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Ma L, Zhang C, Wen Y, Xing K, Li S, Geng Z, Liao S, Yuan S, Li X, Zhong C, Hou J, Zhang J, Gao M, Xu B, Guo R, Wei W, Xie C, Lu L. Imaging-based surrogate classification for risk stratification of hepatocellular carcinoma with microvascular invasion to adjuvant hepatic arterial infusion chemotherapy: a multicenter retrospective study. Int J Surg 2025; 111:872-883. [PMID: 39051653 PMCID: PMC11745592 DOI: 10.1097/js9.0000000000001903] [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: 03/22/2024] [Accepted: 06/24/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND Patients with microvascular invasion (MVI)-positive hepatocellular carcinoma (HCC) have shown promising results with adjuvant hepatic arterial infusion chemotherapy (HAIC) with FOLFOX after curative resection. The authors aim to develop an imaging-derived biomarker to depict MVI-positive HCC patients more precisely and promote individualized treatment strategies of adjuvant HAIC. MATERIALS AND METHODS Patients with MVI-positive HCC were identified from five academic centers and utilized for model development ( n =470). Validation cohorts were pooled from a previously reported prospective clinical study conducted [control cohort ( n =145), adjuvant HAIC cohort ( n =143)] (NCT03192618). The primary endpoint was recurrence-free survival (RFS). Imaging features were thoroughly reviewed, and multivariable logistic regression analysis was employed for model development. Transcriptomic sequencing was conducted to identify the associated biological processes. RESULTS Arterial phase peritumoral enhancement, boundary of the tumor enhancement, tumor necrosis stratification, and boundary of the necrotic area were selected and incorporated into the nomogram for RFS. The imaging-based model successfully stratified patients into two distinct prognostic subgroups in both the training, control, and adjuvant HAIC cohorts (median RFS, 6.00 vs. 66.00 months, 4.86 vs. 24.30 months, 11.46 vs. 39.40 months, all P <0.01). Furthermore, no significant statistical difference was observed between patients at high risk of adjuvant HAIC and those in the control group ( P =0.61). The area under the receiver operating characteristic curve at 2 years was found to be 0.83, 0.84, and 0.73 for the training, control, and adjuvant HAIC cohorts, respectively. Transcriptomic sequencing analyses revealed associations between the radiological features and immune-regulating signal transduction pathways. CONCLUSION The utilization of this imaging-based model could help to better characterize MVI-positive HCC patients and facilitate the precise subtyping of patients who genuinely benefit from adjuvant HAIC treatment.
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Affiliation(s)
- Lidi Ma
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
| | - Cheng Zhang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
| | - Yuhua Wen
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center
| | - Kaili Xing
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Anesthesiology, Sun Yat-Sen University Cancer Center
| | - Shaohua Li
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center
| | - Zhijun Geng
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
| | - Shuting Liao
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
| | - Shasha Yuan
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University
| | - Xinming Li
- Department of Radiology, Zhujiang Hospital, Southern Medical University
| | - Chong Zhong
- Department of Hepatobilliary Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine
| | - Jing Hou
- Department of Radiology, Hunan Cancer Hospital; Changsha
| | - Jie Zhang
- Department of Radiology, Zhuhai People ‘s Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, P.R China
| | - Mingyong Gao
- Department of Radiology, The First People’s Hospital of Foshan, Foshan, Guangdong
| | - Baojun Xu
- Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou
| | - Rongping Guo
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center
| | - Wei Wei
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center
| | - Chuanmiao Xie
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
| | - Lianghe Lu
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center
- Department of Liver Surgery, Sun Yat-sen University Cancer Center
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Stanisavljevic I, Pavlovic S, Simovic Markovic B, Jurisevic M, Krajnovic T, Mijatovic S, Spasojevic M, Mitrovic S, Corovic I, Jovanovic I. Semaglutide decelerates the growth and progression of breast cancer by enhancing the acquired antitumor immunity. Biomed Pharmacother 2024; 181:117668. [PMID: 39536536 DOI: 10.1016/j.biopha.2024.117668] [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: 07/30/2024] [Revised: 10/31/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024] Open
Abstract
Semaglutide, a glucagon-like peptide 1 receptor agonist, is an antidiabetic that has recently shown promising immunomodulatory and antitumor effects. Breast cancer is the most common type of cancer affecting women worldwide. The aim of this study was to analyze the effects of semaglutide on the antitumor immunity in a 4T1 mouse breast cancer model. After induction of breast cancer, BALB/C mice were treated intraperitoneally with semaglutide. Semaglutide administration decelerated tumor appearance, growth and progression. The antidiabetic drug showed neither a direct cytotoxic effect in vitro, nor an angiogenic effect. Furthermore, depletion of NK cells had no affect on tumor growth in semaglutide treated mice suggesting a non-NK cell-dependent mechanism. However, semaglutide increased the accumulation and maturation of CD11c+ dendritic cell, while decreasing the percentage of FoxP3+ regulatory T cells in the spleen and primary tumor. In addition, semaglutide increased tumor infiltration and promoted the antitumor phenotype of T cells, in vivo. Furthermore, semaglutide enhanced the cytotoxic capacity of CD8+ T cells, in vitro. These results suggest that semaglutide enhances the acquired antitumor immune response and has potential for the future treatment of malignancies.
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Affiliation(s)
- Isidora Stanisavljevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.
| | - Sladjana Pavlovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.
| | - Bojana Simovic Markovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.
| | - Milena Jurisevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia; Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.
| | - Tamara Krajnovic
- Department of Immunology, Institute for Biological Research "Siniša Stanković"- National Institute of the Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, Belgrade 11108, Serbia.
| | - Sanja Mijatovic
- Department of Immunology, Institute for Biological Research "Siniša Stanković"- National Institute of the Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, Belgrade 11108, Serbia.
| | - Marija Spasojevic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.
| | - Slobodanka Mitrovic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.
| | - Irfan Corovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia; General Hospital of Novi Pazar, Department of Internal Medicine, Generala Živkovića 1, Novi Pazar 36300, Serbia.
| | - Ivan Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.
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Rodrigues-Jesus J, Canadas-Sousa A, Santos M, Oliveira P, Figueira AC, Marrinhas C, Petrucci GN, Gregório H, Tinoco F, Goulart A, Felga H, Vilhena H, Dias-Pereira P. Level of Necrosis in Feline Mammary Tumors: How to Quantify, Why and for What Purpose? Animals (Basel) 2024; 14:3280. [PMID: 39595332 PMCID: PMC11591325 DOI: 10.3390/ani14223280] [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: 09/28/2024] [Revised: 10/31/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024] Open
Abstract
Necrosis is a common finding in human and animal neoplasms. The percentage of tumor necrosis is included in tumor grading schemes in veterinary oncology; however, evaluation methods are often overlooked. Different studies have assessed the prognostic value of tumor necrosis in feline mammary tumors with contradictory results, which could be related to methodologic variability. In this study, a comprehensive evaluation of tumor necrosis in feline mammary tumors (FMTs) was conducted, by applying a semi-quantitative and a quantitative methodology for assessing necrosis. The interobserver agreement, the relationship with clinicopathological characteristics and the prognostic value of necrosis were analyzed in 154 FMT cases. Although subjectivity in the assessment of necrosis existed, an almost perfect agreement (weighted quadratic k = 0.851) between two observers was obtained. Furthermore, there was a significant positive correlation between the semi-quantitative and quantitative methods. Necrosis was more common and more extensive in malignant tumors than in their benign counterparts. Despite the non-significant results in the survival analysis, extensive necrosis was significantly associated with aggressive clinicopathological features, such as higher histological grade, high mitotic count and lymphovascular invasion. Our results support the potential relevance of necrosis in FMT.
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Affiliation(s)
- Joana Rodrigues-Jesus
- Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences, ICBAS-UP, University of Porto, 4050-313 Porto, Portugal; (J.R.-J.); (A.C.-S.)
| | - Ana Canadas-Sousa
- Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences, ICBAS-UP, University of Porto, 4050-313 Porto, Portugal; (J.R.-J.); (A.C.-S.)
- Centre for Investigation Vasco da Gama (CIVG), Department of Veterinary Sciences, Vasco da Gama University School, 3020-210 Coimbra, Portugal; (A.C.F.); (C.M.); (H.V.)
| | - Marta Santos
- Department of Microscopy, School of Medicine and Biomedical Sciences, ICBAS-UP, University of Porto, 4050-313 Porto, Portugal;
| | - Pedro Oliveira
- Department of Populations Studies, School of Medicine and Biomedical Sciences, ICBAS-UP, University of Porto, 4050-313 Porto, Portugal;
| | - Ana Catarina Figueira
- Centre for Investigation Vasco da Gama (CIVG), Department of Veterinary Sciences, Vasco da Gama University School, 3020-210 Coimbra, Portugal; (A.C.F.); (C.M.); (H.V.)
- OneVet Veterinary University Hospital of Coimbra (HVUC), 3020-210 Coimbra, Portugal
| | - Carla Marrinhas
- Centre for Investigation Vasco da Gama (CIVG), Department of Veterinary Sciences, Vasco da Gama University School, 3020-210 Coimbra, Portugal; (A.C.F.); (C.M.); (H.V.)
- OneVet Veterinary Hospital of Baixo Vouga (HVBV), 3750-742 Águeda, Portugal
| | - Gonçalo N. Petrucci
- OneVet Veterinary Hospital of Porto (HVP), 4250-475 Porto, Portugal;
- Department of Animal and Veterinary Sciences, University Institute for Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes e Alto Douro, 5000-801 Vila Real, Portugal
| | - Hugo Gregório
- Department of Animal and Veterinary Sciences, University Institute for Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
- AniCura Veterinary Hospital Centre (CHV), 4100-320 Porto, Portugal
| | - Flora Tinoco
- Dra. Flora Tinoco Veterinary Clinic, 4475-498 Maia, Portugal;
| | | | - Helena Felga
- Clínica dos Gatos Veterinary Clinic, 4100-207 Porto, Portugal;
| | - Hugo Vilhena
- Centre for Investigation Vasco da Gama (CIVG), Department of Veterinary Sciences, Vasco da Gama University School, 3020-210 Coimbra, Portugal; (A.C.F.); (C.M.); (H.V.)
- OneVet Veterinary University Hospital of Coimbra (HVUC), 3020-210 Coimbra, Portugal
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes e Alto Douro, 5000-801 Vila Real, Portugal
- Associate Laboratory of Animal and Veterinary Sciences AL4AnimaLS, 1300-477 Lisbon, Portugal
| | - Patrícia Dias-Pereira
- Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences, ICBAS-UP, University of Porto, 4050-313 Porto, Portugal; (J.R.-J.); (A.C.-S.)
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Zhu Y, Jia X, Zhan W, Zhou J. Adding contrast-enhanced ultrasound can improve the predictive ability of breast conventional ultrasound and mammography for pathological upgrade of biopsy-confirmed ductal carcinoma in situ. Eur J Radiol 2024; 180:111687. [PMID: 39213762 DOI: 10.1016/j.ejrad.2024.111687] [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: 03/07/2024] [Revised: 08/15/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024]
Abstract
OBJECTIVES To evaluate the added value of contrast-enhanced ultrasound (CEUS) on top of breast conventional imaging for predicting the upgrading of ductal carcinoma in situ (DCIS) to invasive cancer after surgery. METHODS This retrospective study enrolled 140 biopsy-proven DCIS lesions in 138 patients and divided them into two groups based on postoperative histopathology: non-upgrade and upgrade groups. Conventional ultrasound (US), mammography (MMG), CEUS and clinicopathological (CL) features were reviewed and compared between the two groups. The predictive performance of different models (with and without CEUS features) for histologic upgrade were compared to calculate the added value of CEUS. RESULTS Fifty-nine (42.1 %) lesions were histologically upgraded to invasive cancer after surgery. By logistic regression analyses, we found that high-grade DCIS at biopsy (P=0.004), ultrasonographic lesion size > 20 mm (P=0.007), mass-like lesion on US (P=0.030), the presence of suspicious calcification on MMG (P=0.014), the presence of perfusion defect (P=0.005) and the area under TIC>1021.34 ml (P<0.001) on CEUS were six independent factors predicting concomitant invasive components after surgery. The CL+US+MMG model made with the four predictors in the clinicopathologic, US and MMG categories yielded an area under the receiver operating curve (AUROC) value of 0.759 (95 % CI: 0.680-0.828) in predicting histological upgrade. The combination model built by adding the two CEUS predictors to the CL+US+MMG model showed higher predictive efficacy than the CL+US+MMG model (P=0.018), as the AUROC value was improved to 0.861 (95 % CI: 0.793-0.914). CONCLUSIONS The addition of contrast-enhanced ultrasound to breast conventional imaging could improve the preoperative prediction of an upgrade to invasive cancer from CNB -proven DCIS lesions.
