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Chen CH, Reva B, Katabi N, Wizel A, Xu H, Ho AL, Morris LG, Bakst RL, Parikh AS, Drier Y, Deborde S, Wong RJ. Sympathetic axonogenesis promotes adenoid cystic carcinoma progression. J Exp Med 2025; 222:e20242250. [PMID: 40272482 PMCID: PMC12020745 DOI: 10.1084/jem.20242250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/07/2025] [Accepted: 03/12/2025] [Indexed: 04/25/2025] Open
Abstract
Nerves are integral to the adenoid cystic carcinoma (ACC) microenvironment. The strong association of ACC with perineural invasion (PNI) is considered a hallmark of this disease. In human salivary ACC, we identify intratumoral, small-caliber, disorganized sympathetic nerves not observed in other salivary neoplasms. Norepinephrine or sympathetic ganglia explants enhance ACC proliferation in vitro. Two novel orthotopic ACC patient-derived xenograft (PDX) models recapitulate ACC morphology and demonstrate sympathetic innervation. Pharmacologic or surgical blockade of sympathetic nerves decreases ACC PDX growth. Bulk RNA sequencing of salivary ACC reveals correlations between noradrenergic nerve development signatures and worse patient survival. Metastatic ACC foci exhibit lower nerve signature gene expression levels than primary ACC. Sympathetic innervation in ACC is distinct from PNI and reflects tumor axonogenesis driven by noradrenergic neural development programs. These programs support ACC progression, are associated with poor prognosis, and may be inhibited as a therapeutic strategy.
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Affiliation(s)
- Chun-Hao Chen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Boris Reva
- Department of Genetics and Genomic Sciences, Mount Sinai Medical Center, New York, NY, USA
| | - Nora Katabi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Avishai Wizel
- The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Hongbo Xu
- Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Alan L. Ho
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Luc G.T. Morris
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Richard L. Bakst
- Department of Radiation Oncology, Mount Sinai Medical Center, New York, NY, USA
| | - Anuraag S. Parikh
- Department of Otolaryngology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Yotam Drier
- The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Sylvie Deborde
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Richard J. Wong
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Wang M, Pu N, Bo X, Chen F, Zhou Y, Cheng Q. Significance and mechanisms of perineural invasion in malignant tumors. Front Oncol 2025; 15:1572396. [PMID: 40421086 PMCID: PMC12104087 DOI: 10.3389/fonc.2025.1572396] [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: 02/07/2025] [Accepted: 04/18/2025] [Indexed: 05/28/2025] Open
Abstract
Cancer remains the second leading cause of death worldwide. Tumor invasion and metastasis pose significant challenges for clinical management. In addition to the traditional pathways of metastasis such as hematologic or lymphatic transmission, perineural invasion (PNI) has become a unique mechanism of metastasis, which is closely associated with neuropathic pain, motor deficits, and poor prognosis. PNI is often observed in malignant tumors of the pancreas, head and neck, gastrointestinal tract, and lungs, and it reflects a unique neurotropic transfer behavior utilizing neural networks. Despite its clinical significance, targeted therapies for PNI are still lacking. This review synthesizes current evidences regarding PNI, elucidates the clinical significance of PNI in tumor metastasis, prognosis, and neurological dysfunction. By integrating the latest advances in multi-omics, we analyzed the potential key molecular pathways and tumor microenvironment drivers of PNI, and proposed future research directions for developing PNI-specific therapies to improve patient outcomes.
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Affiliation(s)
- Mengyao Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Niu Pu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Xitong Bo
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Fuxiang Chen
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Yilong Zhou
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Qiong Cheng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
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Chen G, Zheng Z, Ji Q, He R, Pan Z, Chen Y, Zhou Y, Wei Z, Sun H, Feng L. Tumor innervation in cervical cancer: Prognostic insights from myelin-associated risk signatures. FASEB Bioadv 2025; 7:e70004. [PMID: 40330434 PMCID: PMC12050960 DOI: 10.1096/fba.2024-00190] [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: 10/21/2024] [Revised: 12/15/2024] [Accepted: 02/10/2025] [Indexed: 05/08/2025] Open
Abstract
The reported frequencies of perineural invasion (PNI) in human cervical cancer, ranging from 7.0% to 35.1%, may underestimate the significant role that nerves play in cervical cancer progression. Neurosecretory factors can promote tumor migration and invasion, even in cases classified as "PNI-negative". This study aimed to clarify whether tumor innervation influences tumor progression and cervical cancer patient outcomes. We first evaluated the gene signatures of human myelinating Schwann cells (SCs) using the Inferring Pathway Activity and Suppression (IPAS) scoring system to predict the degree of tumor innervation in 304 cervical cancer patients from The Cancer Genome Atlas (TCGA) database. Subsequently, we constructed a myelin-associated risk prognostic signature using LASSO regression analysis. Finally, we obtained a risk score using a quantitative formula and categorized all samples into high- and low-risk score groups. Our results indicated that tumor innervation in cervical cancer is associated with poor patient survival. Higher levels of innervation were correlated with an impaired immune response and reduced expression of immune checkpoints, including PD-L1. The prognostic model demonstrated excellent consistency between predicted and actual survival outcomes. Overall, tumor innervation plays a crucial role in regulating cervical cancer prognosis. The identified prognostic risk signatures offer a valuable tool for risk stratification and prognostic prediction in clinical practice.
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Affiliation(s)
- Guoqiang Chen
- Department of GynecologyThe People's Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen UniversityShenzhenChina
| | - Zhen Zheng
- Department of Obstetrics and GynecologyNational Clinical Research Centre for Obstetric and Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Qingqing Ji
- Department of AnesthesiologyShidong Hospital Affiliated to University of Shanghai for Science and TechnologyShanghaiChina
| | - Ruihua He
- Department of PharmacyShanghai Fourth People's Hospital, School of Medicine, Tongji UniversityShanghaiChina
| | - Zhouyuan Pan
- Department of GynecologyThe People's Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen UniversityShenzhenChina
| | - Yunxia Chen
- Department of GynecologyThe People's Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen UniversityShenzhenChina
| | - Yuqing Zhou
- Department of GynecologyThe People's Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen UniversityShenzhenChina
| | - Zhihong Wei
- Department of GynecologyThe People's Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen UniversityShenzhenChina
| | - Hao Sun
- Department of Obstetrics and GynecologyShanghai Changzheng Hospital of Naval Medical UniversityShanghaiChina
| | - Lixia Feng
- Department of GynecologyThe People's Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen UniversityShenzhenChina
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Sun ZG, Chen SX, Sun BL, Zhang DK, Sun HL, Chen H, Hu YW, Zhang TY, Han ZH, Wu WX, Hou ZY, Yao L, Jie JZ. Important role of lymphovascular and perineural invasion in prognosis of colorectal cancer patients with N1c disease. World J Gastroenterol 2025; 31:102210. [PMID: 39926214 PMCID: PMC11718613 DOI: 10.3748/wjg.v31.i5.102210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/04/2024] [Accepted: 12/16/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Lymphovascular invasion (LVI) and perineural invasion (PNI) are associated with decreased survival in colorectal cancer (CRC), but its significance in N1c stage remains to be clearly defined. AIM To evaluate LVI and PNI as potential prognostic indicators in N1c CRC. METHODS We retrospectively identified 107 consecutive patients who had CRC with N1c disease radically resected at our hospital. Tumors were reviewed for LVI and PNI by one pathologist blinded to the patients' outcomes. Disease-free survival (DFS), overall survival (OS) and cancer-specific survival (CSS) were determined using the Kaplan-Meier method, with LVI and PNI prognosis differences determined by multivariate analysis using the Cox multiple hazards model. Results were compared using log-rank test. The receiver operating characteristic (ROC) curve was used to evaluate the prognostic predictive ability. RESULTS The median follow-up time was 63.17 (45.33-81.37) months for DFS, with 33.64% (36/107) of patients experiencing recurrence; 21.5% of tumors were found to be LVI positive and 44.9% PNI positive. The 5-year DFS rate was greater for patients with LVI-negative tumors compared with LVI-positive tumors (74.0% vs 35.6%), and PNI was similar (82.5% vs 45.1%). On multivariate analysis, LVI [hazard ratio (HR) = 3.368, 95% confidence interval (CI): 1.628-6.966, P = 0.001] and PNI (HR = 3.055, 95%CI: 1.478-6.313, P = 0.002) were independent prognostic factors for DFS. All patients could be divided into three groups of patients with different prognosis according to LVI and PNI. The 5-year ROC curve for LVI, PNI and their combination prediction of DFS was 0.646, 0.709 and 0.759, respectively. Similar results were seen for OS and CSS. CONCLUSION LVI and PNI could serve as independent prognostic factors of outcomes in N1c CRC patients. Patients with LVI or PNI should be given more attention during treatment.
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Affiliation(s)
- Zhi-Gang Sun
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shao-Xuan Chen
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Bai-Long Sun
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Da-Kui Zhang
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hong-Liang Sun
- Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Huang Chen
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yu-Wan Hu
- Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Tong-Yin Zhang
- Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Zi-Han Han
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wen-Xiao Wu
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Zhi-Yong Hou
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Li Yao
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jian-Zheng Jie
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
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Rutkowski K, Gola M, Godlewski J, Starzyńska A, Marvaso G, Mastroleo F, Giulia Vincini M, Porazzi A, Zaffaroni M, Jereczek-Fossa BA. Understanding the role of nerves in head and neck cancers - a review. Oncol Rev 2025; 18:1514004. [PMID: 39906323 PMCID: PMC11791411 DOI: 10.3389/or.2024.1514004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 12/03/2024] [Indexed: 02/06/2025] Open
Abstract
Worldwide, head and neck cancers (HNCs) account for approximately 900,000 cases and 500,000 deaths annually, with their incidence continuing to rise. Carcinogenesis is a complex, multidimensional molecular process leading to cancer development, and in recent years, the role of nerves in the pathogenesis of various malignancies has been increasingly recognized. Thanks to the abundant innervation of the head and neck region, peripheral nervous system has gained considerable interest for its possible role in the development and progression of HNCs. Intratumoral parasympathetic, sympathetic, and sensory nerve fibers are emerging as key players and potential targets for novel anti-cancer and pain-relieving medications in different tumors, including HNCs. This review explores nerve-cancer interactions, including perineural invasion (PNI), cancer-related axonogenesis, neurogenesis, and nerve reprogramming, with an emphasis on their molecular mechanisms, mediators and clinical implications. PNI, an adverse histopathologic feature, has been widely investigated in HNCs. However, its prognostic value remains debated due to inconsistent results when classified dichotomously (present/absent). Emerging evidence suggests that quantitative and qualitative descriptions of PNI may better reflect its clinical usefulness. The review also examines therapies targeting nerve-cancer crosstalk and highlights the influence of HPV status on tumor innervation. By synthesizing current knowledge, challenges, and future perspectives, this review offers insights into the molecular basis of nerve involvement in HNCs and the potential for novel therapeutic approaches.
