|
1
|
Cheng J, Wang R, Chen Y. Neuroimmune Interactions in Pancreatic Cancer. Biomedicines 2025; 13:609. [PMID: 40149585 PMCID: PMC11939924 DOI: 10.3390/biomedicines13030609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/16/2025] [Accepted: 02/24/2025] [Indexed: 03/29/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive primary malignancy, and recent technological advances in surgery have opened up more possibilities for surgical treatment. Emerging evidence highlights the critical roles of diverse immune and neural components in driving the aggressive behavior of PDAC. Recent studies have demonstrated that neural invasion, neural plasticity, and altered autonomic innervation contribute to pancreatic neuropathy in PDAC patients, while also elucidating the functional architecture of nerves innervating pancreatic draining lymph nodes. Research into the pathogenesis and therapeutic strategies for PDAC, particularly from the perspective of neuroimmune network interactions, represents a cutting-edge area of investigation. This review focuses on neuroimmune interactions, emphasizing the current understanding and future challenges in deciphering the reciprocal relationship between the nervous and immune systems in PDAC. Despite significant progress, key challenges remain, including the precise molecular mechanisms underlying neuroimmune crosstalk, the functional heterogeneity of neural and immune cell populations, and the development of targeted therapies that exploit these interactions. Understanding the molecular events governing pancreatic neuroimmune signaling axes will not only advance our knowledge of PDAC pathophysiology but also provide novel therapeutic targets. Translational efforts to bridge these findings into clinical applications, such as immunomodulatory therapies and neural-targeted interventions, hold promise for improving patient outcomes. This review underscores the need for further research to address unresolved questions and translate these insights into effective therapeutic strategies for PDAC.
Collapse
Affiliation(s)
- Jun Cheng
- Operating Room, Department of Anesthesiology, West China Hospital/West China School of Nursing, Sichuan University, Chengdu 610041, China;
| | - Rui Wang
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Yonghua Chen
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China;
- Department of General Surgery, West China Tianfu Hospital of Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
2
|
Jiang L, Cai S, Weng Z, Zhang S, Jiang SH. Peripheral, central, and chemotherapy-induced neuropathic changes in pancreatic cancer. Trends Neurosci 2025; 48:124-139. [PMID: 39730257 DOI: 10.1016/j.tins.2024.11.008] [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: 08/21/2024] [Revised: 10/27/2024] [Accepted: 11/27/2024] [Indexed: 12/29/2024]
Abstract
In pancreatic cancer, significant alterations occur in the local nervous system, including axonogenesis, neural remodeling, perineural invasion, and perineural neuritis. Pancreatic cancer can impact the central nervous system (CNS) through cancer cell-intrinsic factors or systemic factors, particularly in the context of cancer cachexia. These peripheral and central neuropathic changes exert substantial influence on cancer initiation and progression. Moreover, chemotherapy-induced neuropathy is common in pancreatic cancer, causing peripheral nerve damage and cognitive dysfunction. Targeting the crosstalk between pancreatic cancer and the nervous system, either peripherally or centrally, holds promise in cancer treatment, pain relief, and improved quality of life. Here, we summarize recent findings on the molecular mechanisms behind these neuropathic changes in pancreatic cancer and discuss potential intervention strategies.
Collapse
Affiliation(s)
- Luju 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
| | - Shuqi Cai
- 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
| | - Zheqi Weng
- 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
| | - Shan Zhang
- 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.
| | - 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.
| |
Collapse
|
|
3
|
Wang H, Huo R, He K, Li W, Gao Y, He W, Yu M, Jiang SH, Xue J. Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth. J Transl Med 2025; 23:112. [PMID: 39849539 PMCID: PMC11760110 DOI: 10.1186/s12967-025-06104-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 01/08/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND The colon and rectum are highly innervated, with neural components within the tumor microenvironment playing a significant role in colorectal cancer (CRC) progression. While perineural invasion (PNI) is associated with poor prognosis in CRC, the impact of nerve density and diameter on tumor behavior remains unclear. This study aims to evaluate the prognostic value of nerve characteristics in CRC and to verify the impact of nerves on tumor growth. METHODS Tissue samples from 129 CRC patients were stained with immunofluorescent markers NF-L and S100B to detect nerves. Nerve diameter and density were measured and normalized. Kaplan-Meier survival analysis and Cox regression models were used to identify prognostic factors. Prognostic models were established using receiver operating characteristic (ROC) curve analysis to assess the predictive value of neural factors. A murine chemical denervation model was employed to disrupt sympathetic nerves using 6-hydroxydopamine, inhibit muscarinic receptor 3 with darifenacin, and ablate sensory neurons with capsaicin. RESULTS The total nerve density was 0.72 ± 0.59/mm², with intratumoral (0.42 ± 0.40/mm²) being significantly lower than extratumoral regions (1.00 ± 0.75/mm²). The average nerve diameter was 28.14 ± 6.04 μm, with no significant difference between intratumoral (28.2 ± 7.65 μm) and extratumoral regions (27.86 ± 6.72 μm). PNI was observed in 65 patients (50.4%). PNI and high normalized nerve density (NND) were associated with shorter overall survival and disease-free survival in CRC patients, with PNI identified as an independent prognostic factor. Patients with PNI exhibit higher NND. Incorporating PNI and NND into ROC curve analysis improved the sensitivity and specificity of survival predictions. In the murine model, chemical denervation of sympathetic, parasympathetic, and sensory nerves significantly reduced rectal tumor volume. CONCLUSIONS PNI and NND are critical factors influencing CRC patient survival and enhance the accuracy of survival prediction models. Moreover, chemical denervation effectively inhibits rectal tumor growth in vivo, highlighting the potential of neural targeting as a therapeutic strategy in CRC.
Collapse
Affiliation(s)
- Hao Wang
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China
| | - Ruixue Huo
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China
| | - Kexin He
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China
| | - Weihan Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China
| | - Yuan Gao
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Wei He
- Department of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Minhao Yu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China.
| | - Shu-Heng Jiang
- State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, 200240, P.R. China.
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China.
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Iżycka-Świeszewska E, Gulczyński J, Sejda A, Kitlińska J, Galli S, Rogowski W, Sigorski D. Remarks on Selected Morphological Aspects of Cancer Neuroscience: A Microscopic Photo Review. Biomedicines 2024; 12:2335. [PMID: 39457647 PMCID: PMC11505290 DOI: 10.3390/biomedicines12102335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND This short review and pictorial essay presents a morphological insight into cancer neuroscience, which is a complex and dynamic area of the pathobiology of tumors. METHODS We discuss the different methods and issues connected with structural research on tumor innervation, interactions between neoplastic cells and the nervous system, and dysregulated neural influence on cancer phenotypes. RESULTS Perineural invasion (PNI), the most-visible cancer-nerve relation, is briefly presented, focusing on its pathophysiology and structural diversity as well as its clinical significance. The morphological approach to cancer neurobiology further includes the analysis of neural density/axonogenesis, neural network topographic distribution, and composition of fiber types and size. Next, the diverse range of neurotransmitters and neuropeptides and the neuroendocrine differentiation of cancer cells are reviewed. Another morphological area of cancer neuroscience is spatial or quantitative neural-related marker expression analysis through different detection, description, and visualization methods, also on experimental animal or cellular models. CONCLUSIONS Morphological studies with systematic methodologies provide a necessary insight into the structure and function of the multifaceted tumor neural microenvironment and in context of possible new therapeutic neural-based oncological solutions.
Collapse
Affiliation(s)
- Ewa Iżycka-Świeszewska
- Department of Pathology and Neuropathology, Medical University of Gdansk, 80-210 Gdansk, Poland;
- Department of Pathomorphology, Copernicus Hospital, 80-803 Gdansk, Poland
| | - Jacek Gulczyński
- Department of Pathology and Neuropathology, Medical University of Gdansk, 80-210 Gdansk, Poland;
- Department of Pathomorphology, Copernicus Hospital, 80-803 Gdansk, Poland
| | - Aleksandra Sejda
- Department of Pathomorphology an Forensic Medicine, Collegium Medicum, University of Warmia and Mazury, 10-561 Olsztyn, Poland
| | - Joanna Kitlińska
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA; (J.K.); (S.G.)
| | - Susana Galli
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA; (J.K.); (S.G.)
| | - Wojciech Rogowski
- Institute of Health Sciences, Pomeranian University, 70-204 Slupsk, Poland
| | - Dawid Sigorski
- Department of Oncology, Collegium Medicum, University of Warmia and Mazury, 10-228 Olsztyn, Poland
| |
Collapse
|
|
6
|
Yaniv D, Mattson B, Talbot S, Gleber-Netto FO, Amit M. Targeting the peripheral neural-tumour microenvironment for cancer therapy. Nat Rev Drug Discov 2024; 23:780-796. [PMID: 39242781 DOI: 10.1038/s41573-024-01017-z] [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] [Accepted: 07/24/2024] [Indexed: 09/09/2024]
Abstract
As the field of cancer neuroscience expands, the strategic targeting of interactions between neurons, cancer cells and other elements in the tumour microenvironment represents a potential paradigm shift in cancer treatment, comparable to the advent of our current understanding of tumour immunology. Cancer cells actively release growth factors that stimulate tumour neo-neurogenesis, and accumulating evidence indicates that tumour neo-innervation propels tumour progression, inhibits tumour-related pro-inflammatory cytokines, promotes neovascularization, facilitates metastasis and regulates immune exhaustion and evasion. In this Review, we give an up-to-date overview of the dynamics of the tumour microenvironment with an emphasis on tumour innervation by the peripheral nervous system, as well as current preclinical and clinical evidence of the benefits of targeting the nervous system in cancer, laying a scientific foundation for further clinical trials. Combining empirical data with a biomarker-driven approach to identify and hone neuronal targets implicated in cancer and its spread can pave the way for swift clinical integration.