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Affiliation(s)
- Ying Zhu
- Department of Ultrasound, Shanghai Ruijin Hospital Affiliated to Medical School of Shanghai Jiaotong University, Shanghai, China
| | - Xiaohong Jia
- Department of Ultrasound, Shanghai Ruijin Hospital Affiliated to Medical School of Shanghai Jiaotong University, Shanghai, China
| | - Weiwei Zhan
- Department of Ultrasound, Shanghai Ruijin Hospital Affiliated to Medical School of Shanghai Jiaotong University, Shanghai, China
| | - Jianqiao Zhou
- Department of Ultrasound, Shanghai Ruijin Hospital Affiliated to Medical School of Shanghai Jiaotong University, Shanghai, China.
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Kote R, Ravina M, Goyal H, Mohanty D, Gupta R, Shukla AK, Reddy M, Prasanth PN. Role of textural and radiomic analysis parameters in predicting histopathological parameters of the tumor in breast cancer patients. Nucl Med Commun 2024; 45:835-847. [PMID: 39113592 DOI: 10.1097/mnm.0000000000001885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
INTRODUCTION Texture and radiomic analysis characterizes the tumor's phenotype and evaluates its microenvironment in quantitative terms. This study aims to investigate the role of textural and radiomic analysis parameters in predicting histopathological factors in breast cancer patients. MATERIALS AND METHODS Two hundred and twelve primary breast cancer patients underwent 18 F-FDG PET/computed tomography for staging. The images were processed in a commercially available textural analysis software. ROI was drawn over the primary tumor with a 40% threshold and was processed further to derive textural and radiomic parameters. These parameters were then compared with histopathological factors of tumor. Receiver-operating characteristic analysis was performed with a P -value <0.05 for statistical significance. The significant parameters were subsequently utilized in various machine learning models to assess their predictive accuracy. RESULTS A retrospective study of 212 primary breast cancer patients was done. Among all the significant parameters, SUVmin, SUVmean, SUVstd, SUVmax, discretized HISTO_Entropy, and gray level co-occurrence matrix_Contrast were found to be significantly associated with ductal carcinoma type. Four parameters (SUVmin, SUVmean, SUVstd, and SUVmax) were significant in differentiating the luminal subtypes of the tumor. Five parameters (SUVmin, SUVmean, SUVstd, SUVmax, and SUV kurtosis) were significant in predicting the grade of the tumor. These parameters showcased robust capabilities in predicting multiple histopathological parameters when tested using machine learning algorithms. CONCLUSION Though textural analysis could not predict hormonal receptor status, lymphovascular invasion status, perineural invasion status, microcalcification status of tumor, and all the molecular subtypes of the tumor, it could predict the tumor's histologic type, triple-negative subtype, and score of the tumor noninvasively.
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Affiliation(s)
| | | | | | | | | | - Arvind Kumar Shukla
- Department of Community and Family Medicine, All India Institute of Medical Sciences, Raipur, India
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Dong S, Xu J, Li M, Xiong G, Wang R. Tumor necrosis serves as an important pathological characteristic of stage I-II colon cancer. INDIAN J PATHOL MICR 2024; 67:794-800. [PMID: 38727689 DOI: 10.4103/ijpm.ijpm_483_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 02/09/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND The long-term prognosis of colon cancer patients remains little changed with relatively high mortality and morbidity. Since the most widely used prognostic parameter TNM staging system is less satisfactory in predicting prognosis in early-stage cancers, numerous clinicopathological factors, including tumor necrosis, have been proposed for prognosis stratification, but substantial evidences are still lacking for early-stage colon cancer. MATERIALS AND METHODS In the retrospective study, a total of eligible 173 stage I-II colon cancer patients, who received tumor radical resection and lymphadenectomy in the local hospital between January 1, 2010, and December 31, 2018, were enrolled for analyzing the prognostic role of tumor necrosis. The primary endpoints included 5-year overall survival (OS) and progression-free survival (PFS). RESULTS The median follow-up of enrolled early-stage colon cancer patients was 58.3 months. The 2-year and 5-year OS rates were 88.3% and 68.2%, respectively, and the 2-year and 5-year PFS rates were 85.6% and 62.7%, respectively. Seventy-eight patients (45.1%) were diagnosed with tumor necrosis by pathological examination. Demographic analysis revealed a significant association of tumor necrosis with larger tumor size and a marginal association with vascular invasion. Kaplan-Meier survival curves demonstrated that tumor necrosis was associated with worse OS (log-rank P = 0.003) and PFS (log-rank P = 0.002). The independent unfavorable prognostic effect of tumor necrosis was further validated in univariate and multivariate Cox regression analysis (hazard ratio = 1.91 (1.52-2.40), P = 0.004). CONCLUSIONS The current study confirmed the independent prognostic role of tumor necrosis from pathological review in early-stage colon cancer patients. This pathological criterion promises to help in identifying high-risk subgroup from early-stage colon cancer patients, who may benefit from strict follow-up and adjuvant therapy.
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Affiliation(s)
- Shuhui Dong
- Department of Pathology, Tianjin Hospital, Tianjin City, China
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Han YJ, Liu S, Hardeman A, Rajagopal PS, Mueller J, Khramtsova G, Sanni A, Ajani M, Clayton W, Hurley IW, Yoshimatsu TF, Zheng Y, Parker J, Perou CM, Olopade OI. The VEGF-Hypoxia Signature Is Upregulated in Basal-like Breast Tumors from Women of African Ancestry and Associated with Poor Outcomes in Breast Cancer. Clin Cancer Res 2024; 30:2609-2618. [PMID: 38564595 DOI: 10.1158/1078-0432.ccr-23-1526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 11/21/2023] [Accepted: 03/29/2024] [Indexed: 04/04/2024]
Abstract
PURPOSE Black women experience the highest breast cancer mortality rate compared with women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry. EXPERIMENTAL DESIGN We developed a NanoString nCounter gene expression panel and applied it to breast tumors from Nigeria (n = 182) and the University of Chicago (Chicago, IL; n = 161). We also analyzed RNA sequencing data from Nigeria (n = 84) and The Cancer Genome Atlas (TCGA) datasets (n = 863). Patient prognosis was analyzed using multiple datasets. RESULTS The VEGF-hypoxia signature was highest in the basal-like subtype compared with other subtypes, with greater expression in Black women compared with White women. In TCGA dataset, necrotic breast tumors had higher scores for the VEGF-hypoxia signature compared with non-necrosis tumors (P < 0.001), with the highest proportion in the basal-like subtype. Furthermore, necrotic breast tumors have higher scores for the proliferation signature, suggesting an interaction between the VEGF-hypoxia signature, proliferation, and necrosis. T-cell gene expression signatures also correlated with the VEGF-hypoxia signature when testing all tumors in TCGA dataset. Finally, we found a significant association of the VEGF-hypoxia profile with poor outcomes when using all patients in the METABRIC (P < 0.0001) and SCAN-B datasets (P = 0.002). CONCLUSIONS These data provide further evidence for breast cancer heterogeneity across diverse populations and molecular subtypes. Interventions selectively targeting VEGF-hypoxia and the immune microenvironment have the potential to improve overall survival in aggressive breast cancers that disproportionately impact Black women in the African Diaspora.
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Affiliation(s)
- Yoo Jane Han
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Siyao Liu
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
| | - Ashley Hardeman
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Padma Sheila Rajagopal
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Jeffrey Mueller
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Galina Khramtsova
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Ayodele Sanni
- Department of Pathology and Forensic Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria
| | - Mustapha Ajani
- Department of Pathology, College of Medicine, University of Ibadan/University College Hospital, Ibadan, Oyo, Nigeria
| | - Wendy Clayton
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Ian W Hurley
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Toshio F Yoshimatsu
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Yonglan Zheng
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Joel Parker
- Department of Genetics, University of North Carolina, Chapel Hill, North Carolina
| | - Charles M Perou
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
| | - Olufunmilayo I Olopade
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois
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Younis SS, Salama AM, Elmehy DA, Heabah NA, Rabah HM, Elakshar SH, Awad RA, Gamea GA. Trichinella spiralis Larval Extract as a Biological Anti-Tumor Therapy in a Murine Model of Ehrlich Solid Carcinoma. Parasite Immunol 2024; 46:e13035. [PMID: 38712475 DOI: 10.1111/pim.13035] [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: 09/07/2023] [Revised: 03/27/2024] [Accepted: 04/04/2024] [Indexed: 05/08/2024]
Abstract
Trichinella spiralis (T. spiralis) is an immunomodulating parasite that can adversely affect tumor growth and extend host lifespan. The aim of this study was to elucidate the mechanisms by which T. spiralis larval antigens achieve this effect using Ehrlich solid carcinoma (ESC) murine model. Assessment was done by histopathological and immunohistochemical analysis of caspase-3, TNF-α, Ki-67 and CD31. Additionally, Bcl2 and Bcl2-associated protein X (Bax) relative gene expression was assessed by molecular analysis for studying the effect of T. spiralis crude larval extract (CLE) antigen on tumor necrosis, apoptosis, cell proliferation and angiogenesis. We found that both T. spiralis infection and CLE caused a decrease in the areas of necrosis in ESC. Moreover, they led to increased apoptosis through activation of caspase-3, up-regulation of pro-apoptotic gene, Bax and down-regulation of anti-apoptotic gene, Bcl2. Also, T. spiralis infection and CLE diminished ESC proliferation, as evidenced by decreasing Ki-67. T. spiralis infection and CLE were able to suppress the development of ESC by inhibiting tumor proliferation, inducing apoptosis and decreasing tumor necrosis, with subsequent decrease in tumor metastasis. T. spiralis CLE antigen may be considered as a promising complementary immunotherapeutic agent in the treatment of cancer.
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Affiliation(s)
- Salwa S Younis
- Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Amina M Salama
- Department of Medical Parasitology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dalia A Elmehy
- Department of Medical Parasitology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Nehal A Heabah
- Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hanem M Rabah
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Sara H Elakshar
- Department of Clinical Oncology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Radwa A Awad
- Department of Clinical Oncology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ghada A Gamea
- Department of Medical Parasitology, Faculty of Medicine, Tanta University, Tanta, Egypt
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Shamis SA, Savioli F, Ammar A, Al-Badran SS, Hatthakarnkul P, Leslie H, Mallon EE, Jamieson NB, McMillan DC, Edwards J. Spatial transcriptomic analysis of tumour with high and low CAIX expression in TNBC tissue samples using GeoMx™ RNA assay. Histol Histopathol 2024; 39:177-200. [PMID: 37681672 DOI: 10.14670/hh-18-655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
PURPOSE Prognostic significance and gene signatures associated with carbonic anhydrase IX (CAIX) was investigated in triple negative breast cancer (TNBC) patients. METHODS Immunohistochemistry (IHC) for CAIX was performed in tissue microarrays (TMAs) of 136 TNBC patients. In a subset of 52 patients Digital Spatial Profiler (DSP) was performed in tumour (pan-cytokeratin+) and stroma (pan-cytokeratin-). Differentially expressed genes (DEGs) with P<0.05 and and log2 fold change (FC)>(±0.25 and ±0.3, for tumour and stromal compartment, respectively) were identified. Four genes were validated at the protein level. RESULT Cytoplasmic CAIX expression was independently associated with poor recurrence free survival in TNBC patients [hazard ratio (HR)=6.59, 95% confidence interval (CI): 1.47-29.58, P=0.014]. DEG analysis identified 4 up-regulated genes (CD68, HIF1A, pan-melanocyte, and VSIR) in the tumour region and 9 down-regulated genes in the stromal region (CD86, CD3E, MS4A1, BCL2, CCL5, NKG7, PTPRC, CD27, and FAS) when low versus high CAIX expression was explored. Employing IHC, high CD68 and HIF-1α was associated with poorer prognosis and high BCL2 and CD3 was associated with good prognosis. CONCLUSIONS DSP technology identified DEGs in TNBC. Selected genes validated by IHC showed involvement of CD3 and BCL2 expression within stroma and HIF-1α, and CD68 expression within tumour. However, further functional analysis is warranted.
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Affiliation(s)
- Suad Ak Shamis
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Alexandria Parade, Glasgow, United Kingdom.