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Affiliation(s)
- Krzysztof Rutkowski
- Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Michał Gola
- Department of Human Histology and Embryology, Collegium Medicum, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland
- Department of Oncology and Immuno-Oncology, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, Olsztyn, Poland
| | - Janusz Godlewski
- Department of Human Histology and Embryology, Collegium Medicum, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland
- Department of Surgical Oncology, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, Olsztyn, Poland
| | - Anna Starzyńska
- Department of Oral Surgery, Medical University of Gdańsk, Gdańsk, Poland
- Department of Otolaryngology, Phoniatrics and Audiology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Giulia Marvaso
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Federico Mastroleo
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Maria Giulia Vincini
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Alice Porazzi
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Mattia Zaffaroni
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Barbara Alicja Jereczek-Fossa
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Garajová I, Giovannetti E. Targeting Perineural Invasion in Pancreatic Cancer. Cancers (Basel) 2024; 16:4260. [PMID: 39766161 PMCID: PMC11674953 DOI: 10.3390/cancers16244260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Pancreatic cancer is an aggressive tumor with dismal prognosis. Neural invasion is one of the pathological hallmarks of pancreatic cancer. Peripheral nerves can modulate the phenotype and behavior of the malignant cells, as well as of different components of the tumor microenvironment, and thus affect tumor growth and metastasis. From a clinical point of view, neural invasion is translated into intractable pain and represents a predictor of tumor recurrence and poor prognosis. Several molecules are implicated in neural invasion and pain onset in PDAC, including neutrophins (e.g., NGF), chemokines, adhesion factors, axon-guidance molecules, different proteins, and neurotransmitters. In this review, we discuss the role of nerves within the pancreatic cancer microenvironment, highlighting how infiltrating nerve fibers promote tumor progression and metastasis, while tumor cells, in turn, drive nerve outgrowth in a reciprocal interaction that fuels tumor advancement. We outline key molecules involved in neural invasion in pancreatic cancer and, finally, explore potential therapeutic strategies to target neural invasion, aiming to both inhibit cancer progression and alleviate cancer-associated pain.
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Affiliation(s)
- Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Lab of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1007 MB Amsterdam, The Netherlands;
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, San Giuliano Terme PI, 56017 Pisa, Italy
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Zhang D, Luo Y, Lin Y, Fang Z, Zheng H, An M, Xie Q, Wu Z, Yu C, Yang J, Yu M, Chen C, Chen R. Endosomal Trafficking Bypassed by the RAB5B-CD109 Interplay Promotes Axonogenesis in KRAS-Mutant Pancreatic Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405092. [PMID: 39488792 DOI: 10.1002/advs.202405092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 10/13/2024] [Indexed: 11/04/2024]
Abstract
Perineural invasion (PNI) represents a unique biological feature associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC), especially in the presence of KRAS mutations. Extracellular vesicle (EV)-packaged circular RNAs (circRNAs) function as essential mediators of tumor microenvironment communication, triggering PDAC cell invasion and distant metastasis. However, the regulatory mechanisms of EV-packaged circRNAs in the PNI of KRAS-mutant PDAC have not yet been elucidated. Herein, a KRASG12D mutation-responsive EV-packaged circRNA, circPNIT, which positively correlated with PNI in PDAC patients is identified. Functionally, KRASG12D PDAC-derived EV-packaged circPNIT promoted axonogenesis and PNI both in vitro and in vivo. Mechanistically, the circPNIT-mediated Rab5B-CD109 interplay bypassed traditional endosomal trafficking to anchor Rab5B to the lipid rafts of multivesicular bodies and packaged circPNIT into CD109+ EVs. Subsequently, CD109+ EVs delivered circPNIT to neurons by binding to TRPV1 and facilitating DSCAML1 transcription-induced axonogenesis, which in turn enhanced the PNI by activating the GFRα1/RET pathway. Importantly, circPNIT-loaded CD109+ EVs are established to dramatically promote PNI in a KRASG12D/+ Trp53R172H/+ Pdx-1-Cre mouse model. Collectively, the findings highlight the mechanism underlying how EV-packaged circRNAs mediate the PNI of KRAS-mutant PDAC cells through the Rab5B endosomal bypass, identifying circPNIT as an effective target for the treatment of neuro-metastatic PDAC.
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Affiliation(s)
- Dingwen Zhang
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, P. R. China
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
| | - Yuming Luo
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
| | - Yan Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China
| | - Zhou Fang
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China
| | - Hanhao Zheng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China
| | - Mingjie An
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China
| | - Qingyu Xie
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China
| | - Zhuo Wu
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, P. R. China
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
| | - Chao Yu
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China
| | - Jiabin Yang
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China
| | - Min Yu
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
| | - Changhao Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China
| | - Rufu Chen
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China
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Pei M, Wiefels M, Harris D, Velez Torres JM, Gomez-Fernandez C, Tang JC, Hernandez Aya L, Samuels SE, Sargi Z, Weed D, Dinh C, Kaye ER. Perineural Invasion in Head and Neck Cutaneous Squamous Cell Carcinoma. Cancers (Basel) 2024; 16:3695. [PMID: 39518134 PMCID: PMC11545267 DOI: 10.3390/cancers16213695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a lifetime risk of 14-20% that is rising every year. Although prognosis for cSCC is generally good, certain high-risk features of cSCC portend increased rates of nodal and distant metastasis, recurrence, and disease-specific mortality. One such high-risk factor is perineural invasion (PNI), which is broadly defined as the invasion of cancer into and around nerves. Compared to other high-risk factors, PNI presence is associated with the highest risk for locoregional and distant metastasis. Still, the mechanisms underlying the pathogenesis of PNI remain poorly understood. Recent studies suggest the migration and invasion of tumors into nerves is a result of complex molecular crosstalk within the tumor-nerve microenvironment, wherein the milieu of signaling molecules simultaneously promote neuronal growth and tumor cell invasion. Methods: Understanding the molecular and cellular mechanisms that promote PNI will lead to future developments of targeted therapies that may improve locoregional control and survival. Results/Conclusions: In our article, we aim to provide a comprehensive review of recent findings about the pathogenesis of PNI, clinical implications of PNI-positive disease in cSCC, available treatment modalities, and potential future therapeutic targets.
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Affiliation(s)
- Michelle Pei
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA (M.W.); (D.W.)
| | - Matthew Wiefels
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA (M.W.); (D.W.)
| | - Danielle Harris
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA (M.W.); (D.W.)
| | - Jaylou M. Velez Torres
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
| | - Carmen Gomez-Fernandez
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA (M.W.); (D.W.)
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
| | - Jennifer C. Tang
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Leonel Hernandez Aya
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
- Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Stuart E. Samuels
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Zoukaa Sargi
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA (M.W.); (D.W.)
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
| | - Donald Weed
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA (M.W.); (D.W.)
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
| | - Christine Dinh
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA (M.W.); (D.W.)
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
| | - Erin R. Kaye
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA (M.W.); (D.W.)
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA (S.E.S.)
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9
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He K, Wang H, Huo R, Jiang SH, Xue J. Schwann cells and enteric glial cells: Emerging stars in colorectal cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189160. [PMID: 39059672 DOI: 10.1016/j.bbcan.2024.189160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 07/21/2024] [Accepted: 07/21/2024] [Indexed: 07/28/2024]
Abstract
Cancer neuroscience, a promising field dedicated to exploring interactions between cancer and the nervous system, has attracted growing attention. The gastrointestinal tracts exhibit extensive innervation, notably characterized by intrinsic innervation. The gut harbors a substantial population of glial cells, including Schwann cells wrapping axons of neurons in the peripheral nervous system and enteric glial cells intricately associated with intrinsic innervation. Glial cells play a crucial role in maintaining the physiological functions of the intestine, encompassing nutrient absorption, barrier integrity, and immune modulation. Nevertheless, it has only been in recent times that the significance of glial cells within colorectal cancer (CRC) has begun to receive considerable attention. Emerging data suggests that glial cells in the gut contribute to the progression and metastasis of CRC, by interacting with cancer cells, influencing inflammation, and modulating the tumor microenvironment. Here, we summarize the significant roles of glial cells in the development and progression of CRC and discuss the latest technologies that can be integrated into this field for in-depth exploration, as well as potential specific targeted strategies for future exploration to benefit patients.
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Affiliation(s)
- Kexin He
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, PR China
| | - Hao Wang
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, PR China
| | - Ruixue Huo
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, PR China
| | - Shu-Heng Jiang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China.
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, PR China.
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10
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Xia Y, Jiang T, Li Y, Gu C, Lv J, Lu C, Xu P, Fang L, Chen Z, Liu H, Zhang D, Xu H, Yang L, Xu Z, Wang L. circVAPA-rich small extracellular vesicles derived from gastric cancer promote neural invasion by inhibiting SLIT2 expression in neuronal cells. Cancer Lett 2024; 592:216926. [PMID: 38714291 DOI: 10.1016/j.canlet.2024.216926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/16/2024] [Accepted: 04/27/2024] [Indexed: 05/09/2024]
Abstract
Gastric cancer (GC) is one of the most common cancer worldwide. Neural invasion (NI) is considered as the symbiotic interaction between nerves and cancers, which strongly affects the prognosis of GC patients. Small extracellular vesicles (sEVs) play a key role in intercellular communication. However, whether sEVs mediate GC-NI remains unexplored. In this study, sEVs release inhibitor reduces the NI potential of GC cells. Muscarinic receptor M3 on GC-derived sEVs regulates their absorption by neuronal cells. The enrichment of sEV-circVAPA in NI-positive patients' serum is validated by serum high throughput sEV-circRNA sequencing and clinical samples. sEV-circVAPA promotes GC-NI in vitro and in vivo. Mechanistically, sEV-circVAPA decreases SLIT2 transcription by miR-548p/TGIF2 and inhibits SLIT2 translation via binding to eIF4G1, thereby downregulates SLIT2 expression in neuronal cells and finally induces GC-NI. Together, this work identifies the preferential absorption mechanism of GC-derived sEVs by neuronal cells and demonstrates a previously undefined role of GC-derived sEV-circRNA in GC-NI, which provides new insight into sEV-circRNA based diagnostic and therapeutic strategies for NI-positive GC patients.