Collapse
Affiliation(s)
- Dan Yaniv
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Brandi Mattson
- The Neurodegeneration Consortium, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sebastien Talbot
- Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Frederico O Gleber-Netto
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Moran Amit
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
7
|
Watanabe M, Fendler WP, Grafe H, Hirmas N, Hamacher R, Lanzafame H, Pabst KM, Hautzel H, Aigner C, Kasper S, von Tresckow B, Stuschke M, Kümmel S, Lugnier C, Hadaschik B, Grünwald V, Zarrad F, Siveke JT, Herrmann K, Weber M. Prognostic Implications of 68Ga-FAPI-46 PET/CT-Derived Parameters on Overall Survival in Various Types of Solid Tumors. J Nucl Med 2024; 65:1027-1034. [PMID: 38782454 DOI: 10.2967/jnumed.123.266981] [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: 10/31/2023] [Revised: 05/07/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Tumoral fibroblast activation protein expression is associated with proliferation and angiogenesis and can be visualized by PET/CT. We examined the prognostic value of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI) (68Ga-FAPI)-46 PET/CT for different tumor entities in patients enrolled in 2 prospective imaging studies (NCT05160051, n = 30; NCT04571086, n = 115). Methods: Within 4 wk, 145 patients underwent 68Ga-FAPI-46 and [18F]FDG (18F-FDG) PET/CT. The association between overall survival (OS) and sex, age, tumor entity, total lesion number, highest SUVmax, and the presence of each nodal, visceral, and bone metastasis was tested using univariate Cox regression analysis. Multivariate analyses were performed for prognostic factors with P values of less than 0.05. Results: In the univariate analysis, shorter OS was associated with total lesion number and the presence of nodal, visceral, and bone metastases on 68Ga-FAPI-46 PET/CT (hazard ratio [HR], 1.06, 2.18, 1.69, and 2.05; P < 0.01, < 0.01, = 0.04, and = 0.02, respectively) and 18F-FDG PET/CT (HR, 1.05, 2.31, 1.76, and 2.30; P < 0.01, < 0.01, = 0.03, and < 0.01, respectively) and with SUVmax on 68Ga-FAPI-46 PET/CT (HR, 1.03; P = 0.03). In the multivariate analysis, total lesion number on 68Ga-FAPI-46 PET/CT was an independent risk factor for shorter OS (HR, 1.05; P = 0.02). In patients with pancreatic cancer, shorter OS was associated with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.09; P < 0.01) and bone metastases on 18F-FDG PET/CT (HR, 31.39; P < 0.01) in the univariate analysis and with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.04) in the multivariate analyses. In breast cancer, total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.02), as well as bone metastases on 18F-FDG PET/CT (HR, 9.64; P = 0.04), was associated with shorter OS in the univariate analysis. The multivariate analysis did not reveal significant prognostic factors. In thoracic cancer (lung cancer and pleural mesothelioma), the univariate and multivariate analyses did not reveal significant prognostic factors. Conclusion: Disease extent on 68Ga-FAPI-46 PET/CT is a predictor of short OS and may aid in future risk stratification by playing a supplemental role alongside 18F-FDG PET/CT.
Collapse
Affiliation(s)
- Masao Watanabe
- Department of Nuclear Medicine, University Clinic Essen, Essen, Germany;
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Wolfgang P Fendler
- Department of Nuclear Medicine, University Clinic Essen, Essen, Germany
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Hong Grafe
- Department of Nuclear Medicine, University Clinic Essen, Essen, Germany
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Nader Hirmas
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Rainer Hamacher
- Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Helena Lanzafame
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Kim M Pabst
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Hubertus Hautzel
- Department of Nuclear Medicine, University Clinic Essen, Essen, Germany
| | - Clemens Aigner
- Department of Thoracic Surgery and Thoracic Endoscopy, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Bastian von Tresckow
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer Consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Martin Stuschke
- Department of Radiation Therapy, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Sherko Kümmel
- Department of Gynecology and Gynecologic Oncology, Evang. Kliniken Essen-Mitte, Essen, Germany, and Department of Gynecology with Breast Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Celine Lugnier
- Department of Hematology and Oncology with Palliative Care, Ruhr University Bochum, Bochum, Germany
| | - Boris Hadaschik
- Department of Urology, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Viktor Grünwald
- Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
- Department of Urology, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Fadi Zarrad
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Jens T Siveke
- Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany; and
- Division of Solid Tumor Translational Oncology, German Cancer Center Consortium (DKTK partner site Essen), and German Cancer Research Center, Heidelberg, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University Clinic Essen, Essen, Germany
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Manuel Weber
- Department of Nuclear Medicine, University Clinic Essen, Essen, Germany
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| |
Collapse
|
|
8
|
Wang Y, Liu Z, Tian Y, Zhao H, Fu X. Periampullary cancer and neurological interactions: current understanding and future research directions. Front Oncol 2024; 14:1370111. [PMID: 38567163 PMCID: PMC10985190 DOI: 10.3389/fonc.2024.1370111] [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: 01/13/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Periampullary cancer is a malignant tumor occurring around the ampullary region of the liver and pancreas, encompassing a variety of tissue types and sharing numerous biological characteristics, including interactions with the nervous system. The nervous system plays a crucial role in regulating organ development, maintaining physiological equilibrium, and ensuring life process plasticity, a role that is equally pivotal in oncology. Investigations into nerve-tumor interactions have unveiled their key part in controlling cancer progression, inhibiting anti-tumor immune responses, facilitating invasion and metastasis, and triggering neuropathic pain. Despite many mechanisms by which nerve fibers contribute to cancer advancement still being incompletely understood, the growing emphasis on the significance of nerves within the tumor microenvironment in recent years has set the stage for the development of groundbreaking therapies. This includes combining current neuroactive medications with established therapeutic protocols. This review centers on the mechanisms of Periampullary cancer's interactions with nerves, the influence of various types of nerve innervation on cancer evolution, and outlines the horizons for ongoing and forthcoming research.
Collapse
Affiliation(s)
- Yuchen Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Zi’ang Liu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yanzhang Tian
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- General Surgery Department , Shanxi Bethune Hospital/General Surgery Department, Third Hospital of Shanxi Medical University, Taiyuan, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haoliang Zhao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- General Surgery Department , Shanxi Bethune Hospital/General Surgery Department, Third Hospital of Shanxi Medical University, Taiyuan, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xifeng Fu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- General Surgery Department , Shanxi Bethune Hospital/General Surgery Department, Third Hospital of Shanxi Medical University, Taiyuan, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
9
|
Xu W, Liu J, Zhang J, Lu J, Guo J. Tumor microenvironment crosstalk between tumors and the nervous system in pancreatic cancer: Molecular mechanisms and clinical perspectives. Biochim Biophys Acta Rev Cancer 2024; 1879:189032. [PMID: 38036106 DOI: 10.1016/j.bbcan.2023.189032] [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: 07/06/2023] [Revised: 11/22/2023] [Accepted: 11/23/2023] [Indexed: 12/02/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits the highest incidence of perineural invasion among all solid tumors. The intricate interplay between tumors and the nervous system plays an important role in PDAC tumorigenesis, progression, recurrence, and metastasis. Various clinical symptoms of PDAC, including anorexia and cancer pain, have been linked to aberrant neural activity, while the presence of perineural invasion is a significant prognostic indicator. The use of conventional neuroactive drugs and neurosurgical interventions for PDAC patients is on the rise. An in-depth exploration of tumor-nervous system crosstalk has revealed novel therapeutic strategies for mitigating PDAC progression and effectively relieving symptoms. In this comprehensive review, we elucidate the regulatory functions of tumor-nervous system crosstalk, provide a succinct overview of the relationship between tumor-nervous system dialogue and clinical symptomatology, and deliberate the current research progress and forthcoming avenues of neural therapy for PDAC.