- Unit of Molecular Pathology, School of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, United Kingdom
| | - Francesca Savioli
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Alexandria Parade, Glasgow, United Kingdom.
| | - Aula Ammar
- Unit of Molecular Pathology, School of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, United Kingdom
| | - Sara Sf Al-Badran
- Unit of Molecular Pathology, School of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, United Kingdom
| | - Phimmada Hatthakarnkul
- Unit of Molecular Pathology, School of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, United Kingdom
| | - Holly Leslie
- Unit of Molecular Pathology, School of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, United Kingdom
| | - Elizabeth Ea Mallon
- Department of Pathology, Queen Elizabeth University Hospital, Glasgow, United Kingdom
| | - Nigel B Jamieson
- Unit of Molecular Pathology, School of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, United Kingdom
| | - Donald C McMillan
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Alexandria Parade, Glasgow, United Kingdom.
| | - Joanne Edwards
- Unit of Molecular Pathology, School of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, United Kingdom
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10
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Dawood M, Vu QD, Young LS, Branson K, Jones L, Rajpoot N, Minhas FUAA. Cancer drug sensitivity prediction from routine histology images. NPJ Precis Oncol 2024; 8:5. [PMID: 38184744 PMCID: PMC10771481 DOI: 10.1038/s41698-023-00491-9] [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: 08/11/2023] [Accepted: 12/08/2023] [Indexed: 01/08/2024] Open
Abstract
Drug sensitivity prediction models can aid in personalising cancer therapy, biomarker discovery, and drug design. Such models require survival data from randomised controlled trials which can be time consuming and expensive. In this proof-of-concept study, we demonstrate for the first time that deep learning can link histological patterns in whole slide images (WSIs) of Haematoxylin & Eosin (H&E) stained breast cancer sections with drug sensitivities inferred from cell lines. We employ patient-wise drug sensitivities imputed from gene expression-based mapping of drug effects on cancer cell lines to train a deep learning model that predicts patients' sensitivity to multiple drugs from WSIs. We show that it is possible to use routine WSIs to predict the drug sensitivity profile of a cancer patient for a number of approved and experimental drugs. We also show that the proposed approach can identify cellular and histological patterns associated with drug sensitivity profiles of cancer patients.
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Affiliation(s)
- Muhammad Dawood
- Tissue Image Analytics Centre, University of Warwick, Coventry, UK.
| | - Quoc Dang Vu
- Tissue Image Analytics Centre, University of Warwick, Coventry, UK
| | - Lawrence S Young
- Warwick Medical School, University of Warwick, Coventry, UK
- Cancer Research Centre, University of Warwick, Coventry, UK
| | - Kim Branson
- Artificial Intelligence & Machine Learning, GlaxoSmithKline, San Francisco, CA, USA
| | - Louise Jones
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Nasir Rajpoot
- Tissue Image Analytics Centre, University of Warwick, Coventry, UK
- Cancer Research Centre, University of Warwick, Coventry, UK
- The Alan Turing Institute, London, UK
| | - Fayyaz Ul Amir Afsar Minhas
- Tissue Image Analytics Centre, University of Warwick, Coventry, UK
- Cancer Research Centre, University of Warwick, Coventry, UK
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11
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Yang SQ, Wang JK, Ma WJ, Liu F, Zou RQ, Dai YS, Lv TR, Li FY, Hu HJ. Prognostic Significance of Tumor Necrosis in Patients with Gallbladder Carcinoma Undergoing Curative-Intent Resection. Ann Surg Oncol 2024; 31:125-132. [PMID: 37884700 DOI: 10.1245/s10434-023-14421-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/25/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND Tumor necrosis has been indicated to correlate with dismal survival outcomes of a variety of solid tumors. However, the significance and prognostic value of tumor necrosis remain unclear in gallbladder carcinoma. The aim of this research is to explore the relationships between necrosis with long-term survival and tumor-related biological characteristics of patients with gallbladder carcinoma. PATIENTS AND METHODS Patients with gallbladder carcinoma who accepted curative-intent resection in West China Hospital of Sichuan University (China) between January 2010 and December 2021 were retrospectively analyzed. Tumor necrosis was determined by staining the patient's original tissue sections with hematoxylin and eosin. Based on the presence of tumor necrosis, the pathologic features and survival outcomes were compared. RESULTS This study enrolled 213 patients with gallbladder carcinoma who underwent curative-intent surgery, of whom 89 had tumor necrosis. Comparative analyses indicated that patients with tumor necrosis had more aggressive clinicopathological features, such as larger tumor size (p = 0.002), poorer tumor differentiation (p = 0.029), more frequent vascular invasion (p < 0.001), presence of lymph node metastasis (p = 0.014), and higher tumor status (p = 0.01), and experienced poorer survival. Univariate and multivariate analyses revealed that tumor necrosis was an independent prognostic factor for overall survival (multivariate: HR 1.651, p = 0.026) and disease-free survival (multivariate: HR 1.589, p = 0.040). CONCLUSIONS Tumor necrosis can be considered as an independent predictive factor for overall survival and disease-free survival among individuals with gallbladder carcinoma, which was a valuable pathologic parameter.
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Affiliation(s)
- Si-Qi Yang
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jun-Ke Wang
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wen-Jie Ma
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Fei Liu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Rui-Qi Zou
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yu-Shi Dai
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tian-Run Lv
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Fu-Yu Li
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Hai-Jie Hu
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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12
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Tan SY, Tan PH, Tan VKM, Leong LCH. Extensively infarcted breast cancer. BMJ Case Rep 2023; 16:e253823. [PMID: 37678940 PMCID: PMC10496683 DOI: 10.1136/bcr-2022-253823] [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] [Indexed: 09/09/2023] Open
Abstract
This is a case of a tumour that appeared largely unviable after near complete infarction. The lesion presented as a regular shaped mass with cystic appearance lacking definitive malignant radiological signs. Together with the initial non-diagnostic histological result, this could have easily led to a missed diagnosis of cancer.
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Affiliation(s)
- Si Ying Tan
- Department of Breast Surgery, National Cancer Centre Singapore, Singapore
- Department of Breast Surgery, Singapore General Hospital, Singapore
- SingHealth Duke-NUS Breast Centre, Singapore
| | | | - Veronique Kiak Mien Tan
- Department of Breast Surgery, National Cancer Centre Singapore, Singapore
- Department of Breast Surgery, Singapore General Hospital, Singapore
- SingHealth Duke-NUS Breast Centre, Singapore
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13
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Shi Y, Zhang Y, Zuo N, Wang L, Sun X, Liang L, Ju M, Di X. Necrotic related-lncRNAs: Prediction of prognosis and differentiation between cold and hot tumors in head and neck squamous cell carcinoma. Medicine (Baltimore) 2023; 102:e33994. [PMID: 37335630 PMCID: PMC10256380 DOI: 10.1097/md.0000000000033994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 05/25/2023] [Indexed: 06/21/2023] Open
Abstract
Treatment of head and neck squamous cell carcinoma (HNSCC) is a substantial clinical challenge due to the high local recurrence rate and chemotherapeutic resistance. This project seeks to identify new potential biomarkers of prognosis prediction and precision medicine to improve this condition. A synthetic data matrix for RNA transcriptome datasets and relevant clinical information on HNSCC and normal tissues was downloaded from the Genotypic Tissue Expression Project and The Cancer Genome Atlas (TCGA). The necrosis-associated long-chain noncoding RNAs (lncRNAs) were identified by Pearson correlation analysis. Then 8-necrotic-lncRNA models in the training, testing and entire sets were established through univariate Cox (uni-Cox) regression and Lasso-Cox regression. Finally, the prognostic ability of the 8-necrotic-lncRNA model was evaluated via survival analysis, nomogram, Cox regression, clinicopathological correlation analysis, and receiver operating characteristic (ROC) curve. Gene enrichment analysis, principal component analysis, immune analysis and prediction of risk group semi-maximum inhibitory concentration (IC50) were also conducted. Correlations between characteristic risk score and immune cell infiltration, immune checkpoint molecules, somatic gene mutations, and anti-cancer drug sensitivity were analyzed. Eight necrosis-associated lncRNAs (AC099850.3, AC243829.2, AL139095.4, SAP30L-AS1, C5orf66-AS1, LIN02084, LIN00996, MIR4435-2HG) were developed to improve the prognosis prediction of HNSCC patients. The risk score distribution, survival status, survival time, and relevant expression standards of these lncRNAs were compared between low- and high-risk groups in the training, testing and entire sets. Kaplan-Meier analysis showed the low-risk patients had significantly better prognosis. The ROC curves revealed the model had an acceptable predictive value in the TCGA training and testing sets. Cox regression and stratified survival analysis indicated that the 8 necrosis-associated lncRNAs were risk factors independent of various clinical parameters. We recombined the patients into 2 clusters through Consensus ClusterPlus R package according to the expressions of necrotic lncRNAs. Significant differences were found in immune cell infiltration, immune checkpoint molecules, and IC50 between clusters, suggesting these characteristics can be used to evaluate the clinical efficacy of chemotherapy and immunotherapy. This risk model may serve as a prognostic signature and provide clues for individualized immunotherapy for HNSCC patients.
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Affiliation(s)
- Yujing Shi
- Department of Oncology, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, China
| | - Yumeng Zhang
- Department of Radiation Oncology, Shanghai First Maternal and Child Health Care Hospital, Shanghai, China
| | - Nian Zuo
- Department of Oncology, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, China
| | - Lan Wang
- Department of Oncology, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, China
| | - Xinchen Sun
- Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Liang Liang
- Department of Oncology, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, China
| | - Mengyang Ju
- Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Xiaoke Di
- Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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14
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Chen J, Li Z, Han Z, Kang D, Ma J, Yi Y, Fu F, Guo W, Zheng L, Xi G, He J, Qiu L, Li L, Zhang Q, Wang C, Chen J. Prognostic value of tumor necrosis based on the evaluation of frequency in invasive breast cancer. BMC Cancer 2023; 23:530. [PMID: 37296414 DOI: 10.1186/s12885-023-10943-x] [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: 02/01/2023] [Accepted: 05/10/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Tumor necrosis (TN) was associated with poor prognosis. However, the traditional classification of TN ignored spatial intratumor heterogeneity, which may be associated with important prognosis. The purpose of this study was to propose a new method to reveal the hidden prognostic value of spatial heterogeneity of TN in invasive breast cancer (IBC). METHODS Multiphoton microscopy (MPM) was used to obtain multiphoton images from 471 patients. According to the relative spatial positions of TN, tumor cells, collagen fibers and myoepithelium, four spatial heterogeneities of TN (TN1-4) were defined. Based on the frequency of individual TN, TN-score was obtained to investigate the prognostic value of TN. RESULTS Patients with high-risk TN had worse 5-year disease-free survival (DFS) than patients with no necrosis (32.5% vs. 64.7%; P < 0.0001 in training set; 45.8% vs. 70.8%; P = 0.017 in validation set), while patients with low-risk TN had a 5-year DFS comparable to patients with no necrosis (60.0% vs. 64.7%; P = 0.497 in training set; 59.8% vs. 70.8%; P = 0.121 in validation set). Furthermore, high-risk TN "up-staged" the patients with IBC. Patients with high-risk TN and stage I tumors had a 5-year DFS comparable to patients with stage II tumors (55.6% vs. 62.0%; P = 0.565 in training set; 62.5% vs. 66.3%; P = 0.856 in validation set), as well as patients with high-risk TN and stage II tumors had a 5-year DFS comparable to patients with stage III tumors (33.3% vs. 24.6%; P = 0.271 in training set; 44.4% vs. 39.3%; P = 0.519 in validation set). CONCLUSIONS TN-score was an independent prognostic factor for 5-year DFS. Only high-risk TN was associated with poor prognosis. High-risk TN "up-staged" the patients with IBC. Incorporating TN-score into staging category could improve its performance to stratify patients.
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Affiliation(s)
- Jianhua Chen
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China
- College of Life Science, Fujian Normal University, Fuzhou, 350117, China
| | - Zhijun Li
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China
| | - Zhonghua Han
- Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Deyong Kang
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Jianli Ma
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yu Yi
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China
| | - Fangmeng Fu
- Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Wenhui Guo
- Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Liqin Zheng
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China
| | - Gangqin Xi
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China
| | - Jiajia He
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China
| | - Lida Qiu
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China
- College of Physics and Electronic Information Engineering, Minjiang University, Fuzhou, 350108, China
| | - Lianhuang Li
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China
| | - Qingyuan Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Chuan Wang
- Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
| | - Jianxin Chen
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350117, China.
