational utility models. GEMMs with Men1 and glucagon receptor gene germline alterations stand out as the most faithful models in recapitulating human disease; RIP-Tag models are unique models of early-onset, highly vascularized, invasive carcinomas. We also include a section of the most recent GEMMs that evaluate pathways related to cell cycle and apoptosis, Pi3k/Akt/mTOR, and Atrx/Daxx. For the latter, their tumorigenic effect is heterogeneous. In particular, for Atrx/Daxx, we will require more in-depth studies to evaluate their contribution; even though they are prevalent genetic events in PanNENs, they have low/inexistent tumorigenic capacity per se in GEMMs. Researchers planning to use GEMMs can find a road map of the main clinical features in this review, presented as a guide that summarizes the chief milestones achieved. We identify pitfalls to overcome, concerning the novel designs and standardization of results, so that future models can replicate human disease more closely.
Collapse
Affiliation(s)
- Tiago Bordeira Gaspar
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto, Porto, Portugal
- FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - José Manuel Lopes
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Department of Pathology, Centro Hospitalar e Universitário de São João, Porto, Portugal
| | - Paula Soares
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - João Vinagre
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
9
|
Lauricella E, Mandriani B, Cavallo F, Pezzicoli G, Chaoul N, Porta C, Cives M. Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications. Front Oncol 2022; 12:957068. [PMID: 36059642 PMCID: PMC9428554 DOI: 10.3389/fonc.2022.957068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are highly vascularized malignancies arising from cells of the diffuse neuroendocrine system. An intricated cross-talk exists between NEN cells and the tumor microenvironment, and three main molecular circuits (VEGF/VEGFR pathway, FGF-dependent signaling and PDGF/PDGFR axis) have been shown to regulate angiogenesis in these neoplasms. Multiple randomized trials have investigated antiangiogenic agents over the past two decades, and sunitinib is currently approved for the treatment of advanced, progressive, G1/G2 pancreatic NENs. In recent years, two phase III clinical trials have demonstrated the efficacy and safety of surufatinib, a multi-tyrosine kinase angioimmune inhibitor, in patients with well-differentiated pancreatic and extrapancreatic NENs, and two studies of this agent are currently underway in Europe and US. The HIF-2α inhibitor belzutifan has recently received regulatory approval for the treatment of tumors arising in the context of Von-Hippel Lindau syndrome including pancreatic NENs, and a study of this drug in patients with sporadic tumors is presently ongoing. Combinations of antiangiogenic agents with chemotherapeutics and targeted drugs have been tested, with accumulating toxicities being a matter of concern. The potential of antiangiogenic agents in fine-tuning the immune microenvironment of NENs to enhance the activity of immune checkpoint inhibitors has been only partially elucidated, and further research should be carried out at this regard. Here, we review the current understanding of the biology of angiogenesis in NENs and provide a summary of the latest clinical investigations on antiangiogenic drugs in this malignancy.
Collapse
Affiliation(s)
- Eleonora Lauricella
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Barbara Mandriani
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Federica Cavallo
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Gaetano Pezzicoli
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Nada Chaoul
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Camillo Porta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Mauro Cives
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
- *Correspondence: Mauro Cives,
| |
Collapse
|
|
10
|
Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14153799. [PMID: 35954462 PMCID: PMC9367608 DOI: 10.3390/cancers14153799] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Metabolism plays a fundamental role in both human physiology and pathology, including pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do not only have energetic implications but are tightly associated with other cellular activities, such as DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype and the observed reduction in tumor growth induced by calorie restriction with in vivo models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC might, therefore, be reduced by interventions on bioenergetic circuits. In this review, we describe the main metabolic mechanisms involved in PDAC growth and the biological features that may favor its onset and progression within an immunometabolic context. We also discuss the need to bridge the gap between basic research and clinical practice in order to offer alternative therapeutic approaches for PDAC patients in the more immediate future.
Collapse
|
|
11
|
Zhang Y, Lan W, Wang C, Xue H, Cao C. Dimeric G‐quadruplex
DNA
Structure in the Proximal Promoter of
VEGFR
‐2 Reveals A New Drug Target to Inhibit Tumor Angiogenesis. CHINESE J CHEM 2022. [DOI: 10.1002/cjoc.202200260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Yipeng Zhang
- State Key Laboratory of Bioorganic and Natural Product Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road Shanghai 200032 China
- University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District Beijing 100049 China
| | - Wenxian Lan
- The Core Facility Centre of CAS Center for Excellence in Molecular Plant Sciences, 300 Fengling Road Shanghai 200032 China
| | - Chunxi Wang
- State Key Laboratory of Bioorganic and Natural Product Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road Shanghai 200032 China
| | - Hongjuan Xue
- National Center for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences,333 Kaike Road Shanghai 201210 China
| | - Chunyang Cao
- State Key Laboratory of Bioorganic and Natural Product Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road Shanghai 200032 China
- University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District Beijing 100049 China
- Collaborative Innovation Center of Chemistry for Life Sciences, Chinese Academy of Sciences, 345 Lingling Road Shanghai 200032 China
| |
Collapse
|
|
12
|
Al-Farsi H, Al-Azwani I, Malek JA, Chouchane L, Rafii A, Halabi NM. Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes. J Transl Med 2022; 20:244. [PMID: 35619151 PMCID: PMC9134657 DOI: 10.1186/s12967-022-03440-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort. METHODS We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line. RESULTS We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a significantly non-mutated gene, affected the morphology, reduced migration, and increased the chemotherapeutic response of SKOV3 cells. CONCLUSION We show that we can identify significantly non-mutated genes in a large ovarian cancer cohort that are well-expressed in patient and cell line data and whose RNAi-induced silencing reduces viability in three ovarian cancer cell lines. Targeting non-mutated genes that are important for tumor growth and metastasis is a promising approach to expand cancer therapeutic options.
Collapse
Affiliation(s)
| | | | - Joel A Malek
- Genomics Core, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha, Qatar
| | - Lotfi Chouchane
- Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha, Qatar
| | - Arash Rafii
- Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha, Qatar.
| | - Najeeb M Halabi
- Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha, Qatar.
| |
Collapse
|
|
13
|
Identification of dysregulated pathways and key genes in human retinal angiogenesis using microarray metadata. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2021.101434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
14
|
Chang A, Sherman SK, Howe JR, Sahai V. Progress in the Management of Pancreatic Neuroendocrine Tumors. Annu Rev Med 2021; 73:213-229. [PMID: 34669433 DOI: 10.1146/annurev-med-042320-011248] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous and orphan group of neoplasms that vary in their histology, clinical features, prognosis, and management. The treatment of PNETs is highly dependent on the stage at presentation, tumor grade and differentiation, presence of symptoms from hormonal overproduction or from local growth, tumor burden, and rate of progression. The US Food and Drug Administration has recently approved many novel treatments, which have altered decision making and positively impacted the care and prognosis of these patients. In this review, we focus on the significant progress made in the management of PNETs over the past decade, as well as the active areas of research. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Collapse
Affiliation(s)
- Amy Chang
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA; ,
| | - Scott K Sherman
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa, Iowa City, Iowa 52242, USA; ,
| | - James R Howe
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa, Iowa City, Iowa 52242, USA; ,
| | - Vaibhav Sahai
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA; ,
| |
Collapse
|
|
15
|
Maharjan CK, Ear PH, Tran CG, Howe JR, Chandrasekharan C, Quelle DE. Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets. Cancers (Basel) 2021; 13:5117. [PMID: 34680266 PMCID: PMC8533967 DOI: 10.3390/cancers13205117] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive 'omic' analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.
Collapse
Affiliation(s)
- Chandra K. Maharjan
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Po Hien Ear
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - Catherine G. Tran
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - James R. Howe
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - Chandrikha Chandrasekharan
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Dawn E. Quelle
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| |
Collapse
|
|
16
|
Ichimata M, Nishiyama S, Matsuyama F, Fukazawa E, Harada K, Katayama R, Toshima A, Kagawa Y, Yamagami T, Kobayashi T. Long-term survival in a dog with primary hepatic neuroendocrine tumor treated with toceranib phosphate. J Vet Med Sci 2021; 83:1554-1558. [PMID: 34408099 PMCID: PMC8569883 DOI: 10.1292/jvms.21-0254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Primary hepatic neuroendocrine tumors (PHNETs) are rare in dogs, and limited information exists about the treatment of these tumors. A 12-year-old castrated male French bulldog was presented to our clinic with gastrointestinal signs. Diagnostic tests revealed increased hepatic enzyme levels, a mass in the hepatic quadrate lobe, multiple intrahepatic nodules, and enlarged hepatic hilar lymph nodes. The liver mass was diagnosed cytologically as a malignant epithelial tumor suspected to be of neuroendocrine origin. The dog was treated with single-agent toceranib phosphate (TOC) and survived 25.1 months after the initial presentation. On necropsy, a liver mass was found and was subsequently diagnosed as a PHNET on histopathology. To the best of our knowledge, this is the first report of long-term survival in a dog with PHNET treated with TOC.