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Affiliation(s)
- Yiwen Xia
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Tianlu Jiang
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ying Li
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Chao Gu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China
| | - Jialun Lv
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Chen Lu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Penghui Xu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Lang Fang
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zetian Chen
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Hongda Liu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Diancai Zhang
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Hao Xu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Li Yang
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zekuan Xu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Linjun Wang
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
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11
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Cheng K, Pan J, Liu Q, Ji Y, Liu L, Guo X, Wang Q, Li S, Sun J, Gong M, Zhang Y, Yuan Y. Exosomal lncRNA XIST promotes perineural invasion of pancreatic cancer cells via miR-211-5p/GDNF. Oncogene 2024; 43:1341-1352. [PMID: 38454138 DOI: 10.1038/s41388-024-02994-6] [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: 07/29/2023] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/09/2024]
Abstract
Perineural invasion (PNI) is an essential form of tumor metastasis in multiple malignant cancers, such as pancreatic cancer, prostate cancer, and head and neck cancer. Growing evidence has revealed that pancreatic cancer recurrence and neuropathic pain positively correlate with PNI. Therefore, targeting PNI is a proper strategy for pancreatic cancer treatment. Exosomal lncRNA derived from pancreatic cancer cells is an essential component of the tumor microenvironment. However, whether exosomal lncXIST derived from pancreatic cancer cells can promote PNI and its exact mechanism remains to be elucidated. We show that lncXIST mediates nerve-tumor crosstalk via exosomal delivery. Our data reveal that exosomal lncXIST derived from pancreatic cancer cells is delivered to neural cells and promotes their release of glial-cell-line-derived neurotrophic factor (GDNF), essential in facilitating the PNI of pancreatic cancer. Mechanistically, microRNA-211-5p negatively regulates GDNF, and lncXIST serves as a miR-211-5p sponge. The function of exosomes in the dynamic interplay between nerves and cancer is confirmed in both in vivo and in vitro PNI models. Therefore, targeting pancreatic cancer cell-derived exosomal lncXIST may provide clues for a promising approach for developing a new strategy to combat PNI of pancreatic cancer.
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Affiliation(s)
- Ke Cheng
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Jinjin Pan
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Qinlong Liu
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Yuke Ji
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Liang Liu
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Xiangqian Guo
- Institute of Biomedical Informatics, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, Academy for Advanced Interdisciplinary Studies, Henan University, Kaifeng, 47500, China
| | - Qiang Wang
- Institute of Biomedical Informatics, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, Academy for Advanced Interdisciplinary Studies, Henan University, Kaifeng, 47500, China
| | - Shao Li
- College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Jinyue Sun
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Miaomiao Gong
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.
| | - Ying Zhang
- Sixth Department of liver disease, Dalian Public Health Clinical Center, Dalian, 116044, China.
| | - Yuhui Yuan
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.
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12
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Cai Z, Yao H, Chen J, Ahmed AA, Li C, Hu X, Tang X, Jiang C. Schwann cells in pancreatic cancer: Unraveling their multifaceted roles in tumorigenesis and neural interactions. Cancer Lett 2024; 587:216689. [PMID: 38367898 DOI: 10.1016/j.canlet.2024.216689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/15/2024] [Accepted: 01/26/2024] [Indexed: 02/19/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), characterized by heightened neural density, presents a challenging prognosis primarily due to perineural invasion. Recognized for their crucial roles in neural support and myelination, Schwann cells (SCs) significantly influence the process of tumorigenesis. This review succinctly outlines the interplay between PDAC and neural systems, positioning SCs as a nexus in the tumor-neural interface. Subsequently, it delves into the cellular origin and influencers of SCs within the pancreatic tumor microenvironment, emphasizing their multifaceted roles in tumor initiation, progression, and modulation of the neural and immune microenvironment. The discussion encompasses potential therapeutic interventions targeting SCs. Lastly, the review underscores pressing issues, advocating for sustained exploration into the diverse contributions of SCs within the intricate landscape of PDAC, with the aim of enhancing our understanding of their involvement in this complex malignancy.
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Affiliation(s)
- Zhiwei Cai
- Department of General Surgery, Pancreatobiliary Surgery Center, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Hongfei Yao
- Department of General Surgery, Pancreatobiliary Surgery Center, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Jiahao Chen
- Department of General Surgery, Pancreatobiliary Surgery Center, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Abousalam Abdoulkader Ahmed
- Department of General Surgery, Pancreatobiliary Surgery Center, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Chunjing Li
- Department of General Surgery, Pancreatobiliary Surgery Center, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Xiao Hu
- Department of General Surgery, Pancreatobiliary Surgery Center, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Xiaoyan Tang
- Department of General Surgery, Pancreatobiliary Surgery Center, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Chongyi Jiang
- Department of General Surgery, Pancreatobiliary Surgery Center, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China.
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13
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Zhu M, Luo F, Xu B, Xu J. Research Progress of Neural Invasion in Pancreatic Cancer. Curr Cancer Drug Targets 2024; 24:397-410. [PMID: 37592782 DOI: 10.2174/1568009623666230817105221] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/13/2023] [Accepted: 07/19/2023] [Indexed: 08/19/2023]
Abstract
Pancreatic cancer is one of the highly malignant gastrointestinal tumors in humans, and patients suffer from cancer pain in the process of cancer. Most patients suffer from severe pain in the later stages of the disease. The latest studies have shown that the main cause of pain in patients with pancreatic cancer is neuroinflammation caused by tumor cells invading nerves and triggering neuropathic pain on this basis, which is believed to be the result of nerve invasion. Peripheral nerve invasion (PNI), defined as the presence of cancer cells along the nerve or in the epineurial, perineural, and endoneurial spaces of the nerve sheath, is a special way for cancer to spread to distant sites. However, due to limited clinical materials, the research on the mechanism of pancreatic cancer nerve invasion has not been carried out in depth. In addition, perineural invasion is considered to be one of the underlying causes of recurrence and metastasis after pancreatectomy and an independent predictor of prognosis. This article systematically reviewed the neural invasion of pancreatic cancer through bioinformatics analysis, clinical manifestations and literature reviews.
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Affiliation(s)
- Mengying Zhu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P.R. China
| | - Feng Luo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, China
| | - Bin Xu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, P.R. China
| | - Jian Xu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P.R. China
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14
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Huang FF, Cui WH, Ma LY, Chen Q, Liu Y. Crosstalk of nervous and immune systems in pancreatic cancer. Front Cell Dev Biol 2023; 11:1309738. [PMID: 38099290 PMCID: PMC10720593 DOI: 10.3389/fcell.2023.1309738] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 11/20/2023] [Indexed: 12/17/2023] Open
Abstract
Pancreatic cancer is a highly malignant tumor known for its extremely low survival rate. The combination of genetic disorders within pancreatic cells and the tumor microenvironment contributes to the emergence and progression of this devastating disease. Extensive research has shed light on the nature of the microenvironmental cells surrounding the pancreatic cancer, including peripheral nerves and immune cells. Peripheral nerves release neuropeptides that directly target pancreatic cancer cells in a paracrine manner, while immune cells play a crucial role in eliminating cancer cells that have not evaded the immune response. Recent studies have revealed the intricate interplay between the nervous and immune systems in homeostatic condition as well as in cancer development. In this review, we aim to summarize the function of nerves in pancreatic cancer, emphasizing the significance to investigate the neural-immune crosstalk during the advancement of this malignant cancer.
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Affiliation(s)
- Fei-Fei Huang
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
| | - Wen-Hui Cui
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
| | - Lan-Yue Ma
- Center for Cell Lineage and Development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qi Chen
- Center for Cell Lineage and Development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
| | - Yang Liu
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
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15
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de Lima PO, Broit N, Huang JD, Lim JH, Gardiner DJ, Brown IS, Panizza BJ, Boyle GM, Simpson F. Development of an in vivo murine model of perineural invasion and spread of cutaneous squamous cell carcinoma of the head and neck. Front Oncol 2023; 13:1231104. [PMID: 37746297 PMCID: PMC10513369 DOI: 10.3389/fonc.2023.1231104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/06/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction Cutaneous squamous cell carcinoma of the head and neck (cSCCHN) can metastasize by invading nerves and spread toward the central nervous system. This metastatic process is called perineural invasion (PNI) and spread (PNS). An in vivo sciatic nerve mouse model is used for cSCCHN PNI/PNS. Here we describe a complementary whisker pad model which allows for molecular studies investigating drivers of PNI/PNS in the head and neck environment. Methods A431 cells were injected into the whisker pads of BALB/c Foxn1nu and NSG-A2 mice. Tumor progression was monitored by bioluminescence imaging and primary tumor resection was performed. PNI was detected by H&E and IHC. Tumor growth and PNI were assessed with inducible ablation of LOXL2. Results The rate of PNI development in mice was 10%-28.6%. Tumors exhibited PNI/PNS reminiscent of the morphology seen in the human disease. Our model's utility was demonstrated with inducible ablation of LOXL2 reducing primary tumor growth and PNI. Discussion This model consists in a feasible way to test molecular characteristics and potential therapies, offers to close a gap in the described in vivo methods for PNI/PNS of cSCCHN and has uses in concert with the established sciatic nerve model.
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Affiliation(s)
| | - Natasa Broit
- Cancer Drug Mechanisms Group, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Johnson D. Huang
- Frazer Institute, University of Queensland, Brisbane, QLD, Australia
| | - Jae H. Lim
- Cancer Drug Mechanisms Group, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Damien J. Gardiner
- Cancer Drug Mechanisms Group, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Ian S. Brown
- Envoi Pathology, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Benedict J. Panizza
- Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
- Department of Otolaryngology-Head and Neck Surgery, Kaiser Moanalua Medical Center, Honolulu, HI, United States
| | - Glen M. Boyle
- Cancer Drug Mechanisms Group, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Fiona Simpson
- Frazer Institute, University of Queensland, Brisbane, QLD, Australia
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16
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Hung YH, Hou YC, Hsu SH, Wang LY, Tsai YL, Shan YS, Su YY, Hung WC, Chen LT. Pancreatic cancer cell-derived semaphorin 3A promotes neuron recruitment to accelerate tumor growth and dissemination. Am J Cancer Res 2023; 13:3417-3432. [PMID: 37693128 PMCID: PMC10492129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 06/20/2023] [Indexed: 09/12/2023] Open
Abstract
Perineural invasion and neurogenesis are frequently observed in pancreatic ductal adenocarcinoma (PDAC), and they are associated with a poor prognosis. Axon guidance factor semaphorin 3A (SEMA3A) is upregulated in PDAC. However, it remains unclear whether cancer-derived SEMA3A influences nerve innervation and pancreatic tumorigenesis. In silico analyses were performed using PROGgene and NetworkAnalyst to clarify the importance of SEMA3A and its receptors, plexin A1 (PLXNA1) and neuropilin 2 (NRP2), in pancreatic cancer. In vitro assays, including migration, neurite outgrowth, and 3D recruitment, were performed to study the effects of SEMA3A on neuronal behaviors. Additionally, an orthotopic animal study using C57BL/6 mice was performed to validate the in vitro findings. Expression of SEMA3A and its receptors predicted worse prognosis for PDAC. Cancer-derived SEMA3A promoted neural migration, neurite outgrowth, and neural recruitment. Furthermore, SEMA3A-induced effects depended on PLXNA1, NRP2, and MAPK activation. Trametinib, an approved MAPK kinase (MEK) inhibitor, counteracted SEMA3A-enhanced neuronal activity in vitro. Inhibition of SEMA3A by shRNA in pancreatic cancer cells resulted in decreased neural recruitment, tumor growth, and dissemination in vivo. Our results suggested that cancer-secreted SEMA3A plays an important role in promoting neo-neurogenesis and progression of PDAC.