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15
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Ye H, Wang Y, Yao S, Liu Z, Liang C, Zhu Y, Cui Y, Zhao K. Necrosis score as a prognostic factor in stage I-III colorectal cancer: a retrospective multicenter study. Discov Oncol 2023; 14:61. [PMID: 37155090 PMCID: PMC10167085 DOI: 10.1007/s12672-023-00655-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/12/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND Tumor necrosis results from failure to meet the requirement for rapid proliferation of tumor, related to unfavorable prognosis in colorectal cancer (CRC). However, previous studies used traditional microscopes to evaluate necrosis on slides, lacking a simultaneous phase and panoramic view for assessment. Therefore, we proposed a whole-slide images (WSIs)-based method to develop a necrosis score and validated its prognostic value in multicenter cohorts. METHODS Necrosis score was defined as the proportion of necrosis in the tumor area, semi-quantitatively classified into 3-level score groups by the cut-off of 10% and 30% on HE-stained WSIs. 768 patients from two centers were enrolled in this study, divided into a discovery (N = 445) and a validation (N = 323) cohort. The prognostic value of necrosis score was evaluated by Kaplan-Meier curves and the Cox model. RESULT Necrosis score was associated with overall survival, with hazard ratio for high vs. low in discovery and validation cohorts being 2.62 (95% confidence interval 1.59-4.32) and 2.51 (1.39-4.52), respectively. The 3-year disease free survival rates of necrosis-low, middle, and high were 83.6%, 80.2%, and 59.8% in discovery cohort, and 86.5%, 84.2%, and 66.5% in validation cohort. In necrosis middle plus high subgroup, there was a trend but no significant difference in overall survival between surgery alone and adjuvant chemotherapy group in stage II CRC (P = .075). CONCLUSION As a stable prognostic factor, high-level necrosis evaluated by the proposed method on WSIs was associated with unfavorable outcomes. Additionally, adjuvant chemotherapy provide survival benefits for patients with high necrosis in stage II CRC.
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Affiliation(s)
- Huifen Ye
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, 106 Zhongshan Er Road, Guangzhou, 510080, China
| | - Yiting Wang
- Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuan Cun 2 Cross Road, TianHe District, Guangzhou, 510655, China
| | - Su Yao
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zaiyi Liu
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, 106 Zhongshan Er Road, Guangzhou, 510080, China
| | - Changhong Liang
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, 106 Zhongshan Er Road, Guangzhou, 510080, China
| | - Yaxi Zhu
- Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuan Cun 2 Cross Road, TianHe District, Guangzhou, 510655, China.
| | - Yanfen Cui
- Department of Radiology, Shanxi Cancer Hospital, Shanxi Medical University, No.3, Xinjie West Alley, Taiyuan, 030013, China.
| | - Ke Zhao
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, 106 Zhongshan Er Road, Guangzhou, 510080, China.
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
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16
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Anderson MA, Knipp DE, Noda Y, Kamran SC, Baliyan V, Kordbacheh H, Hong TS, Kambadakone A. MRI-Based Tumor Necrosis Depiction in Pancreatic Ductal Adenocarcinoma: Can It Predict Tumor Aggressiveness? Cancers (Basel) 2023; 15:cancers15082313. [PMID: 37190241 DOI: 10.3390/cancers15082313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/13/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
The purpose of this study was to investigate whether tumor necrosis depicted on contrast-enhanced abdominal MRI can predict tumor aggressiveness in pancreatic ductal adenocarcinoma (PDAC). In this retrospective analysis, we included 71 patients with pathology-proven PDAC who underwent contrast-enhanced MRI from 2006 to 2020. Assessment for the presence/absence of imaging detected necrosis was performed on T2-weighted and contrast-enhanced T1-weighted images. Primary tumor characteristics, regional lymphadenopathy, metastases, stage, and overall survival were analyzed. Fisher's exact and Mann-Whitney U tests were used for statistical analysis. Of the 72 primary tumors, necrosis was identified on MRI in 58.3% (42/72). Necrotic PDACs were larger (44.6 vs. 34.5 mm, p = 0.0016), had higher rates of regional lymphadenopathy (69.0% vs. 26.7%, p = 0.0007), and more frequent metastases (78.6% vs. 40.0%, p = 0.0010) than those without MRI-evident necrosis. A non-statistically significant reduction in median overall survival was observed in patients with versus without MRI-evident necrosis (15.8 vs. 38.0 months, p = 0.23). PDAC tumor necrosis depicted on MRI was associated with larger tumors and higher frequency of regional lymphadenopathy and metastases.
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Affiliation(s)
- Mark A Anderson
- Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
| | - David E Knipp
- Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
| | - Yoshifumi Noda
- Department of Radiology, Gifu University, 1-1-1 Yanagido Street, Gifu City 501-1194, Japan
| | - Sophia C Kamran
- Department of Radiation Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
| | - Vinit Baliyan
- Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
| | - Hamed Kordbacheh
- Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
| | - Avinash Kambadakone
- Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
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17
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Cope BM, Traweek RS, Lazcano R, Keung EZ, Lazar AJ, Roland CL, Nassif EF. Targeting the Molecular and Immunologic Features of Leiomyosarcoma. Cancers (Basel) 2023; 15:2099. [PMID: 37046760 PMCID: PMC10093078 DOI: 10.3390/cancers15072099] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/25/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies.
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Affiliation(s)
- Brandon M. Cope
- Department of Surgery, Keesler Medical Center, Biloxi, MS 39534, USA
| | - Raymond S. Traweek
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rossana Lazcano
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Emily Z. Keung
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Alexander J. Lazar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Christina L. Roland
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elise F. Nassif
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Yamamoto A, Huang Y, Krajina BA, McBirney M, Doak AE, Qu S, Wang CL, Haffner MC, Cheung KJ. Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7. Proc Natl Acad Sci U S A 2023; 120:e2214888120. [PMID: 36853945 PMCID: PMC10013750 DOI: 10.1073/pnas.2214888120] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 01/06/2023] [Indexed: 03/01/2023] Open
Abstract
Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. How the necrotic core promotes metastasis remains unclear. Here, we report that emergence of necrosis inside the tumor is correlated temporally with increased tumor dissemination in a rat breast cancer model and in human breast cancer patients. By performing spatially focused transcriptional profiling, we identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the perinecrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, perinecrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promotes vascular permeability and supports vascular remodeling in the perinecrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core.
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Affiliation(s)
- Ami Yamamoto
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA98195
| | - Yin Huang
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA98109
| | - Brad A. Krajina
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA98109
| | - Margaux McBirney
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA98109
| | - Andrea E. Doak
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA98195
| | - Sixuan Qu
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA98109
| | - Carolyn L. Wang
- Department of Radiology, University of Washington School of Medicine, Seattle, WA98195
| | - Michael C. Haffner
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA98109
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA98109
| | - Kevin J. Cheung
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA98109
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA98109
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19
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Ouban A, Raddaoui E, Bakir M. The Clinical Significance of CD163+ Tumor-Associated Macrophages (TAMs) in Laryngeal Squamous Cell Carcinoma. Cureus 2023; 15:e36339. [PMID: 37082492 PMCID: PMC10111153 DOI: 10.7759/cureus.36339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2023] [Indexed: 04/22/2023] Open
Abstract
Background and objective The tumor's microenvironment is currently considered an important indicator of the tumor's prognosis, treatment failure, and recurrence. CD163+ tumor-associated macrophages (TAMs) are a marker of poor prognosis in many types of human cancers. In the present study, the expression of CD163+ TAMs was analyzed in laryngeal squamous cell carcinomas (LSCCs) using immunohistochemistry, and this expression was correlated with the clinical and pathological characteristics of LSCC patients. Materials and methods One commercial human larynx microarray with 80 cases of LSCCs, was used for this study. For comparison with normal laryngeal mucosa, a second microarray carrying normal tissues from all human anatomical sites, including normal laryngeal tissues, was used. Immunohistochemical staining was performed, and the primary antibody was a mouse monoclonal against human CD136. The absence of the primary antibody was used as a negative control. The percentage of positive cells was categorized into five scores: 0 (0%); 1, (1%-10%); 2, (11%-50%); 3, (51%-80%); and 4, (>80%). A case was scored as positive for CD163 with a score >= 1. The χ2 test was used to assess the CD163 expression in LSCC cases (N=80). A statistically significant difference was defined as P 0.05. Results The human larynx microarray containing 80 cases of LSCCs was used for this study. The age of the cancer patients in this array was in the range of 39 to 72, with a median of 53. LSCC grades were distributed as follows: 25 patients were designated as grade I, 43 were designated as grade II, and 6 were designated as grade III. Two tumors' (2/80) cores were missing from the microarray. Six tumors on the microarray did not have a grade designation reported by the manufacturer of the array. The expression of CD163 in normal, benign, unmatched laryngeal tissue was absent. In cancer cases, on the other hand, a significant number of LSCCs had TAMs that were positive for CD163 (87% positive tumors, with an IHC score ranging from 1 to 4, χ2=30.634; p<0.001). The rest of the LSCC cases (10 in total) had negative CD163 expression (score of 0). Conclusion A significant majority of LSCCs were found to have CD163+ TAMs expression using tissue microarrays (TMAs). This expression is positively correlated with the tumor's grade, clinical manifestation, and TNM staging. Morphologic evidence shows that the majority of LSCCs express the highest range of immunohistochemistry (IHC) scores for CD163 protein in the membranes and cytoplasm of their TAMs. This study provides evidence of the clinical significance of CD163+TAMs in LSCCs and proposes further studies to pinpoint the exact role of these cells in LSCC patients.
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Affiliation(s)
- Abderrahman Ouban
- Department of Pathology, College of Medicine, Alfaisal University, Riyadh, SAU
| | - Emadeddin Raddaoui
- Department of Pathology, College of Medicine, Alfaisal University, Riyadh, SAU
| | - Mohamad Bakir
- College of Medicine, Alfaisal University, Riyadh, SAU
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20
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Borovcanin MM, Vesić K, Arsenijević D, Milojević-Rakić M, Mijailović NR, Jovanovic IP. Targeting Underlying Inflammation in Carcinoma Is Essential for the Resolution of Depressiveness. Cells 2023; 12:710. [PMID: 36899845 PMCID: PMC10000718 DOI: 10.3390/cells12050710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/03/2023] [Accepted: 02/22/2023] [Indexed: 02/26/2023] Open
Abstract
In modern clinical practice and research on behavioral changes in patients with oncological problems, there are several one-sided approaches to these problems. Strategies for early detection of behavioral changes are considered, but they must take into account the specifics of the localization and phase in the course and treatment of somatic oncological disease. Behavioral changes, in particular, may correlate with systemic proinflammatory changes. In the up-to-date literature, there are a lot of useful pointers on the relationship between carcinoma and inflammation and between depression and inflammation. This review is intended to provide an overview of these similar underlying inflammatory disturbances in both oncological disease and depression. The specificities of acute and chronic inflammation are considered as a basis for causal current and future therapies. Modern therapeutic oncology protocols may also cause transient behavioral changes, so assessment of the quality, quantity, and duration of behavioral symptoms is necessary to prescribe adequate therapy. Conversely, antidepressant properties could be used to ameliorate inflammation. We will attempt to provide some impetus and present some unconventional potential treatment targets related to inflammation. It is certain that only an integrative oncology approach is justifiable in modern patient treatment.
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Affiliation(s)
- Milica M. Borovcanin
- Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Katarina Vesić
- Department of Neurology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Dragana Arsenijević
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | | | - Nataša R. Mijailović
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Ivan P. Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
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21
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Sadowska A, Sawicka D, Godlewska K, Guzińska-Ustymowicz K, Zapora E, Sokołowska E, Car H. Beneficial Proapoptotic Effect of Heterobasidion Annosum Extract in Colorectal Cancer Xenograft Mouse Model. Molecules 2023; 28:molecules28031352. [PMID: 36771018 PMCID: PMC9919637 DOI: 10.3390/molecules28031352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023] Open
Abstract
Fungal extracts possess potential anticancer activity against many malignant neoplastic diseases. In this research, we focused on the evaluation of Heterobasidion annosum (HA) extract in colorectal cancer in an in vivo model. The mice with implanted DLD-1 human cancer cells were given HA extract, the referential drug-5-fluorouracil (5FU), or were treated with its combination. Thereafter, tumor volume was measured and apoptotic proteins such as caspase-8, caspase-3, p53, Bcl-2, and survivin were analyzed in mice serum with an ELISA assay. The Ki-67 protein was assessed in tumor cells by immunohistochemical examination. The biggest volumes of tumors were confirmed in the DLD-1 group, while the lowest were observed in the population treated with 5FU and/or HA extract. The assessment of apoptosis showed increased concentrations of caspase 8 and p53 protein after the combined administration of 5FU and HA extract. The levels of survivin and Bcl-2 were decreased in all tested groups compared to the DLD-1 group. Moreover, we observed a positive reaction for Ki-67 protein in all tested groups. Our findings confirm the apoptotic effect of extract given alone or with 5FU. The obtained results are innovative and provide a basis for further research concerning the antitumor activity of the HA extract, especially in the range of its interaction with an anticancer chemotherapeutic agent.