Collapse
Affiliation(s)
- Masanao Ichimata
- Japan Small Animal Cancer Center, 1-10-4 Higashi-Tokorozawa, Tokorozawa-shi, Saitama 359-0023, Japan
| | | | - Fukiko Matsuyama
- Japan Small Animal Cancer Center, 1-10-4 Higashi-Tokorozawa, Tokorozawa-shi, Saitama 359-0023, Japan
| | - Eri Fukazawa
- Japan Small Animal Cancer Center, 1-10-4 Higashi-Tokorozawa, Tokorozawa-shi, Saitama 359-0023, Japan
| | - Kei Harada
- Japan Small Animal Cancer Center, 1-10-4 Higashi-Tokorozawa, Tokorozawa-shi, Saitama 359-0023, Japan
| | - Ryuzo Katayama
- Japan Small Animal Cancer Center, 1-10-4 Higashi-Tokorozawa, Tokorozawa-shi, Saitama 359-0023, Japan
| | - Atsushi Toshima
- Japan Small Animal Medical Center, 1-10-4 Higashi-Tokorozawa, Tokorozawa-shi, Saitama 359-0023, Japan
| | - Yumiko Kagawa
- North Lab., 8-35 Hondori, 2 Kita, Shiroishi-ku, Sapporo, Hokkaido 003-0027, Japan
| | - Tetsushi Yamagami
- Japan Small Animal Medical Center, 1-10-4 Higashi-Tokorozawa, Tokorozawa-shi, Saitama 359-0023, Japan
| | - Tetsuya Kobayashi
- Japan Small Animal Cancer Center, 1-10-4 Higashi-Tokorozawa, Tokorozawa-shi, Saitama 359-0023, Japan
| |
Collapse
|
|
17
|
RABL6A Promotes Pancreatic Neuroendocrine Tumor Angiogenesis and Progression In Vivo. Biomedicines 2021; 9:biomedicines9060633. [PMID: 34199469 PMCID: PMC8228095 DOI: 10.3390/biomedicines9060633] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis is needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, is highly expressed in patient pNETs and required for pNET cell proliferation and survival in vitro. Here, we investigated the role of RABL6A in pNET progression in vivo using a well-established model of the disease. RIP-Tag2 (RT2) mice develop functional pNETs (insulinomas) due to SV40 large T-antigen expression in pancreatic islet β cells. RABL6A loss in RT2 mice significantly delayed pancreatic tumor formation, reduced tumor angiogenesis and mitoses, and extended survival. Those effects correlated with upregulation of anti-angiogenic p19ARF and downregulation of proangiogenic c-Myc in RABL6A-deficient islets and tumors. Our findings demonstrate that RABL6A is a bona fide oncogenic driver of pNET angiogenesis and development in vivo.
Collapse
|
|
18
|
Vorolanib (X-82), an oral anti-VEGFR/PDGFR/CSF1R tyrosine kinase inhibitor, with everolimus in solid tumors: results of a phase I study. Invest New Drugs 2021; 39:1298-1305. [PMID: 33738668 DOI: 10.1007/s10637-021-01093-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/23/2021] [Indexed: 01/15/2023]
Abstract
Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.
Collapse
|
|
19
|
Khalafi S, Lockhart AC, Livingstone AS, El-Rifai W. Targeted Molecular Therapies in the Treatment of Esophageal Adenocarcinoma, Are We There Yet? Cancers (Basel) 2020; 12:E3077. [PMID: 33105560 PMCID: PMC7690268 DOI: 10.3390/cancers12113077] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/14/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023] Open
Abstract
Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor. Current treatment approaches involve a combination of surgery, chemotherapy, and radiotherapy. Unfortunately, standard first-line approaches are met with high rates of recurrence and metastasis. More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression. These discoveries have driven the development of targeted therapeutic agents in esophageal adenocarcinoma. While many agents have been studied, therapeutics targeting the human epidermal growth factor receptor (HER2) and vascular endothelial growth factor (VEGF) pathways have demonstrated improved survival. More recent advances in immunotherapies have also demonstrated survival advantages with monoclonal antibodies targeting the programmed death ligand 1 (PD-L1). In this review we highlight recent advances of targeted therapies, specifically agents targeting receptor tyrosine kinases, small molecule kinase inhibitors, and immune checkpoint inhibitors. While targeted therapeutics and immunotherapies have significantly improved survival, the benefits are limited to patients whose tumors express biomarkers such as PD-L1 and HER2. Survival remains poor for the remainder of patients with esophageal adenocarcinoma, underscoring the critical need for development of novel treatment strategies.
Collapse
Affiliation(s)
- Shayan Khalafi
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
| | - Albert Craig Lockhart
- Department of Medicine, Miler School of Medicine, University of Miami, Miami, FL 33136, USA;
- Sylvester Comprehensive Cancer Center, Miler School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Alan S. Livingstone
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
| | - Wael El-Rifai
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
- Department of Medicine, Miler School of Medicine, University of Miami, Miami, FL 33136, USA;
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL 33136, USA
| |
Collapse
|
|
20
|
Ashrafizadeh M, Bakhoda MR, Bahmanpour Z, Ilkhani K, Zarrabi A, Makvandi P, Khan H, Mazaheri S, Darvish M, Mirzaei H. Apigenin as Tumor Suppressor in Cancers: Biotherapeutic Activity, Nanodelivery, and Mechanisms With Emphasis on Pancreatic Cancer. Front Chem 2020; 8:829. [PMID: 33195038 PMCID: PMC7593821 DOI: 10.3389/fchem.2020.00829] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 08/05/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is the most lethal malignancy of the gastrointestinal tract. Due to its propensity for early local and distant spread, affected patients possess extremely poor prognosis. Currently applied treatments are not effective enough to eradicate all cancer cells, and minimize their migration. Besides, these treatments are associated with adverse effects on normal cells and organs. These therapies are not able to increase the overall survival rate of patients; hence, finding novel adjuvants or alternatives is so essential. Up to now, medicinal herbs were utilized for therapeutic goals. Herbal-based medicine, as traditional biotherapeutics, were employed for cancer treatment. Of them, apigenin, as a bioactive flavonoid that possesses numerous biological properties (e.g., anti-inflammatory and anti-oxidant effects), has shown substantial anticancer activity. It seems that apigenin is capable of suppressing the proliferation of cancer cells via the induction of cell cycle arrest and apoptosis. Besides, apigenin inhibits metastasis via down-regulation of matrix metalloproteinases and the Akt signaling pathway. In pancreatic cancer cells, apigenin sensitizes cells in chemotherapy, and affects molecular pathways such as the hypoxia inducible factor (HIF), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1). Herein, the biotherapeutic activity of apigenin and its mechanisms toward cancer cells are presented in the current review to shed some light on anti-tumor activity of apigenin in different cancers, with an emphasis on pancreatic cancer.
Collapse
Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Mohammad Reza Bakhoda
- Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Bahmanpour
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khandan Ilkhani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul, Turkey
| | - Pooyan Makvandi
- Centre for Micro-BioRobotics, Istituto Italiano di Tecnologia, Pisa, Italy.,Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Samaneh Mazaheri
- Department of Analytical Chemistry, Faculty of Chemistry, University of Kashan, Kashan, Iran
| | - Maryam Darvish
- Department of Medical Biotechnology, Faculty of Medicine, Arak University of Medical Science, Arak, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| |
Collapse
|
|
21
|
Zhang Y, Cedervall J, Hamidi A, Herre M, Viitaniemi K, D'Amico G, Miao Z, Unnithan RVM, Vaccaro A, van Hooren L, Georganaki M, Thulin Å, Qiao Q, Andrae J, Siegbahn A, Heldin CH, Alitalo K, Betsholtz C, Dimberg A, Olsson AK. Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis. Cancer Res 2020; 80:3345-3358. [PMID: 32586981 DOI: 10.1158/0008-5472.can-19-3533] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 04/24/2020] [Accepted: 06/17/2020] [Indexed: 11/16/2022]
Abstract
Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor β-positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. Here, we show that tumor vascular function, as well as pericyte coverage is significantly impaired in mice with conditional knockout of PDGFB in platelets. A lack of PDGFB in platelets led to enhanced hypoxia and epithelial-to-mesenchymal transition in the primary tumors, elevated levels of circulating tumor cells, and increased spontaneous metastasis to the liver or lungs in two mouse models. These findings establish a previously unknown role for platelet-derived PDGFB, whereby it promotes and maintains vascular integrity in the tumor microenvironment by contributing to the recruitment of pericytes. SIGNIFICANCE: Conditional knockout of PDGFB in platelets demonstrates its previously unknown role in the maintenance of tumor vascular integrity and host protection against metastasis.