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Affiliation(s)
- Yu-Hsuan Hung
- National Institute of Cancer Research, National Health Research InstitutesTainan 704, Taiwan
| | - Ya-Chin Hou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityTainan 704, Taiwan
| | - Shih-Han Hsu
- National Institute of Cancer Research, National Health Research InstitutesTainan 704, Taiwan
| | - Li-Yun Wang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung UniversityTainan 704, Taiwan
| | - Ya-Li Tsai
- National Institute of Cancer Research, National Health Research InstitutesTainan 704, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityTainan 704, Taiwan
- Division of General Surgery, Department of Surgery, National Cheng Kung University HospitalTainan 704, Taiwan
| | - Yung-Yeh Su
- National Institute of Cancer Research, National Health Research InstitutesTainan 704, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityTainan 704, Taiwan
- Department of Oncology, National Cheng Kung University HospitalTainan 704, Taiwan
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research InstitutesTainan 704, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research InstitutesTainan 704, Taiwan
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung UniversityTainan 704, Taiwan
- Department of Oncology, National Cheng Kung University HospitalTainan 704, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University HospitalKaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical UniversityKaohsiung 807, Taiwan
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17
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Marcadis AR, Kao E, Wang Q, Chen CH, Gusain L, Powers A, Bakst RL, Deborde S, Wong RJ. Rapid cancer cell perineural invasion utilizes amoeboid migration. Proc Natl Acad Sci U S A 2023; 120:e2210735120. [PMID: 37075074 PMCID: PMC10151474 DOI: 10.1073/pnas.2210735120] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 02/22/2023] [Indexed: 04/20/2023] Open
Abstract
The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neuroinvasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neuroinvasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from a mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associated more with dorsal root ganglia than nonleading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion.
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Affiliation(s)
- Andrea R. Marcadis
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Elizabeth Kao
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Qi Wang
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Chun-Hao Chen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Laxmi Gusain
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Ann Powers
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Richard L. Bakst
- Department of Radiation Oncology, Mount Sinai Medical Center, New York, NY10029
| | - Sylvie Deborde
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY10065
| | - Richard J. Wong
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY10065
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY10065
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18
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Winkler F, Venkatesh HS, Amit M, Batchelor T, Demir IE, Deneen B, Gutmann DH, Hervey-Jumper S, Kuner T, Mabbott D, Platten M, Rolls A, Sloan EK, Wang TC, Wick W, Venkataramani V, Monje M. Cancer neuroscience: State of the field, emerging directions. Cell 2023; 186:1689-1707. [PMID: 37059069 PMCID: PMC10107403 DOI: 10.1016/j.cell.2023.02.002] [Citation(s) in RCA: 190] [Impact Index Per Article: 95.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/01/2023] [Accepted: 02/01/2023] [Indexed: 04/16/2023]
Abstract
The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new pillar of cancer therapy.
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Affiliation(s)
- Frank Winkler
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg and Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Humsa S Venkatesh
- Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA
| | - Moran Amit
- Department of Head and Neck Surgery, MD Anderson Cancer Center and The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Tracy Batchelor
- Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA
| | - Ihsan Ekin Demir
- Department of Surgery, Technical University of Munich, Munich, Germany
| | - Benjamin Deneen
- Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, Houston, TX, USA
| | - David H Gutmann
- Department of Neurology, Washington University, St Louis, MO, USA
| | - Shawn Hervey-Jumper
- Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas Kuner
- Department of Functional Neuroanatomy, University of Heidelberg, Heidelberg, Germany
| | - Donald Mabbott
- Department of Psychology, University of Toronto and Neuroscience & Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
| | - Michael Platten
- Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Asya Rolls
- Department of Immunology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Erica K Sloan
- Monash Institute of Pharmaceutical Sciences, Drug Discovery Biology Theme, Monash University, Parkville, VIC, Australia
| | - Timothy C Wang
- Department of Medicine, Division of Digestive and Gastrointestinal Diseases, Columbia University, New York, NY, USA
| | - Wolfgang Wick
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg and Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Varun Venkataramani
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg and Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Functional Neuroanatomy, University of Heidelberg, Heidelberg, Germany.
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
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19
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Li YT, Yuan WZ, Jin WL. Vagus innervation in the gastrointestinal tumor: Current understanding and challenges. Biochim Biophys Acta Rev Cancer 2023; 1878:188884. [PMID: 36990250 DOI: 10.1016/j.bbcan.2023.188884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 02/17/2023] [Accepted: 02/28/2023] [Indexed: 03/30/2023]
Abstract
The vagus nerve (VN) is the main parasympathetic nerve of the autonomic nervous system. It is widely distributed in the gastrointestinal tract and maintains gastrointestinal homeostasis with the sympathetic nerve under physiological conditions. The VN communicates with various components of the tumor microenvironment to positively and dynamically affect the progression of gastrointestinal tumors (GITs). The intervention in vagus innervation delays GIT progression. Developments in adeno-associated virus vectors, nanotechnology, and in vivo neurobiological techniques have enabled the creation of precisely regulated "tumor neurotherapies". Furthermore, the combination of neurobiological techniques and single cell sequencing may reveal more insights into VN and GIT. The present review aimed to summarize the mechanisms of communication between the VN and the gastrointestinal TME and to explore the potential and challenges of VN-based tumor neurotherapy in GITs.
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20
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Chen Z, Fang Y, Jiang W. Important Cells and Factors from Tumor Microenvironment Participated in Perineural Invasion. Cancers (Basel) 2023; 15:1360. [PMID: 36900158 PMCID: PMC10000249 DOI: 10.3390/cancers15051360] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Perineural invasion (PNI) as the fourth way for solid tumors metastasis and invasion has attracted a lot of attention, recent research reported a new point that PNI starts to include axon growth and possible nerve "invasion" to tumors as the component. More and more tumor-nerve crosstalk has been explored to explain the internal mechanism for tumor microenvironment (TME) of some types of tumors tends to observe nerve infiltration. As is well known, the interaction of tumor cells, peripheral blood vessels, extracellular matrix, other non-malignant cells, and signal molecules in TME plays a key role in the occurrence, development, and metastasis of cancer, as to the occurrence and development of PNI. We aim to summarize the current theories on the molecular mediators and pathogenesis of PNI, add the latest scientific research progress, and explore the use of single-cell spatial transcriptomics in this invasion way. A better understanding of PNI may help to understand tumor metastasis and recurrence and will be beneficial for improving staging strategies, new treatment methods, and even paradigm shifts in our treatment of patients.
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Affiliation(s)
- Zirong Chen
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yan Fang
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
| | - Weihong Jiang
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
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21
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RET rearrangements in non-small cell lung cancer: Evolving treatment landscape and future challenges. Biochim Biophys Acta Rev Cancer 2022; 1877:188810. [DOI: 10.1016/j.bbcan.2022.188810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/27/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022]
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22
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Pan C, Winkler F. Insights and opportunities at the crossroads of cancer and neuroscience. Nat Cell Biol 2022; 24:1454-1460. [PMID: 36097070 DOI: 10.1038/s41556-022-00978-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 05/17/2022] [Indexed: 11/09/2022]
Abstract
The biological and pathological importance of mutual interactions between the nervous system and cancer have become increasingly evident. The emerging field of cancer neuroscience aims to decipher key signalling factors of cancer-nervous system crosstalk and to exploit these modulators as targets for improved anticancer therapies. Here we discuss the key achievements in cancer neuroscience research, inspire further interactions on a variety of related research topics, and provide a roadmap for future studies.
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Affiliation(s)
- Chenchen Pan
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frank Winkler
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. .,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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23
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The Role of Neural Signaling in the Pancreatic Cancer Microenvironment. Cancers (Basel) 2022; 14:cancers14174269. [PMID: 36077804 PMCID: PMC9454556 DOI: 10.3390/cancers14174269] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Pancreatic cancer is a highly lethal malignant disease with a dense stroma, called the tumor microenvironment. Accumulating evidence indicates the important role of sympathetic, parasympathetic, and sensory nerves in the tumor microenvironment of various cancers, including pancreatic cancer. Cancer cells and neural cells interact with each other to form a complex network and cooperatively promote cancer growth and invasion. In this review article, we describe the current understanding of the role of nerves in the tumor microenvironment. Abstract Pancreatic cancer is one of the most lethal malignant diseases. Various cells in the tumor microenvironment interact with tumor cells and orchestrate to support tumor progression. Several kinds of nerves are found in the tumor microenvironment, and each plays an essential role in tumor biology. Recent studies have shown that sympathetic, parasympathetic, and sensory neurons are found in the pancreatic cancer microenvironment. Neural signaling not only targets neural cells, but tumor cells and immune cells via neural receptors expressed on these cells, through which tumor growth, inflammation, and anti-tumor immunity are affected. Thus, these broad-range effects of neural signaling in the pancreatic cancer microenvironment may represent novel therapeutic targets. The modulation of neural signaling may be a therapeutic strategy targeting the whole tumor microenvironment. In this review, we describe the current understanding of the role of nerves in the tumor microenvironment of various cancers, with an emphasis on pancreatic cancer. We also discuss the underlying mechanisms and the possibility of therapeutic applications.
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24
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Regua AT, Najjar M, Lo HW. RET signaling pathway and RET inhibitors in human cancer. Front Oncol 2022; 12:932353. [PMID: 35957881 PMCID: PMC9359433 DOI: 10.3389/fonc.2022.932353] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Rearranged during transfection (RET) receptor tyrosine kinase was first identified over thirty years ago as a novel transforming gene. Since its discovery and subsequent pathway characterization, RET alterations have been identified in numerous cancer types and are most prevalent in thyroid carcinomas and non-small cell lung cancer (NSCLC). In other tumor types such as breast cancer and salivary gland carcinomas, RET alterations can be found at lower frequencies. Aberrant RET activity is associated with poor prognosis of thyroid and lung carcinoma patients, and is strongly correlated with increased risk of distant metastases. RET aberrations encompass a variety of genomic or proteomic alterations, most of which confer constitutive activation of RET. Activating RET alterations, such as point mutations or gene fusions, enhance activity of signaling pathways downstream of RET, namely PI3K/AKT, RAS/RAF, MAPK, and PLCγ pathways, to promote cell proliferation, growth, and survival. Given the important role that mutant RET plays in metastatic cancers, significant efforts have been made in developing inhibitors against RET kinase activity. These efforts have led to FDA approval of Selpercatinib and Pralsetinib for NSCLC, as well as, additional selective RET inhibitors in preclinical and clinical testing. This review covers the current biological understanding of RET signaling, the impact of RET hyperactivity on tumor progression in multiple tumor types, and RET inhibitors with promising preclinical and clinical efficacy.