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Affiliation(s)
- Anna Sadowska
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
- Correspondence: ; Tel.: +48-85-748-5554
| | - Diana Sawicka
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
| | - Katarzyna Godlewska
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
- Department of Haematology, Medical University of Bialystok, M. Skłodowskiej-Curie 24A, 15-276 Bialystok, Poland
| | | | - Ewa Zapora
- Department of Silviculture and Forest Use, Institute of Forest Sciences, Bialystok University of Technology, Wiejska 45E, 15-351 Bialystok, Poland
| | - Emilia Sokołowska
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
| | - Halina Car
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
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22
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Carbonic Anhydrase IX (CAIX) Expressing Hypoxic Micro-environment Hampers CD8+ Immune Cell Infiltrate in Breast Carcinoma. Appl Immunohistochem Mol Morphol 2023; 31:26-32. [PMID: 36476599 DOI: 10.1097/pai.0000000000001082] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/28/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hypoxia and necrosis are common features of invasive cancer. The dynamic upregulation of carbonic anhydrase IX (CAIX), triggered by hypoxia-inducible factor 1 (HIF-1) is 1 of the mechanisms supporting cellular adaptation to hypoxia in solid tumors, including breast carcinoma. CAIX activity results in extracellular acidosis and in a profound reorganization of the tumor micro-environment, influencing biological behavior and prognosis. The main focus of our study was to evaluate the mass and distribution of the immune infiltrate, more specifically of CD8+ effector T-cells, in relation with tumoral CAIX expression. MATERIALS AND METHODS Formalin-fixed and paraffin-embedded breast carcinoma sections were analyzed following double immunohistochemical staining for CAIX and CD8. Scanned digital slides were evaluated for both labelings, and CD8-related signal was determined within and outside CAIX-positive tumor areas using the HistoQuant (3DHistech) image analysis software. Statistical analysis was performed using GraphPad Prism software. RESULTS Of the 34 breast carcinomas, 18 tested partially positive for CAIX. The remaining 16 cases were used as the CAIX-negative control group. Necrotic foci were generally associated with CAIX overexpression, and tumors exhibiting signs of necrosis had a significantly higher rate of relative CAIX expression compared with samples without necrosis (11.47±5.505 vs. without necrosis 3.765±3.5 P-value=0.0216). On the other hand, no statistically significant difference was found when comparing relative CD8+ lymphocyte counts in cases with necrosis as opposed to those where necrosis was absent (134.7±55.7 vs. 97.70±57.25; P value=0.1579). No difference in gross CD8+ T-lymphocyte infiltrate could be measured between CAIX positive and negative samples (98.48±37.32 vs. 95.99±50 P value=0.5928). However, in CAIX-expressing tumors a statistical correlation between the CD8+ T-lymphocyte infiltrate and the extent of CAIX-positive areas was observed. Within the same tumor, CD8+ T-lymphocyte counts showed a significant difference betweeen CAIX+ and CAIX- areas (13.06±9.4 vs. 135.6±62.2 P value <0.0001). CONCLUSION Our measurements demonstrate for the first time that tumor areas with CAIX expression potentially hamper CD8+ T-lymphocyte infiltration in breast carcinoma. The hypoxia-driven adaptive micro-environment likely interferes with the specific response to biological and immune therapies requiring intact effector T-cell response.
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23
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Culpan M, Iplikci A, Kir G, Cecikoglu GE, Atis G, Yildirim A. The prognostic impact of tumor necrosis in non-muscle invasive bladder cancer. Rev Assoc Med Bras (1992) 2022; 68:1587-1592. [DOI: 10.1590/1806-9282.20220812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 08/01/2022] [Indexed: 11/29/2022] Open
Affiliation(s)
| | | | - Gozde Kir
- Istanbul Medeniyet University, Turkey
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24
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Kazama T, Takahara T, Kwee TC, Nakamura N, Kumaki N, Niikura N, Niwa T, Hashimoto J. Quantitative Values from Synthetic MRI Correlate with Breast Cancer Subtypes. Life (Basel) 2022; 12:life12091307. [PMID: 36143344 PMCID: PMC9501941 DOI: 10.3390/life12091307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/21/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
The purpose of this study is to correlate quantitative T1, T2, and proton density (PD) values with breast cancer subtypes. Twenty-eight breast cancer patients underwent MRI of the breast including synthetic MRI. T1, T2, and PD values were correlated with Ki-67 and were compared between ER-positive and ER-negative cancers, and between Luminal A and Luminal B cancers. The effectiveness of T1, T2, and PD in differentiating the ER-negative from the ER-positive group and Luminal A from Luminal B cancers was evaluated using receiver operating characteristic analysis. Mean T2 relaxation of ER-negative cancers was significantly higher than that of ER-positive cancers (p < 0.05). The T1, T2, and PD values exhibited a strong positive correlation with Ki-67 (Pearson’s r = 0.75, 0.69, and 0.60 respectively; p < 0.001). Among ER-positive cancers, T1, T2, and PD values of Luminal A cancers were significantly lower than those of Luminal B cancers (p < 0.05). The area under the curve (AUC) of T2 for discriminating ER-negative from ER-positive cancers was 0.87 (95% CI: 0.69−0.97). The AUC of T1 for discriminating Luminal A from Luminal B cancers was 0.83 (95% CI: 0.61−0.95). In conclusion, quantitative values derived from synthetic MRI show potential for subtyping of invasive breast cancers.
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Affiliation(s)
- Toshiki Kazama
- Department of Diagnostic Radiology, Tokai University School of Medicine, Isehara 259-1193, Japan
- Correspondence: ; Tel.: +81-463-93-1121
| | - Taro Takahara
- Department of Biomedical Engineering, Tokai University School of Engineering, Hiratsuka 259-1207, Japan
| | - Thomas C. Kwee
- Department of Radiology, Nuclear Medicine, and Molecular Imaging, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
| | - Noriko Nakamura
- Department of Diagnostic Radiology, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Nobue Kumaki
- Department of Pathology, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Naoki Niikura
- Department of Breast Oncology, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Tetsu Niwa
- Department of Diagnostic Radiology, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Jun Hashimoto
- Department of Diagnostic Radiology, Tokai University School of Medicine, Isehara 259-1193, Japan
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25
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Pesta M, Shetti D, Kulda V, Knizkova T, Houfkova K, Bagheri MS, Svaton M, Polivka J. Applications of Liquid Biopsies in Non-Small-Cell Lung Cancer. Diagnostics (Basel) 2022; 12:1799. [PMID: 35892510 PMCID: PMC9330570 DOI: 10.3390/diagnostics12081799] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/19/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022] Open
Abstract
The concept of liquid biopsy as an analysis tool for non-solid tissue carried out for the purpose of providing information about solid tumors was introduced approximately 20 years ago. Additional to the detection of circulating tumor cells (CTCs), the liquid biopsy approach quickly included the analysis of circulating tumor DNA (ctDNA) and other tumor-derived markers such as circulating cell-free RNA or extracellular vesicles. Liquid biopsy is a non-invasive technique for detecting multiple cancer-associated biomarkers that is easy to obtain and can reflect the characteristics of the entire tumor mass. Currently, ctDNA is the key component of the liquid biopsy approach from the point of view of the prognosis assessment, prediction, and monitoring of the treatment of non-small-cell lung cancer (NSCLC) patients. ctDNA in NSCLC patients carries variants or rearrangements that drive carcinogenesis, such as those in EGFR, KRAS, ALK, or ROS1. Due to advances in pharmacology, these variants are the subject of targeted therapy. Therefore, the detection of these variants has gained attention in clinical medicine. Recently, methods based on qPCR (ddPCR, BEAMing) and next-generation sequencing (NGS) are the most effective approaches for ctDNA analysis. This review addresses various aspects of the use of liquid biopsy with an emphasis on ctDNA as a biomarker in NSCLC patients.
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Affiliation(s)
- Martin Pesta
- Department of Biology, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, 323 00 Plzen, Czech Republic; (D.S.); (T.K.); (K.H.)
| | - Dattatrya Shetti
- Department of Biology, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, 323 00 Plzen, Czech Republic; (D.S.); (T.K.); (K.H.)
| | - Vlastimil Kulda
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine in Pilsen, Charles University, Karlovarska 48, 301 66 Plzen, Czech Republic;
| | - Tereza Knizkova
- Department of Biology, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, 323 00 Plzen, Czech Republic; (D.S.); (T.K.); (K.H.)
| | - Katerina Houfkova
- Department of Biology, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/76, 323 00 Plzen, Czech Republic; (D.S.); (T.K.); (K.H.)
| | - Mahyar Sharif Bagheri
- Department of Histology, Faculty of Medicine in Pilsen, Charles University, Karlovarska 48, 301 66 Plzen, Czech Republic; (M.S.B.); (J.P.)
| | - Martin Svaton
- Department of Pneumology and Phthisiology, Faculty of Medicine in Pilsen, Charles University, University Hospital in Pilsen, E. Benese 13, 301 00 Plzen, Czech Republic;
| | - Jiri Polivka
- Department of Histology, Faculty of Medicine in Pilsen, Charles University, Karlovarska 48, 301 66 Plzen, Czech Republic; (M.S.B.); (J.P.)
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26
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Stem Cells in the Tumor Immune Microenvironment -Part of the Cure or Part of the Disease? Ontogeny and Dichotomy of Stem and Immune Cells has Led to better Understanding. Stem Cell Rev Rep 2022; 18:2549-2565. [PMID: 35841518 DOI: 10.1007/s12015-022-10428-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2022] [Indexed: 10/17/2022]
Abstract
Stem cells are at the basis of tissue homeostasis, hematopoiesis and various regenerative processes. Epigenetic changes in their somatically imprinted genes, prolonged exposure to mutagens/carcinogens or alteration of their niche can lead to the development of an enabling environment for tumor growth and progression. The involvement of stem cells in both health and disease becomes even more compelling with ontogeny as embryonic and extraembryonic stem cells which persist into adulthood in well established and specific niche may have distinct implications in tumorigenesis. Immune surveillance plays an important role in this interplay since the response of immune cells toward the oncogenic process can range from reactivity to placidity and even complicity, being orchestrated by intercellular molecular dialogues with the other key players of the tumor microenvironment. With the current understanding that every developing and adult tissue contains inherent stem and progenitor cells, in this manuscript we review the most relevant interactions carried out between the stem cells, tumor cells and immune cells in a bottom-up incursion through the tumor microenvironment beginning from the perivascular niche and going through the tumoral parenchyma and the related stroma. With the exploitation of various factors that influence the behavior of immune effectors toward stem cells and other resting cells in their niche, new therapeutic strategies to tackle the polarization of immune effectors toward a more immunogenic phenotype may arise.
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27
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Sakalauskaitė S, Riškevičienė V, Šengaut J, Juodžiukynienė N. Association of mast cell density, microvascular density and endothelial area with clinicopathological parameters and prognosis in canine mammary gland carcinomas. Acta Vet Scand 2022; 64:14. [PMID: 35761297 PMCID: PMC9235230 DOI: 10.1186/s13028-022-00633-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 06/15/2022] [Indexed: 01/18/2023] Open
Abstract
Background Mast cell density has been shown to have both enhancing and inhibiting effects on tumour progression and the ability to predict breast cancer behaviour in humans. However, prognostic results have been contradictory. Some previous studies suggested involvement of mast cells in the progression of canine mammary tumours. This study investigated total, intratumoural and peritumoural mast cell densities by Giemsa staining, and their association with clinicopathological parameters and the disease outcome of canine mammary tumours. In addition, since mast cells promote angiogenesis, the microvascular density and endothelial area were evaluated by CD31 immunostaining. Results Intratumoural mast cell density was associated with tumour size, lymph node involvement and tumour-infiltrating lymphocyte count, while peritumoural mast cell density was associated with grade. The endothelial area was associated with grade, mitotic index, tubular formation and proliferation index. Tumours with a high grade, high total intratumoural mast cell density and a larger endothelial area were associated with shorter disease-free survival. Intratumoural mast cell density and grade were found to be independent prognostic factors. Conclusions These results suggest that intratumoural mast cell density and the endothelial area can be used to evaluate the aggressiveness of canine mammary carcinomas, while intratumoural mast cell density could be of use as an independent predictor of a prognosis of disease-free survival. Peritumoural mast cell density does not seem to influence tumour behaviour.