Collapse
Affiliation(s)
- Yanyu Zhang
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
| | - Jessica Cedervall
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
| | - Anahita Hamidi
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
| | - Melanie Herre
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
| | - Kati Viitaniemi
- Wihuri Research Institute and Translational Cancer Medicine Research Program, Biomedicum Helsinki, 00014 University of Helsinki, Yliopistonkatu, Helsinki, Finland
| | - Gabriela D'Amico
- Wihuri Research Institute and Translational Cancer Medicine Research Program, Biomedicum Helsinki, 00014 University of Helsinki, Yliopistonkatu, Helsinki, Finland
| | - Zuoxiu Miao
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
| | - Ragaseema Valsala Madhavan Unnithan
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden.,Department of Biotechnology, Govt. Arts College, Thiruvananthapuram, India
| | - Alessandra Vaccaro
- Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
| | - Luuk van Hooren
- Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
| | - Maria Georganaki
- Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
| | - Åsa Thulin
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Qi Qiao
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
| | - Johanna Andrae
- Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
| | - Agneta Siegbahn
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Carl-Henrik Heldin
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Medicine Research Program, Biomedicum Helsinki, 00014 University of Helsinki, Yliopistonkatu, Helsinki, Finland
| | - Christer Betsholtz
- Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.,ICMC (Integrated Cardio Metabolic Centre), Karolinska Institutet, Novum, Blickagången 6, Huddinge, Sweden
| | - Anna Dimberg
- Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
| | - Anna-Karin Olsson
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden.
| |
Collapse
|
|
22
|
The Role of Rho GTPases in VEGF Signaling in Cancer Cells. Anal Cell Pathol (Amst) 2020; 2020:2097214. [PMID: 32377503 PMCID: PMC7182966 DOI: 10.1155/2020/2097214] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/11/2022] Open
Abstract
Vascular endothelial growth factors (VEGFs) consist of five molecules (VEGFA through D as well as placental growth factor) which are crucial for regulating key cellular and tissue functions. The role of VEGF and its intracellular signaling and downstream molecular pathways have been thoroughly studied. Activation of VEGF signal transduction can be initiated by the molecules' binding to two classes of transmembrane receptors: (1) the VEGF tyrosine kinase receptors (VEGF receptors 1 through 3) and (2) the neuropilins (NRP1 and 2). The involvement of Rho GTPases in modulating VEGFA signaling in both cancer cells and endothelial cells has also been well established. Additionally, different isoforms of Rho GTPases, namely, RhoA, RhoC, and RhoG, have been shown to regulate VEGF expression as well as blood vessel formation. This review article will explore how Rho GTPases modulate VEGF signaling and the consequences of such interaction on cancer progression.
Collapse
|
|
23
|
Zhang X, Xiong Y, Xia Q, Wu F, Liu L, Zhou Y, Zeng L, Zhou C, Xia C, Jiang W, Liao D, Xiao L, Liu L, Yang H, Guan R, Li K, Wang J, Lei G, Zhang Y, Yang N. Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced Non-Small Cell Lung Cancer After Second-Line Treatment Failure: A Nonrandomized Clinical Trial. JAMA Netw Open 2020; 3:e201226. [PMID: 32191330 PMCID: PMC7082721 DOI: 10.1001/jamanetworkopen.2020.1226] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
IMPORTANCE There is currently no standard treatment strategy for patients with advanced non-small cell lung cancer (NSCLC) without driver gene variation after failure of 2 or more lines of chemotherapy. OBJECTIVE To assess the efficacy and safety of apatinib combined with oral vinorelbine. DESIGN, SETTING, AND PARTICIPANTS This phase 2 prospective nonrandomized clinical trial evaluating the efficacy and safety of apatinib plus vinorelbine recruited patients from Hunan Cancer Center, Hunan, China, from January 1, 2017, to November 30, 2018. Eligible patients were those with wild-type advanced NSCLC whose disease did not respond to at least 2 lines of chemotherapy. Patients were evaluated until December 31, 2019. Data were analyzed from July 2019 to December 2019. INTERVENTION Apatinib at an initial dose of 500 mg once daily and oral vinorelbine 60 mg/m2 once weekly were administered until disease progression, patient withdrawal, or occurrence of unacceptable toxic effects. MAIN OUTCOMES AND MEASURES The primary end point was overall response rate. Secondary end points were overall survival, progression-free survival, and safety. RESULTS The potential efficacy of apatinib plus vinorelbine was identified using drug susceptibility assay based on 3-dimensional coculture of tumor cells derived from 3 patients with lung adenocarcinoma. Among 30 patients enrolled, the median (range) age was 63 (34-78) years and 18 (60%) were men. Most patients (27 patients [90%]) had stage IV disease, and the median (range) number of prior unsuccessful treatments was 2 (2-5) lines of chemotherapy. Twenty-five patients (83%) completed the treatment, while 5 patients (17%) discontinued treatment owing to intolerable adverse events. The overall response rate was 36.7% (11 patients) and the disease control rate was 76.7% (23 patients). The median progression-free survival was 4.5 (95% CI, 2.4-6.6) months, and the median overall survival was 10.0 (95% CI, 4.8-17.1) months. Hand-foot syndrome was the most common adverse event observed, including grade 3 hand-foot syndrome observed in 5 patients (17%) and grade 4 hand-foot observed in 1 patient (3%). Grade 3 weakness was observed in 1 patient (3%). CONCLUSIONS AND RELEVANCE These findings suggest that apatinib combined with oral vinorelbine is a potentially effective regimen with an acceptable safety profile. This regimen may have potential as a treatment option for patients with wild-type advanced NSCLC whose disease failed at least 2 prior lines of chemotherapy. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03652857.
Collapse
Affiliation(s)
- Xiangyu Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yi Xiong
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Qing Xia
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Department of Oncology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Wu
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Graduate Schools, University of South China, Hengyang, China
| | - Lingli Liu
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Department of Oncology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuling Zhou
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Department of Oncology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Zeng
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Chunhua Zhou
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Chen Xia
- Department of Hepatology, Hunan Cancer Hospital, Changsha, China
| | - Wenjuan Jiang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Dehua Liao
- Department of Pharmacy, Hunan Cancer Hospital, Changsha, China
| | - Lili Xiao
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Li Liu
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Haiyan Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Rui Guan
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Kunyan Li
- Center of New Drug Clinical Trials, Hunan Cancer Hospital, Changsha, China
| | - Jing Wang
- Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Guang Lei
- Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
| | - Yongchang Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Nong Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| |
Collapse
|
|
24
|
Win PW, Oakie A, Li J, Wang R. Beta-cell β1 integrin deficiency affects in utero development of islet growth and vascularization. Cell Tissue Res 2020; 381:163-175. [PMID: 32060653 DOI: 10.1007/s00441-020-03179-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 01/27/2020] [Indexed: 10/25/2022]
Abstract
The β1 integrin subunit contributes to pancreatic beta cell growth and function through communication with the extracellular matrix (ECM). The effects of in vitro and in vivo β1 integrin knockout have been extensively studied in mature islets, yet no study to date has examined how the loss of β1 integrin during specific stages of pancreatic development impacts beta cell maturation. Beta-cell-specific tamoxifen-inducible Cre recombinase (MIP-CreERT) mice were crossed with mice containing floxed Itgb1 (β1 integrin) to create an inducible mouse model (MIPβ1KO) at the second transition stage (e13.5) of pancreas development. By e19.5-20.5, the expression of beta-cell β1 integrin in fetal MIPβ1KO mice was significantly reduced and these mice displayed decreased beta cell mass, density and proliferation. Morphologically, fetal MIPβ1KO pancreata exhibited reduced islet vascularization and nascent endocrine cells in the ductal region. In addition, decreased ERK phosphorylation was observed in fetal MIPβ1KO pancreata. The expression of transcription factors needed for beta-cell development was unchanged in fetal MIPβ1KO pancreata. The findings from this study demonstrate that β1 integrin signaling is required during a transition-specific window in the developing beta-cell to maintain islet mass and vascularization.
Collapse
Affiliation(s)
- Phyo Wei Win
- Children's Health Research Institute, Victoria Research Laboratories, London, Ontario, N6C 2V5, Canada.,Department of Physiology & Pharmacology, University of Western Ontario, London, Ontario, N6A 3K7, Canada
| | - Amanda Oakie
- Children's Health Research Institute, Victoria Research Laboratories, London, Ontario, N6C 2V5, Canada.,Department of Pathology & Laboratory Medicine, University of Western Ontario, London, Ontario, N6A 3K7, Canada
| | - Jinming Li
- Children's Health Research Institute, Victoria Research Laboratories, London, Ontario, N6C 2V5, Canada.,Department of Physiology & Pharmacology, University of Western Ontario, London, Ontario, N6A 3K7, Canada
| | - Rennian Wang
- Children's Health Research Institute, Victoria Research Laboratories, London, Ontario, N6C 2V5, Canada. .,Department of Physiology & Pharmacology, University of Western Ontario, London, Ontario, N6A 3K7, Canada.
| |
Collapse
|
|
25
|
Tanaka I, Morise M, Miyazawa A, Kodama Y, Tamiya Y, Gen S, Matsui A, Hase T, Hashimoto N, Sato M, Hasegawa Y. Potential Benefits of Bevacizumab Combined With Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Cancer Patients With EGFR Mutation. Clin Lung Cancer 2020; 21:273-280.e4. [PMID: 32088115 DOI: 10.1016/j.cllc.2020.01.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 12/26/2019] [Accepted: 01/20/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Oncogenic EGFR signaling has been shown to upregulate vascular endothelial growth factor A (VEGFA) expression involved in tumor angiogenesis. However, the clinical benefits of bevacizumab plus cytotoxic chemotherapy for EGFR mutation-positive patients remain unclear. This study aimed to investigate VEGFA messenger RNA expression in patients with EGFR mutation, and to further compare the efficacy of bevacizumab combined with platinum-based chemotherapy between EGFR-mutant and wild-type patients. PATIENTS AND METHODS Gene expression of various proangiogenic factors was analyzed in nonsquamous, non-small-cell lung cancer (NSCLC) patients using The Cancer Genome Atlas dataset. Additionally, clinical data of patients receiving carboplatin and pemetrexed (CPem; n = 104) or bevacizumab plus CPem (BevCPem; n = 55) at Nagoya University hospital were retrospectively assessed for progression-free survival and best overall response rate (ORR). RESULTS Among various proangiogenic factors, only VEGFA expression was significantly higher in patients with advanced nonsquamous NSCLC with EGFR mutation compared to wild-type patients (P = .0476). Progression-free survival in the BevCPem group was significantly longer in patients with EGFR mutation than in wild-type patients (10.5 vs. 6.6 months; Wilcoxon P = .0278), while the difference in the CPem group was not significant (6.6 vs. 4.5 months; Wilcoxon P = .1822). The ORRs in the BevCPem group were 54.5% and 36.4% for EGFR-mutant and wild-type patients, respectively, and the ORRs in the CPem group were 35.5% and 28.8 % in EGFR-mutant and wild-type patients, respectively. CONCLUSION VEGFA messenger RNA expression was significantly increased in advanced nonsquamous NSCLC harboring EGFR mutation, and BevCPem provided better clinical benefits to patients with EGFR mutation than wild-type carriers.