Collapse
Affiliation(s)
- Wenchao Xu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jianzhou Liu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jianlu Zhang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
| | - Jun Lu
- Department of General Surgery, Peking University Third Hospital, Beijing 100730, China
| | - Junchao Guo
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
| |
Collapse
|
|
10
|
Madhusudanan P, Jerard C, Raju G, Katiyar N, Shankarappa SA. Nerve terminals in the tumor microenvironment as targets for local infiltration analgesia. Neurosci Res 2023; 196:40-51. [PMID: 37336292 DOI: 10.1016/j.neures.2023.06.006] [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: 01/07/2023] [Revised: 05/19/2023] [Accepted: 06/16/2023] [Indexed: 06/21/2023]
Abstract
Nerve terminals within the tumor microenvironment as potential pain-mitigating targets for local infiltration analgesia is relatively less explored. In this study, we examine the role of key analgesics administered as local infiltration analgesia in a model of cancer-induced bone pain (CIBP). CIBP was induced by administration of allogenic MRMT1 breast cancer cells in the proximal tibia of rats, and tumor mass characterized using radiogram, micro-CT, and histological analysis. In vitro responsiveness to key analgesics δ-opioid receptor agonist (DOPr), Ca2+ channel and TRPV1 antagonists was assessed using ratiometric Ca2+ imaging in sensory neurons innervating the tumor site. Effectiveness of locally infiltrated analgesics administered independently or in combination was assessed by quantifying evoked limb withdrawal thresholds at two distinct sites for up to 14 days. CIBP animals demonstrated DOPr, N-, and L-type and TRPV1 expression in lumbar dorsal root ganglion neurons (DRG), comparable to controls. Evoked Ca2+ transients in DRG neurons from CIBP animals were significantly reduced in response to treatment with compounds targeting DOPr, N-, L-type Ca2+ channels and TRPV1 proteins. Behaviourally, evoked hyperalgesia at the tumor site was strongly mitigated by peritumoral injection of the DOPr agonist and T-type calcium antagonist, via its activity on bone afferents. Results from this study suggest that nerve terminals at tumor site could be utilized as targets for specific analgesics, using local infiltration analgesia.
Collapse
Affiliation(s)
- Pallavi Madhusudanan
- Amrita School of Nanosciences & Molecular Medicine, Amrita Institute of Medical Sciences & Research Center, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Chinnu Jerard
- Amrita School of Nanosciences & Molecular Medicine, Amrita Institute of Medical Sciences & Research Center, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Gayathri Raju
- Amrita School of Nanosciences & Molecular Medicine, Amrita Institute of Medical Sciences & Research Center, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Neeraj Katiyar
- Biomedical Engineering Division, Department of Materials Science and Engineering, Uppsala University, Lagerhyddsvagen 1, 752 37 Uppsala, Sweden
| | - Sahadev A Shankarappa
- Amrita School of Nanosciences & Molecular Medicine, Amrita Institute of Medical Sciences & Research Center, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India.
| |
Collapse
|
|
11
|
Ni B, Yin Y, Li Z, Wang J, Wang X, Wang K. Crosstalk Between Peripheral Innervation and Pancreatic Ductal Adenocarcinoma. Neurosci Bull 2023; 39:1717-1731. [PMID: 37347365 PMCID: PMC10603023 DOI: 10.1007/s12264-023-01082-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/04/2023] [Indexed: 06/23/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to a poor overall prognosis. Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape. The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets. In this review, we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC, summarize the potential signaling pathways modulating the neuronal-cancer interaction, and discuss the current and future therapeutic possibilities for this condition.
Collapse
Affiliation(s)
- Bo Ni
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yiqing Yin
- Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zekun Li
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Junjin Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xiuchao Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Kaiyuan Wang
- Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| |
Collapse
|
|
12
|
Weitz J, Garg B, Martsinkovskiy A, Patel S, Tiriac H, Lowy AM. Pancreatic ductal adenocarcinoma induces neural injury that promotes a transcriptomic and functional repair signature by peripheral neuroglia. Oncogene 2023; 42:2536-2546. [PMID: 37433986 PMCID: PMC10880465 DOI: 10.1038/s41388-023-02775-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/23/2023] [Accepted: 06/30/2023] [Indexed: 07/13/2023]
Abstract
Perineural invasion (PNI) is the phenomenon whereby cancer cells invade the space surrounding nerves. PNI occurs frequently in epithelial malignancies, but is especially characteristic of pancreatic ductal adenocarcinoma (PDAC). The presence of PNI portends an increased incidence of local recurrence, metastasis and poorer overall survival. While interactions between tumor cells and nerves have been investigated, the etiology and initiating cues for PNI development is not well understood. Here, we used digital spatial profiling to reveal changes in the transcriptome and to allow for a functional analysis of neural-supportive cell types present within the tumor-nerve microenvironment of PDAC during PNI. We found that hypertrophic tumor-associated nerves within PDAC express transcriptomic signals of nerve damage including programmed cell death, Schwann cell proliferation signaling pathways, as well as macrophage clearance of apoptotic cell debris by phagocytosis. Moreover, we identified that neural hypertrophic regions have increased local neuroglial cell proliferation which was tracked using EdU tumor labeling in KPC mice, as well as frequent TUNEL positivity, suggestive of a high turnover rate. Functional calcium imaging studies using human PDAC organotypic slices confirmed nerve bundles had neuronal activity, as well as contained NGFR+ cells with high sustained calcium levels, which are indicative of apoptosis. This study reveals a common gene expression pattern that characterizes solid tumor-induced damage to local nerves. These data provide new insights into the pathobiology of the tumor-nerve microenvironment during PDAC as well as other gastrointestinal cancers.
Collapse
Affiliation(s)
- Jonathan Weitz
- Department of Surgery, University of California, San Diego, La Jolla, CA, CA 92093, USA.
| | - Bharti Garg
- Department of Surgery, University of California, San Diego, La Jolla, CA, CA 92093, USA
| | - Alexei Martsinkovskiy
- Department of Surgery, University of California, San Diego, La Jolla, CA, CA 92093, USA
| | - Sandip Patel
- Division of Hematology-Oncology in the Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Herve Tiriac
- Department of Surgery, University of California, San Diego, La Jolla, CA, CA 92093, USA
| | - Andrew M Lowy
- Department of Surgery, University of California, San Diego, La Jolla, CA, CA 92093, USA.
| |
Collapse
|
|
13
|
Târtea EA, Petrescu M, Udriștoiu I, Gheorman V, Biciușcă V, Petrescu AR, Ciurea AM, Vere CC. Clinical Outcomes Depending on Sympathetic Innervation in Pancreatic Cancer. Cancers (Basel) 2023; 15:cancers15113040. [PMID: 37297000 DOI: 10.3390/cancers15113040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND The aim of our study was to evaluate sympathetic neuronal remodeling in patients with pancreatic cancer, together with its correlation with clinical outcomes. METHODS In this descriptive, retrospective study, we analyzed pancreatic cancer specimens and peritumoral pancreatic tissue from 122 patients. We also investigated tyrosine hydroxylase immunoreactivity for the analysis of sympathetic nerve fibers and beta 2 adrenoreceptors immunoreactivity. To investigate the potential interaction between tyrosine hydroxylase (TH), beta 2 adrenoreceptors (B2A) immunoreactivity, and clinicopathological outcomes, we used the median to classify each case as TH+, respectively, B2A+ (if it presented a value higher than the median). RESULTS Firstly, the overall survival was analyzed according to TH and B2A immunoreactivity, in both intratumoral and peritumoral tissue. Only B2A immunoreactivity in the peritumoral pancreatic tissue influenced overall survival at 5 years of follow-up; thus, B2A+ patients recorded a 5-year survival of only 3% compared to B2A- patients who recorded an overall survival at 5 years of follow-up of 14% (HR = 1.758, 95% CI of ratio 1.297 to 2.938, p = 0.0004). Additionally, the increased immunoreactivity of B2A in the peritumoral tissue was also associated with other factors of poor prognosis, such as moderately or poorly differentiated tumors, the absence of response to first-line chemotherapy, or metastatic disease. CONCLUSIONS The increased immunoreactivity of beta 2 adrenoreceptors in pancreatic peritumoral tissue represents a poor prognostic factor in pancreatic cancer.
