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Li Y, Ladd Z, Xiong Z, Bui-Linh C, Paiboonrungruang C, Subramaniyan B, Li H, Wang H, Balch C, Shersher DD, Spitz F, Chen X. Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2 and Therapeutic Strategies. Cancers (Basel) 2025; 17:1853. [PMID: 40507333 PMCID: PMC12153707 DOI: 10.3390/cancers17111853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2025] [Revised: 05/26/2025] [Accepted: 05/28/2025] [Indexed: 06/16/2025] Open
Abstract
The lethality of esophageal squamous cell carcinoma (ESCC), and other epithelial cancers, is primarily due to its aggressive nature and frequent lymphatic metastasis, both of which impact prognosis. In this review, we explore the underlying molecular mechanisms of ESCC lymphatic metastasis, specifically, the functional role of NRF2 and therapeutic strategies. Current data suggest that NRF2 hyperactivation (NRF2high) may promote lymphatic metastasis of ESCC by affecting the extracellular matrix (ECM), epithelial-mesenchymal transition (EMT), lymphangiogenesis, immune evasion, metabolic programming, and Hippo signaling. We also update the latest developments in NRF2 inhibitors, their mechanisms of action, screening strategies, and approaches for evaluating compound efficacy. Finally, we highlight the utility of animal models for mechanistic studies and therapeutic development. We believe elucidation of the functional role of NRF2 in ESCC lymphatic metastasis and developing proper NRF2 inhibitors will greatly improve the clinical prognosis of ESCC in human patients.
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Affiliation(s)
- Yahui Li
- Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Y.L.); (Z.L.); (B.S.); (H.L.); (D.D.S.); (F.S.)
| | - Zachary Ladd
- Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Y.L.); (Z.L.); (B.S.); (H.L.); (D.D.S.); (F.S.)
- Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Zhaohui Xiong
- Coriell Institute for Medical Research, Camden, NJ 08103, USA; (Z.X.); (C.B.-L.); (C.P.); (C.B.)
| | - Candice Bui-Linh
- Coriell Institute for Medical Research, Camden, NJ 08103, USA; (Z.X.); (C.B.-L.); (C.P.); (C.B.)
| | | | - Boopathi Subramaniyan
- Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Y.L.); (Z.L.); (B.S.); (H.L.); (D.D.S.); (F.S.)
| | - Huan Li
- Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Y.L.); (Z.L.); (B.S.); (H.L.); (D.D.S.); (F.S.)
| | - Haining Wang
- Insilico Medicine Canada Inc., Montreal, QC H3B 4W8, Canada;
| | - Curt Balch
- Coriell Institute for Medical Research, Camden, NJ 08103, USA; (Z.X.); (C.B.-L.); (C.P.); (C.B.)
| | - David D. Shersher
- Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Y.L.); (Z.L.); (B.S.); (H.L.); (D.D.S.); (F.S.)
- Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- MD Anderson Cancer Center at Cooper, Camden, NJ 08103, USA
| | - Francis Spitz
- Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Y.L.); (Z.L.); (B.S.); (H.L.); (D.D.S.); (F.S.)
- Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- MD Anderson Cancer Center at Cooper, Camden, NJ 08103, USA
| | - Xiaoxin Chen
- Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Y.L.); (Z.L.); (B.S.); (H.L.); (D.D.S.); (F.S.)
- Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- Coriell Institute for Medical Research, Camden, NJ 08103, USA; (Z.X.); (C.B.-L.); (C.P.); (C.B.)
- MD Anderson Cancer Center at Cooper, Camden, NJ 08103, USA
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von Renesse J, Lin MC, Ho PC. Tumor-draining lymph nodes - friend or foe during immune checkpoint therapy? Trends Cancer 2025:S2405-8033(25)00104-9. [PMID: 40348668 DOI: 10.1016/j.trecan.2025.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/20/2025] [Accepted: 04/21/2025] [Indexed: 05/14/2025]
Abstract
The pivotal role of tumor-draining lymph nodes (TDLNs) in supporting antitumor immunity and serving as sites for cancer metastasis presents a clinical challenge: eliminate tumors while preserving antitumor immune responses. In this article, we explore the initiation of tumor-specific immune responses within lymph nodes (LNs), the immunocompromised microenvironment induced by tumors within LNs, and the crucial involvement of TDLNs in immunotherapy. Additionally, we examine the clinical prospects of modifying surgical procedures or therapy sequences to enhance the efficacy of cancer treatment.
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Affiliation(s)
- Janusz von Renesse
- Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Mei-Chun Lin
- Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland; Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
| | - Ping-Chih Ho
- Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
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Varvarousis DN, Marini AA, Ntritsos G, Barbouti A, Kitsoulis PV, Kanavaros PE. Relationship of lymphatic vessel invasion and density with clinicopathological parameters and survival in patients with gastric carcinoma: A systematic review and meta-analysis. Pathol Res Pract 2025; 269:155877. [PMID: 40024076 DOI: 10.1016/j.prp.2025.155877] [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: 01/19/2025] [Revised: 02/16/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
The purpose of this study was to conduct a comprehensive review and meta-analysis to investigate the possible relationship of lymphatic vessel invasion (LVI) and lymphatic vessel density (LVD), evaluated using immunohistochemistry, with survival and clinicopathological parameters in patients with gastric carcinoma. The principal result of this meta-analysis was the statistically significant correlation between LVI and presence of lymph node metastasis. This finding, in view of previous data showing that lymph node metastasis is associated with decreased survival, suggests that LVI may be a negative prognostic factor in gastric carcinoma. In contrast, LVD, whether assessed overall, intratumorally, or peritumorally, showed no statistically significant correlation with survival. The major conclusion of this meta-analysis is that LVI is an important indicator of aggressiveness of gastric carcinomas and may be a negative prognostic factor because of the strong association between LVI and presence of lymph node metastasis.
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Affiliation(s)
| | - Aikaterini A Marini
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Greece
| | - Georgios Ntritsos
- Department of Economics, University of Ioannina, University Campus, Ioannina, Greece; Department of Informatics and Telecommunications, School of Informatics & Telecommunications, University of Ioannina, Arta, Greece
| | - Alexandra Barbouti
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Greece
| | - Panagiotis V Kitsoulis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Greece
| | - Panagiotis E Kanavaros
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Greece
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Masmoudi D, Villalba M, Alix-Panabières C. Natural killer cells: the immune frontline against circulating tumor cells. J Exp Clin Cancer Res 2025; 44:118. [PMID: 40211394 PMCID: PMC11983744 DOI: 10.1186/s13046-025-03375-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 03/25/2025] [Indexed: 04/14/2025] Open
Abstract
Natural killer (NK) play a key role in controlling tumor dissemination by mediating cytotoxicity towards cancer cells without the need of education. These cells are pivotal in eliminating circulating tumor cells (CTCs) from the bloodstream, thus limiting cancer spread and metastasis. However, aggressive CTCs can evade NK cell surveillance, facilitating tumor growth at distant sites. In this review, we first discuss the biology of NK cells, focusing on their functions within the tumor microenvironment (TME), the lymphatic system, and circulation. We then examine the immune evasion mechanisms employed by cancer cells to inhibit NK cell activity, including the upregulation of inhibitory receptors. Finally, we explore the clinical implications of monitoring circulating biomarkers, such as NK cells and CTCs, for therapeutic decision-making and emphasize the need to enhance NK cell-based therapies by overcoming immune escape mechanisms.
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Affiliation(s)
- Doryan Masmoudi
- Laboratory of Rare Circulating Human Cells, University Medical Center of Montpellier, Montpellier, France
| | - Martin Villalba
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Catherine Alix-Panabières
- Laboratory of Rare Circulating Human Cells, University Medical Center of Montpellier, Montpellier, France.
- CREEC/CANECEV, MIVEGEC (CREES), University of Montpellier, CNRS, Montpellier, IRD, France.
- European Liquid Biopsy Society (ELBS), Hamburg, Germany.
- LCCRH, Site Unique de Biologie (SUB), 641, Avenue du Doyen Gaston Giraud, Montpellier, 34093, France.
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Jacome MA, Wu Q, Chen J, Mohamed ZS, Mokhtari S, Piña Y, Etame AB. Molecular Underpinnings of Brain Metastases. Int J Mol Sci 2025; 26:2307. [PMID: 40076927 PMCID: PMC11900073 DOI: 10.3390/ijms26052307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 02/28/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Brain metastases are the most commonly diagnosed type of central nervous system tumor, yet the mechanisms of their occurrence are still widely unknown. Lung cancer, breast cancer, and melanoma are the most common etiologies, but renal and colorectal cancers have also been described as metastasizing to the brain. Regardless of their origin, there are common mechanisms for progression to all types of brain metastases, such as the creation of a suitable tumor microenvironment in the brain, priming of tumor cells, adaptations to survive spreading in lymphatic and blood vessels, and development of mechanisms to penetrate the blood-brain barrier. However, there are complex genetic and molecular interactions that are specific to every type of primary tumor, making the understanding of the metastatic progression of tumors to the brain a challenging field of study. In this review, we aim to summarize current knowledge on the pathophysiology of brain metastases, from specific genetic characteristics of commonly metastatic tumors to the molecular and cellular mechanisms involved in progression to the central nervous system. We also briefly discuss current challenges in targeted therapies for brain metastases and how there is still a gap in knowledge that needs to be overcome to improve patient outcomes.
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Affiliation(s)
- Maria A. Jacome
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
| | - Qiong Wu
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (Q.W.); (J.C.); (S.M.); (Y.P.)
| | - Jianan Chen
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (Q.W.); (J.C.); (S.M.); (Y.P.)
| | | | - Sepideh Mokhtari
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (Q.W.); (J.C.); (S.M.); (Y.P.)
| | - Yolanda Piña
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (Q.W.); (J.C.); (S.M.); (Y.P.)
| | - Arnold B. Etame
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (Q.W.); (J.C.); (S.M.); (Y.P.)
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Sun M, Angelillo J, Hugues S. Lymphatic transport in anti-tumor immunity and metastasis. J Exp Med 2025; 222:e20231954. [PMID: 39969537 PMCID: PMC11837853 DOI: 10.1084/jem.20231954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/18/2024] [Accepted: 02/06/2025] [Indexed: 02/20/2025] Open
Abstract
Although lymphatic vessels (LVs) are present in many tumors, their importance in cancer has long been underestimated. In contrast to the well-studied tumor-associated blood vessels, LVs were previously considered to function as passive conduits for tumor metastasis. However, emerging evidence over the last two decades has shed light on their critical role in locally shaping the tumor microenvironment (TME). Here we review the involvement of LVs in tumor progression, metastasis, and modulation of anti-tumor immune response.