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Affiliation(s)
- Angelina T. Regua
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Mariana Najjar
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, United States
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25
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Szymoński K, Milian-Ciesielska K, Lipiec E, Adamek D. Current Pathology Model of Pancreatic Cancer. Cancers (Basel) 2022; 14:2321. [PMID: 35565450 PMCID: PMC9105915 DOI: 10.3390/cancers14092321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. Daily reports reveal new aspects of tumor biology, including its molecular and morphological heterogeneity, explain complicated "cross-talk" that happens between the cancer cells and tumor stroma, or the nature of the PC-associated neural remodeling (PANR). Staying up-to-date is hard and crucial at the same time. In this review, we are focusing on a comprehensive summary of PC aspects that are important in pathologic reporting, impact patients' outcomes, and bring meaningful information for clinicians. Finally, we show promising new trends in diagnostic technologies that might bring a difference in PC early diagnosis.
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Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
- Department of Pathomorphology, University Hospital, 30-688 Cracow, Poland;
| | | | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, 30-348 Cracow, Poland;
| | - Dariusz Adamek
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
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26
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Guo Y, Gil Z. The Role of Extracellular Vesicles in Cancer-Nerve Crosstalk of the Peripheral Nervous System. Cells 2022; 11:cells11081294. [PMID: 35455973 PMCID: PMC9027707 DOI: 10.3390/cells11081294] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 03/30/2022] [Accepted: 04/05/2022] [Indexed: 02/06/2023] Open
Abstract
Although the pathogenic operations of cancer–nerve crosstalk (e.g., neuritogenesis, neoneurogensis, and perineural invasion—PNI) in the peripheral nervous system (PNS) during tumorigenesis, as well as the progression of all cancer types is continuing to emerge as an area of unique scientific interest and study, extensive, wide-ranging, and multidisciplinary investigations still remain fragmented and unsystematic. This is especially so in regard to the roles played by extracellular vesicles (EVs), which are lipid bilayer-enclosed nano- to microsized particles that carry multiple-function molecular cargos, facilitate intercellular communication in diverse processes. Accordingly, the biological significance of EVs has been greatly elevated in recent years, as there is strong evidence that they could contribute to important and possibly groundbreaking diagnostic and therapeutic innovations. This can be achieved and the pace of discoveries accelerated through cross-pollination from existing knowledge and studies regarding nervous system physiology and pathology, as well as thoroughgoing collaborations between oncologists, neurobiologists, pathologists, clinicians, and researchers. This article offers an overview of current and recent past investigations on the roles of EVs in cancer–nerve crosstalk, as well as in neural development, physiology, inflammation, injury, and regeneration in the PNS. By highlighting the mechanisms involved in physiological and noncancerous pathological cellular crosstalk, we provide hints that may inspire additional translational studies on cancer–nerve interplay.
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Affiliation(s)
- Yuanning Guo
- Rappaport Family Institute for Research in the Medical Sciences, Technion—Israel Institute of Technology, Haifa 31096, Israel;
| | - Ziv Gil
- Rappaport Family Institute for Research in the Medical Sciences, Technion—Israel Institute of Technology, Haifa 31096, Israel;
- Head and Neck Institute, The Holy Family Hospital Nazareth, Nazareth 1641100, Israel
- Correspondence: ; Tel.: +972-4-854-2480
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27
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Jiang SH, Zhang S, Wang H, Xue JL, Zhang ZG. Emerging experimental models for assessing perineural invasion in human cancers. Cancer Lett 2022; 535:215610. [PMID: 35283209 DOI: 10.1016/j.canlet.2022.215610] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/23/2022] [Accepted: 02/26/2022] [Indexed: 12/13/2022]
Abstract
Cancer neuroscience has emerged as a burgeoning field for the investigation of cancer-nervous system interactions. Perineural invasion (PNI) is defined as the presence of cancer cells that surround and/or invade the nerves infiltrating the tumor microenvironment. PNI is closely associated with increased tumor recurrence and diminished survival in many cancer types. Based on diverse in vitro, ex vivo, and in vivo models, mounting evidence suggests that the reciprocal crosstalk between nerves and cancer cells drives PNI, which is mediated by several factors including secreted neurotrophins, chemokines, exosomes, and inflammatory cells. Typical in vitro models using dorsal root ganglia (DRG) cells cocultured with cancer cells or other cell types allow the study of isolated factors. Ex vivo PNI models created by cocultivating cancer cells with explanted vagus and sciatic nerves enable the study of neuroaffinity in a time-saving and cost-efficient manner. In vivo models such as genetically engineered mouse models (GEMMs) and the chicken embryo chorioallantoic membrane (CAM)-DRG model, provide the nerve microenvironment needed to recapitulate the complex pathophysiological processes of PNI. Here, we summarize the current methods commonly used for modeling PNI and discuss the inherent pros and cons of these approaches for understanding PNI biology.
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Affiliation(s)
- Shu-Heng Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
| | - Shan Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Hao Wang
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, PR China
| | - Jun-Li Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, PR China.
| | - Zhi-Gang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
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28
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Zhang L, Yang L, Jiang S, Yu M. Nerve Dependence in Colorectal Cancer. Front Cell Dev Biol 2022; 10:766653. [PMID: 35223829 PMCID: PMC8866866 DOI: 10.3389/fcell.2022.766653] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 01/13/2022] [Indexed: 12/28/2022] Open
Abstract
Cancerous invasion of nerves has been reported in a list of malignant tumors as a high-risk pathological feature and marker of poor disease outcome especially in neurotrophic cancers (such as in pancreas and prostate), indicating that although once neglected, nerves could have played a pivotal role in tumorigenesis and cancer progression. In colorectal cancer, perineural invasion, a specific form of tumor-nerve interaction referring to the identification of tumor cells in proximity to the nerve, has been recognized as a strong and independent prognosis predictor; denervation of autonomic nerves and enteric nerves have shown that the existence of these nerves in the gut are accompanied by promoted cancer proliferation, further supporting that nerve is a potential accomplice to shield and nurture tumor cells. However, the precise role of nerve in CRC and the pattern of interaction between CRC cells and nerve has not been unveiled yet. Here we aim to review some basic knowledge of the importance of nerves in CRC and attempt to depict a mechanistic view of tumor-nerve interaction during CRC development.
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Affiliation(s)
- Lincheng Zhang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ludi Yang
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuheng Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Minhao Yu, ; Shuheng Jiang,
| | - Minhao Yu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Minhao Yu, ; Shuheng Jiang,
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29
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Shi DD, Guo JA, Hoffman HI, Su J, Mino-Kenudson M, Barth JL, Schenkel JM, Loeffler JS, Shih HA, Hong TS, Wo JY, Aguirre AJ, Jacks T, Zheng L, Wen PY, Wang TC, Hwang WL. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities. Lancet Oncol 2022; 23:e62-e74. [PMID: 35114133 PMCID: PMC9516432 DOI: 10.1016/s1470-2045(21)00596-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/28/2021] [Accepted: 10/08/2021] [Indexed: 02/03/2023]
Abstract
With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.
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Affiliation(s)
- Diana D Shi
- Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA
| | - Jimmy A Guo
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; School of Medicine, University of California, San Francisco, San Francisco, CA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard University, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Hannah I Hoffman
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Health Sciences and Technology Program, Harvard Medical School, Boston, MA, USA
| | - Jennifer Su
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jaimie L Barth
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jason M Schenkel
- Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jay S Loeffler
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Helen A Shih
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Tyler Jacks
- Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Lei Zheng
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY, USA
| | - William L Hwang
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
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30
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Li Q, Cao Z, Zhao S. The Emerging Portrait of Glial Cell Line-derived Neurotrophic Factor Family Receptor Alpha (GFRα) in Cancers. Int J Med Sci 2022; 19:659-668. [PMID: 35582425 PMCID: PMC9108399 DOI: 10.7150/ijms.64133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 03/06/2022] [Indexed: 11/05/2022] Open
Abstract
Glial cell line-derived neurotrophic factor family receptor alpha (GFRα) members have been widely connected to the mechanisms contributing to cell growth, differentiation, cell migration and tissue maturation. Here we review GFRα biological functions and discussed the evidence indicating whether GFRα signaling complex present novel opportunities for oncogenic intervention and treatment resistance. Thus, our work systematically reviewed the emerging role of GFRα family members in cancers, and provided novel insights for further researches.
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Affiliation(s)
- Qingshang Li
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health. 145 Middle Shandong Road, Shanghai, China
| | - Zhijun Cao
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health. 145 Middle Shandong Road, Shanghai, China
| | - Shuliang Zhao
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health. 145 Middle Shandong Road, Shanghai, China
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31
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Molecular and Cellular Mechanisms of Perineural Invasion in Oral Squamous Cell Carcinoma: Potential Targets for Therapeutic Intervention. Cancers (Basel) 2021; 13:cancers13236011. [PMID: 34885121 PMCID: PMC8656475 DOI: 10.3390/cancers13236011] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Squamous cell carcinoma is the most common type of oral cavity cancer. It can spread along and invade nerves in a process called perineural invasion. Perineural invasion can increase the chances of tumor recurrence and reduce survival in patients with oral cancer. Understanding how oral cancer interacts with nerves to facilitate perineural invasion is an important area of research. Targeting key events that contribute to perineural invasion in oral cavity cancer may reduce tumor recurrence and improve survival. In this review, we describe the impact of perineural invasion in oral cancer and the mechanisms that contribute to perineural invasion. Highlighting the key events of perineural invasion is important for the identification and testing of novel therapies for oral cancer with perineural invasion. Abstract The most common oral cavity cancer is squamous cell carcinoma (SCC), of which perineural invasion (PNI) is a significant prognostic factor associated with decreased survival and an increased rate of locoregional recurrence. In the classical theory of PNI, cancer was believed to invade nerves directly through the path of least resistance in the perineural space; however, more recent evidence suggests that PNI requires reciprocal signaling interactions between tumor cells and nerve components, particularly Schwann cells. Specifically, head and neck SCC can express neurotrophins and neurotrophin receptors that may contribute to cancer migration towards nerves, PNI, and neuritogenesis towards cancer. Through reciprocal signaling, recent studies also suggest that Schwann cells may play an important role in promoting PNI by migrating toward cancer cells, intercalating, and dispersing cancer, and facilitating cancer migration toward nerves. The interactions of neurotrophins with their high affinity receptors is a new area of interest in the development of pharmaceutical therapies for many types of cancer. In this comprehensive review, we discuss diagnosis and treatment of oral cavity SCC, how PNI affects locoregional recurrence and survival, and the impact of adjuvant therapies on tumors with PNI. We also describe the molecular and cellular mechanisms associated with PNI, including the expression of neurotrophins and their receptors, and highlight potential targets for therapeutic intervention for PNI in oral SCC.