Collapse
Affiliation(s)
- Elena-Anca Târtea
- Department of Neurology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihai Petrescu
- Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Ion Udriștoiu
- Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Victor Gheorman
- Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Viorel Biciușcă
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - Ana-Maria Ciurea
- Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cristin Constantin Vere
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| |
Collapse
|
|
14
|
Lu WL, Kuang H, Gu J, Hu X, Chen B, Fan Y. GAP-43 targeted indocyanine green-loaded near-infrared fluorescent probe for real-time mapping of perineural invasion lesions in pancreatic cancer in vivo. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2023; 50:102671. [PMID: 37054805 DOI: 10.1016/j.nano.2023.102671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/22/2023] [Accepted: 03/26/2023] [Indexed: 04/15/2023]
Abstract
OBJECTIVE Perineural invasion (PNI) is associated with local recurrence, distant metastasis, and a poor prognosis in pancreatic cancer. However, rare attempt was made to identified the PNI intraoperative. To facilitate precise R0 excision of the tumor, we planned to develop a fluorescent probe for intraoperative imaging of the PNI using GAP-43 as the target and indocyanine green (ICG) as the carrier. METHODS The probe was created by binding peptide antibody and ICG. Its targeting was tested in vitro and in vivo using a co-culture model of PC12 and tumor cells to create an in vitro neural invasion model and a mouse sciatic nerve invasion model. The small animal imaging system and surgical navigation system confirmed the probe's potential clinical applicability. The sciatic nerve damage model was created to confirm the probe's targeting. RESULTS We used the pancreatic cancer samples and the public database to confirm that GAP-43 was preferentially overexpressed in pancreatic cancer, particularly in PNI. PC12 cells showed high GAP-43RA-PEG-ICG probe-specific absorption after being co-cultured with tumor cells in vitro. In the sciatic nerve invasion experiment, animals in probe group displayed a significantly stronger fluorescence signal at the PNI compared to ICG-NP and the contralateral normal nerves groups. Although only 60 % of mice appeared to have R0 resections by the naked eye, small animal imaging systems and surgical fluorescence navigation systems could remove the tumor with R0 precision. The injury model used in the probe imaging experimental trials demonstrated that the probe was specifically targeted to the injured nerve, regardless of whether the injury was infiltrated by a tumor or physical. CONCLUSION We developed the GAP-43Ra-ICG-PEG, an active-targeting near-infrared fluorescent (NIF) probe, that specifically binds to GAP-43-positive neural cells in an in vitro model of PNI. The probe efficiently visualized PNI lesions in pancreatic cancer in preclinical models, opening up new possibilities for NIRF-guided pancreatic surgery, particularly for PNI patients.
Collapse
Affiliation(s)
- Wen Liang Lu
- The Department of General Surgery & Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; Department of Thyroid and breast surgery, Maternal and Child Health Hospital of Hubei Province, Wuhan 430070, China
| | - Houfang Kuang
- Department of General Surgery, Wuhan Children(,) hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, China
| | - Jianyou Gu
- The Department of General Surgery & Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Xiaojun Hu
- The Department of General Surgery & Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; Department of Hepatobiliary Surgery, The Fifth Affifiliated Hospital of Southern Medical University, Guangzhou 510920, China
| | - Bo Chen
- Department of Thyroid and breast surgery, Maternal and Child Health Hospital of Hubei Province, Wuhan 430070, China
| | - Yingfang Fan
- The Department of General Surgery & Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| |
Collapse
|
|
15
|
Weitz J, Garg B, Tiriac H, Martsinkovskiy A, Patel S, Lowy A. Pancreatic Ductal Adenocarcinoma Induces Neural Injury that Promotes a Transcriptomic and Functional Repair Signature by Peripheral Neuroglia. RESEARCH SQUARE 2023:rs.3.rs-2715023. [PMID: 37034696 PMCID: PMC10081383 DOI: 10.21203/rs.3.rs-2715023/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Perineural invasion (PNI) is the phenomenon whereby cancer cells invade the space surrounding nerves. PNI occurs frequently in epithelial malignancies, but is especially characteristic of pancreatic ductal adenocarcinoma (PDAC). The presence of PNI portends an increased incidence of local recurrence, metastasis and poorer overall survival. While interactions between tumor cells and nerves have been investigated, the etiology and initiating cues for PNI development is not well understood. Here, we used digital spatial profiling to reveal changes in the transcriptome and to allow for a functional analysis of neural-supportive cell types present within the tumor-nerve microenvironment of PDAC during PNI. We found that hypertrophic tumor-associated nerves within PDAC express transcriptomic signals of nerve damage including programmed cell death, Schwann cell proliferation signaling pathways, as well as macrophage clearance of apoptotic cell debris by phagocytosis. Moreover, we identified that neural hypertrophic regions have increased local neuroglial cell proliferation which was tracked using EdU tumor labeling in KPC mice. This study reveals a common gene expression pattern that characterizes solid tumor-induced damage to local nerves. These data provide new insights into the pathobiology of the tumor-nerve microenvironment during PDAC as well as other gastrointestinal cancers.
Collapse
|
|
16
|
Prognostic analysis of curatively resected pancreatic cancer using harmonized positron emission tomography radiomic features. Eur J Hybrid Imaging 2023; 7:5. [PMID: 36872413 PMCID: PMC9986192 DOI: 10.1186/s41824-023-00163-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/18/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Texture features reflecting tumour heterogeneity enable us to investigate prognostic factors. The R package ComBat can harmonize the quantitative texture features among several positron emission tomography (PET) scanners. We aimed to identify prognostic factors among harmonized PET radiomic features and clinical information from pancreatic cancer patients who underwent curative surgery. METHODS Fifty-eight patients underwent preoperative enhanced dynamic computed tomography (CT) scanning and fluorodeoxyglucose PET/CT using four PET scanners. Using LIFEx software, we measured PET radiomic parameters including texture features with higher order and harmonized these PET parameters. For progression-free survival (PFS) and overall survival (OS), we evaluated clinical information, including age, TNM stage, and neural invasion, and the harmonized PET radiomic features based on univariate Cox proportional hazard regression. Next, we analysed the prognostic indices by multivariate Cox proportional hazard regression (1) by using either significant (p < 0.05) or borderline significant (p = 0.05-0.10) indices in the univariate analysis (first multivariate analysis) or (2) by using the selected features with random forest algorithms (second multivariate analysis). Finally, we checked these multivariate results by log-rank test. RESULTS Regarding the first multivariate analysis for PFS after univariate analysis, age was the significant prognostic factor (p = 0.020), and MTV and GLCM contrast were borderline significant (p = 0.051 and 0.075, respectively). Regarding the first multivariate analysis of OS, neural invasion, Shape sphericity and GLZLM LZLGE were significant (p = 0.019, 0.042 and 0.0076). In the second multivariate analysis, only MTV was significant (p = 0.046) for PFS, whereas GLZLM LZLGE was significant (p = 0.047), and Shape sphericity was borderline significant (p = 0.088) for OS. In the log-rank test, age, MTV and GLCM contrast were borderline significant for PFS (p = 0.08, 0.06 and 0.07, respectively), whereas neural invasion and Shape sphericity were significant (p = 0.03 and 0.04, respectively), and GLZLM LZLGE was borderline significant for OS (p = 0.08). CONCLUSIONS Other than the clinical factors, MTV and GLCM contrast for PFS and Shape sphericity and GLZLM LZLGE for OS may be prognostic PET parameters. A prospective multicentre study with a larger sample size may be warranted.
Collapse
|
|
17
|
Gola M, Sejda A, Godlewski J, Cieślak M, Starzyńska A. Neural Component of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:5246. [PMID: 36358664 PMCID: PMC9657005 DOI: 10.3390/cancers14215246] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/04/2022] [Accepted: 10/25/2022] [Indexed: 10/15/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive primary malignancy of the pancreas, with a dismal prognosis and limited treatment options. It possesses a unique tumor microenvironment (TME), generating dense stroma with complex elements cross-talking with each other to promote tumor growth and progression. Diversified neural components makes for not having a full understanding of their influence on its aggressive behavior. The aim of the study was to summarize and integrate the role of nerves in the pancreatic tumor microenvironment. The role of autonomic nerve fibers on PDAC development has been recently studied, which resulted in considering the targeting of sympathetic and parasympathetic pathways as a novel treatment opportunity. Perineural invasion (PNI) is commonly found in PDAC. As the severity of the PNI correlates with a poorer prognosis, new quantification of this phenomenon, distinguishing between perineural and endoneural invasion, could feature in routine pathological examination. The concepts of cancer-related neurogenesis and axonogenesis in PDAC are understudied; so, further research in this field may be warranted. A better understanding of the interdependence between the neural component and cancer cells in the PDAC microenvironment could bring new nerve-oriented treatment options into clinical practice and improve outcomes in patients with pancreatic cancer. In this review, we aim to summarize and integrate the current state of knowledge and future challenges concerning nerve-cancer interactions in PDAC.