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Affiliation(s)
- Mengzhu Sun
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Julien Angelillo
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Stéphanie Hugues
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
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Poghosyan S, Frenkel N, van den Bent L, Raats D, Spaapen T, Laoukili J, Borel Rinkes I, Kranenburg O, Hagendoorn J. VEGF-C propagates 'onward' colorectal cancer metastasis from liver to lung. Br J Cancer 2025; 132:69-80. [PMID: 39521880 PMCID: PMC11724081 DOI: 10.1038/s41416-024-02892-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/09/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The formation of lung metastasis as part of the progression of colon cancer is a poorly understood process. Theoretically, liver metastases could seed lung metastases. METHODS To assess the contribution of the liver lymphatic vasculature to metastatic spread to the lungs, we generated murine liver-metastasis-derived organoids overexpressing vascular endothelial growth factor (VEGF)-C. The organoids were reimplanted into the mouse liver for tumour generation and onward metastasis. RESULTS Liver metastases from patients with concomitant lung metastases showed higher expression of VEGF-C, lymphatic vessel hyperplasia, and tumour cell invasion into lymphatic vessels when compared to those without lung metastases. Reimplantation of VEGF-C overexpressing organoids into the mouse liver showed that VEGF-C caused peritumoral lymphatic vessel hyperplasia, lymphatic tumour cell invasion, and lung metastasis formation. This change in metastatic organotropism was accompanied by reduced expression of WNT-driven adult stem cell markers, and increased expression of fetal stem cell markers and NOTCH pathway genes. Further NOTCH pathway inhibition with γ-secretase inhibitor (DAPT) in vivo results in a slight reduction in lung metastases and a decrease in lymphatic hyperplasia and invasion in VEGF-C-overexpressing tumours. CONCLUSION Collectively, these data indicate that VEGF-C can drive onward metastasis from the liver to the lung and suggest that targeting VEGF-C/NOTCH pathways may impair the progression of colorectal cancer.
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Affiliation(s)
- Susanna Poghosyan
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.
| | - Nicola Frenkel
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Lotte van den Bent
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Danielle Raats
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Tessa Spaapen
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Jamila Laoukili
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Inne Borel Rinkes
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Onno Kranenburg
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Jeroen Hagendoorn
- Laboratory for Translational Oncology and Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
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Tian L, Syed-Abdul MM, Lewis GF. Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport. GASTRO HEP ADVANCES 2024; 4:100605. [PMID: 40242171 PMCID: PMC12001124 DOI: 10.1016/j.gastha.2024.100605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/21/2024] [Indexed: 04/18/2025]
Abstract
Background and Aims A significant proportion of absorbed dietary triglycerides (TGs) remain in various intracellular and extracellular intestinal compartments for many hours after fat ingestion, including in the lymphatic circulation. TGs retained in the intestine or lymphatics can be mobilized by the gut peptide glucagon-like peptide 2 (GLP-2) and other stimuli. Our previous published data demonstrated that GLP-2 enhances lymph flow by acting distal to the enterocyte, specifically by enhancing lacteal contractility, in an enteric nervous system-dependent fashion. The objective of the present study was to further explore various intermediates in the signaling pathway whereby GLP-2 enhances mesenteric lymph flow. In this study we focused on the roles of vascular endothelial growth factor receptor 3 (VEGFR3) and myosin light chain 2 (MLC2), known to play important roles in lymphangiogenesis and lymphatic contractility, respectively. Methods A rat lymph fistula model was utilized in this study. An intraduodenal lipid bolus was applied to the rats 5 hours before the following intraperitoneal (i.p.) administrations: 1) saline (placebo), 2) GLP-2, 3) GLP-2 + MAZ-51 (a VEGFR3 inhibitor), 4) GLP-2 + SAR131675 (a second VEGFR3 inhibitor), 5) GLP-2 + ML-7 (a MLCK inhibitor). Lymph flow and TG output were assessed for 60 minutes after the i.p. administrations. In another set of animals, post-i.p. administration, tissue samples were collected to quantify VEGFR3 and MLC2 activation (via phosphorylation). Results We showed that GLP-2 treatment acutely activated VEGFR3 and MLC2, and that inhibition of VEGFR3 (via MAZ-51/SAR131675) and MLC2 (via ML-7) abolished GLP-2-induced lymph flow and TG output. Furthermore, VEGFR3 inhibition blocked MLC2 activation. Conclusion Our data suggest that the activation of VEGFR3 and MLC2 play critical roles in GLP-2's enhancement of chylomicron secretion and that VEGFR3 activation is an important intermediary step in GLP-2's activation of MLC2.
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Affiliation(s)
| | | | - Gary F. Lewis
- Division of Endocrinology, Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada
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Lin W, Li Q, Sheng J, Zhao Y, Cui W. Quantitative analysis of peri-intestinal lymph node metastasis using indocyanine green fluorescence imaging technology. Medicine (Baltimore) 2024; 103:e39240. [PMID: 39213221 PMCID: PMC11365658 DOI: 10.1097/md.0000000000039240] [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: 01/10/2024] [Revised: 06/25/2024] [Accepted: 07/19/2024] [Indexed: 09/04/2024] Open
Abstract
We evaluated the efficacy of indocyanine green fluorescence imaging compared to that of traditional nanocarbon dyes in assessing peri-intestinal lymph node metastasis in patients with colorectal cancer, which is a key prognostic factor. The relationship between indocyanine green fluorescence imaging and histopathological outcomes in patients with colon cancer has also been explored. A retrospective analysis was conducted on 30 patients with colon cancer (from May to October 2023) confirmed by surgical pathology. Tumors were marked with indocyanine green (ICG) or nanocarbon via colonoscopy 16 to 24 hours before surgery. Within 15 minutes after surgery, peri-intestinal lymph node fluorescence imaging and hematoxylin and eosin staining were used to assess the distribution of cancer foci. The correlation between cancer foci distribution, fluorescence intensity, and area under the receiver operating characteristic curve was measured. Among 243 metastatic lymph nodes from 30 patients, 18 were found. After the patients were divided into metastatic and nonmetastatic groups, significant differences in tumor differentiation and stage were noted (P < .001). The fluorescence intensity was strongly correlated with the presence and proportion of metastasis (area under the receiver operating characteristic curve = 0.931), whereas nanocarbon staining showed no significant correlation (P = .81). All P values were two-sided, with P < .05 indicating statistical significance. Lymph nodes with malignant intestinal tumor metastasis displayed weaker ICG fluorescence than did nonmetastatic nodes. Combining ICG and nanocarbon staining techniques enhances intraoperative lymph node dissection and postoperative analysis, indicating their potential utility in colorectal cancer surgery.
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Affiliation(s)
- Weiyang Lin
- Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Qi Li
- Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Jie Sheng
- Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Yibing Zhao
- Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
| | - Wei Cui
- Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China
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Paladiya R, Khoury N, Shah M, Moond V, Patel N, Bahirwani J, Garg A, Sohal A, Vaziri H. Exploring the Protective Role of Aspirin Use in Mitigating Colorectal Cancer (CRC) Metastasis: A Nationwide Analysis (2016 to 2020). J Clin Gastroenterol 2024:00004836-990000000-00324. [PMID: 39042482 DOI: 10.1097/mcg.0000000000002045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/12/2024] [Indexed: 07/25/2024]
Abstract
Despite advancements in treatment strategies, the mortality from colorectal cancer (CRC) remains high. Evidence suggests that aspirin (ASA) may have a protective effect on CRC incidence and metastasis through various mechanisms. The 2016 to 2020 National Inpatient Sample was used to identify adult patients (age above 18 y) with the principal diagnosis of CRC. Patients were stratified into 2 groups based on ASA use. The outcomes studied were in-hospital mortality and rates of total, gastrointestinal (GI), non-GI, and lymphoid metastasis. A multivariate logistic regression analysis was performed to evaluate the impact of ASA use on outcomes after adjusting for patient demographics, comorbidities, and the Elixhauser Comorbidity Index (ECI). Of the 814,270 patients, 88,620 (10.8%) used ASA, with the majority being aged above 65 years (78%), male (57%), white (77.6%), and had Medicare insurance (74.5%). There was a higher prevalence of Diabetes mellitus, Hypertension, Chronic pulmonary disease, Coronary artery disease, Chronic kidney disease, Chronic heart failure, Obesity, and Smoking among aspirin users than among non-ASA users. Patients who used ASA had a lower prevalence of total (47.3% vs. 32.5%, P<0.001), GI (22.2% vs. 32.4%, P<0.001), non-GI (9.9% vs. 15.3%, P<0.001), and lymphoid (9.3% vs. 10.9%, P<0.001) metastasis compared with those who did not use ASA. After adjusting for confounding factors, patients with ASA use had lower odds of total (aOR: 0.75, 95% CI: 0.72-0.78, P<0.001), GI (aOR: 0.74, 95% CI: 0.71-0.77, P<0.001), non-GI (aOR: 0.72, 95% CI: 0.68-0.77, P<0.1), and statistically insignificant odds of lymphoid (aOR: 0.95, 95% CI: 0.90-1.00, P=0.098) metastasis. The use of ASA is associated with a decrease in the prevalence of metastasis among individuals diagnosed with CRC, but additional studies are required to elucidate the mechanism and duration of therapy needed to be effective.
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Affiliation(s)
| | - Neil Khoury
- Gastroenterology, University of Connecticut Health Center, Farmington, CT
| | - Mihir Shah
- Department of Medicine, John H Stroger Jr Hospital of Cook County, Chicago, IL
| | - Vishali Moond
- Department of Medicine, Saint Peter's University Hospital, New Brunswick, NJ
| | - Nishit Patel
- Department of Gastroenterology, St Luke's University Health Network, Bethlehem, PA
| | - Janak Bahirwani
- Department of Gastroenterology, St Luke's University Health Network, Bethlehem, PA
| | - Ayushi Garg
- Department of Medicine, Trident Medical Center, Charleston, SC
| | - Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, WA
| | - Haleh Vaziri
- Gastroenterology, University of Connecticut Health Center, Farmington, CT
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11
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Fan S, Qi M, Qi Q, Miao Q, Deng L, Pan J, Qiu S, He J, Huang M, Li X, Huang J, Lin J, Lyu W, Deng W, He Y, Liu X, Gao L, Zhang D, Ye W, Chen M. Targeting FAP α-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis. Acta Pharm Sin B 2024; 14:682-697. [PMID: 38322324 PMCID: PMC10840431 DOI: 10.1016/j.apsb.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/18/2023] [Accepted: 10/24/2023] [Indexed: 02/08/2024] Open
Abstract
Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.
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Affiliation(s)
- Shuran Fan
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Ming Qi
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Qi Qi
- School of Medicine, Jinan University, Guangzhou 510632, China
| | - Qun Miao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Lijuan Deng
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510630, China
| | - Jinghua Pan
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Shenghui Qiu
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Jiashuai He
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Maohua Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiaobo Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jie Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jiapeng Lin
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Wenyu Lyu
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Weiqing Deng
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yingyin He
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xuesong Liu
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Lvfen Gao
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Dongmei Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Wencai Ye
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Minfeng Chen
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China
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12
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Dahms P, Lyons TR. Toward Characterizing Lymphatic Vasculature in the Mammary Gland During Normal Development and Tumor-Associated Remodeling. J Mammary Gland Biol Neoplasia 2024; 29:1. [PMID: 38218743 PMCID: PMC10787674 DOI: 10.1007/s10911-023-09554-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 12/24/2023] [Indexed: 01/15/2024] Open
Abstract
Lymphatic vasculature has been shown to promote metastatic spread of breast cancer. Lymphatic vasculature, which is made up of larger collecting vessels and smaller capillaries, has specialized cell junctions that facilitate cell intravasation. Normally, these junctions are designed to collect immune cells and other cellular components for immune surveillance by lymph nodes, but they are also utilized by cancer cells to facilitate metastasis. Although lymphatic development overall in the body has been well-characterized, there has been little focus on how the lymphatic network changes in the mammary gland during stages of remodeling such as pregnancy, lactation, and postpartum involution. In this review, we aim to define the currently known lymphangiogenic factors and lymphatic remodeling events during mammary gland morphogenesis. Furthermore, we juxtapose mammary gland pubertal development and postpartum involution to show similarities of pro-lymphangiogenic signaling as well as other molecular signals for epithelial cell survival that are critical in these morphogenic stages. The similar mechanisms include involvement of M2-polarized macrophages that contribute to matrix remodeling and vasculogenesis; signal transducer and activator of transcription (STAT) survival and proliferation signaling; and cyclooxygenase 2 (COX2)/Prostaglandin E2 (PGE2) signaling to promote ductal and lymphatic expansion. Investigation and characterization of lymphangiogenesis in the normal mammary gland can provide insight to targetable mechanisms for lymphangiogenesis and lymphatic spread of tumor cells in breast cancer.