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Eukaryotic initiation factor 2 signaling behind neural invasion linked with lymphatic and vascular invasion in pancreatic cancer. Sci Rep 2021; 11:21197. [PMID: 34707166 PMCID: PMC8551178 DOI: 10.1038/s41598-021-00727-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 10/15/2021] [Indexed: 12/12/2022] Open
Abstract
Perineural invasion (PNI) is a typical poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC). The mechanisms linking PNI to poor prognosis remain unclear. This study aimed to clarify what changes occurred alongside PNI in PDAC. A 128-patient cohort undergoing surgery for early-stage PDAC was evaluated. Subdivided into two groups, according to pathological state, a pancreatic nerve invasion (ne) score of less than three (from none to moderate invasion) was designated as the low-grade ne group. The high-grade (marked invasion) ne group (74 cases, 57.8%) showed a higher incidence of lymphatic metastasis (P = 0.002), a higher incidence of early recurrence (P = 0.004), decreased RFS (P < 0.001), and decreased DSS (P < 0.001). The severity of lymphatic (r = 0.440, P = 0.042) and venous (r = 0.610, P = 0.002) invasions was positively correlated with the ne score. Tumors having abundant stroma often displayed severe ne. Proteomics identified eukaryotic initiation factor 2 (EIF2) signaling as the most significantly enriched pathway in high-grade ne PDAC. Additionally, EIF2 signaling-related ribosome proteins decreased according to severity. Results showed that PNI is linked with lymphatic and vascular invasion in early-stage PDAC. Furthermore, the dysregulation of proteostasis and ribosome biogenesis can yield a difference in PNI severity.
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Zhu H, Huang M, Luo J, Ji X, Liu Q. Deficiency of GFRα1 promotes hepatocellular carcinoma progression but enhances oxaliplatin-mediated anti-tumor efficacy. Pharmacol Res 2021; 172:105815. [PMID: 34391932 DOI: 10.1016/j.phrs.2021.105815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 11/18/2022]
Abstract
Neurotrophic factors and their receptors have been identified to promote tumor progression. GFRα1, the receptor for glial cell line-derived neurotrophic factor (GDNF), has been demonstrated to be predominantly expressed in adult liver tissue. Our preliminary data showed that GFRα1 is significantly downregulated in hepatocellular carcinoma (HCC) tissue, compared to the matched non-neoplastic tissue. However, the role of GFRα1 in HCC progression remains unknown. Here we found that the expression of GFRα1 in HCC tissue is inversely correlated with the poorer prognosis of HCC patients. Silencing of GFRα1 expression markedly enhances HCC cell growth, tumor metastasis, as well as shortens the survival of HCC tumor-bearing mice. Forced expression of GFRα1 in HCC cells significantly reverses the tumor-promoting effects of GFRα1 silencing, and AAV8-mediated GFRα1 transfection in HCC tumor tissues significantly impedes tumor growth and prolongs the survival of HCC tumor-bearing mice. These results are also verified in vivo in GFRα1 knock-out mice model, with increased DEN-induced HCC carcinogenesis. Mechanistically, GFRα1 could inhibit epithelial-to-mesenchymal transition (EMT) of HCC cells, by upregulating expression of Claudin-1 and ZO-1. Of note, silencing of GFRα1 expression promotes oxaliplatin-mediated HCC cell apoptosis resulting in prolonged survival of HCC-bearing mice, and forced expression of GFRα1 markedly increased oxaliplatin resistance of HCC cells. These results demonstrate that deficiency of GFRα1 promotes HCC progression but enhances chemotherapeutic anti-tumor efficacy, suggesting that GFRα1 may be a candidate prognostic biomarker and a potential therapeutic target in HCC.
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Affiliation(s)
- Ha Zhu
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Mingyan Huang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Jianhua Luo
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Xinpei Ji
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China; School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Qiuyan Liu
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
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Wang J, Chen Y, Li X, Zou X. Perineural Invasion and Associated Pain Transmission in Pancreatic Cancer. Cancers (Basel) 2021; 13:4594. [PMID: 34572820 PMCID: PMC8467801 DOI: 10.3390/cancers13184594] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural and functional reprogramming. In turn, neurons and the surrounding glial cells promote the development of pancreatic cancer through autocrine and/or paracrine signaling. In addition, hyperalgesia in PDAC patients implies alterations of pain transmission in the peripheral and central nervous systems. Currently, the studies on this topic are relatively limited. This review will elaborate on the mechanisms of tumor-neural interactions and its possible relationship with pain from several aspects that have been focused on in recent years.
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Affiliation(s)
| | | | | | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; (J.W.); (Y.C.); (X.L.)
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Roda N, Blandano G, Pelicci PG. Blood Vessels and Peripheral Nerves as Key Players in Cancer Progression and Therapy Resistance. Cancers (Basel) 2021; 13:cancers13174471. [PMID: 34503281 PMCID: PMC8431382 DOI: 10.3390/cancers13174471] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The interactions between cancer cells and the surrounding blood vessels and peripheral nerves are critical in all the phases of tumor development. Accordingly, therapies that specifically target vessels and nerves represent promising anticancer approaches. The first aim of this review is to document the importance of blood vessels and peripheral nerves in both cancer onset and local or distant growth of tumoral cells. We then focus on the state-of-the-art therapies that limit cancer progression through the impairment of blood vessels and peripheral nerves. The mentioned literature is helpful for the scientific community to appreciate the recent advances in these two fundamental components of tumors. Abstract Cancer cells continuously interact with the tumor microenvironment (TME), a heterogeneous milieu that surrounds the tumor mass and impinges on its phenotype. Among the components of the TME, blood vessels and peripheral nerves have been extensively studied in recent years for their prominent role in tumor development from tumor initiation. Cancer cells were shown to actively promote their own vascularization and innervation through the processes of angiogenesis and axonogenesis. Indeed, sprouting vessels and axons deliver several factors needed by cancer cells to survive and proliferate, including nutrients, oxygen, and growth signals, to the expanding tumor mass. Nerves and vessels are also fundamental for the process of metastatic spreading, as they provide both the pro-metastatic signals to the tumor and the scaffold through which cancer cells can reach distant organs. Not surprisingly, continuously growing attention is devoted to the development of therapies specifically targeting these structures, with promising initial results. In this review, we summarize the latest evidence that supports the importance of blood vessels and peripheral nerves in cancer pathogenesis, therapy resistance, and innovative treatments.
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Affiliation(s)
- Niccolò Roda
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
| | - Giada Blandano
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
| | - Pier Giuseppe Pelicci
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
- Correspondence:
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Wakiya T, Ishido K, Yoshizawa T, Kanda T, Hakamada K. Roles of the nervous system in pancreatic cancer. Ann Gastroenterol Surg 2021; 5:623-633. [PMID: 34585047 PMCID: PMC8452481 DOI: 10.1002/ags3.12459] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/04/2021] [Accepted: 03/14/2021] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), with its extremely poor prognosis, presents a substantial health problem worldwide. Outcomes have improved thanks to progress in surgical technique, chemotherapy, pre-/postoperative management, and centralization of patient care to high-volume centers. However, our goals are yet to be met. Recently, exome sequencing using PDAC surgical specimens has demonstrated that the most frequently altered genes were the axon guidance genes, indicating involvement of the nervous system in PDAC carcinogenesis. Moreover, perineural invasion has been widely identified as one poor prognostic factor. The combination of innovative technologies and extensive clinician experience with the nervous system come together here to create a new treatment option. However, evidence has emerged that suggests that the relationship between cancer and nerves in PDAC, the underlying mechanism, is not fully understood. In an attempt to tackle this lethal cancer, this review summarizes the anatomy and physiology of the pancreas and discusses the role of the nervous system in the pathophysiology of PDAC.
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Affiliation(s)
- Taiichi Wakiya
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
| | - Keinosuke Ishido
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
| | - Tadashi Yoshizawa
- Department of Pathology and BioscienceHirosaki University Graduate School of MedicineHirosakiJapan
| | - Taishu Kanda
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
| | - Kenichi Hakamada
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
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Saha D, Ryan KR, Lakkaniga NR, Acharya B, Garcia NG, Smith EL, Frett B. Targeting Rearranged during Transfection in Cancer: A Perspective on Small-Molecule Inhibitors and Their Clinical Development. J Med Chem 2021; 64:11747-11773. [PMID: 34402300 DOI: 10.1021/acs.jmedchem.0c02167] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Rearranged during transfection (RET) is a receptor tyrosine kinase essential for the normal development and maturation of a diverse range of tissues. Aberrant RET signaling in cancers, due to RET mutations, gene fusions, and overexpression, results in the activation of downstream pathways promoting survival, growth, and metastasis. Pharmacological manipulation of RET is effective in treating RET-driven cancers, and efforts toward developing RET-specific therapies have increased over the last 5 years. In 2020, RET-selective inhibitors pralsetinib and selpercatinib achieved clinical approval, which marked the first approvals for kinase inhibitors specifically developed to target the RET oncoprotein. This Perspective discusses current development and clinical applications for RET precision medicine by providing an overview of the incremental improvement of kinase inhibitors for use in RET-driven malignancies.
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Affiliation(s)
- Debasmita Saha
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 United States
| | - Katie Rose Ryan
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 United States
| | - Naga Rajiv Lakkaniga
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 United States
| | - Baku Acharya
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 United States
| | - Noemi Garcia Garcia
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 United States
| | - Erica Lane Smith
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 United States
| | - Brendan Frett
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 United States
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Li J, Kang R, Tang D. Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma. Cancer Commun (Lond) 2021; 41:642-660. [PMID: 34264020 PMCID: PMC8360640 DOI: 10.1002/cac2.12188] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/11/2021] [Accepted: 06/18/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.
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Affiliation(s)
- Jingbo Li
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
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Eviston TJ, Minaei E, Mueller SA, Ahmadi N, Ashford B, Clark JR, West N, Zhang P, Gupta R, Ranson M. Gene expression profiling of perineural invasion in head and neck cutaneous squamous cell carcinoma. Sci Rep 2021; 11:13192. [PMID: 34162930 PMCID: PMC8222302 DOI: 10.1038/s41598-021-92335-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/24/2021] [Indexed: 11/09/2022] Open
Abstract
Perineural invasion (PNI) is frequently associated with aggressive clinical behaviour in head and neck cutaneous squamous cell carcinoma (HNcSCC) leading to local recurrence and treatment failure. This study evaluates the gene expression profiles of HNcSCC with PNI using a differential expression analysis approach and constructs a tailored gene panel for sensitivity and specificity analysis. 45 cases of HNcSCC were stratified into three groups (Extensive, Focal and Non PNI) based on predefined clinicopathological criteria. Here we show HNcSCC with extensive PNI demonstrates significant up- and down-regulation of 144 genes associated with extracellular matrix interactions, epithelial to mesenchymal transition, cell adhesion, cellular motility, angiogenesis, and cellular differentiation. Gene expression of focal and non PNI cohorts were indistinguishable and were combined for further analyses. There is clinicopathological correlation between gene expression analysis findings and disease behaviour and a tailored panel of 10 genes was able to identify extensive PNI with 96% sensitivity and 95% specificity.