Collapse
Affiliation(s)
- Michał Gola
- Department of Human Histology and Embryology, Collegium Medicum, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland
| | - Aleksandra Sejda
- Department of Pathomorphology and Forensic Medicine, Collegium Medicum, School of Medicine, University of Warmia and Mazury, 18 Żołnierska Street, 10-561 Olsztyn, Poland
| | - Janusz Godlewski
- Department of Human Histology and Embryology, Collegium Medicum, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland
| | - Małgorzata Cieślak
- Department of Pathomorphology and Forensic Medicine, Collegium Medicum, School of Medicine, University of Warmia and Mazury, 18 Żołnierska Street, 10-561 Olsztyn, Poland
| | - Anna Starzyńska
- Department of Oral Surgery, Medical University of Gdańsk, 7 Dębinki Street, 80-211 Gdańsk, Poland
| |
Collapse
|
|
18
|
Trinh VQH, Roland JT, Wong J, Revetta F, Patel K, Shi C, DelGiorno KE, Carter BD, Tan MCB. Peak density of immature nerve cells occurs with high-grade dysplasia in intraductal papillary mucinous neoplasms of the pancreas. J Pathol 2022; 258:69-82. [PMID: 35686747 PMCID: PMC9378585 DOI: 10.1002/path.5978] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 05/10/2022] [Accepted: 06/07/2022] [Indexed: 11/11/2022]
Abstract
The development of neural structures within tumors is now considered vital for carcinogenesis. However, the time course of this development in human pre-invasive neoplasia has been incompletely described. Therefore, we performed a detailed analysis of nerves across the neoplastic spectrum in resected intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Histology and multiplexed immunochemistry demonstrated that nerve density increased from low-grade (LG) to high-grade dysplasia (HG) but did not further increase once invasive IPMN (INV IPMN) was present. Higher nerve density correlated with increasing expression of nerve growth factor (NGF) by the tumor cells. Intra-tumoral nerves were immature and lacked markers of sympathetic, parasympathetic, and sensory lineages. Here, we show for the first time the presence of neural precursor cells (NPCs) within the stroma of pancreatic tumors. The density of these doublecortin (DCX)-positive NPCs increased from LG to HG, but not from HG to INV IPMN. We conclude that peak neural density of tumors is reached in high-grade dysplasia (often termed carcinoma in situ) rather than after invasion. These findings suggest that nerve-tumor interactions are important in IPMN progression and may serve as the basis for future mechanistic studies and novel therapeutic modalities. © 2022 The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Vincent Quoc-Huy Trinh
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Joseph Thomas Roland
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Jahg Wong
- Département de pathologie et biologie cellulaire, Université de Montréal, Montréal, Québec, Canada
| | - Frank Revetta
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Krutika Patel
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Chanjuan Shi
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Kathleen E. DelGiorno
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
- Cell and Developmental Biology, Vanderbilt University, Nashville TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Bruce D. Carter
- Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Marcus Chuan Beng Tan
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA
- Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| |
Collapse
|
|
19
|
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.
Collapse
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;
| |
Collapse
|
|
20
|
Limitations of Nerve Fiber Density as a Prognostic Marker in Predicting Oncological Outcomes in Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14092237. [PMID: 35565366 PMCID: PMC9103173 DOI: 10.3390/cancers14092237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 02/07/2023] Open
Abstract
It has been shown that the presence and density of nerve fibers (NFs; NFD) in the tumor microenvironment (TME) may play an important prognostic role in predicting long-term oncological outcomes in various malignancies. However, the role of NFD in the prognosis of hepatocellular carcinoma (HCC) is yet to be explored. To this end, we aimed to investigate the impact of NFs on oncological outcomes in a large European single-center cohort of HCC patients. In total, 153 HCC patients who underwent partial hepatectomy in a curative-intent setting between 2010 and 2021 at our university hospital were included in this study. Group comparisons between patients with and without NFs were conducted and the association of recurrence-free survival (RFS) and overall survival (OS) with the presence of NFs and other clinico-pathological variables were determined by univariate and multivariable Cox regression models. Patients with NFs in the TME presented with a median OS of 66 months (95% CI: 30−102) compared to 42 months (95% CI: 20−63) for patients without NFs (p = 0.804 log-rank). Further, RFS was 26 months (95% CI: 12−40) for patients with NFs compared to 18 months (95% CI: 9−27) for patients without NFs (p = 0.666 log-rank). In a subgroup analysis, patients with NFD ≤ 5 showed a median OS of 54 months (95% CI: 11−97) compared to 48 months (95% CI: 0−106) for the group of patients with NFD > 5 (p = 0.787 log-rank). Correspondingly, the RFS was 26 months (95% CI: 10−42) in patients with NFD ≤ 5 and 29 months (95% CI: 14−44) for the subcohort with NFD > 5 (p = 0.421 log-rank). Further, group comparisons showed no clinico-pathological differences between patients with NFs (n = 76) and without NFs (n = 77) and NFs were not associated with OS (p = 0.806) and RFS (p = 0.322) in our Cox regression models. In contrast to observations in various malignancies, NFs in the TME and NFD are not associated with long-term oncological outcomes in HCC patients undergoing surgery.
Collapse
|
|
21
|
Astono IP, Welsh JS, Rowe CW, Jobling P. Objective quantification of nerves in immunohistochemistry specimens of thyroid cancer utilising deep learning. PLoS Comput Biol 2022; 18:e1009912. [PMID: 35226665 PMCID: PMC8912900 DOI: 10.1371/journal.pcbi.1009912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/10/2022] [Accepted: 02/10/2022] [Indexed: 11/18/2022] Open
Abstract
Accurate quantification of nerves in cancer specimens is important to understand cancer behaviour. Typically, nerves are manually detected and counted in digitised images of thin tissue sections from excised tumours using immunohistochemistry. However the images are of a large size with nerves having substantial variation in morphology that renders accurate and objective quantification difficult using existing manual and automated counting techniques. Manual counting is precise, but time-consuming, susceptible to inconsistency and has a high rate of false negatives. Existing automated techniques using digitised tissue sections and colour filters are sensitive, however, have a high rate of false positives. In this paper we develop a new automated nerve detection approach, based on a deep learning model with an augmented classification structure. This approach involves pre-processing to extract the image patches for the deep learning model, followed by pixel-level nerve detection utilising the proposed deep learning model. Outcomes assessed were a) sensitivity of the model in detecting manually identified nerves (expert annotations), and b) the precision of additional model-detected nerves. The proposed deep learning model based approach results in a sensitivity of 89% and a precision of 75%. The code and pre-trained model are publicly available at https://github.com/IA92/Automated_Nerves_Quantification. The study of nerves as a prognostic marker for cancer is becoming increasingly important. However, accurate quantification of nerves in cancer specimens is difficult to achieve due to limitations in the existing manual and automated quantification methods. Manual quantification is time-consuming and subject to bias, whilst automated quantification, in general, has a high rate of false detections that makes it somewhat unreliable. In this paper, we propose an automated nerve quantification approach based on a novel deep learning model structure for objective nerve quantification in immunohistochemistry specimens of thyroid cancer. We evaluate the performance of the proposed approach by comparing it with existing manual and automated quantification methods. We show that our proposed approach is superior to the existing manual and automated quantification methods. The proposed approach is shown to have a high precision as well as being able to detect a significant number of nerves not detected by the experts in manual counting.
Collapse
Affiliation(s)
- Indriani P. Astono
- School of Engineering, The University of Newcastle, Newcastle, Australia
- * E-mail:
| | - James S. Welsh
- School of Engineering, The University of Newcastle, Newcastle, Australia
| | - Christopher W. Rowe
- School of Medicine and Public Health, The University of Newcastle, Newcastle, Australia
| | - Phillip Jobling
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, Australia
| |
Collapse
|
|
22
|
Opitz FV, Haeberle L, Daum A, Esposito I. Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia. Cancers (Basel) 2021; 13:cancers13246188. [PMID: 34944807 PMCID: PMC8699458 DOI: 10.3390/cancers13246188] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive neoplasm with a poor survival rate. This is mainly due to late detection, which substantially limits therapy options. A better understanding of the early phases of pancreatic carcinogenesis is fundamental for improving patient prognosis in the future. In this article, we focused on the tumor microenvironment (TME), which provides the biological niche for the development of PDAC from its most common precursor lesions, PanIN (pancreatic intraepithelial neoplasias). Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.
Collapse
|
|
23
|
Yang B, Zhou M, Wu Y, Ma Y, Tan Q, Yuan W, Ma J. The Impact of Immune Microenvironment on the Prognosis of Pancreatic Ductal Adenocarcinoma Based on Multi-Omics Analysis. Front Immunol 2021; 12:769047. [PMID: 34777388 PMCID: PMC8580856 DOI: 10.3389/fimmu.2021.769047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 10/07/2021] [Indexed: 01/02/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor characterized by rapid progression, early metastasis, high recurrence, and limited responsiveness to conventional therapies. The 5-year survival rate of PDAC is extremely low (<8%), which lacks effective prognostic evaluation indicators. In this study, we used xCell to analyze infiltrating immune cells in a tumor and through the univariate and multivariate Cox analyses screened out two prognosis-related immune cells, CD4+TN and common lymphoid progenitor (CLP), which were used to construct a Cox model and figure out the risk-score. It was found that the constructed model could greatly improve the sensitivity of prognostic evaluation, that the higher the risk-score, the worse the prognosis. In addition, the risk-score could also identify molecular subtypes with poor prognosis and immunotherapy sensitivity. Through transcriptome and whole-exome sequencing analysis of PDAC dataset from The Cancer Genome Atlas (TCGA), it was found that copy number deletion and low expression of CCL19 might be crucial factors to affect the risk-score. Lastly, validation of the above findings was confirmed not only in Gene Expression Omnibus (GEO) datasets but also in our PDAC patient samples, Peking2020 cohort.