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Affiliation(s)
- Petra Dahms
- Division of Medical Oncology Senior Scientist, Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, 12801 E 17th Ave, RC1 South, Mailstop 8117, 80045, Aurora, CO, USA
- Division of Medical Oncology, Anschutz Medical Center, University of Colorado, Aurora, CO, USA
- Anschutz Medical Campus Graduate Program in Cancer Biology, University of Colorado, Aurora, USA
| | - Traci R Lyons
- Division of Medical Oncology Senior Scientist, Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, 12801 E 17th Ave, RC1 South, Mailstop 8117, 80045, Aurora, CO, USA.
- Division of Medical Oncology, Anschutz Medical Center, University of Colorado, Aurora, CO, USA.
- Anschutz Medical Campus Graduate Program in Cancer Biology, University of Colorado, Aurora, USA.
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13
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Vimalraj S, Hariprabu KNG, Rahaman M, Govindasami P, Perumal K, Sekaran S, Ganapathy D. Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis. 3 Biotech 2023; 13:326. [PMID: 37663750 PMCID: PMC10474002 DOI: 10.1007/s13205-023-03719-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 07/13/2023] [Indexed: 09/05/2023] Open
Abstract
The cancer-promoting ligand vascular endothelial growth factor-C (VEGF-C) activates VEGF receptor-3 (VEGFR-3). The VEGF-C/VEGFR-3 axis is expressed by a range of human tumor cells in addition to lymphatic endothelial cells. Activating the VEGF-C/VEGFR-3 signaling enhances metastasis by promoting lymphangiogenesis and angiogenesis inside and around tumors. Stimulation of VEGF-C/VEGFR-3 signaling promotes tumor metastasis in tumors, such as ovarian, renal, pancreatic, prostate, lung, skin, gastric, colorectal, cervical, leukemia, mesothelioma, Kaposi sarcoma, and endometrial carcinoma. We discuss and update the role of VEGF-C/VEGFR-3 signaling in tumor development and the research is still needed to completely comprehend this multifunctional receptor.
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Affiliation(s)
- Selvaraj Vimalraj
- Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology, Madras, Chennai, India
| | | | - Mostafizur Rahaman
- Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451 Saudi Arabia
| | - Periyasami Govindasami
- Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451 Saudi Arabia
| | - Karthikeyan Perumal
- Department of Chemistry and Biochemistry, The Ohio State University, 151 W. Woodruff Ave, Columbus, OH 43210 USA
| | - Saravanan Sekaran
- Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu 600 077 India
| | - Dhanraj Ganapathy
- Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu 600 077 India
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14
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Leichner GS, Schweitzer I, Dror S, Levin L, Geva P, Golan T, Zaremba L, Shapira G, Parikh R, Shomron N, Barzilai A, Hoheisel JD, Levy C, Greenberger S. Primary Melanoma miRNA Trafficking Induces Lymphangiogenesis. J Invest Dermatol 2023; 143:1788-1798.e7. [PMID: 36934839 DOI: 10.1016/j.jid.2023.02.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 01/29/2023] [Accepted: 02/12/2023] [Indexed: 03/19/2023]
Abstract
Melanoma, the deadliest cutaneous tumor, initiates within the epidermis; during progression, cells invade into the dermis and become metastatic through the lymphatic and blood system. Before melanoma cell invasion into the dermis, an increased density of dermal lymphatic vessels is observed, generated by a mechanism which is not fully understood. In this study, we show that, while at the primary epidermal stage (in situ), melanoma cells secrete extracellular vesicles termed melanosomes, which are uptaken by dermal lymphatic cells, leading to transcriptional and phenotypic pro-lymphangiogenic changes. Mechanistically, melanoma-derived melanosomes traffic mature let-7i to lymphatic endothelial cells, which mediate pro-lymphangiogenic phenotypic changes by the induction of type I IFN signaling. Furthermore, transcriptome analysis upon treatment with melanosomes or let-7i reveals the enhancement of IFI6 expression in lymphatic cells. Because melanoma cells metastasize primarily via lymphatic vessels, our data suggest that blocking lymphangiogenesis by repressing either melanosome release or type I IFN signaling will prevent melanoma progression to the deadly metastatic stage.
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Affiliation(s)
- Gil S Leichner
- Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel
| | - Inbal Schweitzer
- Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel
| | - Shani Dror
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Lotan Levin
- Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel
| | - Polina Geva
- Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel
| | - Tamar Golan
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Laureen Zaremba
- Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Guy Shapira
- Department of Cell and Development Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Roma Parikh
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Noam Shomron
- Department of Cell and Development Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Aviv Barzilai
- Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jörg D Hoheisel
- Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Carmit Levy
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shoshana Greenberger
- Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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15
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Peng JM, Su YL. Lymph node metastasis and tumor-educated immune tolerance: Potential therapeutic targets against distant metastasis. Biochem Pharmacol 2023; 215:115731. [PMID: 37541450 DOI: 10.1016/j.bcp.2023.115731] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/30/2023] [Accepted: 08/01/2023] [Indexed: 08/06/2023]
Abstract
Lymph node metastasis has been shown to positively associated with the prognosis of many cancers. However, in clinical treatment, lymphadenectomy is not always successful, suggesting that immune cells in the tumor and sentinel lymph nodes still play a pivotal role in tumor immunosuppression. Recent studies had shown that tumors can tolerate immune cells through multiple strategies, including tumor-induced macrophage reprogramming, T cells inactivation, production of B cells pathogenic antibodies and activation of regulatory T cells to promote tumor colonization, growth, and metastasis in lymph nodes. We reviewed the bidirectional effect of immune cells on anti-tumor or promotion of cancer cell metastasis during lymph node metastasis, and the mechanisms by which malignant cancer cells modify immune cells to create a more favorable environment for the growth and survival of cancer cells. Research and treatment strategies focusing on the immune system in lymph nodes and potential immune targets in lymph node metastasis were also be discussed.
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Affiliation(s)
- Jei-Ming Peng
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist., Kaohsiung, 83301, Taiwan.
| | - Yu-Li Su
- Division of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, No. 123, Dapi Rd., Niaosong Dist., Kaohsiung, 83301, Taiwan.
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16
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Knopf P, Stowbur D, Hoffmann SHL, Fransen MF, Schwenck J, Pichler BJ, Kneilling M. Preclinical Identification Of Tumor-Draining Lymph Nodes Using a Multimodal Non-invasive In vivo Imaging Approach. Mol Imaging Biol 2023; 25:606-618. [PMID: 36600172 PMCID: PMC10172276 DOI: 10.1007/s11307-022-01797-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/21/2022] [Accepted: 12/06/2022] [Indexed: 01/05/2023]
Abstract
PURPOSE Resection of the tumor-draining lymph -node (TDLN) represents a standard method to identify metastasis for several malignancies. Interestingly, recent preclinical studies indicate that TDLN resection diminishes the efficacy of immune checkpoint inhibitor-based cancer immunotherapies. Thus, accurate preclinical identification of TDLNs is pivotal to uncovering the underlying immunological mechanisms. Therefore, we validated preclinically, and clinically available non-invasive in vivo imaging approaches for precise TDLN identification. PROCEDURES For visualization of the lymphatic drainage into the TDLNs by non-invasive in vivo optical imaging, we injected the optical imaging contrast agents Patent Blue V (582.7 g mol-1) and IRDye® 800CW polyethylene glycol (PEG; 25,000-60,000 g mol-1), subcutaneously (s.c.) in close proximity to MC38 adenocarcinomas at the right flank of experimental mice. For determination of the lymphatic drainage and the glucose metabolism in TDLNs by non-invasive in vivo PET/magnetic resonance imaging (PET/MRI), we injected the positron emission tomography (PET) tracer (2-deoxy-2[18F]fluoro-D-glucose (18F-FDG) [181.1 g mol-1]) in a similar manner. For ex vivo cross-correlation, we isolated TDLNs and contralateral nontumor-draining lymph nodes (NTDLNs) and performed optical imaging, biodistribution, and autoradiography analysis. RESULTS The clinically well-established Patent Blue V was superior for intraoperative macroscopic identification of the TDLNs compared with IRDye® 800CW PEG but was not sensitive enough for non-invasive in vivo detection by optical imaging. Ex vivo Patent Blue V biodistribution analysis clearly identified the right accessory axillary and the proper axillary lymph node (LN) as TDLNs, whereas ex vivo IRDye® 800CW PEG completely failed. In contrast, functional non-invasive in vivo 18F-FDG PET/MRI identified a significantly elevated uptake exclusively within the ipsilateral accessory axillary TDLN of experimental mice and was able to differentiate between the accessory axillary and the proper LN. Ex vivo biodistribution and autoradiography confirmed our in vivo 18F-FDG PET/MRI results. CONCLUSIONS When taken together, our results demonstrate the feasibility of 18F-FDG-PET/MRI as a valid method for non-invasive in vivo, intraoperative, and ex vivo identification of the lymphatic drainage and glucose metabolism within the TDLNs. In addition, using Patent Blue V provides additive value for the macroscopic localization of the lymphatic drainage both visually and by ex vivo optical imaging analysis. Thus, both methods are valuable, easy to implement, and cost-effective for preclinical identification of the TDLN.
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Affiliation(s)
- Philipp Knopf
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - Dimitri Stowbur
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", 72076, Tübingen, Germany
| | - Sabrina H L Hoffmann
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - Marieke F Fransen
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Johannes Schwenck
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", 72076, Tübingen, Germany.,Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard Karls University, Tübingen, Germany
| | - Bernd J Pichler
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", 72076, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center, Heidelberg, Germany
| | - Manfred Kneilling
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany. .,Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", 72076, Tübingen, Germany. .,Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
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17
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Shi S, Ye L, Yu X, Jin K, Wu W. Focus on mast cells in the tumor microenvironment: Current knowledge and future directions. Biochim Biophys Acta Rev Cancer 2023; 1878:188845. [PMID: 36476563 DOI: 10.1016/j.bbcan.2022.188845] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/01/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
Mast cells (MCs) are crucial cells participating in both innate and adaptive immune processes that play important roles in protecting human health and in the pathophysiology of various diseases, such as allergies, cardiovascular diseases, and autoimmune diseases. In the context of tumors, MCs are a non-negligible population of immune cells in the tumor microenvironment (TME). In most tumor types, MCs accumulate in both the tumor tissue and the surrounding tissue. MCs interact with multiple components of the TME, affecting TME remodeling and the tumor cell fate. However, controversy persists regarding whether MCs contribute to tumor progression or trigger an anti-tumor immune response. This review focuses on the context of the TME to explore the specific properties and functions of MCs and discusses the crosstalk that occurs between MCs and other components of the TME, which affect tumor angiogenesis and lymphangiogenesis, invasion and metastasis, and tumor immunity through different mechanisms. We also anticipate the potential role of MCs in cancer immunotherapy, which might expand upon the success achieved with existing cancer therapies.