Collapse
Affiliation(s)
- Ichidai Tanaka
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Masahiro Morise
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ayako Miyazawa
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuta Kodama
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yutaro Tamiya
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Soei Gen
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Matsui
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsunari Hase
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naozumi Hashimoto
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuo Sato
- Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshinori Hasegawa
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| |
Collapse
|
|
26
|
VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake. Sci Rep 2020; 10:923. [PMID: 31969592 PMCID: PMC6976647 DOI: 10.1038/s41598-020-57599-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.
Collapse
|
|
27
|
Gastroenteropancreatic neuroendocrine neoplasms and inflammation: A complex cross-talk with relevant clinical implications. Crit Rev Oncol Hematol 2019; 146:102840. [PMID: 31918344 DOI: 10.1016/j.critrevonc.2019.102840] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 11/21/2019] [Accepted: 11/23/2019] [Indexed: 02/07/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a group of tumors originating from the neuroendocrine system. They mainly occur in the digestive system and the respiratory tract. It is well-know a strict interaction between neuroendocrine system and inflammation, which can play an important role in NEN carcinogenesis. Inflammatory mediators, which are produced by the tumor microenvironment, can favor cancer induction and progression, and can promote immune editing. On the other hand, a balanced immune system represents a relevant step in cancer prevention through the elimination of dysplastic and cancer cells. Therefore, an inflammatory response may be both pro- and anti-tumorigenic. In this review, we provide an overview concerning the complex interplay between inflammation and gastroenteropancreatic NENs, focusing on the tumorigenesis and clinical implications in these tumors.
Collapse
|
|
28
|
Abstract
All solid tumours require a vascular supply in order to progress. Although the ability to induce angiogenesis (new blood vessel growth) has long been regarded as essential to this purpose, thus far, anti-angiogenic therapies have shown only modest efficacy in patients. Importantly, overshadowed by the literature on tumour angiogenesis is a long-standing, but continually emerging, body of research indicating that tumours can grow instead by hijacking pre-existing blood vessels of the surrounding nonmalignant tissue. This process, termed vessel co-option, is a frequently overlooked mechanism of tumour vascularization that can influence disease progression, metastasis and response to treatment. In this Review, we describe the evidence that tumours located at numerous anatomical sites can exploit vessel co-option. We also discuss the proposed molecular mechanisms involved and the multifaceted implications of vessel co-option for patient outcomes.
Collapse
Affiliation(s)
- Elizabeth A Kuczynski
- Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
| | - Peter B Vermeulen
- HistoGeneX, Antwerp, Belgium
- Translational Cancer Research Unit, GZA Hospitals St Augustinus, University of Antwerp, Wilrijk-Antwerp, Belgium
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Francesco Pezzella
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Robert S Kerbel
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
- Oncology Translational Medicine Unit, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
| |
Collapse
|
|
29
|
Román CL, Maiztegui B, Mencucci MV, Ahrtz L, Algañarás M, Del Zotto H, Gagliardino JJ, Flores LE. Effects of islet neogenesis associated protein depend on vascular endothelial growth factor gene expression modulated by hypoxia-inducible factor 1-alpha. Peptides 2019; 117:170090. [PMID: 31121197 DOI: 10.1016/j.peptides.2019.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 05/13/2019] [Accepted: 05/14/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Pharmacology has provided efficient tools to improve insulin effect/secretion but the decrease in β-cell mass remains elusive. INGAP-PP could provide a therapeutic alternative to meet that challenge. AIM To further understand the mechanism that links INGAP-PP effects upon β-cell mass and function with islet angiogenesis. METHODOLOGY Normal male Wistar rats were divided into 2 groups and injected with a single dose of 100 mg/Kg suramin or saline. Both groups were divided into 2 subgroups that received daily doses of 2 mg/kg INGAP-PP or saline for ten days. Plasma glucose, triacylglycerol, TBARS, and insulin levels were measured. Pancreas immunomorphometric analyses were also performed. Pancreatic islets were isolated to measure glucose-stimulated insulin secretion (GSIS). Specific islet mRNA levels were studied by qRT-PCR. Statistical analysis was done using ANOVA. RESULTS No differences were recorded in body weight, food intake, or any other plasma parameter measured in all groups. Islets from INGAP-PP-treated rats significantly increased GSIS, β-cell mass, and mRNA levels of Bcl-2, Ngn-3, VEGF-A, VEGF-R2, CD31, Ang1 and Ang2, Laminin β-1, and Integrin β-1, and decreased mRNA levels of Caspase-8, Bad, and Bax. Islets from suramin-treated rats showed significant opposite effects, but INGAPP-PP administration rescued most of the suramin effects in animals treated with both compounds. CONCLUSION Our results reinforce the concept that INGAP-PP enhances insulin secretion and β-cell mass, acting through PI3K/Akt/mTOR pathways and simultaneously activating angiogenesis through HIF-1α-mediated VEGF-A secretion. Therefore, INGAP-PP might be a suitable antidiabetic agent able to overcome two major alterations present in T2D.
Collapse
Affiliation(s)
- C L Román
- CENEXA. Centro de Endocrinología Experimental y Aplicada (UNLP-CONICETLa Plata), Facultad de Ciencias Médicas UNLP. 60 y 120 (s/n) 4to piso 1900 La Plata, Argentina
| | - B Maiztegui
- CENEXA. Centro de Endocrinología Experimental y Aplicada (UNLP-CONICETLa Plata), Facultad de Ciencias Médicas UNLP. 60 y 120 (s/n) 4to piso 1900 La Plata, Argentina
| | - M V Mencucci
- CENEXA. Centro de Endocrinología Experimental y Aplicada (UNLP-CONICETLa Plata), Facultad de Ciencias Médicas UNLP. 60 y 120 (s/n) 4to piso 1900 La Plata, Argentina
| | - L Ahrtz
- CENEXA. Centro de Endocrinología Experimental y Aplicada (UNLP-CONICETLa Plata), Facultad de Ciencias Médicas UNLP. 60 y 120 (s/n) 4to piso 1900 La Plata, Argentina
| | - M Algañarás
- CENEXA. Centro de Endocrinología Experimental y Aplicada (UNLP-CONICETLa Plata), Facultad de Ciencias Médicas UNLP. 60 y 120 (s/n) 4to piso 1900 La Plata, Argentina
| | - H Del Zotto
- CENEXA. Centro de Endocrinología Experimental y Aplicada (UNLP-CONICETLa Plata), Facultad de Ciencias Médicas UNLP. 60 y 120 (s/n) 4to piso 1900 La Plata, Argentina
| | - J J Gagliardino
- CENEXA. Centro de Endocrinología Experimental y Aplicada (UNLP-CONICETLa Plata), Facultad de Ciencias Médicas UNLP. 60 y 120 (s/n) 4to piso 1900 La Plata, Argentina
| | - L E Flores
- CENEXA. Centro de Endocrinología Experimental y Aplicada (UNLP-CONICETLa Plata), Facultad de Ciencias Médicas UNLP. 60 y 120 (s/n) 4to piso 1900 La Plata, Argentina.
| |
Collapse
|
|
30
|
Krug S, Mordhorst JP, Moser F, Theuerkorn K, Ruffert C, Egidi M, Rinke A, Gress TM, Michl P. Interaction between somatostatin analogues and targeted therapies in neuroendocrine tumor cells. PLoS One 2019; 14:e0218953. [PMID: 31237925 PMCID: PMC6592550 DOI: 10.1371/journal.pone.0218953] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 06/12/2019] [Indexed: 01/17/2023] Open
Abstract
Somatostatin analogues (SSA) represent the standard of care for symptom control in patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In addition, SSA exert significant anti-proliferative effects in mid-gut and pancreatic NET (PanNET). In parallel, molecularly targeted therapies (MTT) have been shown to improve progression free survival (PFS) in patients with PanNET. However, due to either primary or acquired resistance to MTT, their impact on overall survival (OS) remains unclear. To date, various hypotheses exist to explain differences in patient responsiveness to SSA and MTT. However, data addressing one of the most pivotal questions, whether combining SSA with novel MTT will result in synergistic or additive efficacy compared to monotherapy, are lacking. The aim of this study is to characterize the interaction, optimal sequence and dosing of SSA-based and molecularly targeted therapies in PanNET. Somatostatin receptor subtypes 1–5 (SSTR) were evaluated in the neuroendocrine cell lines Bon1, QGP1 and Ins-1 via immunoblot and qRT-PCR. The impact of the SSA-analogue lanreotide alone or in combination with the MTT sunitinib, everolimus and regorafenib on intracellular signalling, hormone secretion and cell proliferation was determined in cell lysates and supernatants. In addition, synergistic effects of SSA and MTT in various sequential therapeutic approaches were investigated. SSTR were differently expressed in the examined neuroendocrine tumor cell lines. SSTR modulation via lanreotide moderately influenced proliferation, mainly via modulating AKT and ERK signalling, which was paralleled by decreased chromogranin A (CgA) expression and secretion. Interestingly, MTT treatment with regorafenib upregulated the expression of SSTR-2 and -5, while sunitinib and everolimus did not significantly alter SSTR expression. Cell viability was significantly reduced by all MTT, with regorafenib exerting the most significant effects. However, compared to the marked effects of MTT alone, synergistic effects of combined MTT and lanreotide treatment were only modest and time- and dose-dependent. SSTR are differentially expressed in various NEN cell lines. Their expression is influenced by MTT treatment. Various sequential or simultaneous combinations of lanreotide and MTT did not lead to significant synergistic effects.