Collapse
Affiliation(s)
- Bing Yang
- Center of Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Peking University Fifth School of Clinical Medicine, Beijing, China
| | - Mingyao Zhou
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunzi Wu
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuanyuan Ma
- Center of Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Qin Tan
- Center of Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Yuan
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Ma
- Center of Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
24
|
Schmitd LB, Perez‐Pacheco C, D'Silva NJ. Nerve density in cancer: Less is better. FASEB Bioadv 2021; 3:773-786. [PMID: 34632313 PMCID: PMC8493966 DOI: 10.1096/fba.2021-00046] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/14/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
The density of nerves in cancer is emerging as a relevant clinical parameter for patient survival. Nerves in the tumor microenvironment have been associated with poor survival and recurrence, particularly if involved in perineural invasion. However, usually only a few nerves inside a tumor are affected by perineural invasion, while most nerves are not. Mechanistic studies have shown nerve-secreted factors promote tumor growth and invasion thereby making tumors more aggressive. Therefore, the overall number of nerves in the tumor microenvironment should be more representative of the nerve-tumor biological interaction than perineural invasion. This review summarizes the available clinical information about nerve density as a measure of clinical outcome in cancer and explores the mechanisms underlying nerve density in cancer, specifically, neurogenesis, axonogenesis, and neurotropism.
Collapse
Affiliation(s)
- Ligia B. Schmitd
- Department of Periodontics and Oral MedicineUniversity of Michigan School of DentistryAnn ArborMIUSA
| | - Cindy Perez‐Pacheco
- Department of Periodontics and Oral MedicineUniversity of Michigan School of DentistryAnn ArborMIUSA
| | - Nisha J. D'Silva
- Department of Periodontics and Oral MedicineUniversity of Michigan School of DentistryAnn ArborMIUSA
- Department of PathologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Rogel Cancer CenterUniversity of MichiganAnn ArborMIUSA
| |
Collapse
|
|
25
|
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.
Collapse
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.)
| |
Collapse
|
|
26
|
Bednarsch J, Tan X, Czigany Z, Liu D, Lang SA, Sivakumar S, Kather JN, Appinger S, Rosin M, Boroojerdi S, Dahl E, Gaisa NT, den Dulk M, Coolsen M, Ulmer TF, Neumann UP, Heij LR. The Presence of Small Nerve Fibers in the Tumor Microenvironment as Predictive Biomarker of Oncological Outcome Following Partial Hepatectomy for Intrahepatic Cholangiocarcinoma. Cancers (Basel) 2021; 13:cancers13153661. [PMID: 34359564 PMCID: PMC8345152 DOI: 10.3390/cancers13153661] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Nerve fibers in the microenvironment of malignant tumors have been shown to be an important prognostic factor for long-term survival in various cancer types; however, their role in intrahepatic cholangiocarcinoma remains to be determined. Therefore, the impact of nerve fibers on long-term survival was investigated in a large European cohort of patients with intrahepatic cholangiocarcinoma who were treated by curative-intent surgical resection. By univariate and multivariate statistics, the absence of nerve fibers was determined to be an independent predictor of impaired long-term survival. A group comparison between patients with and without nerve fibers showed a statically significant difference with a cancer-specific 5-year-survival of 47% in patients with nerve fibers compared to 21% in patients without nerve fibers. Thus, the presence of nerve fibers in the microenvironment of intrahepatic cholangiocarcinoma is revealed as a novel and important prognostic biomarker in these patients. Abstract The oncological role of the density of nerve fibers (NFs) in the tumor microenvironment (TME) in intrahepatic cholangiocarcinoma (iCCA) remains to be determined. Therefore, data of 95 iCCA patients who underwent hepatectomy between 2010 and 2019 was analyzed regarding NFs and long-term outcome. Extensive group comparisons were carried out and the association of cancer-specific survival (CSS) and recurrence-free survival (RFS) with NFs were assessed using Cox regression models. Patients with iCCA and NFs showed a median CSS of 51 months (5-year-CSS = 47%) compared to 27 months (5-year-CSS = 21%) in patients without NFs (p = 0.043 log rank). Further, NFs (hazard ratio (HR) = 0.39, p = 0.002) and N-category (HR = 2.36, p = 0.010) were identified as independent predictors of CSS. Patients with NFs and without nodal metastases displayed a mean CSS of 89 months (5-year-CSS = 62%), while patients without NFs or with nodal metastases but not both showed a median CCS of 27 months (5-year-CSS = 25%) and patients with both positive lymph nodes and without NFs showed a median CCS of 10 months (5-year-CSS = 0%, p = 0.001 log rank). NFs in the TME are, therefore, a novel and important prognostic biomarker in iCCA patients. NFs alone and in combination with nodal status is suitable to identify iCCA patients at risk of poor oncological outcomes following curative-intent surgery.
Collapse
Affiliation(s)
- Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
| | - Xiuxiang Tan
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6211 LK Maastricht, The Netherlands
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
| | - Dong Liu
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
| | - Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
| | - Shivan Sivakumar
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK;
- Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
| | - Jakob Nikolas Kather
- Department of Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany;
| | - Simone Appinger
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
| | - Mika Rosin
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
| | - Shiva Boroojerdi
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
| | - Edgar Dahl
- Institute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, Germany; (E.D.); (N.T.G.)
| | - Nadine Therese Gaisa
- Institute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, Germany; (E.D.); (N.T.G.)
| | - Marcel den Dulk
- Department of Surgery, Maastricht University Medical Center (MUMC), 6229 HX Maastricht, The Netherlands; (M.d.D.); (M.C.)
| | - Mariëlle Coolsen
- Department of Surgery, Maastricht University Medical Center (MUMC), 6229 HX Maastricht, The Netherlands; (M.d.D.); (M.C.)
| | - Tom Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
- Department of Surgery, Maastricht University Medical Center (MUMC), 6229 HX Maastricht, The Netherlands; (M.d.D.); (M.C.)
| | - Lara Rosaline Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (J.B.); (X.T.); (Z.C.); (D.L.); (S.A.L.); (S.A.); (M.R.); (S.B.); (T.F.U.); (U.P.N.)
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6211 LK Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center (MUMC), 6229 HX Maastricht, The Netherlands; (M.d.D.); (M.C.)
- Correspondence:
| |
Collapse
|
|
27
|
Sigorski D, Gulczyński J, Sejda A, Rogowski W, Iżycka-Świeszewska E. Investigation of Neural Microenvironment in Prostate Cancer in Context of Neural Density, Perineural Invasion, and Neuroendocrine Profile of Tumors. Front Oncol 2021; 11:710899. [PMID: 34277455 PMCID: PMC8281889 DOI: 10.3389/fonc.2021.710899] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/21/2021] [Indexed: 12/20/2022] Open
Abstract
Background Cancer stroma contains the neural compartment with specific components and action. Neural microenvironment processing includes among others axonogenesis, perineural invasion (PNI), neurosignaling, and tumor cell neural/neuroendocrine differentiation. Growing data suggest that tumor-neural crosstalk plays an important function in prostate cancer (PCa) biology. However, the mechanisms involved in PNI and axonogenesis, as well as their patho-clinical correlations in this tumor are unclear. Methods The present study was carried out on FFPE samples of 73 PCa and 15 benign prostate (BP) cases. Immunohistochemistry with neural markers PGP9.5, TH, and NFP was performed on constructed TMAs and selected tissue sections. The analyzed parameters of tumor innervation included small nerve density (ND) measured on pan-neural marker (PGP9.5) and TH s4tained slides, as well assessment of PNI presence and morphology. The qualitative and topographic aspects were studied. In addition, the expression of neuroendocrine marker chromogranin and NPY was assessed with dedicated indexes. The correlations of the above parameters with basic patho-clinical data such as patients’ age, tumor stage, grade, angioinvasion, and ERG status were examined. Results The study showed that innervation parameters differed between cancer and BP. The neural network in PCa revealed heterogeneity, and ND PGP9.5 in tumor was significantly lower than in its periphery. The density of sympathetic TH-positive fibers and its proportion to all fibers was lower in cancer than in the periphery and BP samples. Perineural invasion was confirmed in 76% of cases, usually multifocally, occurring more commonly in tumors with a higher grade. NPY expression in PCa cells was common with its intensity often rising towards PNI. ERG+ tumors showed higher ND, more frequent PNI, and a higher stage. Moreover, chromogranin-positive cells were more pronounced in PCa with higher NPY expression. Conclusions The analysis showed an irregular axonal network in prostate cancer with higher neural density (panneural and adrenergic) in the surroundings and the invasive front. ND and PNI interrelated with NPY expression, neuroendocrine differentiation, and ERG status. The above findings support new evidence for the presence of autocrine and paracrine interactions in prostate cancer neural microenvironment.