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Affiliation(s)
- Saimeng Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Longyun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Weiding Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
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18
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Michielon E, de Gruijl TD, Gibbs S. From simplicity to complexity in current melanoma models. Exp Dermatol 2022; 31:1818-1836. [PMID: 36103206 PMCID: PMC10092692 DOI: 10.1111/exd.14675] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 08/30/2022] [Accepted: 09/11/2022] [Indexed: 12/14/2022]
Abstract
Despite the recent impressive clinical success of immunotherapy against melanoma, development of primary and adaptive resistance against immune checkpoint inhibitors remains a major issue in a large number of treated patients. This highlights the need for melanoma models that replicate the tumor's intricate dynamics in the tumor microenvironment (TME) and associated immune suppression to study possible resistance mechanisms in order to improve current and test novel therapeutics. While two-dimensional melanoma cell cultures have been widely used to perform functional genomics screens in a high-throughput fashion, they are not suitable to answer more complex scientific questions. Melanoma models have also been established in a variety of experimental (humanized) animals. However, due to differences in physiology, such models do not fully represent human melanoma development. Therefore, fully human three-dimensional in vitro models mimicking melanoma cell interactions with the TME are being developed to address this need for more physiologically relevant models. Such models include melanoma organoids, spheroids, and reconstructed human melanoma-in-skin cultures. Still, while major advances have been made to complement and replace animals, these in vitro systems have yet to fully recapitulate human tumor complexity. Lastly, technical advancements have been made in the organ-on-chip field to replicate functions and microstructures of in vivo human tissues and organs. This review summarizes advancements made in understanding and treating melanoma and specifically aims to discuss the progress made towards developing melanoma models, their applications, limitations, and the advances still needed to further facilitate the development of therapeutics.
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Affiliation(s)
- Elisabetta Michielon
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands.,Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands.,Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
| | - Tanja D de Gruijl
- Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands.,Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands.,Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands
| | - Susan Gibbs
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands.,Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands.,Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, The Netherlands
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19
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Yang Y, Cao Y. The impact of VEGF on cancer metastasis and systemic disease. Semin Cancer Biol 2022; 86:251-261. [PMID: 35307547 DOI: 10.1016/j.semcancer.2022.03.011] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/08/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023]
Abstract
Metastasis is the leading cause of cancer-associated mortality and the underlying mechanisms of cancer metastasis remain elusive. Both blood and lymphatic vasculatures are essential structures for mediating distal metastasis. The vasculature plays multiple functions, including accelerating tumor growth, sustaining the tumor microenvironment, supplying growth and invasive signals, promoting metastasis, and causing cancer-associated systemic disease. VEGF is one of the key angiogenic factors in tumors and participates in the initial stage of tumor development, progression and metastasis. Consequently, VEGF and its receptor-mediated signaling pathways have become one of the most important therapeutic targets for treating various cancers. Today, anti-VEGF-based antiangiogenic drugs (AADs) are widely used in the clinic for treating different types of cancer in human patients. Despite nearly 20-year clinical experience with AADs, the impact of these drugs on cancer metastasis and systemic disease remains largely unknown. In this review article, we focus our discussion on tumor VEGF in cancer metastasis and systemic disease and mechanisms underlying AADs in clinical benefits.
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Affiliation(s)
- Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institute, 171 77 Stockholm, Sweden.
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20
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钟 江, 王 洁, 叶 秀, 范 松, 王 友, 陈 伟. [High expression of CCBE1 in adjacent tissues of tongue squamous cell carcinoma is correlated with pericancerous lymphatic vessel proliferation and poor 5-year survival outcomes]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:1545-1551. [PMID: 36329590 PMCID: PMC9637508 DOI: 10.12122/j.issn.1673-4254.2022.10.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To examine the correlation of CCBE1 expression in adjacent tissues of tongue squamous cell carcinoma (TSCC) with pericancerous lymphatic vessel proliferation, cervical lymph node metastasis and survival outcomes of the patients. METHODS Lymphatic vessel density was quantified in pericancerous tissue sections of 44 cases of cT1-2N0 TSCC using D2-40 as the lymphatic vessel endothelial marker for calibration and counting of the lymphatic vessels. Of these 44 cases, 22 showed a relatively low lymphatic vessel density (group A) and the other 22 had a high lymphatic vessel density (group B), and the expression levels of CCBE1 in the adjacent tissues determined using immunohistochemistry, immunofluorescence assay and Western blotting were compared between the two groups. The expression level of CCBE1 was also measured in another 90 patients with TSCC using immunohistochemistry, and all the patients were followed up for their survival outcomes. RESULTS Immunohistochemistry and Western blotting showed a significantly lower rate of high CCBE1 expression in group A than in group B (P < 0.05). Immunofluorescence assay showed co-localization of CCBE1 and D2-40 in the adjacent tissues of TSCC. In the 90 TSCC patients with complete follow-up data, a high expression of CCBE1 was found to correlate with lymph node metastasis and a poor 5-year survival outcomes of the patients (P < 0.05). CONCLUSION A high expression of CCBE1 in the adjacent tissues of TSCC is closely related with pericancerous lymphatic vessel proliferation, cervical lymph node metastasis and a poor 5-year survival of the patients, suggesting the value of CCBE1 as a potential prognostic predictor for TSCC.
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Affiliation(s)
- 江龙 钟
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 洁琪 王
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 秀华 叶
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 松 范
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 友元 王
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 伟良 陈
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
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21
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Khadria A, Paavola CD, Zhang Y, Davis SPX, Grealish PF, Maslov K, Shi J, Beals JM, Oladipupo SS, Wang LV. Long-Duration and Non-Invasive Photoacoustic Imaging of Multiple Anatomical Structures in a Live Mouse Using a Single Contrast Agent. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202907. [PMID: 35975459 PMCID: PMC9534965 DOI: 10.1002/advs.202202907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/29/2022] [Indexed: 06/15/2023]
Abstract
Long-duration in vivo simultaneous imaging of multiple anatomical structures is useful for understanding physiological aspects of diseases, informative for molecular optimization in preclinical models, and has potential applications in surgical settings to improve clinical outcomes. Previous studies involving simultaneous imaging of multiple anatomical structures, for example, blood and lymphatic vessels as well as peripheral nerves and sebaceous glands, have used genetically engineered mice, which require expensive and time-consuming methods. Here, an IgG4 isotype control antibody is labeled with a near-infrared dye and injected into a mouse ear to enable simultaneous visualization of blood and lymphatic vessels, peripheral nerves, and sebaceous glands for up to 3 h using photoacoustic microscopy. For multiple anatomical structure imaging, peripheral nerves and sebaceous glands are imaged inside the injected dye-labeled antibody mass while the lymphatic vessels are visualized outside the mass. The efficacy of the contrast agent to label and localize deep medial lymphatic vessels and lymph nodes using photoacoustic computed tomography is demonstrated. The capability of a single injectable contrast agent to image multiple structures for several hours will potentially improve preclinical therapeutic optimization, shorten discovery timelines, and enable clinical treatments.
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Affiliation(s)
- Anjul Khadria
- Caltech Optical Imaging LaboratoryAndrew and Peggy Cherng Department of Medical EngineeringCalifornia Institute of TechnologyPasadenaCA91125USA
| | - Chad D. Paavola
- Lilly Research LaboratoriesEli Lilly and CompanyLilly Corporate CenterIndianapolisIN46285USA
| | - Yang Zhang
- Caltech Optical Imaging LaboratoryAndrew and Peggy Cherng Department of Medical EngineeringCalifornia Institute of TechnologyPasadenaCA91125USA
| | - Samuel P. X. Davis
- Caltech Optical Imaging LaboratoryAndrew and Peggy Cherng Department of Medical EngineeringCalifornia Institute of TechnologyPasadenaCA91125USA
| | - Patrick F. Grealish
- Lilly Research LaboratoriesEli Lilly and CompanyLilly Corporate CenterIndianapolisIN46285USA
| | - Konstantin Maslov
- Caltech Optical Imaging LaboratoryAndrew and Peggy Cherng Department of Medical EngineeringCalifornia Institute of TechnologyPasadenaCA91125USA
| | - Junhui Shi
- Caltech Optical Imaging LaboratoryAndrew and Peggy Cherng Department of Medical EngineeringCalifornia Institute of TechnologyPasadenaCA91125USA
| | - John M. Beals
- Lilly Research LaboratoriesEli Lilly and CompanyLilly Biotechnology CenterSan DiegoCA92121USA
| | - Sunday S. Oladipupo
- Lilly Research LaboratoriesEli Lilly and CompanyLilly Corporate CenterIndianapolisIN46285USA
| | - Lihong V. Wang
- Caltech Optical Imaging LaboratoryAndrew and Peggy Cherng Department of Medical EngineeringCalifornia Institute of TechnologyPasadenaCA91125USA
- Caltech Optical Imaging LaboratoryDepartment of Electrical EngineeringCalifornia Institute of TechnologyPasadenaCA91125USA
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22
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Salavati H, Debbaut C, Pullens P, Ceelen W. Interstitial fluid pressure as an emerging biomarker in solid tumors. Biochim Biophys Acta Rev Cancer 2022; 1877:188792. [PMID: 36084861 DOI: 10.1016/j.bbcan.2022.188792] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/12/2022] [Accepted: 08/30/2022] [Indexed: 11/28/2022]
Abstract
The physical microenvironment of cancer is characterized by elevated stiffness and tissue pressure, the main component of which is the interstitial fluid pressure (IFP). Elevated IFP is an established negative predictive and prognostic parameter, directly affecting malignant behavior and therapy response. As such, measurement of the IFP would allow to develop strategies aimed at engineering the physical microenvironment of cancer. Traditionally, IFP measurement required the use of invasive methods. Recent progress in dynamic and functional imaging methods such as dynamic contrast enhanced (DCE) magnetic resonance imaging and elastography, combined with numerical models and simulation, allows to comprehensively assess the biomechanical landscape of cancer, and may help to overcome physical barriers to drug delivery and immune cell infiltration. Here, we provide a comprehensive overview of the origin of elevated IFP, and its role in the malignant phenotype. Also, we review the methods used to measure IFP using invasive and imaging based methods, and highlight remaining obstacles and potential areas of progress in order to implement IFP measurement in clinical practice.