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28
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Li G, Wang X, Liu Y, Li H, Mu H, Zhang Y, Li Q. Multi-omics analysis reveals the panoramic picture of necroptosis-related regulators in pan-cancer. Aging (Albany NY) 2022; 14:5034-5058. [PMID: 35748782 PMCID: PMC9271292 DOI: 10.18632/aging.204124] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/19/2022] [Indexed: 11/25/2022]
Abstract
Background: Unlike apoptosis, necroptosis is a tightly regulated form of programmed cell death (PCD) that occurs in a caspase-independent manner and is mainly triggered by receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 and the RIPK3 substrate mixed-lineage kinase domain-like protein (MLKL). A growing body of evidence has documented that necroptosis, as a novel therapeutic strategy to overcome apoptosis resistance, has potential pro- or anti-tumoral effects in tumorigenesis, metastasis, and immunosurveillance. However, comprehensive multi-omics studies on regulators of necroptosis from a pan-cancer perspective are lacking. Methods: In the present study, a pan-cancer multi-omics analysis of necroptosis-related regulators was performed by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from TCGA, 481 small-molecule drug response data from CTRP, and normal tissue data from GTEx. Pan-cancer pathway-level analyses of necroptosis were conducted by gene set variation analysis (GSVA), including differential expression, clinical relevance, immune cell infiltration, and regulation of cancer-related pathways. Results: Genomic alterations and abnormal epigenetic modifications were associated with dysregulated gene expression levels of necroptosis-related regulators. Changes in the gene expression levels of necroptosis-related regulators significantly influenced cancer progression, intratumoral heterogeneity, alterations in the immunological condition, and regulation of cancer marker-related pathways. These changes, in turn, caused differences in potential drug sensitivity and the prognosis of patients. Conclusion: Necroptosis-related regulators are expected to become novel biomarkers of prognosis and provide a fresh perspective on cancer diagnosis and treatment.
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Affiliation(s)
- Guanghao Li
- 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.,Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xiaoxuan Wang
- 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.,Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Sino-US Center for Lymphoma and Leukemia Research, Tianjin 300060, China
| | - Yongheng Liu
- 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
| | - Huikai Li
- 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.,Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Han Mu
- 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.,Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yanting Zhang
- 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
| | - Qiang Li
- 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.,Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
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Safaei S, Sajed R, Saeednejad Zanjani L, Rahimi M, Fattahi F, Ensieh Kazemi-Sefat G, Razmi M, Dorafshan S, Eini L, Madjd Z, Ghods R. Overexpression of cytoplasmic dynamin 2 is associated with worse outcomes in patients with clear cell renal cell carcinoma. Cancer Biomark 2022; 35:27-45. [PMID: 35662107 DOI: 10.3233/cbm-210514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: Dynamin 2 (DNM2) involved in tumor progression in various malignancies. OBJECTIVE: For the first time, we evaluated DNM2 expression pattern, its association with clinicopathological characteristics and survival outcomes in RCC subtypes. METHODS: We evaluated the DNM2 expression pattern in RCC tissues as well as adjacent normal tissue using immunohistochemistry on tissue microarray (TMA) slides. RESULTS: Our findings revealed increased DNM2 expression in RCC samples rather than in adjacent normal tissues. The results indicated that there was a statistically significant difference between cytoplasmic expression of DNM2 among subtypes of RCC in terms of intensity of staining, percentage of positive tumor cells, and H-score (P= 0.024, 0.049, and 0.009, respectively). The analysis revealed that increased cytoplasmic expression of DNM2 in ccRCC is associated with worse OS (log rank: P= 0.045), DSS (P= 0.049), and PFS (P= 0.041). Furthermore, cytoplasmic expression of DNM2 was found as an independent prognostic factor affecting DSS and PFS in multivariate analysis. CONCLUSIONS: Our results indicated that DNM2 cytoplasmic expression is associated with tumor aggressiveness and poor outcomes. DNM2 could serve as a promising prognostic biomarker and therapeutic target in patients with ccRCC.
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Affiliation(s)
- Sadegh Safaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Roya Sajed
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | | | - Mandana Rahimi
- Hasheminejad Kidney Center, Pathology department, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Fahimeh Fattahi
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Golnaz Ensieh Kazemi-Sefat
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahdieh Razmi
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Shima Dorafshan
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Leila Eini
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Division of Histology, Department of Basic Science, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Zahra Madjd
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Roya Ghods
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
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30
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Controlling Cancer Cell Death Types to Optimize Anti-Tumor Immunity. Biomedicines 2022; 10:biomedicines10050974. [PMID: 35625711 PMCID: PMC9138898 DOI: 10.3390/biomedicines10050974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/16/2022] [Accepted: 04/17/2022] [Indexed: 11/17/2022] Open
Abstract
Over several decades, cell biology research has characterized distinct forms of regulated cell death, identified master regulators such as nuclear factor kappa B (NFκB), and contributed to translating these findings in order to improve anti-cancer therapies. In the era of immunotherapy, however, the field warrants a new appraisal-the targeted induction of immunogenic cell death may offer personalized strategies to optimize anti-tumor immunity. Once again, the spotlight is on NFκB, which is not only a master regulator of cancer cell death, survival, and inflammation, but also of adaptive anti-tumor immune responses that are triggered by dying tumor cells.
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31
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Kazama T, Takahara T, Hashimoto J. Breast Cancer Subtypes and Quantitative Magnetic Resonance Imaging: A Systemic Review. Life (Basel) 2022; 12:life12040490. [PMID: 35454981 PMCID: PMC9028183 DOI: 10.3390/life12040490] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/20/2022] [Accepted: 03/08/2022] [Indexed: 12/12/2022] Open
Abstract
Magnetic resonance imaging (MRI) is the most sensitive imaging modality for breast cancer detection. This systematic review investigated the role of quantitative MRI features in classifying molecular subtypes of breast cancer. We performed a literature search of articles published on the application of quantitative MRI features in invasive breast cancer molecular subtype classification in PubMed from 1 January 2002 to 30 September 2021. Of the 1275 studies identified, 106 studies with a total of 12,989 patients fulfilled the inclusion criteria. Bias was assessed based using the Quality Assessment of Diagnostic Studies. All studies were case-controlled and research-based. Most studies assessed quantitative MRI features using dynamic contrast-enhanced (DCE) kinetic features and apparent diffusion coefficient (ADC) values. We present a summary of the quantitative MRI features and their correlations with breast cancer subtypes. In DCE studies, conflicting results have been reported; therefore, we performed a meta-analysis. Significant differences in the time intensity curve patterns were observed between receptor statuses. In 10 studies, including a total of 1276 lesions, the pooled difference in proportions of type Ⅲ curves (wash-out) between oestrogen receptor-positive and -negative cancers was not significant (95% confidence interval (CI): [−0.10, 0.03]). In nine studies, including a total of 1070 lesions, the pooled difference in proportions of type 3 curves between human epidermal growth factor receptor 2-positive and -negative cancers was significant (95% CI: [0.01, 0.14]). In six studies including a total of 622 lesions, the pooled difference in proportions of type 3 curves between the high and low Ki-67 groups was significant (95% CI: [0.17, 0.44]). However, the type 3 curve itself is a nonspecific finding in breast cancer. Many studies have examined the relationship between mean ADC and breast cancer subtypes; however, the ADC values overlapped significantly between subtypes. The heterogeneity of ADC using kurtosis or difference, diffusion tensor imaging parameters, and relaxation time was reported recently with promising results; however, current evidence is limited, and further studies are required to explore these potential applications.
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Affiliation(s)
- Toshiki Kazama
- Department of Diagnostic Radiology, Tokai University School of Medicine, Isehara 259-1193, Japan;
- Correspondence: ; Tel.: +81-463-93-1121
| | - Taro Takahara
- Department of Biomedical Engineering, Tokai University School of Engineering, Hiratsuka 259-1207, Japan;
| | - Jun Hashimoto
- Department of Diagnostic Radiology, Tokai University School of Medicine, Isehara 259-1193, Japan;
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32
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Tsilimigras DI, Ejaz A, Cloyd J, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Soubrane O, Koerkamp BG, Endo I, Pawlik TM. Tumor Necrosis Impacts Prognosis of Patients Undergoing Resection for T1 Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2022; 29:10.1245/s10434-022-11462-y. [PMID: 35298762 DOI: 10.1245/s10434-022-11462-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/05/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND The prognostic impact of tumor necrosis among patients undergoing resection for intrahepatic cholangiocarcinoma (ICC) remains ill-defined. METHODS Patients who underwent curative-intent resection for ICC between 2000 and 2017 were identified using a multi-institutional database. The association of pathologic tumor necrosis with overall survival (OS) and recurrence-free survival (RFS) was examined. RESULTS Among 757 patients who underwent resection for ICC, tumor necrosis was present in 384 (50.7%) patients (no necrosis: n = 373, 49.3%; <50% necrosis: n = 291, 38.4%; ≥50% necrosis: n = 93, 12.3%). Tumor necrosis was associated with worse OS (5-year OS: no necrosis 39.3% vs. <50% necrosis 34.7% and ≥50% necrosis 24.0%; p = 0.03) and RFS (5-year RFS: no necrosis 25.7% vs. <50% necrosis 13.9% and ≥50% necrosis 18.8%; p < 0.001). After stratifying by T stage, tumor necrosis was able to further stratify prognosis among patients with T1a ICC (5-year RFS: T1a and no necrosis 46.7% vs. T1a and necrosis 36.1%; p = 0.02), and T1b ICC (5-year RFS: T1b and no necrosis 31.1% vs. T1b and necrosis 11.2%; p = 0.006), but was not associated with outcomes among patients with more advanced T2-T3 disease. Patients with T1a ICC and tumor necrosis had similar 5-year RFS as individuals with T1b ICC and no tumor necrosis (36.1% vs. 31.1%; p = 0.66). CONCLUSION Tumor necrosis was associated with worse prognosis among patients with T1 ICC. Tumor necrosis for T1 ICC should be considered as an important factor to further stratify outcomes of patients with early T-stage ICC.
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Affiliation(s)
- Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Aslam Ejaz
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Jordan Cloyd
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | | | | | - Matthew Weiss
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Todd W Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | | | | | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | | | - Carlo Pulitano
- Department of Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Olivier Soubrane
- Department of Hepatobiliopancreatic Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, Clichy, France
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
- Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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33
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Mohammad Mirzaei N, Changizi N, Asadpoure A, Su S, Sofia D, Tatarova Z, Zervantonakis IK, Chang YH, Shahriyari L. Investigating key cell types and molecules dynamics in PyMT mice model of breast cancer through a mathematical model. PLoS Comput Biol 2022; 18:e1009953. [PMID: 35294447 PMCID: PMC8959189 DOI: 10.1371/journal.pcbi.1009953] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 03/28/2022] [Accepted: 02/22/2022] [Indexed: 02/07/2023] Open
Abstract
The most common kind of cancer among women is breast cancer. Understanding the tumor microenvironment and the interactions between individual cells and cytokines assists us in arriving at more effective treatments. Here, we develop a data-driven mathematical model to investigate the dynamics of key cell types and cytokines involved in breast cancer development. We use time-course gene expression profiles of a mouse model to estimate the relative abundance of cells and cytokines. We then employ a least-squares optimization method to evaluate the model's parameters based on the mice data. The resulting dynamics of the cells and cytokines obtained from the optimal set of parameters exhibit a decent agreement between the data and predictions. We perform a sensitivity analysis to identify the crucial parameters of the model and then perform a local bifurcation on them. The results reveal a strong connection between adipocytes, IL6, and the cancer population, suggesting them as potential targets for therapies.
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Affiliation(s)
- Navid Mohammad Mirzaei
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America
| | - Navid Changizi
- Department of Civil and Environmental Engineering, University of Massachusetts, Dartmouth, Massachusetts, United States of America
| | - Alireza Asadpoure
- Department of Civil and Environmental Engineering, University of Massachusetts, Dartmouth, Massachusetts, United States of America
| | - Sumeyye Su
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America
| | - Dilruba Sofia
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America
| | - Zuzana Tatarova
- Department of Biomedical Engineering and OHSU Center for Spatial Systems Biomedicine (OCSSB), Oregon Health and Science University, Portland, Oregon, United States of America
| | - Ioannis K. Zervantonakis
- Department of Bioengineering, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Young Hwan Chang
- Department of Biomedical Engineering and OHSU Center for Spatial Systems Biomedicine (OCSSB), Oregon Health and Science University, Portland, Oregon, United States of America
| | - Leili Shahriyari
- Department of Mathematics and Statistics, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America
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Iscaro A, Jones C, Forbes N, Mughal A, Howard FN, Janabi HA, Demiral S, Perrie Y, Essand M, Weglarz A, Cruz LJ, Lewis CE, Muthana M. Targeting circulating monocytes with CCL2-loaded liposomes armed with an oncolytic adenovirus. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 40:102506. [PMID: 34875352 DOI: 10.1016/j.nano.2021.102506] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 09/17/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022]
Abstract
Oncolytic viruses (OVs) selectively replicate in and destroy cancer cells resulting in anti-tumor immunity. However, clinical use remains a challenge because of virus clearance upon intravenous delivery. OV packaging using a nanomedicine approach could overcome this. Here we encapsulate an oncolytic adenovirus (Ad[I/PPT-E1A]) into CCL2-coated liposomes in order to exploit recruitment of CCR2-expressing circulating monocytes into tumors. We demonstrate successful encapsulation of Ad[I/PPT-E1A] into CCL2-coated liposomes that were preferentially taken up by CCR2-expressing monocytes. No complex-related toxicities were observed following incubation with prostate tumor cells and the encapsulation did not affect virus oncolytic activity in vitro. Furthermore, intravenous administration of our nanomedicine resulted in a significant reduction in tumor size and pulmonary metastasis in prostate cancer-bearing mice whereby a 1000-fold less virus was needed compared to Ad[I/PPT-E1A] alone. Taken together our data provide an opportunity to target OVs via circulation to inaccessible tumors using liposome-assisted drug delivery.