Collapse
Affiliation(s)
- Sebastian Krug
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Jan-Philipp Mordhorst
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Fabian Moser
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Katharina Theuerkorn
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Claudia Ruffert
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Maren Egidi
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Anja Rinke
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Thomas M. Gress
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Patrick Michl
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
- * E-mail:
| |
Collapse
|
|
31
|
Zhan K, Bai L, Wang G, Zuo B, Xie L, Wang X. Different angiogenesis modes and endothelial responses in implanted porous biomaterials. Integr Biol (Camb) 2019; 10:406-418. [PMID: 29951652 DOI: 10.1039/c8ib00061a] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
An in vivo experimental model based on implanting porous biomaterials to study angiogenesis was proposed. In the implanted porous polyvinyl alcohol, three major modes of angiogenesis, sprouting, intussusception and splitting, were found. By electron microscopy and three-dimensional simulation of the angiogenic vessels, we investigated the morphological characteristics of the three modes and paid special attention to the initial morphological difference between intussusception and splitting, and it was confirmed that the endothelial abluminal invagination and intraluminal protrusion are pre-representations of intussusception and splitting, respectively. Based on immunohistochemical analysis of HIF-1α, VEGF and Flt-1 expressions, it was demonstrated that the dominant mode of angiogenesis is related to the local hypoxic condition, and that there is difference in the response of endothelial cells to hypoxia-induced VEGF between sprouting and splitting. Specifically, in the biomaterials implanted for 3 days, the higher expression and gradient of VEGF induced by severe hypoxia in the avascular area caused sprouting of the peripheral capillaries, and in the biomaterial implanted for 9 days, with moderate hypoxia, splitting became a dominant mode. Whether on day 3 or day 9, Flt-1 expression in sprouting endothelia was significantly higher than that in splitting endothelia, which indicates that sprouting is caused by the strong response of endothelial cells to VEGF, while splitting is associated with their weaker response. As a typical experimental example, these results show the effectiveness of the porous biomaterial implantation model for studying angiogenesis, which is expected to become a new general model.
Collapse
Affiliation(s)
- Kuihua Zhan
- School of Mechanical and Electric Engineering, Soochow University, 8 Jixue Road, Suzhou, 215131, China.
| | | | | | | | | | | |
Collapse
|
|
32
|
Zhang Q, Lu S, Li T, Yu L, Zhang Y, Zeng H, Qian X, Bi J, Lin Y. ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:173. [PMID: 31023337 PMCID: PMC6482513 DOI: 10.1186/s13046-019-1156-5] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 03/27/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear. METHODS The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model. RESULTS ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs. CONCLUSIONS Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway. TRIAL REGISTRATION Retrospectively registered.
Collapse
Affiliation(s)
- Qi Zhang
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.,Guangdong Key Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Sihong Lu
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.,Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Tianfu Li
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Liang Yu
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Yunjian Zhang
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Huijuan Zeng
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China
| | - Xueke Qian
- The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China
| | - Jiong Bi
- Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.
| | - Ying Lin
- Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, No.58 of Zhongshan 2nd road, Yuexiu district, Guangzhou, 510080, China.
| |
Collapse
|
|
33
|
Valle JW, Borbath I, Rosbrook B, Fernandez K, Raymond E. Sunitinib in patients with pancreatic neuroendocrine tumors: update of safety data. Future Oncol 2019; 15:1219-1230. [DOI: 10.2217/fon-2018-0882] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Aim: To describe the long-term safety of sunitinib in patients with progressive, well-differentiated, advanced/metastatic pancreatic neuroendocrine tumors. Patients & methods: Sunitinib- and placebo-treated patients from the Phase III study continued to receive sunitinib (37.5 mg on a continuous daily-dosing regimen) in two open-label extension studies. Results: Median (range) treatment exposure: 30.2 (0.7–269.4) and 87.1 (3.9–319.4) weeks for medium-term (n = 41) and long-term-treated (n = 61) populations, respectively. All patients experienced ≥1 adverse event (AE); 47 (45.6%) reported serious AEs. Common all-causality AEs: diarrhea (63.1%); neutropenia (43.7%); abdominal pain (40.8%). Fifteen (14.6%) patients discontinued treatment due to treatment-related AEs. Conclusion: The safety of extended sunitinib treatment was consistent with the known safety profile of sunitinib in pancreatic neuroendocrine tumors.
Collapse
Affiliation(s)
- Juan W Valle
- Division of Cancer Sciences/Department of Medical Oncology, The Christie NHS Foundation Trust, University of Manchester, Manchester M20 4BX, UK
| | - Ivan Borbath
- Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc, Av Hippocrate, 10 - 1200 Brussels, Belgium
| | - Brad Rosbrook
- Pfizer Inc., 10646 Science Center Dr, San Diego, CA 92121, USA
| | | | - Eric Raymond
- Paris Saint-Joseph Hospital Group, 185 Rue Raymond Losserand, Paris 75014, France
| |
Collapse
|
|
34
|
Abstract
The idea of tumor dormancy originated from clinical findings that recurrence of cancer occurs several years or even several decades after surgical resection of the primary tumor. Tumor mass dormancy was proposed as a model, where there is equal balance between increases in the number of cancer cells by proliferation and decreases as a result of cell death. Tumor mass dormancy includes angiogenic dormancy and immune-mediated dormancy. Another emerging type of tumor dormancy is cellular dormancy in which cancer cells are in a quiescent state. Cellular dormancy is induced by cues such as the extracellular matrix environment, metastatic niches, a hypoxic microenvironment, and endoplasmic reticulum stress. Even the oncogenic pathways, on which active cancer cells depend for survival and growth, are suppressed in the dormant state. As tumor dormancy is one of the mechanisms of resistance against various cancer therapies, targeting dormant cancer cells should be considered for future treatment strategies.
Collapse
Affiliation(s)
- Hiroko Endo
- Department of Molecular Cellular BiologyOsaka International Cancer InstituteOsakaJapan
- Department of BiochemistryOsaka International Cancer InstituteOsakaJapan
| | - Masahiro Inoue
- Department of BiochemistryOsaka International Cancer InstituteOsakaJapan
- Department of Clinical Bio‐resource Research and DevelopmentGraduate School of Medicine Kyoto UniversityKyotoJapan
| |
Collapse
|
|
35
|
Abstract
Pancreatic neuroendocrine tumors are rare tumors of the pancreas originating from the islets of the Langerhans. These tumors comprise 1% to 3% of all newly diagnosed pancreatic cancers every year and have a unique heterogeneity in clinical presentation. Whole-genome sequencing has led to an increased understanding of the molecular biology of these tumors. In this review, we will summarize the current knowledge of the signaling pathways involved in the tumorigenesis of pancreatic neuroendocrine tumors as well as the major studies targeting these pathways at preclinical and clinical levels.
Collapse
|
|
36
|
Cives M, Pelle' E, Quaresmini D, Rizzo FM, Tucci M, Silvestris F. The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications. Neuroendocrinology 2019; 109:83-99. [PMID: 30699437 DOI: 10.1159/000497355] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 01/30/2019] [Indexed: 12/12/2022]
Abstract
Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, semaphorins, and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor β primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely, major complications of functioning NETs. However, at present, little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells, and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs' surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs' microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.
Collapse
Affiliation(s)
- Mauro Cives
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Eleonora Pelle'
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Davide Quaresmini
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Francesca Maria Rizzo
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Marco Tucci
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy,
| |
Collapse
|
|
37
|
Sato K, Toyoshima Y, Moriyama S, Endo Y, Ito T, Ohki E. Real-world use of sunitinib in Japanese patients with pancreatic neuroendocrine tumors: results from a post-marketing surveillance study. Cancer Chemother Pharmacol 2018; 83:201-207. [PMID: 30413868 PMCID: PMC6373178 DOI: 10.1007/s00280-018-3724-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 11/01/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND Sunitinib is approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced or metastatic disease. Safety and efficacy data in Japanese patients are limited. We report outcomes from a post-marketing surveillance study of sunitinib treatment in Japanese patients. METHODS Sunitinib 37.5 mg once daily was orally administered in Japanese patients aged ≥ 15 years with pNETs. The primary endpoints included adverse events (AEs) occurring during the observation period of 168 days and objective response rate (ORR). RESULTS Sunitinib was administered in 62 patients with pNETs. The median duration of treatment was 165 days. At 168 days from the start of treatment, 31 patients were still receiving sunitinib treatment and treatment continuation rate was 50.0%. Of the 31 patients who discontinued treatment, 18 (58.1%) discontinued because of AEs and 16 (51.6%) patients discontinued due to insufficient clinical effect. Of the 18 patients who discontinued due to AEs, 10 did so within 42 days of treatment initiation. The most common all-grade AEs were platelet count decreased (33.9%), diarrhea (29.0%), neutrophil count decreased (27.4%), hypertension (24.2%), and palmar-plantar erythrodysesthesia syndrome (24.2%). In the 51 patients eligible for the efficacy analysis, ORR was 13.7% (95% confidence interval, 5.7-26.3) and clinical benefit rate was 70.6%. CONCLUSIONS There were no new safety concerns in real-world use of sunitinib in Japanese patients with pNETs. The short treatment duration likely led to low tumor response. Appropriate AEs management through dose interruption/reduction is essential for sunitinib treatment success in this patient population.