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Affiliation(s)
- Hooman Salavati
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium; IBitech- Biommeda, Department of Electronics and Information Systems, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Charlotte Debbaut
- IBitech- Biommeda, Department of Electronics and Information Systems, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Pim Pullens
- Department of Radiology, Ghent University Hospital, Ghent, Belgium; Ghent Institute of Functional and Metabolic Imaging (GIFMI), Ghent University, Ghent, Belgium; IBitech- Medisip, Ghent University, Ghent, Belgium
| | - Wim Ceelen
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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23
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Jinesh GG, Brohl AS. Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis. Signal Transduct Target Ther 2022; 7:296. [PMID: 35999218 PMCID: PMC9399134 DOI: 10.1038/s41392-022-01132-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 07/14/2022] [Accepted: 07/24/2022] [Indexed: 12/13/2022] Open
Abstract
Metastasis is a pivotal event that accelerates the prognosis of cancer patients towards mortality. Therapies that aim to induce cell death in metastatic cells require a more detailed understanding of the metastasis for better mitigation. Towards this goal, we discuss the details of two distinct but overlapping pathways of metastasis: a classical reversible epithelial-to-mesenchymal transition (hybrid-EMT)-driven transport pathway and an alternative cell death process-driven blebbishield metastatic-witch (BMW) transport pathway involving reversible cell death process. The knowledge about the EMT and BMW pathways is important for the therapy of metastatic cancers as these pathways confer drug resistance coupled to immune evasion/suppression. We initially discuss the EMT pathway and compare it with the BMW pathway in the contexts of coordinated oncogenic, metabolic, immunologic, and cell biological events that drive metastasis. In particular, we discuss how the cell death environment involving apoptosis, ferroptosis, necroptosis, and NETosis in BMW or EMT pathways recruits immune cells, fuses with it, migrates, permeabilizes vasculature, and settles at distant sites to establish metastasis. Finally, we discuss the therapeutic targets that are common to both EMT and BMW pathways.
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Affiliation(s)
- Goodwin G Jinesh
- Department of Molecular Oncology, 12902 USF Magnolia Drive, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 33612, FL, USA. .,Sarcoma Department, 12902 USF Magnolia Drive, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 33612, FL, USA.
| | - Andrew S Brohl
- Department of Molecular Oncology, 12902 USF Magnolia Drive, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 33612, FL, USA. .,Sarcoma Department, 12902 USF Magnolia Drive, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 33612, FL, USA.
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24
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Brogi E, Forfori F. Anesthesia and cancer recurrence: an overview. JOURNAL OF ANESTHESIA, ANALGESIA AND CRITICAL CARE (ONLINE) 2022; 2:33. [PMID: 37386584 DOI: 10.1186/s44158-022-00060-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/05/2022] [Indexed: 07/01/2023]
Abstract
Several perioperative factors are responsible for the dysregulation or suppression of the immune system with a possible impact on cancer cell growth and the development of new metastasis. These factors have the potential to directly suppress the immune system and activate hypothalamic-pituitary-adrenal axis and the sympathetic nervous system with a consequent further immunosuppressive effect.Anesthetics and analgesics used during the perioperative period may modulate the innate and adaptive immune system, inflammatory system, and angiogenesis, with a possible impact on cancer recurrence and long-term outcome. Even if the current data are controversial and contrasting, it is crucial to increase awareness about this topic among healthcare professionals for a future better and conscious choice of anesthetic techniques.In this article, we aimed to provide an overview regarding the relationship between anesthesia and cancer recurrence. We reviewed the effects of surgery, perioperative factors, and anesthetic agents on tumor cell survival and tumor recurrence.
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Affiliation(s)
- Etrusca Brogi
- Department of Anesthesia and Intensive Care, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy.
| | - Francesco Forfori
- Department of Anesthesia and Intensive Care, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy
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25
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dos Santos CL, dos Santos LL, Tavares G, Tristão LS, Orlandini MF, Serafim MCA, Datrino LN, Bernardo WM, Tustumi F. Prophylactic thoracic duct obliteration and resection during esophagectomy: What is the impact on perioperative risks and long‐term survival? A systematic review and meta‐analysis. J Surg Oncol 2022; 126:90-98. [DOI: 10.1002/jso.26827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/06/2022] [Accepted: 02/08/2022] [Indexed: 01/27/2023]
Affiliation(s)
- Clara L. dos Santos
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Laura L. dos Santos
- Department of Gastroenterology Universidade de São Paulo Sao Paulo SP Brazil
| | - Guilherme Tavares
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Luca S. Tristão
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Marina F. Orlandini
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Maria C. A. Serafim
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Letícia N. Datrino
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Wanderley M. Bernardo
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
- Department of Gastroenterology Universidade de São Paulo Sao Paulo SP Brazil
| | - Francisco Tustumi
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
- Department of Gastroenterology Universidade de São Paulo Sao Paulo SP Brazil
- Department of Surgery Hospital Israelita Albert Einstein Sao Paulo SP Brazil
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26
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Abstract
The lymphatic system, composed of initial and collecting lymphatic vessels as well as lymph nodes that are present in almost every tissue of the human body, acts as an essential transport system for fluids, biomolecules and cells between peripheral tissues and the central circulation. Consequently, it is required for normal body physiology but is also involved in the pathogenesis of various diseases, most notably cancer. The important role of tumor-associated lymphatic vessels and lymphangiogenesis in the formation of lymph node metastasis has been elucidated during the last two decades, whereas the underlying mechanisms and the relation between lymphatic and peripheral organ dissemination of cancer cells are incompletely understood. Lymphatic vessels are also important for tumor-host communication, relaying molecular information from a primary or metastatic tumor to regional lymph nodes and the circulatory system. Beyond antigen transport, lymphatic endothelial cells, particularly those residing in lymph node sinuses, have recently been recognized as direct regulators of tumor immunity and immunotherapy responsiveness, presenting tumor antigens and expressing several immune-modulatory signals including PD-L1. In this review, we summarize recent discoveries in this rapidly evolving field and highlight strategies and challenges of therapeutic targeting of lymphatic vessels or specific lymphatic functions in cancer patients.
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Affiliation(s)
- Lothar C Dieterich
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Carlotta Tacconi
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.,Department of Biosciences, University of Milan, Milan, Italy
| | - Luca Ducoli
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
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27
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Nanomaterial-Based Drug Delivery System Targeting Lymph Nodes. Pharmaceutics 2022; 14:pharmaceutics14071372. [PMID: 35890268 PMCID: PMC9325242 DOI: 10.3390/pharmaceutics14071372] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/28/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023] Open
Abstract
The lymphatic system plays an indispensable role in humoral balance, lipid metabolism, and immune regulation. The lymph nodes (LNs) are known as the primary sites of tumor metastasis and the metastatic LNs largely affected the prognosis of the patiens. A well-designed lymphatic-targeted system favors disease treatment as well as vaccination efficacy. In recent years, development of nanotechnologies and emerging biomaterials have gained increasing attention in developing lymph-node-targeted drug-delivery systems. By mimicking the endogenous macromolecules or lipid conjugates, lymph-node-targeted nanocarries hold potential for disease diagnosis and tumor therapy. This review gives an introduction to the physiological functions of LNs and the roles of LNs in diseases, followed by a review of typical lymph-node-targeted nanomaterial-based drug-delivery systems (e.g., liposomes, micelles, inorganic nanomaterials, hydrogel, and nanocapsules). Future perspectives and conclusions concerned with lymph-node-targeted drug-delivery systems are also provided.
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28
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Garnier L, Pick R, Montorfani J, Sun M, Brighouse D, Liaudet N, Kammertoens T, Blankenstein T, Page N, Bernier-Latamani J, Tran NL, Petrova TV, Merkler D, Scheiermann C, Hugues S. IFN-γ-dependent tumor-antigen cross-presentation by lymphatic endothelial cells promotes their killing by T cells and inhibits metastasis. SCIENCE ADVANCES 2022; 8:eabl5162. [PMID: 35675399 PMCID: PMC9176743 DOI: 10.1126/sciadv.abl5162] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Tumor-associated lymphatic vessels promote metastasis and regulate antitumor immune responses. Here, we assessed the impact of cytotoxic T cells on the local lymphatic vasculature and concomitant tumor dissemination during an antitumor response. Interferon-γ (IFN-γ) released by effector T cells enhanced the expression of immunosuppressive markers by tumor-associated lymphatic endothelial cells (LECs). However, at higher effector T cell densities within the tumor, T cell-based immunotherapies induced LEC apoptosis and decreased tumor lymphatic vessel density. As a consequence, lymphatic flow was impaired, and lymph node metastasis was reduced. Mechanistically, T cell-mediated tumor cell death induced the release of tumor antigens and cross-presentation by tumor LECs, resulting in antigen-specific LEC killing by T cells. When LECs lacked the IFN-γ receptor expression, LEC killing was abrogated, indicating that IFN-γ is indispensable for reducing tumor-associated lymphatic vessel density and drainage. This study provides insight into how cytotoxic T cells modulate tumor lymphatic vessels and may help to improve immunotherapeutic protocols.
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Affiliation(s)
- Laure Garnier
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
- Corresponding author. (S.H.); (L.G.)
| | - Robert Pick
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Julien Montorfani
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Mengzhu Sun
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Dale Brighouse
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Nicolas Liaudet
- Bioimaging Core Facility, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Thomas Kammertoens
- Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
| | - Thomas Blankenstein
- Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
- Berlin Institute of Health, 10117 Berlin, Germany
| | - Nicolas Page
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
- Department of Pathology and Immunology, Division of Clinical Pathology, University of Geneva and University Hospital of Geneva, Geneva, Switzerland
| | - Jeremiah Bernier-Latamani
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Division of Experimental Pathology, University of Lausanne and University of Lausanne Hospital, 1066 Lausanne, Switzerland
| | - Ngoc Lan Tran
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Tatiana V. Petrova
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Division of Experimental Pathology, University of Lausanne and University of Lausanne Hospital, 1066 Lausanne, Switzerland
| | - Doron Merkler
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
- Department of Pathology and Immunology, Division of Clinical Pathology, University of Geneva and University Hospital of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Christoph Scheiermann
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
- Walter-Brendel-Centre of Experimental Medicine, BioMedical Centre, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Stéphanie Hugues
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
- Corresponding author. (S.H.); (L.G.)
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29
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Singla B, Aithabathula RV, Kiran S, Kapil S, Kumar S, Singh UP. Reactive Oxygen Species in Regulating Lymphangiogenesis and Lymphatic Function. Cells 2022; 11:1750. [PMID: 35681445 PMCID: PMC9179518 DOI: 10.3390/cells11111750] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/18/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
The lymphatic system is pivotal for immunosurveillance and the maintenance of tissue homeostasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vessels, has both physiological and pathological roles. Recent advances in the molecular mechanisms regulating lymphangiogenesis have opened a new area of research on reparative lymphangiogenesis for the treatment of various pathological disorders comprising neurological disorders, cardiac repair, autoimmune disease, obesity, atherosclerosis, etc. Reactive oxygen species (ROS) produced by the various cell types serve as signaling molecules in several cellular mechanisms and regulate various aspects of growth-factor-mediated responses, including lymphangiogenesis. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Low ROS levels are essential for lymphangiogenesis. On the contrary, oxidative stress due to enhanced ROS generation and/or reduced levels of antioxidants suppresses lymphangiogenesis via promoting lymphatic endothelial cell apoptosis and death. In this review article, we provide an overview of types and sources of ROS, discuss the role of ROS in governing lymphangiogenesis and lymphatic function, and summarize the role of lymphatics in various diseases.