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Affiliation(s)
- Alessandra Iscaro
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Christian Jones
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Neil Forbes
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland
| | - Amina Mughal
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | | | - Haider Al Janabi
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Secil Demiral
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Yvonne Perrie
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland
| | - Magnus Essand
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Aleksandra Weglarz
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Luis J Cruz
- Department of Radiology, Division Translational Nanobiomaterials and Imaging, Leiden University Medical Center, Leiden, The Netherlands
| | - Claire E Lewis
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Munitta Muthana
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.
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Chowdhury P, Ghosh U, Samanta K, Jaggi M, Chauhan SC, Yallapu MM. Bioactive nanotherapeutic trends to combat triple negative breast cancer. Bioact Mater 2021; 6:3269-3287. [PMID: 33778204 PMCID: PMC7970221 DOI: 10.1016/j.bioactmat.2021.02.037] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 02/27/2021] [Accepted: 02/28/2021] [Indexed: 02/09/2023] Open
Abstract
The management of aggressive breast cancer, particularly, triple negative breast cancer (TNBC) remains a formidable challenge, despite treatment advancement. Although newer therapies such as atezolizumab, olaparib, and sacituzumab can tackle the breast cancer prognosis and/or progression, but achieved limited survival benefit(s). The current research efforts are aimed to develop and implement strategies for improved bioavailability, targetability, reduce systemic toxicity, and enhance therapeutic outcome of FDA-approved treatment regimen. This review presents various nanoparticle technology mediated delivery of chemotherapeutic agent(s) for breast cancer treatment. This article also documents novel strategies to employ cellular and cell membrane cloaked (biomimetic) nanoparticles for effective clinical translation. These technologies offer a safe and active targeting nanomedicine for effective management of breast cancer, especially TNBC.
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Affiliation(s)
- Pallabita Chowdhury
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Upasana Ghosh
- Department of Biomedical Engineering, School of Engineering, Rutgers University, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Kamalika Samanta
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Meena Jaggi
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C. Chauhan
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Murali M. Yallapu
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
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36
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Li B, Xia Y, Lv J, Wang W, Xuan Z, Chen C, Jiang T, Fang L, Wang L, Li Z, He Z, Li Q, Xie L, Qiu S, Zhang L, Zhang D, Xu H, Xu Z. miR-151a-3p-rich small extracellular vesicles derived from gastric cancer accelerate liver metastasis via initiating a hepatic stemness-enhancing niche. Oncogene 2021; 40:6180-6194. [PMID: 34535770 DOI: 10.1038/s41388-021-02011-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 08/18/2021] [Accepted: 09/06/2021] [Indexed: 12/24/2022]
Abstract
Liver metastasis (LM) severely affects gastric cancer (GC) patients' prognosis. Small extracellular vesicles (sEVs) play key roles in intercellular communication. Specific sEV-miRNAs from several types of cancer were found to induce a premetastatic niche in target organs before tumor cell arrive. However, whether the primary GC affects hepatic microenvironment or the role of sEV-miRNAs in GC-LM is yet unclear. We report that GC-derived sEVs are primarily absorbed by Kupffer cells (KCs). sEV-miR-151a-3p is highly expressed in GC-LM patients' plasma and presents poor prognosis. Treating mice with sEVs-enriched in miR-151a-3p promotes GC-LM, whereas has no influence on the proliferation of GC cells in situ. Mechanistically, sEV-miR-151a-3p inhibits SP3 in KCs. Simultaneously, sEV-miR-151a-3p targets YTHDF3 to decrease the transcriptional inhibitory activity of SP3 by reducing SUMO1 translation in a N6-methyladenosine-dependent manner. These factors contribute to TGF-β1 transactivation in KCs, subsequently activating the SMAD2/3 pathway and enhancing the stem cell-like properties of incoming GC cells. Furthermore, sEV-miR-151a-3p induces miR-151a-3p transcription in KCs to form a positive feedback loop. In summary, our results reveal a previously unidentified regulatory axis initiated by sEV-miR-151a-3p that establishes a hepatic stemness-permissive niche to support GC-LM. sEV-miR-151a-3p could be a promising diagnostic biomarker and preventive treatment candidate for GC-LM.
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Affiliation(s)
- Bowen Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Yiwen Xia
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Jialun Lv
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Zhe Xuan
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Cen Chen
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, the First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu Province, China
| | - Tianlu Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Lang Fang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Linjun Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Zhongyuan He
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Qingya Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Li Xie
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Shengkui Qiu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.,Department of General Surgery, the Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Lu Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Diancai Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China. .,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
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Badodekar N, Sharma A, Patil V, Telang G, Sharma R, Patil S, Vyas N, Somasundaram I. Angiogenesis induction in breast cancer: A paracrine paradigm. Cell Biochem Funct 2021; 39:860-873. [PMID: 34505714 DOI: 10.1002/cbf.3663] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/22/2021] [Accepted: 06/29/2021] [Indexed: 12/14/2022]
Abstract
Breast cancer is the most prevalent type of cancer among women globally. Angiogenesis contributes significantly to breast cancer progression and dissemination. Neovascularization is concurrent with the progression and growth of breast cancer. Breast cancer cells control angiogenesis by secreting pro-angiogenic factors like fibroblast growth factor, vascular endothelial growth factor, interleukin, transforming growth factor-β, platelet-derived growth factor and several others. These pro-angiogenic factors trigger neovascularization, and thereby lead to breast cancer development and metastasis. The hypoxia-inducible factor (HIF)-regulated angiogenesis cascade is a crucial underlying factor in breast cancer growth and metastasis. To that end, several efforts have been made to identify druggable targets within the HIF-angiogenesis components. However, escape pathways are a major hindrance for targeted therapies against angiogenesis. Thus, understanding the key factors that trigger breast cancer angiogenesis is critical in elucidating ways to inhibit breast cancer. The current review provides an overview of the key growth factors that trigger breast cancer angiogenesis.
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Affiliation(s)
| | - Akshita Sharma
- Department of Stem Cell and Regenerative Medicine, D. Y. Patil Education Society, Kolhapur, India
| | | | | | - Rakesh Sharma
- Department of Obstetrics and Gynaecology, D. Y. Patil Medical College, Kolhapur, India
| | - Shankargouda Patil
- Department of Maxilofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | | | - Indumathi Somasundaram
- Department of Stem Cell and Regenerative Medicine, D. Y. Patil Education Society, Kolhapur, India
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Ye Q, Zhang Q, Tian Y, Zhou T, Ge H, Wu J, Lu N, Bai X, Liang T, Li J. Method of Tumor Pathological Micronecrosis Quantification Via Deep Learning From Label Fuzzy Proportions. IEEE J Biomed Health Inform 2021; 25:3288-3299. [PMID: 33822729 DOI: 10.1109/jbhi.2021.3071276] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The presence of necrosis is associated with tumor progression and patient outcomes in many cancers, but existing analyses rarely adopt quantitative methods because the manual quantification of histopathological features is too expensive. We aim to accurately identify necrotic regions on hematoxylin and eosin (HE)-stained slides and to calculate the ratio of necrosis with minimal annotations on the images. An adaptive method named Learning from Label Fuzzy Proportions (LLFP) was introduced to histopathological image analysis. Two datasets of liver cancer HE slides were collected to verify the feasibility of the method by training on the internal set using cross validation and performing validation on the external set, along with ensemble learning to improve performance. The models from cross validation performed relatively stably in identifying necrosis, with a Concordance Index of the Slide Necrosis Score (CISNS) of 0.9165±0.0089 in the internal test set. The integration model improved the CISNS to 0.9341 and achieved a CISNS of 0.8278 on the external set. There were significant differences in survival (p = 0.0060) between the three groups divided according to the calculated necrosis ratio. The proposed method can build an integration model good at distinguishing necrosis and capable of clinical assistance as an automatic tool to stratify patients with different risks or as a cluster tool for the quantification of histopathological features. We presented a method effective for identifying histopathological features and suggested that the extent of necrosis, especially micronecrosis, in liver cancer is related to patient outcomes.
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Ribatti D, Annese T, Tamma R. Controversial role of mast cells in breast cancer tumor progression and angiogenesis. Clin Breast Cancer 2021; 21:486-491. [PMID: 34580034 DOI: 10.1016/j.clbc.2021.08.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/16/2021] [Accepted: 08/26/2021] [Indexed: 10/20/2022]
Abstract
Breast cancer is a neoplastic disease and is a cause of cancer-related mortality for women. Among cellular and molecular regulators of the microenvironment, mast cells and vascular endothelial growth factor (VEGF), are correlated with tumor progression and prognosis in breast cancer. Clinical and experimental studies on breast cancer have revealed a marked correlation between increased angiogenesis, metastasization, and poorer prognosis. After a brief introduction on angiogenesis evidence and angiogenic factors role in different breast cancer subtypes, in this article, we have discerned the relationship between mast cell infiltration, angiogenesis, and tumor progression in human breast cancer with particular reference to the dual role of mast cells, in terms of both pro- or anti-tumoral activity and poor or good biomarker.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.
| | - Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
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Song SE, Cho KR, Cho Y, Kim K, Jung SP, Seo BK, Woo OH. Machine learning with multiparametric breast MRI for prediction of Ki-67 and histologic grade in early-stage luminal breast cancer. Eur Radiol 2021; 32:853-863. [PMID: 34383145 DOI: 10.1007/s00330-021-08127-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/20/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To investigate whether machine learning-based prediction models using 3-T multiparametric MRI (mpMRI) can predict Ki-67 and histologic grade in stage I-II luminal cancer. METHODS Between 2013 and 2019, consecutive women with luminal cancers who underwent preoperative MRI with diffusion-weighted imaging (DWI) and surgery were included. For prediction models, morphology, kinetic features using computer-aided diagnosis (CAD), and apparent diffusion coefficient (ADC) at DWI were evaluated by two radiologists. Logistic regression analysis was used to identify mpMRI features for predicting Ki-67 and grade. Diagnostic performance was assessed using eight machine learning algorithms incorporating mpMRI features and compared using the DeLong method. RESULTS Of 300 women, 203 (67.7%) had low Ki-67 and 97 (32.3%) had high Ki-67; 242 (80.7%) had low grade and 58 (19.3%) had high grade. In multivariate analysis, independent predictors for higher Ki-67 were washout component > 13.5% (odds ratio [OR] = 4.16; p < 0.001) and intratumoral high SI on T2-weighted image (OR = 1.89; p = 0.022). Those for higher grade were washout component > 15.5% (OR = 7.22; p < 0.001), rim enhancement (OR = 2.59; p = 0.022), and ADC value < 0.945 × 10-3 mm2/s (OR = 2.47; p = 0.015). Among eight models using these predictors, six models showed the equivalent performance for Ki-67 (area under the receiver operating characteristic curve [AUC]: 0.70) and Naive Bayes classifier showed the highest performance for grade (AUC: 0.79). CONCLUSIONS A prediction model incorporating mpMRI features shows good diagnostic performance for predicting Ki-67 and histologic grade in patients with luminal breast cancers. KEY POINTS • Among multiparametric MRI features, kinetic feature of washout component >13.5% and intratumoral high signal intensity on T2-weighted image were associated with higher Ki-67. • Washout component >15.5%, rim enhancement, and mean apparent diffusion coefficient value < 0.945 × 10-3 mm2/s were associated with higher histologic grade. • Machine learning-based prediction models incorporating multiparametric MRI features showed good diagnostic performance for Ki-67 and histologic grade in luminal breast cancers.