Collapse
Affiliation(s)
| | | | | | | | - Tetsuhide Ito
- Fukuoka Sanno Hospital, International University of Health and Welfare, Tokyo, Japan
| | | |
Collapse
|
|
38
|
Cuny T, de Herder W, Barlier A, Hofland LJ. Role of the tumor microenvironment in digestive neuroendocrine tumors. Endocr Relat Cancer 2018; 25:R519-R544. [PMID: 30306777 DOI: 10.1530/erc-18-0025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a group of heterogeneous tumors whose incidence increased over the past few years. Around half of patients already present with metastatic disease at the initial diagnosis. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with metastatic GEP-NETs, mainly due to the development of a certain state of resistance. One factor contributing to both the failure of systemic therapies and the emergence of an aggressive tumor phenotype may be the tumor microenvironment (TME), comprising dynamic and adaptative assortment of extracellular matrix components and non-neoplastic cells, which surround the tumor niche. Accumulating evidence shows that the TME can simultaneously support both tumor growth and metastasis and contribute to a certain state of resistance to treatment. In this review, we summarize the current knowledge of the TME of GEP-NETs and discuss the current therapeutic agents that target GEP-NETs and those that could be of interest in the (near) future.
Collapse
Affiliation(s)
- Thomas Cuny
- Division Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
- Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France
- Department of Endocrinology, Assistance Publique - Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares Hypophysaires HYPO, Marseille, France
| | - Wouter de Herder
- Division Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Anne Barlier
- Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France
- Department of Endocrinology, Assistance Publique - Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares Hypophysaires HYPO, Marseille, France
| | - Leo J Hofland
- Division Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| |
Collapse
|
|
39
|
How to Modulate Tumor Hypoxia for Preclinical In Vivo Imaging Research. CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:4608186. [PMID: 30420794 PMCID: PMC6211155 DOI: 10.1155/2018/4608186] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/24/2018] [Accepted: 08/13/2018] [Indexed: 01/20/2023]
Abstract
Tumor hypoxia is related with tumor aggressiveness, chemo- and radiotherapy resistance, and thus a poor clinical outcome. Therefore, over the past decades, every effort has been made to develop strategies to battle the negative prognostic influence of tumor hypoxia. For appropriate patient selection and follow-up, noninvasive imaging biomarkers such as positron emission tomography (PET) radiolabeled ligands are unprecedentedly needed. Importantly, before being able to implement these new therapies and potential biomarkers into the clinical setting, preclinical in vivo validation in adequate animal models is indispensable. In this review, we provide an overview of the different attempts that have been made to create differential hypoxic in vivo cancer models with a particular focus on their applicability in PET imaging studies.
Collapse
|
|
40
|
Grillo F, Florio T, Ferraù F, Kara E, Fanciulli G, Faggiano A, Colao A. Emerging multitarget tyrosine kinase inhibitors in the treatment of neuroendocrine neoplasms. Endocr Relat Cancer 2018; 25:R453-R466. [PMID: 29769293 DOI: 10.1530/erc-17-0531] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022]
Abstract
In the last few years, the therapeutic approach for neuroendocrine neoplasms (NENs) has changed dramatically following the approval of several novel targeted treatments. The multitarget tyrosine kinase inhibitor (MTKI), sunitinib malate, has been approved by Regulatory Agencies in pancreatic NENs. The MTKI class, however, includes several other molecules (approved for other conditions), which are currently being studied in NENs. An in-depth review on the studies published on the MTKIs in neuroendocrine tumors such as axitinib, cabozantinib, famitinib, lenvatinib, nintedanib, pazopanib, sorafenib and sulfatinib was performed. Furthermore, we extensively searched on the Clinical Trial Registries databases worldwide, in order to collect information on the ongoing clinical trials related to this topic. Our systematic analysis on emerging MTKIs in the treatment of gastroenteropancreatic and lung NENs identifies in vitro and in vivo studies, which demonstrate anti-tumor activity of diverse MTKIs on neuroendocrine cells and tumors. Moreover, for the first time in the literature, we report an updated view concerning the upcoming clinical trials in this field: presently, phase I, II and III clinical trials are ongoing and will include, overall, a staggering 1667 patients. This fervid activity underlines the increasing interest of the scientific community in the use of emerging MTKIs in NEN treatment.
Collapse
Affiliation(s)
- Federica Grillo
- Pathology UnitDepartment of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Genova, Italy
- Ospedale Policlinico San Martino IRCCSGenova, Italy
| | - Tullio Florio
- Pharmacology UnitDepartment of Internal Medicine (DIMI), University of Genova, Genova, Italy
| | - Francesco Ferraù
- Department of Human Pathology of Adulthood and ChildhoodUniversity of Messina, Messina, Italy
| | - Elda Kara
- Unit of EndocrinologyMetabolism, Diabetology and Nutrition, Azienda Sanitaria Universitaria Integrata di Udine, Ospedale Santa Maria della Misericordia, Udine, Italy
| | - Giuseppe Fanciulli
- Neuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, Italy
| | - Antongiulio Faggiano
- Department of Clinical Medicine and SurgeryUniversity 'Federico II', Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and SurgeryUniversity 'Federico II', Naples, Italy
| | | |
Collapse
|
|
41
|
Nowak-Sliwinska P, Alitalo K, Allen E, Anisimov A, Aplin AC, Auerbach R, Augustin HG, Bates DO, van Beijnum JR, Bender RHF, Bergers G, Bikfalvi A, Bischoff J, Böck BC, Brooks PC, Bussolino F, Cakir B, Carmeliet P, Castranova D, Cimpean AM, Cleaver O, Coukos G, Davis GE, De Palma M, Dimberg A, Dings RPM, Djonov V, Dudley AC, Dufton NP, Fendt SM, Ferrara N, Fruttiger M, Fukumura D, Ghesquière B, Gong Y, Griffin RJ, Harris AL, Hughes CCW, Hultgren NW, Iruela-Arispe ML, Irving M, Jain RK, Kalluri R, Kalucka J, Kerbel RS, Kitajewski J, Klaassen I, Kleinmann HK, Koolwijk P, Kuczynski E, Kwak BR, Marien K, Melero-Martin JM, Munn LL, Nicosia RF, Noel A, Nurro J, Olsson AK, Petrova TV, Pietras K, Pili R, Pollard JW, Post MJ, Quax PHA, Rabinovich GA, Raica M, Randi AM, Ribatti D, Ruegg C, Schlingemann RO, Schulte-Merker S, Smith LEH, Song JW, Stacker SA, Stalin J, Stratman AN, Van de Velde M, van Hinsbergh VWM, Vermeulen PB, Waltenberger J, Weinstein BM, Xin H, Yetkin-Arik B, Yla-Herttuala S, Yoder MC, Griffioen AW. Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 2018; 21:425-532. [PMID: 29766399 PMCID: PMC6237663 DOI: 10.1007/s10456-018-9613-x] [Citation(s) in RCA: 458] [Impact Index Per Article: 65.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
Collapse
Affiliation(s)
- Patrycja Nowak-Sliwinska
- Molecular Pharmacology Group, School of Pharmaceutical Sciences, Faculty of Sciences, University of Geneva, University of Lausanne, Rue Michel-Servet 1, CMU, 1211, Geneva 4, Switzerland.
- Translational Research Center in Oncohaematology, University of Geneva, Geneva, Switzerland.