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Affiliation(s)
- Bhupesh Singla
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
| | - Ravi Varma Aithabathula
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
| | - Sonia Kiran
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
| | - Shweta Kapil
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children′s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Santosh Kumar
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
| | - Udai P. Singh
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
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30
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Hypoxia orchestrates the lymphovascular–immune ensemble in cancer. Trends Cancer 2022; 8:771-784. [DOI: 10.1016/j.trecan.2022.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/31/2022] [Accepted: 04/25/2022] [Indexed: 11/18/2022]
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31
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Miller IS, Khan S, Shiels LP, Das S, O' Farrell AC, Connor K, Lafferty A, Moran B, Isella C, Loadman P, Conroy E, Cohrs S, Schibli R, Kerbel RS, Gallagher WM, Marangoni E, Bennett K, O' Connor DP, Dwyer RM, Byrne AT. Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects. Cancer Med 2022; 11:3820-3836. [PMID: 35434898 PMCID: PMC9582689 DOI: 10.1002/cam4.4756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 03/31/2022] [Accepted: 04/07/2022] [Indexed: 11/13/2022] Open
Abstract
Backgorund Prior data suggest pre‐diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple‐negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes. Method NOD/SCID mice were implanted with HER2+ MDA‐MB‐231/LN/2‐4/H2N, trastuzumab‐resistant HER2+ HCC1954 or a TNBC patient‐derived xenograft (PDX). A daily low‐dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA‐MB‐231/LN/2‐4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre‐treatment aspirin, 3 weeks post‐resection, HCC1954/TNBC animals received standard‐of‐care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry. Results Aspirin delayed time to metastasis in MDA‐MB‐231/LN/2‐4/H2N xenografts and decreased growth of HER2+/TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre‐treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co‐culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF‐C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability. Conclusion Our data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo‐preventative agent in the HER2+ or TNBC setting.
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Affiliation(s)
- Ian S Miller
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland.,National Preclinical Imaging Centre, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland
| | - Sonja Khan
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Liam P Shiels
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland
| | - Sudipto Das
- School of Pharmacy and Biomedical Sciences, Royal College of Surgeons in Ireland, St Stepehen's Green, Dublin, Ireland
| | - Alice C O' Farrell
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland
| | - Kate Connor
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland
| | - Adam Lafferty
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland
| | - Bruce Moran
- UCD School of Bimolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Claudio Isella
- Institute for Cancer Research and Treatment, University of Turin, Turin, Italy
| | - Paul Loadman
- School of Pharmacy and Medical Sciences, University of Bradford, Bradford, UK
| | - Emer Conroy
- UCD School of Bimolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Susan Cohrs
- Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland
| | - Roger Schibli
- Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland
| | - Robert S Kerbel
- Sunnybrook Research Institute, University of Toronto, Ontario, Canada
| | - William M Gallagher
- UCD School of Bimolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Elisabetta Marangoni
- Translational Research Department, Institute Curie, PSL Research University, Paris, France
| | - Kathleen Bennett
- Division of Population Health Science, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Darran P O' Connor
- School of Pharmacy and Biomedical Sciences, Royal College of Surgeons in Ireland, St Stepehen's Green, Dublin, Ireland
| | - Róisín M Dwyer
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Annette T Byrne
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland.,National Preclinical Imaging Centre, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland.,UCD School of Bimolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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32
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Shou Y, Johnson SC, Quek YJ, Li X, Tay A. Integrative lymph node-mimicking models created with biomaterials and computational tools to study the immune system. Mater Today Bio 2022; 14:100269. [PMID: 35514433 PMCID: PMC9062348 DOI: 10.1016/j.mtbio.2022.100269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/16/2022] [Accepted: 04/18/2022] [Indexed: 11/17/2022] Open
Abstract
The lymph node (LN) is a vital organ of the lymphatic and immune system that enables timely detection, response, and clearance of harmful substances from the body. Each LN comprises of distinct substructures, which host a plethora of immune cell types working in tandem to coordinate complex innate and adaptive immune responses. An improved understanding of LN biology could facilitate treatment in LN-associated pathologies and immunotherapeutic interventions, yet at present, animal models, which often have poor physiological relevance, are the most popular experimental platforms. Emerging biomaterial engineering offers powerful alternatives, with the potential to circumvent limitations of animal models, for in-depth characterization and engineering of the lymphatic and adaptive immune system. In addition, mathematical and computational approaches, particularly in the current age of big data research, are reliable tools to verify and complement biomaterial works. In this review, we first discuss the importance of lymph node in immunity protection followed by recent advances using biomaterials to create in vitro/vivo LN-mimicking models to recreate the lymphoid tissue microstructure and microenvironment, as well as to describe the related immuno-functionality for biological investigation. We also explore the great potential of mathematical and computational models to serve as in silico supports. Furthermore, we suggest how both in vitro/vivo and in silico approaches can be integrated to strengthen basic patho-biological research, translational drug screening and clinical personalized therapies. We hope that this review will promote synergistic collaborations to accelerate progress of LN-mimicking systems to enhance understanding of immuno-complexity.
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Key Words
- ABM, agent-based model
- APC, antigen-presenting cell
- BV, blood vessel
- Biomaterials
- CPM, Cellular Potts model
- Computational models
- DC, dendritic cell
- ECM, extracellular matrix
- FDC, follicular dendritic cell
- FRC, fibroblastic reticular cell
- Immunotherapy
- LEC, lymphatic endothelial cell
- LN, lymph node
- LV, lymphatic vessel
- Lymph node
- Lymphatic system
- ODE, ordinary differential equation
- PDE, partial differential equation
- PDMS, polydimethylsiloxane
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Affiliation(s)
- Yufeng Shou
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
| | - Sarah C. Johnson
- Department of Bioengineering, Stanford University, CA, 94305, USA
- Department of Bioengineering, Imperial College London, South Kensington, SW72AZ, UK
| | - Ying Jie Quek
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
- Singapore Immunology Network, Agency for Science, Technology and Research, 138648, Singapore
| | - Xianlei Li
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
| | - Andy Tay
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
- Institute for Health Innovation & Technology, National University of Singapore, 117599, Singapore
- NUS Tissue Engineering Program, National University of Singapore, 117510, Singapore
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Li CY, Brown S, Mehrara BJ, Kataru RP. Lymphatics in Tumor Progression and Immunomodulation. Int J Mol Sci 2022; 23:2127. [PMID: 35216243 PMCID: PMC8875298 DOI: 10.3390/ijms23042127] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/06/2022] [Accepted: 02/08/2022] [Indexed: 12/18/2022] Open
Abstract
The lymphatic system consists of a unidirectional hierarchy of vessels responsible for fluid homeostasis, lipid absorption, and the transport of immune cells and antigens to secondary lymphoid organs. In cancer, lymphatics play complex and heterogenous roles that can promote or inhibit tumor growth. While lymphatic proliferation and remodeling promote tumor dissemination, functional lymphatics are necessary for generating an effective immune response. Recent reports have noted lymphatic-dependent effects on the efficacy of immunotherapy. These findings suggest that the impact of lymphatic vessels on tumor progression is organ- and context-specific and that a greater understanding of the interaction of tumor cells, lymphatics, and the tumor microenvironment can unveil novel therapies.
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Affiliation(s)
| | | | | | - Raghu P. Kataru
- The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (C.Y.L.); (S.B.); (B.J.M.)
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Brown S, Dayan JH, Coriddi M, Campbell A, Kuonqui K, Shin J, Park HJ, Mehrara BJ, Kataru RP. Pharmacological Treatment of Secondary Lymphedema. Front Pharmacol 2022; 13:828513. [PMID: 35145417 PMCID: PMC8822213 DOI: 10.3389/fphar.2022.828513] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Lymphedema is a chronic disease that results in swelling and decreased function due to abnormal lymphatic fluid clearance and chronic inflammation. In Western countries, lymphedema most commonly develops following an iatrogenic injury to the lymphatic system during cancer treatment. It is estimated that as many as 10 million patients suffer from lymphedema in the United States alone. Current treatments for lymphedema are palliative in nature, relying on compression garments and physical therapy to decrease interstitial fluid accumulation in the affected extremity. However, recent discoveries have increased the hopes of therapeutic interventions that may promote lymphatic regeneration and function. The purpose of this review is to summarize current experimental pharmacological strategies in the treatment of lymphedema.
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35
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Lim AR, Ghajar CM. Thorny ground, rocky soil: Tissue-specific mechanisms of tumor dormancy and relapse. Semin Cancer Biol 2022; 78:104-123. [PMID: 33979673 PMCID: PMC9595433 DOI: 10.1016/j.semcancer.2021.05.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 02/07/2023]
Abstract
Disseminated tumor cells (DTCs) spread systemically yet distinct patterns of metastasis indicate a range of tissue susceptibility to metastatic colonization. Distinctions between permissive and suppressive tissues are still being elucidated at cellular and molecular levels. Although there is a growing appreciation for the role of the microenvironment in regulating metastatic success, we have a limited understanding of how diverse tissues regulate DTC dormancy, the state of reversible quiescence and subsequent awakening thought to contribute to delayed relapse. Several themes of microenvironmental regulation of dormancy are beginning to emerge, including vascular association, co-option of pre-existing niches, metabolic adaptation, and immune evasion, with tissue-specific nuances. Conversely, DTC awakening is often associated with injury or inflammation-induced activation of the stroma, promoting a proliferative environment with DTCs following suit. We review what is known about tissue-specific regulation of tumor dormancy on a tissue-by-tissue basis, profiling major metastatic organs including the bone, lung, brain, liver, and lymph node. An aerial view of the barriers to metastatic growth may reveal common targets and dependencies to inform the therapeutic prevention of relapse.
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Affiliation(s)
- Andrea R Lim
- Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Graduate Program in Molecular and Cellular Biology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Cyrus M Ghajar
- Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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Kemp SS, Penn MR, Koller GM, Griffin CT, Davis GE. Proinflammatory mediators, TNFα, IFNγ, and thrombin, directly induce lymphatic capillary tube regression. Front Cell Dev Biol 2022; 10:937982. [PMID: 35927983 PMCID: PMC9343954 DOI: 10.3389/fcell.2022.937982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/30/2022] [Indexed: 11/30/2022] Open
Abstract
In this work, we sought to investigate the direct effects of proinflammatory mediators on lymphatic endothelial cell (LEC) capillaries and whether they might induce regression. Our laboratory has developed novel in-vitro, serum-free, lymphatic tubulogenesis assay models whereby human LEC tube networks readily form in either three-dimensional collagen or fibrin matrices. These systems were initially conceptualized in the hopes of better understanding the influence of proinflammatory mediators on LEC capillaries. In this work, we have screened and identified proinflammatory mediators that cause regression of LEC tube networks, the most potent of which is TNFα (tumor necrosis factor alpha), followed by IFNγ (interferon gamma) and thrombin. When these mediators were combined, even greater and more rapid lymphatic capillary regression occurred. Surprisingly, IL-1β (interleukin-1 beta), one of the most potent and pathologic cytokines known, had no regressive effect on these tube networks. Finally, we identified new pharmacological drug combinations capable of rescuing LEC capillaries from regression in response to the potent combination of TNFα, IFNγ, and thrombin. We speculate that protecting lymphatic capillaries from regression may be an important step toward mitigating a wide variety of acute and chronic disease states, as lymphatics are believed to clear both proinflammatory cells and mediators from inflamed and damaged tissue beds. Overall, these studies identify key proinflammatory mediators, including TNFα, IFNγ, and thrombin, that induce regression of LEC tube networks, as well as identify potential therapeutic agents to diminish LEC capillary regression responses.