Collapse
Affiliation(s)
- Dawid Sigorski
- Department of Oncology, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland.,Department of Oncology and Immuno-Oncology, Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration Hospital, Olsztyn, Poland
| | - Jacek Gulczyński
- Department of Pathology and Neuropathology, Medical University of Gdańsk, Gdańsk, Poland.,Department of Pathomorphology, Copernicus Hospital, Gdańsk, Poland
| | - Aleksandra Sejda
- Department of Pathomorphology, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
| | - Wojciech Rogowski
- Department of Health, Pomeranian University in Słupsk, Słupsk, Poland.,Department of Oncology, Chemotherapy, Clinical trials, Regional Hospital, Słupsk, Poland
| | - Ewa Iżycka-Świeszewska
- Department of Pathology and Neuropathology, Medical University of Gdańsk, Gdańsk, Poland.,Department of Pathomorphology, Copernicus Hospital, Gdańsk, Poland
| |
Collapse
|
|
28
|
Bednarsch J, Kather J, Tan X, Sivakumar S, Cacchi C, Wiltberger G, Czigany Z, Ulmer F, Neumann UP, Heij LR. Nerve Fibers in the Tumor Microenvironment as a Novel Biomarker for Oncological Outcome in Patients Undergoing Surgery for Perihilar Cholangiocarcinoma. Liver Cancer 2021; 10:260-274. [PMID: 34239812 PMCID: PMC8237795 DOI: 10.1159/000515303] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/12/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Perihilar cholangiocarcinoma (pCCA) is a biliary tract cancer with a dismal prognosis, with surgery being the only chance of cure. A characteristic aggressive biological feature of pCCA is perineural growth which is defined by the invasion of cancer cells to nerves and nerve fibers. Recently, nerve fiber density (NFD) was linked to oncological outcomes in various malignancies; however, its prognostic role in pCCA remains to be elucidated. MATERIALS AND METHODS Data of 101 pCCA patients who underwent curative-intent surgery between 2010 and 2019 were included in this study. Extensive group comparisons between patients with high and low NFD were carried out, and the association of cancer-specific survival (CSS) and recurrence-free survival with NFD and other clinicopathological characteristics was assessed using univariate and multivariable cox regression models. RESULTS Patients with high NFD showed a median CSS of 90 months (95% CI: 48-132, 3-year CSS = 77%, 5-year CSS = 72%) compared to 33 months (95% CI: 19-47, 3-year CSS = 46%, 5-year CSS = 32%) in patients with low NFD (p = 0.006 log rank). Further, N1 category (HR = 2.84, p = 0.001) and high NFD (HR = 0.41, p = 0.024) were identified as independent predictors of CSS in multivariable analysis. Patients with high NFD and negative lymph nodes showed a median CSS of 90 months (3-year CSS = 88%, 5-year CSS = 80%), while patients with either positive lymph nodes or low NFD displayed a median CSS of 51 months (3-year CSS = 59%, 5-year CSS = 45%) and patients with both positive lymph nodes and low NFD a median CSS of 24 months (3-year CSS = 26%, 5-year CSS = 16%, p = 0.001 log rank). CONCLUSION NFD has been identified as an important novel prognostic biomarker in pCCA patients. NFD alone and in combination with nodal status in particular allows to stratify pCCA patients based on their risk for inferior oncological outcomes after curative-intent surgery.
Collapse
Affiliation(s)
- Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Jakob Kather
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Xiuxiang Tan
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany,Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Shivan Sivakumar
- Department of Oncology, University of Oxford, Oxford, United Kingdom,Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Claudio Cacchi
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Georg Wiltberger
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany,Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Lara Rosaline Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands,Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany,*Lara Rosaline Heij,
| |
Collapse
|
|
29
|
Ferdoushi A, Griffin N, Marsland M, Xu X, Faulkner S, Gao F, Liu H, King SJ, Denham JW, van Helden DF, Jobling P, Jiang CC, Hondermarck H. Tumor innervation and clinical outcome in pancreatic cancer. Sci Rep 2021; 11:7390. [PMID: 33795769 PMCID: PMC8017010 DOI: 10.1038/s41598-021-86831-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 03/09/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy. Nerves infiltrate the microenvironment of pancreatic cancers and contribute to tumor progression, however the clinicopathological significance of tumor innervation is unclear. In this study, the presence of nerves and their cross-sectional size were quantified by immunohistochemistry for the neuronal markers S-100, PGP9.5 and GAP-43 in a series of 99 pancreatic cancer cases versus 71 normal adjacent pancreatic tissues. A trend was observed between the presence of nerves in the tumor microenvironment of pancreatic cancer and worse overall patient survival (HR = 1.8, 95% CI 0.77-4.28, p = 0.08). The size of nerves, as measured by cross-sectional area, were significantly higher in pancreatic cancer than in the normal adjacent tissue (p = 0.002) and larger nerves were directly associated with worse patient survival (HR = 0.41, 95% CI 0.19-0.87, p = 0.04). In conclusion, this study suggests that the presence and size of nerves within the pancreatic cancer microenvironment are associated with tumor aggressiveness.
Collapse
Affiliation(s)
- Aysha Ferdoushi
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, 1902, Bangladesh
| | - Nathan Griffin
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
| | - Mark Marsland
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
| | - Xiaoyue Xu
- School of Population Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Sam Faulkner
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
| | - Fangfang Gao
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
| | - Hui Liu
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233030, People's Republic of China
| | - Simon J King
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
| | - James W Denham
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, 2308, Australia
| | - Dirk F van Helden
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
| | - Phillip Jobling
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
| | - Chen Chen Jiang
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, 2308, Australia
| | - Hubert Hondermarck
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia.
- Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, 2305, Australia.
| |
Collapse
|
|
30
|
Tan X, Sivakumar S, Bednarsch J, Wiltberger G, Kather JN, Niehues J, de Vos-Geelen J, Valkenburg-van Iersel L, Kintsler S, Roeth A, Hao G, Lang S, Coolsen ME, den Dulk M, Aberle MR, Koolen J, Gaisa NT, Olde Damink SWM, Neumann UP, Heij LR. Nerve fibers in the tumor microenvironment in neurotropic cancer-pancreatic cancer and cholangiocarcinoma. Oncogene 2021; 40:899-908. [PMID: 33288884 PMCID: PMC7862068 DOI: 10.1038/s41388-020-01578-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/06/2020] [Accepted: 11/18/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are both deadly cancers and they share many biological features besides their close anatomical location. One of the main histological features is neurotropism, which results in frequent perineural invasion. The underlying mechanism of cancer cells favoring growth by and through the nerve fibers is not fully understood. In this review, we provide knowledge of these cancers with frequent perineural invasion. We discuss nerve fiber crosstalk with the main different components of the tumor microenvironment (TME), the immune cells, and the fibroblasts. Also, we discuss the crosstalk between the nerve fibers and the cancer. We highlight the shared signaling pathways of the mechanisms behind perineural invasion in PDAC and CCA. Hereby we have focussed on signaling neurotransmitters and neuropeptides which may be a target for future therapies. Furthermore, we have summarized retrospective results of the previous literature about nerve fibers in PDAC and CCA patients. We provide our point of view in the potential for nerve fibers to be used as powerful biomarker for prognosis, as a tool to stratify patients for therapy or as a target in a (combination) therapy. Taking the presence of nerves into account can potentially change the field of personalized care in these neurotropic cancers.
Collapse
Affiliation(s)
- Xiuxiang Tan
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Shivan Sivakumar
- Department of Oncology, University of Oxford, Oxford, UK
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Jan Bednarsch
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Georg Wiltberger
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | | | - Jan Niehues
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Judith de Vos-Geelen
- Division of Medical Oncology, Department of Internal Medicine, GROW School for Oncology and Development Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Liselot Valkenburg-van Iersel
- Division of Medical Oncology, Department of Internal Medicine, GROW School for Oncology and Development Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Svetlana Kintsler
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Anjali Roeth
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Guangshan Hao
- Translational Neurosurgery and Neurobiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Sven Lang
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Mariëlle E Coolsen
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Marcel den Dulk
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Merel R Aberle
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Jarne Koolen
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Nadine T Gaisa
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Steven W M Olde Damink
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Ulf P Neumann
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Lara R Heij
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands.
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany.
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
| |
Collapse
|
|
31
|
Petrusel L, Rusu I, Leucuta DC, Seicean R, Suharoschi R, Zamfir P, Seicean A. Relationship between cachexia and perineural invasion in pancreatic adenocarcinoma. World J Gastrointest Oncol 2019; 11:1126-1140. [PMID: 31908718 PMCID: PMC6937437 DOI: 10.4251/wjgo.v11.i12.1126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 09/09/2019] [Accepted: 10/14/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma (PDAC). The rapid disease progression and patient deterioration seems related to perineural invasion, but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied. As perineural invasion is difficult to be highlighted, a biomarker such as the neurotrophic factor Midkine (MK) which promotes the neuronal differentiation and the cell migration could be helpful. Also, Activin (ACV) has been described as cachexia related to PDAC. However, their role for assessing and predicting the disease course in daily practice is not known. AIM To assess the relationship between perineural invasion and cachexia and their biomarkers, MK and ACV, respectively, and their prognostic value. METHODS This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies. Patients with other causes of malnutrition were excluded. The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data. These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease. RESULTS The study comprised 114 patients with PDAC, 125 controls and a supplementary group of 14 benign pancreatic tissue samples. ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls (63% vs 32% for ACV, P < 0.001; 47% vs 16% for MK, P < 0.001), with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage (P = 0.006), the presence of metastasis (P = 0.04), perineural invasion (P = 0.03) and diabetes (P = 0.002), but with no influence on survival. No correlation between clinicopathological factors and ACV expression was noted. Cachexia, present in 19% of patients, was unrelated to ACV or MK level. Higher ACV expression was associated with a shorter survival (P = 0.008). CONCLUSION The MK was a biomarker of perineural invasion, associated with tumor stage and diabetes, but without prognostic value as ACV. Cachexia was unrelated to perineural invasion, ACV level or survival.