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Elizabeth Allen
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Louvain, Belgium
| | - Andrey Anisimov
- Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
| | - Alfred C Aplin
- Department of Pathology, University of Washington, Seattle, WA, USA
| | | | - Hellmut G Augustin
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Division of Vascular Oncology and Metastasis Research, German Cancer Research Center, Heidelberg, Germany
- German Cancer Consortium, Heidelberg, Germany
| | - David O Bates
- Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Judy R van Beijnum
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - R Hugh F Bender
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
| | - Gabriele Bergers
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Louvain, Belgium
- Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Andreas Bikfalvi
- Angiogenesis and Tumor Microenvironment Laboratory (INSERM U1029), University Bordeaux, Pessac, France
| | - Joyce Bischoff
- Vascular Biology Program and Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Barbara C Böck
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Division of Vascular Oncology and Metastasis Research, German Cancer Research Center, Heidelberg, Germany
- German Cancer Consortium, Heidelberg, Germany
| | - Peter C Brooks
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA
| | - Federico Bussolino
- Department of Oncology, University of Torino, Turin, Italy
- Candiolo Cancer Institute-FPO-IRCCS, 10060, Candiolo, Italy
| | - Bertan Cakir
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Daniel Castranova
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Anca M Cimpean
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Ondine Cleaver
- Department of Molecular Biology, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - George Coukos
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne, Lausanne, Switzerland
| | - George E Davis
- Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine and Dalton Cardiovascular Center, Columbia, MO, USA
| | - Michele De Palma
- School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland
| | - Anna Dimberg
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Ruud P M Dings
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | | | - Andrew C Dudley
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
- Emily Couric Cancer Center, The University of Virginia, Charlottesville, VA, USA
| | - Neil P Dufton
- Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London, UK
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
| | | | - Marcus Fruttiger
- Institute of Ophthalmology, University College London, London, UK
| | - Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bart Ghesquière
- Metabolomics Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium
- Department of Oncology, Metabolomics Expertise Center, KU Leuven, Leuven, Belgium
| | - Yan Gong
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Robert J Griffin
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Adrian L Harris
- Molecular Oncology Laboratories, Oxford University Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
| | - Christopher C W Hughes
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
| | - Nan W Hultgren
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
| | | | - Melita Irving
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne, Lausanne, Switzerland
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joanna Kalucka
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Robert S Kerbel
- Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
| | - Jan Kitajewski
- Department of Physiology and Biophysics, University of Illinois, Chicago, IL, USA
| | - Ingeborg Klaassen
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Hynda K Kleinmann
- The George Washington University School of Medicine, Washington, DC, USA
| | - Pieter Koolwijk
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Elisabeth Kuczynski
- Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
| | - Brenda R Kwak
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | | | - Juan M Melero-Martin
- Department of Cardiac Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Lance L Munn
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Roberto F Nicosia
- Department of Pathology, University of Washington, Seattle, WA, USA
- Pathology and Laboratory Medicine Service, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Agnes Noel
- Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Jussi Nurro
- Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland
| | - Anna-Karin Olsson
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Tatiana V Petrova
- Department of oncology UNIL-CHUV, Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Kristian Pietras
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund, Sweden
| | - Roberto Pili
- Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
| | - Jeffrey W Pollard
- Medical Research Council Centre for Reproductive Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - Mark J Post
- Department of Physiology, Maastricht University, Maastricht, The Netherlands
| | - Paul H A Quax
- Einthoven Laboratory for Experimental Vascular Medicine, Department Surgery, LUMC, Leiden, The Netherlands
| | - Gabriel A Rabinovich
- Laboratory of Immunopathology, Institute of Biology and Experimental Medicine, National Council of Scientific and Technical Investigations (CONICET), Buenos Aires, Argentina
| | - Marius Raica
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Anna M Randi
- Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London, UK
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
- National Cancer Institute "Giovanni Paolo II", Bari, Italy
| | - Curzio Ruegg
- Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Reinier O Schlingemann
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Stefan Schulte-Merker
- Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU, Münster, Germany
| | - Lois E H Smith
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Jonathan W Song
- Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Steven A Stacker
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre and The Sir Peter MacCallum, Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
| | - Jimmy Stalin
- Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU, Münster, Germany
| | - Amber N Stratman
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Maureen Van de Velde
- Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Victor W M van Hinsbergh
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Peter B Vermeulen
- HistoGeneX, Antwerp, Belgium
- Translational Cancer Research Unit, GZA Hospitals, Sint-Augustinus & University of Antwerp, Antwerp, Belgium
| | - Johannes Waltenberger
- Medical Faculty, University of Münster, Albert-Schweitzer-Campus 1, Münster, Germany
| | - Brant M Weinstein
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Hong Xin
- University of California, San Diego, La Jolla, CA, USA
| | - Bahar Yetkin-Arik
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Seppo Yla-Herttuala
- Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland
| | - Mervin C Yoder
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
| |
Collapse
|
|
42
|
Román CL, Maiztegui B, Del Zotto H, Gagliardino JJ, Flores LE. INGAP-PP effects on β-cell mass and function are related to its positive effect on islet angiogenesis and VEGFA production. Mol Cell Endocrinol 2018; 470:269-280. [PMID: 29146554 DOI: 10.1016/j.mce.2017.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 11/10/2017] [Accepted: 11/10/2017] [Indexed: 01/09/2023]
Abstract
Our aim was to determine whether islet angiogenesis and VEGFA production/release participate in the mechanism by which INGAP-PP enhances β-cell function and mass. We used two models: a) in vivo (normal rats injected with INGAP-PP for 10 days) and b) in vitro (normal islets cultured for 4 days with INGAP-PP, VEGFA, Rapamycin, and the specific VEGF-Receptor inhibitor, SU5416). INGAP-PP administration enhanced insulin secretion, β-cell mass, islet vascularization, and angiogenesis without affecting glucose homeostasis. Normal islets cultured with INGAP-PP and VEGFA increased insulin and VEGFA secretion while apoptosis decreased. INGAP-PP-induced effects were prevented by both Rapamycin and SU5416. INGAP-PP effects on β-cell mass and function were significantly associated with a positive effect on islet angiogenesis and VEGFA production/release. VEGF-A possibly potentiates INGAP-PP effect through mTORC pathway.
Collapse
Affiliation(s)
- Carolina Lisi Román
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), Facultad de Ciencias Médicas UNLP, 60 y 120 (s/n) 4to piso, 1900 La Plata, Argentina
| | - Bárbara Maiztegui
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), Facultad de Ciencias Médicas UNLP, 60 y 120 (s/n) 4to piso, 1900 La Plata, Argentina
| | - Héctor Del Zotto
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), Facultad de Ciencias Médicas UNLP, 60 y 120 (s/n) 4to piso, 1900 La Plata, Argentina
| | - Juan José Gagliardino
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), Facultad de Ciencias Médicas UNLP, 60 y 120 (s/n) 4to piso, 1900 La Plata, Argentina
| | - Luis Emilio Flores
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET La Plata), Facultad de Ciencias Médicas UNLP, 60 y 120 (s/n) 4to piso, 1900 La Plata, Argentina.
| |
Collapse
|
|
43
|
Yang Y, Yang L, Li Y. Neuropilin-1 (NRP-1) upregulated by IL-6/STAT3 signaling contributes to invasion in pancreatic neuroendocrine neoplasms. Hum Pathol 2018; 81:192-200. [PMID: 30420046 DOI: 10.1016/j.humpath.2018.06.030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/19/2018] [Accepted: 06/22/2018] [Indexed: 12/18/2022]
Abstract
Although the upregulation of Neuropilin-1 (NRP-1) is associated with many solid tumors, its role in pancreatic neuroendocrine neoplasms (pNEN) has not been well elucidated. The aim of this study was to investigate the role of NRP-1 in improving treatment and determining the prognosis of pNEN. In this study, the expression of NRP-1 in pNEN tissue samples and pNEN cell line BON1 was analyzed by Western blot, polymerase chain reaction (PCR) and immunocytochemistry upon exposure to interleukin-6 (IL-6). Additionally, pNEN cell line BON1 was transfected with small interfering RNAs against NRP-1 or signal transducer and activator of transcription 3 (STAT3) and assessed by in vitro invasion assays. The expression of NRP-1 in pNEN tissues was markedly increased compared with adjacent normal pancreatic tissues. High NRP-1 expression was strongly correlated with tumor grades (P = .026), lymph node metastasis (P = .025), and tumor-node-metastasis stages (P = .012). Furthermore, NRP-1 downregulation notably inhibited the metastatic capacity of pNEN cells, and STAT3 knockdown was found to downregulate the expression of NRP-1. BON1 cells upregulated NRP-1 expression upon stimulation with IL-6. This was accompanied by activation/phosphorylation of the AKT and STAT3 signaling pathways. Western blot of extracts of human pNENs confirmed increased NRP-1 expression, as well as AKT/STAT3 phosphorylation in tissue of pNENs with elevated expression levels of IL-6. In conclusion, our findings suggest that NRP-1 is upregulated in pNEN and is correlated with the metastatic capacity of pNEN cells, potentially via interaction with the IL-6/STAT3 signaling pathway.
Collapse
Affiliation(s)
- Yongchao Yang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Linfei Yang
- Center for Medical Experiments, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yixiong Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China.
| |
Collapse
|
|
44
|
Abbas M, Faggian A, Sintali DN, Khan GJ, Naeem S, Shi M, Dingding C. Current and future biomarkers in gastric cancer. Biomed Pharmacother 2018; 103:1688-1700. [DOI: 10.1016/j.biopha.2018.04.178] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/24/2018] [Accepted: 04/24/2018] [Indexed: 02/06/2023] Open
|
|
45
|
Yadav DK, Bai X, Yadav RK, Singh A, Li G, Ma T, Chen W, Liang T. Liquid biopsy in pancreatic cancer: the beginning of a new era. Oncotarget 2018; 9:26900-26933. [PMID: 29928492 PMCID: PMC6003564 DOI: 10.18632/oncotarget.24809] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 02/25/2018] [Indexed: 12/21/2022] Open
Abstract
With dismal survival rate pancreatic cancer remains one of the most aggressive and devastating malignancy. Predominantly, due to the absence of a dependable methodology for early identification and limited therapeutic options for advanced disease. However, it takes over 17 years to develop pancreatic cancer from initiation of mutation to metastatic cancer; therefore, if diagnosed early; it may increase overall survival dramatically, thus, providing a window of opportunity for early detection. Recently, genomic expression analysis defined 4 subtypes of pancreatic cancer based on mutated genes. Hence, we need simple and standard, minimally invasive test that can monitor those altered genes or their associated pathways in time for the success of precision medicine, and liquid biopsy seems to be one answer to all these questions. Again, liquid biopsy has an ability to pair with genomic tests. Additionally, liquid biopsy based development of circulating tumor cells derived xenografts, 3D organoids system, real-time monitoring of genetic mutations by circulating tumor DNA and exosome as the targeted drug delivery vehicle holds lots of potential for the treatment and cure of pancreatic cancer. At present, diagnosis of pancreatic cancer is frantically done on the premise of CA19-9 and radiological features only, which doesn't give a picture of genetic mutations and epigenetic alteration involved. In this manner, the current diagnostic paradigm for pancreatic cancer diagnosis experiences low diagnostic accuracy. This review article discusses the current state of liquid biopsy in pancreatic cancer as diagnostic and therapeutic tools and future perspectives of research in the light of circulating tumor cells, circulating tumor DNA and exosomes.