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Affiliation(s)
- Timothy J Eviston
- The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, NSW, Australia.
| | - Elahe Minaei
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
- Illawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, Australia
- Centre for Oncology Education and Research Translation (CONCERT), Sydney, NSW, Australia
| | - Simon A Mueller
- The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, NSW, Australia
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Navid Ahmadi
- The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, NSW, Australia
- Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Bruce Ashford
- The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, NSW, Australia
- Illawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, Australia
- Centre for Oncology Education and Research Translation (CONCERT), Sydney, NSW, Australia
- Illawarra and Shoalhaven Local Health District (ISLHD), Wollongong, NSW, Australia
- School of Medicine, University of Wollongong, Wollongong, NSW, Australia
| | - Jonathan R Clark
- The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, NSW, Australia
- Royal Prince Alfred Institute of Academic Surgery, Sydney Local Health District, Sydney, Australia
- Sydney Medical School, Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, Australia
| | - Nicholas West
- Systems Biology and Data Science, Griffith Systems Biology Centre, Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia
| | - Ping Zhang
- Systems Biology and Data Science, Griffith Systems Biology Centre, Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia
| | - Ruta Gupta
- Sydney Medical School, Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, Australia
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, NSW Health Pathology, Sydney, Australia
| | - Marie Ranson
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
- Illawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, Australia
- Centre for Oncology Education and Research Translation (CONCERT), Sydney, NSW, Australia
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Hunt PJ, Andújar FN, Silverman DA, Amit M. Mini-review: Trophic interactions between cancer cells and primary afferent neurons. Neurosci Lett 2021; 746:135658. [PMID: 33482305 PMCID: PMC7899767 DOI: 10.1016/j.neulet.2021.135658] [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: 08/21/2020] [Revised: 01/05/2021] [Accepted: 01/11/2021] [Indexed: 10/22/2022]
Abstract
Cancer neurobiology is an emerging discipline that inevitably unfurls new perspectives in oncology. The role that nerves play in cancer progression resonates with the long-reported dependency of tumors on neuro-molecular mechanisms that remain insufficiently elucidated. Whereas interactions between neurotrophic growth factors and receptors have been heavily studied in the nervous system, their expression in cancers and their impact on tumor cell growth and metastasis through their corresponding signaling pathways has been undervalued. Accumulating evidence suggests that trophic factors released by nerves strongly influence tumor development and that this neural contribution appears to not only play a stimulatory role but also function as an essential part of the tumor's microenvironment. This bidirectional communication between proliferating cells and tumor-infiltrating nerves drives axonogenesis and tumor growth and migration. Acquiring a better understanding of the trophic interactions between primary afferent neurons and invading tumors will guide clinically actionable strategies to prevent tumor-associated axonogenesis, disrupting the chemical crosstalk between neurons and tumors and ultimately decreasing tumor growth and spread.
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Affiliation(s)
- Patrick J Hunt
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, United States; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United States.
| | - Fabiola N Andújar
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United States; Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Deborah A Silverman
- University of Texas Medical Scientist Training Program at Houston, Houston, TX, United States; Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Moran Amit
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
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Yin L, Li J, Wang J, Pu T, Wei J, Li Q, Wu BJ. MAOA promotes prostate cancer cell perineural invasion through SEMA3C/PlexinA2/NRP1-cMET signaling. Oncogene 2021; 40:1362-1374. [PMID: 33420365 DOI: 10.1038/s41388-020-01615-2] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/05/2023]
Abstract
Perineural invasion (PNI), a pathologic feature defined as cancer cell invasion in, around, and through nerves, is an indicator of poor prognosis and survival in prostate cancer (PC). Despite widespread recognition of the clinical significance of PNI, the molecular mechanisms are largely unknown. Here, we report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PNI in PC. MAOA promotes PNI of PC cells in vitro and tumor innervation in an orthotopic xenograft model. Mechanistically, MAOA activates SEMA3C in a Twist1-dependent transcriptional manner, which in turn stimulates cMET to facilitate PNI via autocrine or paracrine interaction with coactivated PlexinA2 and NRP1. Furthermore, MAOA inhibitor treatment effectively reduces PNI of PC cells in vitro and tumor-infiltrating nerve fiber density along with suppressed xenograft tumor growth and progression in mice. Collectively, these findings characterize the contribution of MAOA to the pathogenesis of PNI and provide a rationale for using MAOA inhibitors as a targeted treatment for PNI in PC.
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Affiliation(s)
- Lijuan Yin
- Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.,Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jingjing Li
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.,Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA
| | - Tianjie Pu
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA
| | - Jing Wei
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA
| | - Qinlong Li
- Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Boyang Jason Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
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Daniel-García L, Vergara P, Navarrete A, González RO, Segovia J. Simultaneous Treatment with Soluble Forms of GAS1 and PTEN Reduces Invasiveness and Induces Death of Pancreatic Cancer Cells. Onco Targets Ther 2020; 13:11769-11779. [PMID: 33235464 PMCID: PMC7680188 DOI: 10.2147/ott.s260671] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/06/2020] [Indexed: 12/14/2022] Open
Abstract
Introduction Pancreatic carcinoma cells exhibit a pronounced tendency to invade along and through intra and extrapancreatic nerves, even during the early stages of the disease, a phenomenon called perineural invasion (PNI). Thus, we sought to determine the effects of the simultaneous expression of soluble forms of GAS1 and PTEN (tGAS1 and PTEN-L) inhibiting tumor growth and invasiveness. Materials and Methods We employed a lentiviral system to simultaneously express tGAS1 and PTEN-L; in order to determine the effects of the treatments, cell viability and apoptosis as well as the expression of the transgenes by ELISA and intracellular signaling as ascertained by the activation of AKT and ERK1/2 were measured; cell invasiveness was determined using a Boyden chamber assay; and the effects of the treatment were measured in vivo in a mouse model. Results In the present work, we show that the combined treatment with tGAS1 and PTEN-L inhibits the growth of pancreatic cancer cells, by reducing the activities of both AKT and ERK 1/2, decreases cell invasiveness, and restrains tumor growth in a mouse model. Conclusion The combined administration of tGAS1 and PTEN-L could be a valuable adjunct therapy for the treatment of pancreatic cancer.
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Affiliation(s)
- Lizbeth Daniel-García
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City 07300, Mexico
| | - Paula Vergara
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City 07300, Mexico
| | - Araceli Navarrete
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City 07300, Mexico
| | - Rosa O González
- Departamento de Matemáticas, Universidad Autónoma Metropolitana-Iztapala, Mexico City 09340, México
| | - Jose Segovia
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City 07300, Mexico
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Dong Z, Dai L, Zhang Y, Fang C, Shi G, Chen Y, Li J, Wang Q, Fu J, Yu Y, Wang W, Cheng L, Liu Y, Lin Y, Wang Y, Wang Q, Wang H, Zhang H, Zhang Y, Su X, Zhang S, Wang F, Qiu M, Zhou Z, Deng H. Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer. PLoS Genet 2020; 16:e1009159. [PMID: 33175846 PMCID: PMC7682896 DOI: 10.1371/journal.pgen.1009159] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 11/23/2020] [Accepted: 09/28/2020] [Indexed: 02/05/2023] Open
Abstract
Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylation data in CRC patients from The Cancer Genome Altlas (TCGA), followed by further analysis of the correlation between the GFRA1 expression, methylation, and prognosis of patients. Our results show DNA hypomethylation-mediated upregulation of GFRA1 in invasive CRC, and it was found to be correlated with poor prognosis of CRC patients. Furthermore, GFRA1 methylation-modified sequences were found to have potential as methylation diagnostic markers of highly metastatic CRC. The targeted demethylation of GFRA1 by dCas9-TET1CD and gRNA promoted CRC metastasis in vivo and in vitro. Mechanistically, demethylation of GFRA1 induces epithelial-mesenchymal transition (EMT) by promoting AKT phosphorylation and increasing c-Jun expression in CRC cells. Collectively, our findings indicate that GFRA1 hypomethylation can promote CRC invasion via inducing EMT, and thus, GFRA1 methylation can be used as a biomarker for the early diagnosis of highly metastasis CRC.
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Affiliation(s)
- Zhexu Dong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Yong Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Chao Fang
- Department of Gastrointestinal Surgery, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, the People’s Republic of China
| | - Gang Shi
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Ye Chen
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, the People’s Republic of China
| | - Junshu Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Qin Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Jiamei Fu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Yan Yu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Wenshuang Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Lin Cheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Yi Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Yi Lin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Yuan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Qingnan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Huiling Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Hantao Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Yujing Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Xiaolan Su
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Shuang Zhang
- Department of biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
| | - Feng Wang
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, the People’s Republic of China
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, the People’s Republic of China
| | - Meng Qiu
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, the People’s Republic of China
| | - Zongguang Zhou
- Department of Gastrointestinal Surgery, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, the People’s Republic of China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, the People’s Republic of China
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Zhu JH, Yan QL, Wang JW, Chen Y, Ye QH, Wang ZJ, Huang T. The Key Genes for Perineural Invasion in Pancreatic Ductal Adenocarcinoma Identified With Monte-Carlo Feature Selection Method. Front Genet 2020; 11:554502. [PMID: 33193628 PMCID: PMC7593847 DOI: 10.3389/fgene.2020.554502] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/17/2020] [Indexed: 12/20/2022] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive form of pancreatic cancer. Its 5-year survival rate is only 3–5%. Perineural invasion (PNI) is a process of cancer cells invading the surrounding nerves and perineural spaces. It is considered to be associated with the poor prognosis of PDAC. About 90% of pancreatic cancer patients have PNI. The high incidence of PNI in pancreatic cancer limits radical resection and promotes local recurrence, which negatively affects life quality and survival time of the patients with pancreatic cancer. Objectives To investigate the mechanism of PNI in pancreatic cancer, we analyzed the gene expression profiles of tumors and adjacent tissues from 50 PDAC patients which included 28 patients with perineural invasion and 22 patients without perineural invasion. Method Using Monte-Carlo feature selection and Incremental Feature Selection (IFS) method, we identified 26 key features within which 15 features were from tumor tissues and 11 features were from adjacent tissues. Results Our results suggested that not only the tumor tissue, but also the adjacent tissue, was informative for perineural invasion prediction. The SVM classifier based on these 26 key features can predict perineural invasion accurately, with a high accuracy of 0.94 evaluated with leave-one-out cross validation (LOOCV). Conclusion The in-depth biological analysis of key feature genes, such as TNFRSF14, XPO1, and ATF3, shed light on the understanding of perineural invasion in pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Jin-Hui Zhu
- Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiu-Liang Yan
- Department of General Surgery, Jinhua People's Hospital, Jinhua, China
| | - Jian-Wei Wang
- Department of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan Chen
- Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qing-Huang Ye
- Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhi-Jiang Wang
- Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Huang
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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Liu X, Yang X, Zhan C, Zhang Y, Hou J, Yin X. Perineural Invasion in Adenoid Cystic Carcinoma of the Salivary Glands: Where We Are and Where We Need to Go. Front Oncol 2020; 10:1493. [PMID: 33014792 PMCID: PMC7461905 DOI: 10.3389/fonc.2020.01493] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/13/2020] [Indexed: 12/25/2022] Open
Abstract
Adenoid cystic carcinoma of the salivary gland (SACC) is a rare malignant tumors of the head and neck region, but it is one of the most common malignant tumors that are prone to perineural invasion (PNI) of the head and neck. The prognosis of patients with SACC is strongly associated with the presence of perineural spread (PNS). Although many contributing factors have been reported, the mechanisms underlying the preferential destruction of the blood-nerve barrier (BNB) by tumors and the infiltration of the tumor microenvironment by nerve fibers in SACC, have received little research attention. This review summarizes the current knowledge concerning the characteristics of SACC in relation to the PNI, and then highlights the interplay between components of the tumor microenvironment and perineural niche, as well as their contributions to the PNI. Finally, we provide new insights into the possible mechanisms underlying the pathogenesis of PNI, with particular emphasis on the role of extracellular vesicles that may serve as an attractive entry point in future studies.