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Affiliation(s)
- Scott S Kemp
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Marlena R Penn
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Gretchen M Koller
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Courtney T Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - George E Davis
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
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Sun Z, Jiang Y, Chen C, Zheng H, Huang W, Xu B, Tang W, Yuan Q, Zhou K, Liang X, Chen H, Han Z, Feng H, Yu S, Hu Y, Yu J, Zhou Z, Wang W, Xu Y, Li G. Radiomics signature based on computed tomography images for the preoperative prediction of lymph node metastasis at individual stations in gastric cancer: A multicenter study. Radiother Oncol 2021; 165:179-190. [PMID: 34774652 DOI: 10.1016/j.radonc.2021.11.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 10/19/2021] [Accepted: 11/03/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND Specific diagnosis and treatment of gastric cancer (GC) require accurate preoperative predictions of lymph node metastasis (LNM) at individual stations, such as estimating the extent of lymph node dissection. This study aimed to develop a radiomics signature based on preoperative computed tomography (CT) images, for predicting the LNM status at each individual station. METHODS We enrolled 1506 GC patients retrospectively from two centers as training (531) and external (975) validation cohorts, and recruited 112 patients prospectively from a single center as prospective validation cohort. Radiomics features were extracted from preoperative CT images and integrated with clinical characteristics to construct nomograms for LNM prediction at individual lymph node stations. Performance of the nomograms was assessed through calibration, discrimination and clinical usefulness. RESULTS In training, external and prospective validation cohorts, radiomics signature was significantly associated with LNM status. Moreover, radiomics signature was an independent predictor of LNM status in the multivariable logistic regression analysis. The radiomics nomograms revealed good prediction performances, with AUCs of 0.716-0.871 in the training cohort, 0.678-0.768 in the external validation cohort and 0.700-0.841 in the prospective validation cohort for 12 nodal stations. The nomograms demonstrated a significant agreement between the actual probability and predictive probability in calibration curves. Decision curve analysis showed that nomograms had better net benefit than clinicopathologic characteristics. CONCLUSION Radiomics nomograms for individual lymph node stations presented good prediction accuracy, which could provide important information for individual diagnosis and treatment of gastric cancer.
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Affiliation(s)
- Zepang Sun
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yuming Jiang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Chuanli Chen
- Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huan Zheng
- Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weicai Huang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | | | - Weijing Tang
- Department of Pathology, Stanford University School of Medicine, USA
| | - Qingyu Yuan
- Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kangneng Zhou
- School of Computer and Communication Engineering, University of Science and Technology Beijing, China
| | - Xiaokun Liang
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Shenzhen Colleges of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen, China
| | - Hao Chen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zhen Han
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hao Feng
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shitong Yu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yanfeng Hu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiang Yu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zhiwei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - Wei Wang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - Yikai Xu
- Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Guoxin Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.
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Tasdogan A, Ubellacker JM, Morrison SJ. Redox Regulation in Cancer Cells during Metastasis. Cancer Discov 2021; 11:2682-2692. [PMID: 34649956 DOI: 10.1158/2159-8290.cd-21-0558] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/15/2021] [Accepted: 07/07/2021] [Indexed: 12/19/2022]
Abstract
Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We review the changes in redox regulation that cancer cells undergo during metastasis. By better understanding these mechanisms, it may be possible to develop pro-oxidant therapies that block disease progression by exacerbating oxidative stress in cancer cells. SIGNIFICANCE: Oxidative stress often limits cancer cell survival during metastasis, raising the possibility of inhibiting cancer progression with pro-oxidant therapies. This is the opposite strategy of treating patients with antioxidants, an approach that worsened outcomes in large clinical trials.
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Affiliation(s)
- Alpaslan Tasdogan
- Children's Research Institute and Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jessalyn M Ubellacker
- Children's Research Institute and Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sean J Morrison
- Children's Research Institute and Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas. .,Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas
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Wang K, Pan Y, Tong S, Liang H, Qiu P. Deep-skin multiphoton microscopy of lymphatic vessels excited at the 1700-nm window in vivo. BIOMEDICAL OPTICS EXPRESS 2021; 12:6474-6484. [PMID: 34745750 PMCID: PMC8548020 DOI: 10.1364/boe.437482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/10/2021] [Accepted: 09/15/2021] [Indexed: 06/13/2023]
Abstract
Visualization of lymphatic vessels is key to the understanding of their structure, function, and dynamics. Multiphoton microscopy (MPM) is a potential technology for imaging lymphatic vessels, but tissue scattering prevents its deep penetration in skin. Here we demonstrate deep-skin MPM of the lymphatic vessels in mouse hindlimb in vivo, excited at the 1700 nm window. Our results show that with contrast provided by indocyanine green (ICG), 2-photon fluorescence (2PF) imaging enables noninvasive imaging of lymphatic vessels 300 μm below the skin surface, visualizing both its structure and contraction dynamics. Simultaneously acquired second-harmonic generation (SHG) and third-harmonic generation (THG) images visualize the local environment in which the lymphatic vessels reside. After removing the surface skin layer, 2PF and THG imaging visualize finer structures of the lymphatic vessels: most notably, the label-free THG imaging visualizes lymphatic valves and their open-and-close dynamics in real time. MPM excited at the 1700-nm window thus provides a promising technology for the study of lymphatic vessels.
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40
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Soofiyani SR, Hosseini K, Forouhandeh H, Ghasemnejad T, Tarhriz V, Asgharian P, Reiner Ž, Sharifi-Rad J, Cho WC. Quercetin as a Novel Therapeutic Approach for Lymphoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:3157867. [PMID: 34381559 PMCID: PMC8352693 DOI: 10.1155/2021/3157867] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/15/2021] [Accepted: 07/12/2021] [Indexed: 11/19/2022]
Abstract
Lymphoma is a name for malignant diseases of the lymphatic system including Hodgkin's lymphoma and non-Hodgkin's lymphoma. Although several approaches are used for the treatment of these diseases, some of them are not successful and have serious adverse effects. Therefore, other effective treatment methods might be interesting. Studies have indicated that plant ingredients play a key role in treating several diseases. Some plants have already shown a potential therapeutic effect on many malignant diseases. Quercetin is a flavonoid found in different plants and could be useful in the treatment of different malignant diseases. Quercetin has its antimalignant effects through targeting main survival pathways activated in tumor cells. In vitro/in vivo experimental studies have demonstrated that quercetin possesses a cytotoxic effect on lymphoid cancer cells. Regardless of the optimum results that have been obtained from both in vitro/in vivo studies, few clinical studies have analyzed the antitumor effects of quercetin in lymphoid cancers. Thus, it seems that more clinical studies should introduce quercetin as a therapeutic, alone or in combination with other chemotherapy agents. Here, in this study, we reviewed the anticancer effects of quercetin and highlighted the potential therapeutic effects of quercetin in various types of lymphoma.
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Affiliation(s)
- Saiedeh Razi Soofiyani
- Clinical Research Development Unit of Sina Educational, Research, and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kamran Hosseini
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Forouhandeh
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Ghasemnejad
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parina Asgharian
- Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
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41
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Martin JD, Miyazaki T, Cabral H. Remodeling tumor microenvironment with nanomedicines. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 13:e1730. [PMID: 34124849 DOI: 10.1002/wnan.1730] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 12/17/2022]
Abstract
The tumor microenvironment (TME) has been recognized as a major contributor to cancer malignancy and therapeutic resistance. Thus, strategies directed to re-engineer the TME are emerging as promising approaches for improving the efficacy of antitumor therapies by enhancing tumor perfusion and drug delivery, as well as alleviating the immunosuppressive TME. In this regard, nanomedicine has shown great potential for developing effective treatments capable of re-modeling the TME by controlling drug action in a spatiotemporal manner and allowing long-lasting modulatory effects on the TME. Herein, we review recent progress on TME re-engineering by using nanomedicine, particularly focusing on formulations controlling TME characteristics through targeted interaction with cellular components of the TME. Importantly, the TME should be re-engineering to a quiescent phenotype rather than be destroyed. Finally, immediate challenges and future perspectives of TME-re-engineering nanomedicines are discussed, anticipating further innovation in this growing field. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
| | - Takuya Miyazaki
- Kanagawa Institute of Industrial Science and Technology, Ebina, Japan
| | - Horacio Cabral
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
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42
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Jin C, Jiang Y, Yu H, Wang W, Li B, Chen C, Yuan Q, Hu Y, Xu Y, Zhou Z, Li G, Li R. Deep learning analysis of the primary tumour and the prediction of lymph node metastases in gastric cancer. Br J Surg 2021; 108:542-549. [PMID: 34043780 DOI: 10.1002/bjs.11928] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/29/2020] [Accepted: 06/25/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Lymph node metastasis (LNM) in gastric cancer is a prognostic factor and has implications for the extent of lymph node dissection. The lymphatic drainage of the stomach involves multiple nodal stations with different risks of metastases. The aim of this study was to develop a deep learning system for predicting LNMs in multiple nodal stations based on preoperative CT images in patients with gastric cancer. METHODS Preoperative CT images from patients who underwent gastrectomy with lymph node dissection at two medical centres were analysed retrospectively. Using a discovery patient cohort, a system of deep convolutional neural networks was developed to predict pathologically confirmed LNMs at 11 regional nodal stations. To gain understanding about the networks' prediction ability, gradient-weighted class activation mapping for visualization was assessed. The performance was tested in an external cohort of patients by analysis of area under the receiver operating characteristic (ROC) curves (AUC), sensitivity and specificity. RESULTS The discovery and external cohorts included 1172 and 527 patients respectively. The deep learning system demonstrated excellent prediction accuracy in the external validation cohort, with a median AUC of 0·876 (range 0·856-0·893), sensitivity of 0·743 (0·551-0·859) and specificity of 0·936 (0·672-0·966) for 11 nodal stations. The imaging models substantially outperformed clinicopathological variables for predicting LNMs (median AUC 0·652, range 0·571-0·763). By visualizing nearly 19 000 subnetworks, imaging features related to intratumoral heterogeneity and the invasive front were found to be most useful for predicting LNMs. CONCLUSION A deep learning system for the prediction of LNMs was developed based on preoperative CT images of gastric cancer. The models require further validation but may be used to inform prognosis and guide individualized surgical treatment.