Collapse
Affiliation(s)
- Livia Petrusel
- Department of Gastroenterology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania
| | - Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400162, Romania
| | - Daniel Corneliu Leucuta
- Medical Informatics and Biostatistics Department, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400012, Romania
| | - Radu Seicean
- First Surgery Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400006, Romania
| | - Ramona Suharoschi
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca 400372, Romania
| | - Paula Zamfir
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400162, Romania
| | - Andrada Seicean
- Department of Gastroenterology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania
| |
Collapse
|
|
32
|
Gasparini G, Pellegatta M, Crippa S, Lena MS, Belfiori G, Doglioni C, Taveggia C, Falconi M. Nerves and Pancreatic Cancer: New Insights into a Dangerous Relationship. Cancers (Basel) 2019; 11:E893. [PMID: 31248001 PMCID: PMC6678884 DOI: 10.3390/cancers11070893] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/21/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer-particularly in pancreatic ductal adenocarcinoma (PDAC)-PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously ("present" or "absent"). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC.
Collapse
Affiliation(s)
- Giulia Gasparini
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Marta Pellegatta
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Stefano Crippa
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Vita Salute San Raffaele University, 20132 Milan, Italy.
| | - Marco Schiavo Lena
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Giulio Belfiori
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Claudio Doglioni
- Vita Salute San Raffaele University, 20132 Milan, Italy.
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Carla Taveggia
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Massimo Falconi
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Vita Salute San Raffaele University, 20132 Milan, Italy.
| |
Collapse
|
|
33
|
Iwasaki T, Hiraoka N, Ino Y, Nakajima K, Kishi Y, Nara S, Esaki M, Shimada K, Katai H. Reduction of intrapancreatic neural density in cancer tissue predicts poorer outcome in pancreatic ductal carcinoma. Cancer Sci 2019; 110:1491-1502. [PMID: 30776178 PMCID: PMC6447831 DOI: 10.1111/cas.13975] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 02/12/2019] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
Neural invasion is one of the malignant features contributing to locally advanced and/or metastatic disease progression in patients with pancreatic ductal adenocarcinoma (PDAC). Few studies exist on the distribution and state of nerve fibers in PDAC tissue and their clinicopathological impacts. The aim of the present study was to investigate the clinicopathological characteristics and prognostic value of intrapancreatic neural alterations in patients with PDAC. We retrospectively analyzed 256 patients with PDAC who underwent macroscopic curative surgery. Nerve fibers, immunolabeled with a specific neural marker GAP-43, were digitally counted and compared among PDAC, chronic pancreatitis (CP) and normal pancreatic tissues. Interlobular nerve fibers were apparently hypertrophic in both CP and PDAC, although intrapancreatic neural density and nerve number decreased characteristically in PDAC. They tended to decrease toward the center of the tumor. Kaplan-Meier survival analyses revealed a statistically significant correlation between low neural density and shorter overall survival (OS) (P = 0.014), and between high neural invasion and shorter OS (P = 0.017). Neural density (P = 0.04; HR = 1.496; 95% CI 1.018-2.199) and neural invasion ratio (P = 0.064; HR = 1.439; 95% CI .980-2.114) were prognostic factors of shorter OS in the multivariate analysis. These findings suggest low intrapancreatic neural density in patients with PDAC as an independent prognosticator, which may represent aggressive tumor behavior. Furthermore, we propose a simple, practical and reproducible method (to measure neural density and the neural invasion ratio during conventional histopathological diagnosis of PDAC), which has been validated using another cohort (n = 81).
Collapse
Affiliation(s)
- Toshimitsu Iwasaki
- Division of Molecular PathologyNational Cancer Center Research InstituteTokyoJapan
- Division of Pathology and Clinical LaboratoriesNational Cancer Center HospitalTokyoJapan
- Hepatobiliary and Pancreatic Surgery DivisionNational Cancer Center HospitalTokyoJapan
- Course of Advanced Clinical Research of CancerJuntendo University Graduate School of MedicineTokyoJapan
| | - Nobuyoshi Hiraoka
- Division of Molecular PathologyNational Cancer Center Research InstituteTokyoJapan
- Division of Pathology and Clinical LaboratoriesNational Cancer Center HospitalTokyoJapan
| | - Yoshinori Ino
- Division of Molecular PathologyNational Cancer Center Research InstituteTokyoJapan
| | - Kosei Nakajima
- Division of Molecular PathologyNational Cancer Center Research InstituteTokyoJapan
| | - Yoji Kishi
- Hepatobiliary and Pancreatic Surgery DivisionNational Cancer Center HospitalTokyoJapan
| | - Satoshi Nara
- Hepatobiliary and Pancreatic Surgery DivisionNational Cancer Center HospitalTokyoJapan
| | - Minoru Esaki
- Hepatobiliary and Pancreatic Surgery DivisionNational Cancer Center HospitalTokyoJapan
| | - Kazuaki Shimada
- Hepatobiliary and Pancreatic Surgery DivisionNational Cancer Center HospitalTokyoJapan
| | - Hitoshi Katai
- Course of Advanced Clinical Research of CancerJuntendo University Graduate School of MedicineTokyoJapan
- Gastric Surgery DivisionNational Cancer Center HospitalTokyoJapan
| |
Collapse
|
|
34
|
Mu W, Wang Z, Zöller M. Ping-Pong-Tumor and Host in Pancreatic Cancer Progression. Front Oncol 2019; 9:1359. [PMID: 31921628 PMCID: PMC6927459 DOI: 10.3389/fonc.2019.01359] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022] Open
Abstract
Metastasis is the main cause of high pancreatic cancer (PaCa) mortality and trials dampening PaCa mortality rates are not satisfying. Tumor progression is driven by the crosstalk between tumor cells, predominantly cancer-initiating cells (CIC), and surrounding cells and tissues as well as distant organs, where tumor-derived extracellular vesicles (TEX) are of major importance. A strong stroma reaction, recruitment of immunosuppressive leukocytes, perineural invasion, and early spread toward the peritoneal cavity, liver, and lung are shared with several epithelial cell-derived cancer, but are most prominent in PaCa. Here, we report on the state of knowledge on the PaCIC markers Tspan8, alpha6beta4, CD44v6, CXCR4, LRP5/6, LRG5, claudin7, EpCAM, and CD133, which all, but at different steps, are engaged in the metastatic cascade, frequently via PaCIC-TEX. This includes the contribution of PaCIC markers to TEX biogenesis, targeting, and uptake. We then discuss PaCa-selective features, where feedback loops between stromal elements and tumor cells, including distorted transcription, signal transduction, and metabolic shifts, establish vicious circles. For the latter particularly pancreatic stellate cells (PSC) are responsible, furnishing PaCa to cope with poor angiogenesis-promoted hypoxia by metabolic shifts and direct nutrient transfer via vesicles. Furthermore, nerves including Schwann cells deliver a large range of tumor cell attracting factors and Schwann cells additionally support PaCa cell survival by signaling receptor binding. PSC, tumor-associated macrophages, and components of the dysplastic stroma contribute to perineural invasion with signaling pathway activation including the cholinergic system. Last, PaCa aggressiveness is strongly assisted by the immune system. Although rich in immune cells, only immunosuppressive cells and factors are recovered in proximity to tumor cells and hamper effector immune cells entering the tumor stroma. Besides a paucity of immunostimulatory factors and receptors, immunosuppressive cytokines, myeloid-derived suppressor cells, regulatory T-cells, and M2 macrophages as well as PSC actively inhibit effector cell activation. This accounts for NK cells of the non-adaptive and cytotoxic T-cells of the adaptive immune system. We anticipate further deciphering the molecular background of these recently unraveled intermingled phenomena may turn most lethal PaCa into a curatively treatable disease.
Collapse
Affiliation(s)
- Wei Mu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Wei Mu
| | - Zhe Wang
- Department of Oncology, The First Affiliated Hospital of Guangdong, Pharmaceutical University, Guangzhou, China
| | - Margot Zöller
- Department of Oncology, The First Affiliated Hospital of Guangdong, Pharmaceutical University, Guangzhou, China
| |
Collapse
|