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Affiliation(s)
- Xiaohao Liu
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaojun Yang
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chaoning Zhan
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan Zhang
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jin Hou
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuemin Yin
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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RET isoforms contribute differentially to invasive processes in pancreatic ductal adenocarcinoma. Oncogene 2020; 39:6493-6510. [PMID: 32884116 DOI: 10.1038/s41388-020-01448-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 08/14/2020] [Accepted: 08/24/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a therapeutically challenging disease with poor survival rates, owing to late diagnosis and early dissemination. These tumors frequently undergo perineural invasion, spreading along nerves regionally and to distant sites. The RET receptor tyrosine kinase is implicated in increased aggressiveness, local invasion, and metastasis in multiple cancers, including PDAC. RET mediates directional motility and invasion towards sources of its neurotrophic factor ligands, suggesting that it may enhance perineural invasion of tumor cells towards nerves. RET is expressed as two main isoforms, RET9 and RET51, which differ in their protein interactions and oncogenic potentials, however, the contributions of RET isoforms to neural invasion have not been investigated. In this study, we generated total RET and isoform-specific knockdown PDAC cell lines and assessed the contributions of RET isoforms to PDAC invasive spread. Our data show that RET activity induces cell polarization and actin remodeling through activation of CDC42 and RHOA GTPases to promote directional motility in PDAC cells. Further, we show that RET interacts with the adaptor protein TKS5 to induce invadopodia formation, enhance matrix degradation and promote tumor cell invasion through a SRC and GRB2-dependent mechanism. Finally, we show that RET51 is the predominant isoform contributing to these RET-mediated invasive processes in PDAC. Together, our work suggests that RET expression in pancreatic cancers may enhance tumor aggressiveness by promoting perineural invasion, and that RET expression may be a valuable marker of invasiveness, and a potential therapeutic target in the treatment of these cancers.
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Gregory E, Dugan R, David G, Song YH. The biology and engineered modeling strategies of cancer-nerve crosstalk. Biochim Biophys Acta Rev Cancer 2020; 1874:188406. [PMID: 32827578 DOI: 10.1016/j.bbcan.2020.188406] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/23/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023]
Abstract
A recent finding critical to cancer aggravation is the interaction between cancer cells and nerves. There exist two main modes of cancer-nerve interaction: perineural invasion (PNI) and tumor innervation. PNI occurs when cancer cells infiltrate the adjacent nerves, and its relative opposite, tumor innervation, occurs when axons extend into tumor bodies. Like most cancer studies, these crosstalk interactions have mostly been observed in patient samples and animal models at this point, making it difficult to understand the mechanisms in a controlled manner. As such, in recent years in vitro studies have emerged that have helped identify various microenvironmental factors responsible for cancer-nerve crosstalk, including but not limited to neurotrophic factors, neurotransmitters, chemokines, cancer-derived exosomes, and Schwann cells. The versatility of in vitro systems warrants continuous development to increase physiological relevance to study PNI and tumor innervation, for example by utilizing biomimetic three-dimensional (3D) culture systems. Despite the wealth of 3D in vitro cancer models, comparatively there exists a lack of 3D in vitro models of nerve, PNI, and tumor innervation. Native-like 3D in vitro models of cancer-nerve interactions may further help develop therapeutic strategies to curb nerve-mediated cancer aggravation. As such, we provide an overview of the key players of cancer-nerve crosstalk and current in vitro models of the crosstalk, as well as cancer and nerve models. We also discuss a few future directions in cancer-nerve crosstalk research.
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Affiliation(s)
- Emory Gregory
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, United States of America.
| | - Reagan Dugan
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, United States of America.
| | - Gabriel David
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, United States of America.
| | - Young Hye Song
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, United States of America.
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Plasma membrane localization of the GFL receptor components: a nexus for receptor crosstalk. Cell Tissue Res 2020; 382:57-64. [PMID: 32767110 PMCID: PMC7529631 DOI: 10.1007/s00441-020-03235-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 06/04/2020] [Indexed: 12/26/2022]
Abstract
The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) comprise a group of four homologous and potent growth factors that includes GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). The survival, growth, and mitotic activities of the GFLs are conveyed by a single receptor tyrosine kinase, Ret. The GFLs do not bind directly to Ret in order to activate it, and instead bind with high affinity to glycerophosphatidylinositol (GPI)-anchored coreceptors called the GDNF family receptor-αs (GFRαs). Several mechanisms have recently been identified that influence the trafficking of Ret and GFRαs in and out of the plasma membrane, thereby affecting their availability for ligand binding, as well as their levels by targeting to degradative pathways. This review describes these mechanisms and their powerful effects on GFL signaling and function. We also describe the recent discovery that p75 and Ret form a signaling complex, also regulated by plasma membrane shuttling, that either enhances GFL survival signals or p75 pro-apoptotic signals, dependent on the cellular context.
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RET-independent signaling by GDNF ligands and GFRα receptors. Cell Tissue Res 2020; 382:71-82. [PMID: 32737575 PMCID: PMC7529620 DOI: 10.1007/s00441-020-03261-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/15/2020] [Indexed: 12/19/2022]
Abstract
The discovery in the late 1990s of the partnership between the RET receptor tyrosine kinase and the GFRα family of GPI-anchored co-receptors as mediators of the effects of GDNF family ligands galvanized the field of neurotrophic factors, firmly establishing a new molecular framework besides the ubiquitous neurotrophins. Soon after, however, it was realized that many neurons and brain areas expressed GFRα receptors without expressing RET. These observations led to the formulation of two new concepts in GDNF family signaling, namely, the non-cell-autonomous functions of GFRα molecules, so-called trans signaling, as well as cell-autonomous functions mediated by signaling receptors distinct from RET, which became known as RET-independent signaling. To date, the best studied RET-independent signaling pathway for GDNF family ligands involves the neural cell adhesion molecule NCAM and its association with GFRα co-receptors. Among the many functions attributed to this signaling system are neuronal migration, neurite outgrowth, dendrite branching, spine formation, and synaptogenesis. This review summarizes our current understanding of this and other mechanisms of RET-independent signaling by GDNF family ligands and GFRα receptors, as well as their physiological importance.
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Cervantes-Villagrana RD, Albores-García D, Cervantes-Villagrana AR, García-Acevez SJ. Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies. Signal Transduct Target Ther 2020; 5:99. [PMID: 32555170 PMCID: PMC7303203 DOI: 10.1038/s41392-020-0205-z] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 05/15/2020] [Accepted: 05/24/2020] [Indexed: 12/11/2022] Open
Abstract
Normal cells are hijacked by cancer cells forming together heterogeneous tumor masses immersed in aberrant communication circuits that facilitate tumor growth and dissemination. Besides the well characterized angiogenic effect of some tumor-derived factors; others, such as BDNF, recruit peripheral nerves and leukocytes. The neurogenic switch, activated by tumor-derived neurotrophins and extracellular vesicles, attracts adjacent peripheral fibers (autonomic/sensorial) and neural progenitor cells. Strikingly, tumor-associated nerve fibers can guide cancer cell dissemination. Moreover, IL-1β, CCL2, PGE2, among other chemotactic factors, attract natural immunosuppressive cells, including T regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, to the tumor microenvironment. These leukocytes further exacerbate the aberrant communication circuit releasing factors with neurogenic effect. Furthermore, cancer cells directly evade immune surveillance and the antitumoral actions of natural killer cells by activating immunosuppressive mechanisms elicited by heterophilic complexes, joining cancer and immune cells, formed by PD-L1/PD1 and CD80/CTLA-4 plasma membrane proteins. Altogether, nervous and immune cells, together with fibroblasts, endothelial, and bone-marrow-derived cells, promote tumor growth and enhance the metastatic properties of cancer cells. Inspired by the demonstrated, but restricted, power of anti-angiogenic and immune cell-based therapies, preclinical studies are focusing on strategies aimed to inhibit tumor-induced neurogenesis. Here we discuss the potential of anti-neurogenesis and, considering the interplay between nervous and immune systems, we also focus on anti-immunosuppression-based therapies. Small molecules, antibodies and immune cells are being considered as therapeutic agents, aimed to prevent cancer cell communication with neurons and leukocytes, targeting chemotactic and neurotransmitter signaling pathways linked to perineural invasion and metastasis.
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Affiliation(s)
- Rodolfo Daniel Cervantes-Villagrana
- Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), 07360, Mexico City, Mexico.
| | - Damaris Albores-García
- Department of Environmental Health Sciences, Florida International University (FIU), Miami, Florida, 33199, USA
| | - Alberto Rafael Cervantes-Villagrana
- Laboratorio de investigación en Terapéutica Experimental, Unidad Académica de Ciencias Químicas, Área de Ciencias de la Salud, Universidad Autónoma de Zacatecas (UAZ), Zacatecas, México
| | - Sara Judit García-Acevez
- Dirección de Proyectos e Investigación, Grupo Diagnóstico Médico Proa, 06400 CDMX, Cuauhtémoc, México
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