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Affiliation(s)
- C Jin
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford California, USA
| | - Y Jiang
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford California, USA
| | - H Yu
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford California, USA
| | - W Wang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - B Li
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford California, USA
| | - C Chen
- Departments of Medical Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Q Yuan
- Departments of Medical Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Y Hu
- General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory on Precision and Minimally Invasive Medicine for Gastrointestinal Cancers, Guangzhou, China
| | - Y Xu
- Departments of Medical Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Z Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - G Li
- General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory on Precision and Minimally Invasive Medicine for Gastrointestinal Cancers, Guangzhou, China
| | - R Li
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford California, USA
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Jana S, Muscarella RA, Jones D. The Multifaceted Effects of Breast Cancer on Tumor-Draining Lymph Nodes. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1353-1363. [PMID: 34043978 DOI: 10.1016/j.ajpath.2021.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 05/07/2021] [Accepted: 05/12/2021] [Indexed: 12/31/2022]
Abstract
Breast cancer (BC) accounts for significant morbidity and mortality among women worldwide. About one in three patients with breast cancer present with lymph node (LN) metastasis and LN status is one of the most important prognostic predictors in patients with BC. In addition to their prognostic value, LNs initiate adaptive immunity against BC. Yet, BC cells often avoid immune-mediated destruction in LNs. This review provides an overview of the ways by which BC cells modulate LN stromal and hematopoietic cells to promote metastasis and immune evasion.
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Affiliation(s)
- Samir Jana
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Ronald A Muscarella
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Dennis Jones
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts.
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44
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Progression of Metastasis through Lymphatic System. Cells 2021; 10:cells10030627. [PMID: 33808959 PMCID: PMC7999434 DOI: 10.3390/cells10030627] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 02/06/2023] Open
Abstract
Lymph nodes are the most common sites of metastasis in cancer patients. Nodal disease status provides great prognostic power, but how lymph node metastases should be treated is under debate. Thus, it is important to understand the mechanisms by which lymph node metastases progress and how they can be targeted to provide therapeutic benefits. In this review, we focus on delineating the process of cancer cell migration to and through lymphatic vessels, survival in draining lymph nodes and further spread to other distant organs. In addition, emerging molecular targets and potential strategies to inhibit lymph node metastasis are discussed.
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Polomska AK, Proulx ST. Imaging technology of the lymphatic system. Adv Drug Deliv Rev 2021; 170:294-311. [PMID: 32891679 DOI: 10.1016/j.addr.2020.08.013] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/16/2020] [Accepted: 08/31/2020] [Indexed: 12/17/2022]
Abstract
The lymphatic system plays critical roles in tissue fluid homeostasis and immunity and has been implicated in the development of many different pathologies, ranging from lymphedema, the spread of cancer to chronic inflammation. In this review, we first summarize the state-of-the-art of lymphatic imaging in the clinic and the advantages and disadvantages of these existing techniques. We then detail recent progress on imaging technology, including advancements in tracer design and injection methods, that have allowed visualization of lymphatic vessels with excellent spatial and temporal resolution in preclinical models. Finally, we describe the different approaches to quantifying lymphatic function that are being developed and discuss some emerging topics for lymphatic imaging in the clinic. Continued advancements in lymphatic imaging technology will be critical for the optimization of diagnostic methods for lymphatic disorders and the evaluation of novel therapies targeting the lymphatic system.
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Affiliation(s)
- Anna K Polomska
- ETH Zürich, Institute of Pharmaceutical Sciences, Vladimir-Prelog Weg 1-5/10, 8093 Zürich, Switzerland
| | - Steven T Proulx
- University of Bern, Theodor Kocher Institute, Freiestrasse 1, 3012 Bern, Switzerland.
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Gaustad JV, Simonsen TG, Hansem LMK, Rofstad EK. Intravital microscopy of tumor vessel morphology and function using a standard fluorescence microscope. Eur J Nucl Med Mol Imaging 2021; 48:3089-3100. [PMID: 33606081 PMCID: PMC8426228 DOI: 10.1007/s00259-021-05243-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/04/2021] [Indexed: 11/26/2022]
Abstract
Purpose The purpose of the study was to demonstrate the performance and possible applications of an intravital microscopy assay using a standard fluorescence microscope. Methods Melanoma and pancreatic ductal adenocarcinoma xenografts were initiated in dorsal window chambers and subjected to repeated intravital microscopy. The entire tumor vasculature as well as the normal tissue surrounding the tumor was imaged simultaneously with high spatial and temporal resolution. Vascular morphology images were recorded by using transillumination, and vascular masks were produced to quantify vessel density, vessel diameter, vessel segment length, and vessel tortuosity. First-pass imaging movies were recorded after an intervenous injection of a fluorescent marker and were used to investigate vascular function. Lymphatics were visualized by intradermal injections of a fluorescent marker. Results The intravital microscopy assay was used to study tumor growth and vascularization, tumor vessel morphology and function, tumor-associated lymphatics, and vascular effects of acute cyclic hypoxia and antiangiogenic treatment. The assay was sensitive to tumor-line differences in vascular morphology and function and detected tumor-induced lymphatic dilation. Acute cyclic hypoxia induced angiogenesis and increased the density of small diameter vessels and blood supply times, whereas antiangiogenic treatment selectively removed small-diameter vessels, reduced blood supply times, and induced hypoxia. Moreover, the window chamber was compatible with magnetic resonance imaging (MRI), and parametric images derived by dynamic contrast-enhanced MRI were shown to reflect vascular morphology and function. Conclusions The presented assay represents a useful and affordable alternative to intravital microscopy assays using confocal and multi-photon microscopes. Supplementary Information The online version contains supplementary material available at 10.1007/s00259-021-05243-0.
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Affiliation(s)
- Jon-Vidar Gaustad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Box 4953 Nydalen, 0424, Oslo, Norway.
| | - Trude G Simonsen
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Box 4953 Nydalen, 0424, Oslo, Norway
| | - Lise Mari K Hansem
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Box 4953 Nydalen, 0424, Oslo, Norway
| | - Einar K Rofstad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Box 4953 Nydalen, 0424, Oslo, Norway
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Arcucci V, Stacker SA, Achen MG. Control of Gene Expression by Exosome-Derived Non-Coding RNAs in Cancer Angiogenesis and Lymphangiogenesis. Biomolecules 2021; 11:249. [PMID: 33572413 PMCID: PMC7916238 DOI: 10.3390/biom11020249] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/29/2021] [Accepted: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
Abstract: Tumour angiogenesis and lymphangiogenesis are hallmarks of cancer and have been associated with tumour progression, tumour metastasis and poor patient prognosis. Many factors regulate angiogenesis and lymphangiogenesis in cancer including non-coding RNAs which are a category of RNAs that do not encode proteins and have important regulatory functions at transcriptional and post-transcriptional levels. Non-coding RNAs can be encapsulated in extracellular vesicles called exosomes which are secreted by tumour cells or other cells in the tumour microenvironment and can then be taken up by the endothelial cells of blood vessels and lymphatic vessels. The "delivery" of these non-coding RNAs to endothelial cells in tumours can facilitate tumour angiogenesis and lymphangiogenesis. Here we review recent findings about exosomal non-coding RNAs, specifically microRNAs and long non-coding RNAs, which regulate tumour angiogenesis and lymphangiogenesis in cancer. We then focus on the potential use of these molecules as cancer biomarkers and opportunities for exploiting ncRNAs for the treatment of cancer.
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Affiliation(s)
- Valeria Arcucci
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne VIC 3000, Australia; (V.A.); (S.A.S.)
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville VIC 3010, Australia
| | - Steven A. Stacker
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne VIC 3000, Australia; (V.A.); (S.A.S.)
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville VIC 3010, Australia
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville VIC 3050, Australia
| | - Marc G. Achen
- O’Brien Institute Department, St Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy VIC 3065, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy VIC 3065, Australia
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A PET/CT nomogram incorporating SUVmax and CT radiomics for preoperative nodal staging in non-small cell lung cancer. Eur Radiol 2021; 31:6030-6038. [PMID: 33560457 PMCID: PMC8270849 DOI: 10.1007/s00330-020-07624-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/08/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022]
Abstract
Objectives To develop and validate a PET/CT nomogram for preoperative estimation of lymph node (LN) staging in patients with non-small cell lung cancer (NSCLC). Methods A total of 263 pathologically confirmed LNs from 124 patients with NCSLC were retrospectively analyzed. Positron-emission tomography/computed tomography (PET/CT) examination was performed before treatment according to the clinical schedule. In the training cohort (N = 185), malignancy-related features, such as SUVmax, short-axis diameter (SAD), and CT radiomics features, were extracted from the regions of LN based on the PET/CT scan. The Minimum-Redundancy Maximum-Relevance (mRMR) algorithm and the Least Absolute Shrinkage and Selection Operator (LASSO) regression model were used for feature selection and radiomics score building. The radiomics score (Rad-Score) and SUVmax were incorporated in a PET/CT nomogram using the multivariable logistic regression analysis. The performance of the proposed model was evaluated with discrimination, calibration, and clinical application in an independent testing cohort (N = 78). Results The radiomics scores consisting of 14 selected features were significantly associated with LN status for both training cohort with AUC of 0.849 (95% confidence interval (CI), 0.796–0.903) and testing cohort with AUC of 0.828 (95% CI, 0.782–0.919). The PET/CT nomogram incorporating radiomics score and SUVmax showed moderate improvement of the efficiency with AUC of 0.881 (95% CI, 0.834–0.928) in the training cohort and AUC of 0.872 (95% CI, 0.797–0.946) in the testing cohort. The decision curve analysis indicated that the PET/CT nomogram was clinically useful. Conclusion The PET/CT nomogram, which incorporates Rad-Score and SUVmax, can improve the diagnostic performance of LN metastasis. Key Points • The PET/CT nomogram (Int-Score) based on lymph node (LN) PET/CT images can reliably predict LN status in NSCLC. • Int-Score is a relatively objective diagnostic method, which can play an auxiliary role in the process of clinicians making treatment decisions. Supplementary Information The online version contains supplementary material available at 10.1007/s00330-020-07624-9.
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Affiliation(s)
- Xianlei Li
- Department of Biomedical Engineering National University of Singapore 117583 Singapore
| | - Yufeng Shou
- Department of Biomedical Engineering National University of Singapore 117583 Singapore
| | - Andy Tay
- Department of Biomedical Engineering National University of Singapore 117583 Singapore
- Institute for Health Innovation and Technology National University of Singapore 117599 Singapore
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Suresh R, Ziemys A, Holder AM. Dissecting the Lymphatic System to Predict Melanoma Metastasis. Front Oncol 2020; 10:576190. [PMID: 33330052 PMCID: PMC7729077 DOI: 10.3389/fonc.2020.576190] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022] Open
Abstract
Melanoma is the most lethal form of skin cancer in the United States. Current American Joint Committee on Cancer (AJCC) staging uses Breslow depth and ulceration as the two primary tumor factors that predict metastatic risk in cutaneous melanoma. Early disease stages are generally associated with high survival rates. However, in some cases, patients with thin melanomas develop advanced disease, suggesting other factors may contribute to the metastatic potential of an individual patient’s melanoma. This review focuses on the role of the lymphatic system in the metastasis of cutaneous melanoma, from recent discoveries in mechanisms of lymphangiogenesis to elements of the lymphatic system that ultimately may aid clinicians in determining which patients are at highest risk. Ultimately, this review highlights the need to integrate pathological, morphological, and molecular characteristics of lymphatics into a “biomarker” for metastatic potential.
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Affiliation(s)
- Rishi Suresh
- Texas A&M College of Medicine, Bryan, TX, United States
| | - Arturas Ziemys
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, United States
| | - Ashley M Holder
- Department of Surgery, Division of Surgical Oncology, University of Alabama at Birmingham, Birmingham, AL, United States
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