Collapse
Affiliation(s)
- Dipesh Kumar Yadav
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Rajesh Kumar Yadav
- Department of Pharmacology, Gandaki Medical College, Tribhuwan University, Institute of Medicine, Pokhara 33700, Nepal
| | - Alina Singh
- Department of Surgery, Bir Hospital, National Academy of Medical Science, Kanti Path, Kathmandu 44600, Nepal
| | - Guogang Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| |
Collapse
|
|
46
|
Camilli M, Papadimitriou K, Nogueira A, Incorvaia L, Galvano A, D'Antonio F, Ferri J, Santini D, Silvestris N, Russo A, Peeters M, Rolfo C. Molecular profiling of pancreatic neuroendocrine tumors (pNETS) and the clinical potential. Expert Rev Gastroenterol Hepatol 2018; 12:471-478. [PMID: 29629846 DOI: 10.1080/17474124.2018.1463157] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Pancreatic neuroendocrine tumors (pNETs) represent a small part of pancreatic neoplasms, and the knowledge about their indolent clinical course remains a subject of investigation. They occur sporadically or as part of familial cancer syndromes and are classified by WHO in 3 categories. There is ongoing research to understand their molecular profiling and leading mutations. Areas covered: The aim of this review is to clarify the overall aspects of tumorigenesis, to expose the latest developments in understanding the course of the disease and the possible therapeutic implications of these. The review also discusses functional and non-functional pNETs and associated inherited syndromes as well as pNET molecular profiling and its possible guidance in the use of targeted therapy. Expert commentary: In the next decade, a more extensive application of new technologies will help improve quality of life and survival, individualizing treatment protocols and identifying which therapeutic strategy is more suitable for each kind of NET.
Collapse
Affiliation(s)
| | | | - Amanda Nogueira
- c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium
| | - Lorena Incorvaia
- d Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy
| | - Antonio Galvano
- d Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy
| | - Federica D'Antonio
- a Department of Oncology , University Campus Biomedico of Rome , Rome , Italy
| | - Jose Ferri
- c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium
| | - Daniele Santini
- c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium
| | - Nicola Silvestris
- e Medical Oncology Department , Oncological institute Giovanni Paolo II , Bari , Italy
| | - Antonio Russo
- d Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy
| | - Marc Peeters
- b Oncology Department , Antwerp University Hospital , Edegem , Belgium
| | - Christian Rolfo
- c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium
| |
Collapse
|
|
47
|
Liu Y, Lan W, Wang C, Cao C. A putative G-quadruplex structure in the proximal promoter of VEGFR-2 has implications for drug design to inhibit tumor angiogenesis. J Biol Chem 2018; 293:8947-8955. [PMID: 29666187 DOI: 10.1074/jbc.ra118.002666] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 04/03/2018] [Indexed: 01/11/2023] Open
Abstract
Tumor angiogenesis is mainly regulated by vascular endothelial growth factor (VEGF) produced by cancer cells. It is active on the endothelium via VEGF receptor 2 (VEGFR-2). G-quadruplexes are DNA secondary structures formed by guanine-rich sequences, for example, within gene promoters where they may contribute to transcriptional activity. The proximal promoter of VEGFR-2 contains a G-quadruplex, which has been suggested to interact with small molecules that inhibit VEGFR-2 expression and thereby tumor angiogenesis. However, its structure is not known. Here, we determined its NMR solution structure, which is composed of three stacked G-tetrads containing three syn guanines. The first guanine (G1) is positioned within the central G-tetrad. We also observed that a noncanonical, V-shaped loop spans three G-tetrad planes, including no bridging nucleotides. A long and diagonal loop, which includes six nucleotides, connects reversal double chains. With a melting temperature of 54.51 °C, the scaffold of this quadruplex is stabilized by one G-tetrad plane stacking with one nonstandard bp, G3-C8, whose bases interact with each other through only one hydrogen bond. In summary, the NMR solution structure of the G-quadruplex in the proximal promoter region of the VEGFR-2 gene reported here has uncovered its key features as a potential anticancer drug target.
Collapse
Affiliation(s)
- Yaping Liu
- From the State Key Laboratory of Bioorganic and Natural Product Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry and.,University of Chinese Academy of Sciences, Number 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China.,Collaborative Innovation Center of Chemistry for Life Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China and
| | - Wenxian Lan
- From the State Key Laboratory of Bioorganic and Natural Product Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry and.,University of Chinese Academy of Sciences, Number 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China
| | - Chunxi Wang
- From the State Key Laboratory of Bioorganic and Natural Product Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry and.,University of Chinese Academy of Sciences, Number 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China
| | - Chunyang Cao
- From the State Key Laboratory of Bioorganic and Natural Product Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry and .,University of Chinese Academy of Sciences, Number 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China.,Collaborative Innovation Center of Chemistry for Life Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China and
| |
Collapse
|
|
48
|
Shimizu A, Zankov DP, Kurokawa-Seo M, Ogita H. Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap. Int J Mol Sci 2018; 19:ijms19041203. [PMID: 29659486 PMCID: PMC5979568 DOI: 10.3390/ijms19041203] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/03/2018] [Accepted: 04/12/2018] [Indexed: 12/18/2022] Open
Abstract
Vascular endothelial growth factors (VEGFs) include five molecules (VEGF-A, -B, -C, -D, and placental growth factor), and have various roles that crucially regulate cellular functions in many kinds of cells and tissues. Intracellular signal transduction induced by VEGFs has been extensively studied and is usually initiated by their binding to two classes of transmembrane receptors: receptor tyrosine kinase VEGF receptors (VEGF receptor-1, -2 and -3) and neuropilins (NRP1 and NRP2). In addition to many established results reported by other research groups, we have previously identified small G proteins, especially Ras homologue gene (Rho) and Ras-related protein (Rap), as important mediators of VEGF-A-stimulated signaling in cancer cells as well as endothelial cells. This review article describes the VEGF-A-induced signaling pathways underlying diverse cellular functions, including cell proliferation, migration, and angiogenesis, and the involvement of Rho, Rap, and their related molecules in these pathways.
Collapse
Affiliation(s)
- Akio Shimizu
- Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
| | - Dimitar P Zankov
- Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
| | - Misuzu Kurokawa-Seo
- Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
| | - Hisakazu Ogita
- Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
| |
Collapse
|
|
49
|
Wei YL, Bai JA, He N, Tang QY. Tumor microenvironment of gastroenteropancreatic neuroendocrine neoplasms. Shijie Huaren Xiaohua Zazhi 2017; 25:2896-2905. [DOI: 10.11569/wcjd.v25.i32.2896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tumor microenvironment provides a unique environment for tumor development, where the biology behavior of tumor cells is regulated not only by their genetics but also by the surrounding environment. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) originating from the neuroendocrine cells of the gastroenteropancreatic system are characterized by a propensity to secrete a variety of peptide hormones and biogenic amines. The symptoms of GEP-NENs at early stages are often atypical, thus delaying the diagnosis. A further understanding of the pathobiology of GEP-NENs on the basis of studies on GEP-NENs tumor microenvironment can provide new evidence for clinical diagnosis and treatment. This review aims to introduce different cell types, several proteins involved in extracellular matrix remodeling, some growth factors, and chromogranin A (CgA) in the tumor microenvironment of GEP-NENs, in order to highlight their indispensable roles in GEP-NENs progression.
Collapse
Affiliation(s)
- Ya-Ling Wei
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Jian-An Bai
- Department of Gastroenterology, the Third Affiliated Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China
| | - Na He
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Qi-Yun Tang
- Department of General Practice, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| |
Collapse
|
|
50
|
Wiedmer T, Blank A, Pantasis S, Normand L, Bill R, Krebs P, Tschan MP, Marinoni I, Perren A. Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism. Mol Cancer Ther 2017; 16:2502-2515. [PMID: 28729403 DOI: 10.1158/1535-7163.mct-17-0136] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 06/08/2017] [Accepted: 07/05/2017] [Indexed: 12/28/2022]
Abstract
Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis in vitro, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials. Mol Cancer Ther; 16(11); 2502-15. ©2017 AACR.
Collapse
Affiliation(s)
- Tabea Wiedmer
- Institute of Pathology, University of Bern, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Annika Blank
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Sophia Pantasis
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Lea Normand
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Ruben Bill
- Department of Internal Medicine, Regional Hospital Emmental Burgdorf, Burgdorf, Switzerland
| | - Philippe Krebs
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Mario P Tschan
- Institute of Pathology, University of Bern, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Ilaria Marinoni
- Institute of Pathology, University of Bern, Bern, Switzerland.
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland.
| |
Collapse
|