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Affiliation(s)
- Sung Eun Song
- Department of Radiology, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Kyu Ran Cho
- Department of Radiology, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
| | - Yongwon Cho
- Department of Radiology, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Kwangsoo Kim
- Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seung Pil Jung
- Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Bo Kyoung Seo
- Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Gyeonggi-do, Republic of Korea
| | - Ok Hee Woo
- Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
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Tumor Necrosis with Adjunction of Preoperative Monocyte-to-Lymphocyte Ratio as a New Risk Stratification Marker Can Independently Predict Poor Outcomes in Upper Tract Urothelial Carcinoma. J Clin Med 2021; 10:jcm10132983. [PMID: 34279467 PMCID: PMC8267944 DOI: 10.3390/jcm10132983] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/28/2021] [Accepted: 07/01/2021] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES This study aimed at investigating the prognostic impact of tumor necrosis and preoperative monocyte-to-lymphocyte ratio (MLR) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). METHODS A total of 521 patients with UTUC treated with RNU from January 2008 to June 2019 at our institution were enrolled. Histological tumor necrosis was defined as the presence of microscopic coagulative necrosis. The optimal value of MLR was determined as 0.4 by receiver operating characteristic (ROC) analysis based on cancer-specific mortality. The Kaplan-Meier method with log-rank test and Cox proportional hazards regression models were performed to evaluate the impact of tumor necrosis and MLR on overall (OS), cancer-specific (CSS), and recurrence-free survival (RFS). Furthermore, ROC analysis was used to estimate the predictive ability of potential prognostic factors for oncological outcomes. RESULTS Tumor necrosis was present in 106 patients (20%), which was significantly associated with tumor location, high pathological tumor stage, lymph node metastasis, high tumor grade, lymphovascular invasion, tumor size, and increased monocyte counts. On multivariate analysis, the combination of tumor necrosis and preoperative MLR was an independent prognosticator of OS, CSS, and RFS (all p < 0.05). Moreover, ROC analyses revealed the predictive accuracy of a combination of tumor necrosis and preoperative MLR for OS, CSS, and RFS with the area under the ROC curve of 0.745, 0.810, and 0.782, respectively (all p < 0.001). CONCLUSIONS The combination of tumor necrosis and preoperative MLR can be used as an independent prognosticator in patients with UTUC after RNU. The identification of this combination could help physicians to recognize high-risk patients with unfavorable outcomes and devise more appropriate postoperative treatment plans.
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Yee PP, Li W. Tumor necrosis: A synergistic consequence of metabolic stress and inflammation. Bioessays 2021; 43:e2100029. [PMID: 33998010 PMCID: PMC8217290 DOI: 10.1002/bies.202100029] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/01/2021] [Accepted: 04/07/2021] [Indexed: 12/14/2022]
Abstract
Tumor necrosis is a common histological feature and poor prognostic predictor in various cancers. Despite its significant clinical implications, the mechanism underlying tumor necrosis remains largely unclear due to lack of appropriate pre-clinical modeling. We propose that tumor necrosis is a synergistic consequence of metabolic stress and inflammation, which lead to oxidative stress-induced cell death, such as ferroptosis. As a natural consequence of tumor expansion, tumor cells are inevitably stripped of vascular supply, resulting in deprivation of oxygen and nutrients. The resulting metabolic stress has commonly been considered the cause of tumor necrosis. Recent studies found that immune cells, such as neutrophils, when recruited to tumors, can directly trigger ferroptosis in tumor cells, suggesting that immune cells can be involved in amplifying tumor necrosis. This article will discuss potential mechanisms underlying tumor necrosis development and its impact on tumor progression as well as the immune response to tumors.
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Affiliation(s)
- Patricia P. Yee
- Division of Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA
- Medical Scientist Training Program, Penn State College of Medicine, Hershey, PA, USA
| | - Wei Li
- Division of Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA
- Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA
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Avila-Ponce de León U, Vázquez-Jiménez A, Matadamas-Guzman M, Pelayo R, Resendis-Antonio O. Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis. Front Immunol 2021; 12:642842. [PMID: 34177892 PMCID: PMC8222808 DOI: 10.3389/fimmu.2021.642842] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
The balance between pro- and anti-inflammatory immune system responses is crucial to face and counteract complex diseases such as cancer. Macrophages are an essential population that contributes to this balance in collusion with the local tumor microenvironment. Cancer cells evade the attack of macrophages by liberating cytokines and enhancing the transition to the M2 phenotype with pro-tumoral functions. Despite this pernicious effect on immune systems, the M1 phenotype still exists in the environment and can eliminate tumor cells by liberating cytokines that recruit and activate the cytotoxic actions of TH1 effector cells. Here, we used a Boolean modeling approach to understand how the tumor microenvironment shapes macrophage behavior to enhance pro-tumoral functions. Our network reconstruction integrates experimental data and public information that let us study the polarization from monocytes to M1, M2a, M2b, M2c, and M2d subphenotypes. To analyze the dynamics of our model, we modeled macrophage polarization in different conditions and perturbations. Notably, our study identified new hybrid cell populations, undescribed before. Based on the in vivo macrophage behavior, we explained the hybrid macrophages’ role in the tumor microenvironment. The in silico model allowed us to postulate transcriptional factors that maintain the balance between macrophages with anti- and pro-tumoral functions. In our pursuit to maintain the balance of macrophage phenotypes to eliminate malignant tumor cells, we emulated a theoretical genetically modified macrophage by modifying the activation of NFκB and a loss of function in HIF1-α and discussed their phenotype implications. Overall, our theoretical approach is as a guide to design new experiments for unraveling the principles of the dual host-protective or -harmful antagonistic roles of transitional macrophages in tumor immunoediting and cancer cell fate decisions.
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Affiliation(s)
- Ugo Avila-Ponce de León
- Programa de Doctorado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.,Human Systems Biology Laboratory, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, Mexico
| | - Aarón Vázquez-Jiménez
- Human Systems Biology Laboratory, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, Mexico
| | - Meztli Matadamas-Guzman
- Human Systems Biology Laboratory, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, Mexico.,Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Rosana Pelayo
- Oncoimmunology Laboratory, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Puebla, Mexico
| | - Osbaldo Resendis-Antonio
- Human Systems Biology Laboratory, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, Mexico.,Coordinación de la Investigación Científica - Red de Apoyo a la Investigación, UNAM, Ciudad de México, Mexico
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Mehta AK, Kadel S, Townsend MG, Oliwa M, Guerriero JL. Macrophage Biology and Mechanisms of Immune Suppression in Breast Cancer. Front Immunol 2021; 12:643771. [PMID: 33968034 PMCID: PMC8102870 DOI: 10.3389/fimmu.2021.643771] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 02/17/2021] [Indexed: 12/14/2022] Open
Abstract
Macrophages are crucial innate immune cells that maintain tissue homeostasis and defend against pathogens; however, their infiltration into tumors has been associated with adverse outcomes. Tumor-associated macrophages (TAMs) represent a significant component of the inflammatory infiltrate in breast tumors, and extensive infiltration of TAMs has been linked to poor prognosis in breast cancer. Here, we detail how TAMs impede a productive tumor immunity cycle by limiting antigen presentation and reducing activation of cytotoxic T lymphocytes (CTLs) while simultaneously supporting tumor cell survival, angiogenesis, and metastasis. There is an urgent need to overcome TAM-mediated immune suppression for durable anti-tumor immunity in breast cancer. To date, failure to fully characterize TAM biology and classify multiple subsets has hindered advancement in therapeutic targeting. In this regard, the complexity of TAMs has recently taken center stage owing to their subset diversity and tightly regulated molecular and metabolic phenotypes. In this review, we reveal major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with breast cancer, before and after treatment. Future work to characterize TAM subsets, location, and crosstalk with neighboring cells will be critical to counteract TAM pro-tumor functions and to identify novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance.
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Affiliation(s)
- Anita K Mehta
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Sapana Kadel
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Madeline G Townsend
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Madisson Oliwa
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Jennifer L Guerriero
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
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Medler TR, Blair TC, Crittenden MR, Gough MJ. Defining Immunogenic and Radioimmunogenic Tumors. Front Oncol 2021; 11:667075. [PMID: 33816320 PMCID: PMC8017281 DOI: 10.3389/fonc.2021.667075] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/02/2021] [Indexed: 12/21/2022] Open
Abstract
In the cancer literature tumors are inconsistently labeled as ‘immunogenic’, and experimental results are occasionally dismissed since they are only tested in known ‘responsive’ tumor models. The definition of immunogenicity has moved from its classical definition based on the rejection of secondary tumors to a more nebulous definition based on immune infiltrates and response to immunotherapy interventions. This review discusses the basis behind tumor immunogenicity and the variation between tumor models, then moves to discuss how these principles apply to the response to radiation therapy. In this way we can identify radioimmunogenic tumor models that are particularly responsive to immunotherapy only when combined with radiation, and identify the interventions that can convert unresponsive tumors so that they can also respond to these treatments.
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Affiliation(s)
- Terry R Medler
- Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, United States
| | - Tiffany C Blair
- Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, United States.,Molecular Microbiology and Immunology, OHSU, Portland, OR, United States
| | - Marka R Crittenden
- Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, United States.,Molecular Microbiology and Immunology, OHSU, Portland, OR, United States.,The Oregon Clinic, Portland, OR, United States
| | - Michael J Gough
- Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, United States.,Molecular Microbiology and Immunology, OHSU, Portland, OR, United States
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Yurtsever I, Sari L, Gultekin MA, Toprak H, Turk HM, Aliyev A, Peker AA, Yabaci A, Alkan A. Diffusion Tensor Imaging of Brain Metastases in Patients with Breast Cancer According to Molecular Subtypes. Curr Med Imaging 2021; 17:120-128. [PMID: 32564758 DOI: 10.2174/1573405616666200621195655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 05/05/2020] [Accepted: 05/09/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND PURPOSE Recent studies have shown that diffusion tensor imaging (DTI) parameters are used to follow the patients with breast cancer and correlate well as a prognostic parameter of breast cancer. However, as far as we know, there is no data to compare the DTI features of breast cancer brain metastases according to molecular subtypes in the literature. Our aim is to evaluate whether there are any differences in DTI parameters of brain metastases in patients with breast cancer according to molecular subtypes. METHODS Twenty-seven patients with breast cancer and 82 metastatic brain lesions were included. We classified subjects into three subgroups according to their hormone expression; Group 0, triple- negative (n; 6, 19 lesions), group 1, HER2-positive (n;16, 54 lesions) and group 2, hormone-- positive group (n; 5, 9 lesions). The apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) values in DTI were measured and compared between three groups. RESULTS ADC, AD and RD values of group 2 were significantly lower compared to group 0. No significant differences were found in FA, ADC, AD and RD values between the group 0 and 1 and the group 1 and 2. CONCLUSION Metastasis of aggressive triple-negative breast cancer showed higher ADC values compared to the less aggressive hormone-positive group. Higher ADC values in brain metastases of breast cancer may indicate a poor prognosis, so DTI findings could play a role in planning appropriate treatment.
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Affiliation(s)
- Ismail Yurtsever
- Department of Radiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Lutfullah Sari
- Department of Radiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Mehmet Ali Gultekin
- Department of Radiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Huseyin Toprak
- Department of Radiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Haci Mehmet Turk
- Department of Medical Oncology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Altay Aliyev
- Department of Medical Oncology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Abdusselim Adil Peker
- Department of Radiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Aysegul Yabaci
- Department of Biostatistics, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Alpay Alkan
- Department of Radiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
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O'Connor T, Heikenwalder M. CCL2 in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1302:1-14. [PMID: 34286437 DOI: 10.1007/978-3-030-62658-7_1] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The C-C motif chemokine ligand 2 (CCL2) is a crucial mediator of immune cell recruitment during microbial infections and tissue damage. CCL2 is also frequently overexpressed in cancer cells and other cells in the tumor microenvironment, and a large body of evidence indicates that high CCL2 levels are associated with more aggressive malignancies, a higher probability of metastasis, and poorer outcomes in a wide range of cancers. CCL2 plays a role in recruiting tumor-associated macrophages (TAMs), which adopt a pro-tumorigenic phenotype and support cancer cell survival, facilitate tumor cell invasion, and promote angiogenesis. CCL2 also has direct, TAM-independent effects on tumor cells and the tumor microenvironment, including recruitment of other myeloid subsets and non-myeloid cells, maintaining an immunosuppressive environment, stimulating tumor cell growth and motility, and promoting angiogenesis. CCL2 also plays important roles in the metastatic cascade, such as creating a pre-metastatic niche in distant organs and promoting tumor cell extravasation across endothelia. Due to its many roles in tumorigenesis and metastatic processes, the CCL2-CCR2 signaling axis is currently being pursued as a potential therapeutic target for cancer.
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Affiliation(s)
- Tracy O'Connor
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Institute of Virology, Technical University of Munich, Munich, Germany.
- Helmholtz Center Munich, Neuherberg, Germany.
- Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany.
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Institute of Virology, Technical University of Munich, Munich, Germany.
- Helmholtz Center Munich, Neuherberg, Germany.
- Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany.
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Enhanced antitumor efficacy of bile acid-lipid complex-anchored docetaxel nanoemulsion via oral metronomic scheduling. J Control Release 2020; 328:368-394. [DOI: 10.1016/j.jconrel.2020.08.067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 08/27/2020] [Accepted: 08/31/2020] [Indexed: 01/12/2023]
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Wei T, Zhang XF, Bagante F, Ratti F, Marques HP, Silva S, Soubrane O, Lam V, Poultsides GA, Popescu I, Grigorie R, Alexandrescu S, Martel G, Workneh A, Guglielmi A, Hugh T, Aldrighetti L, Endo I, Pawlik TM. Tumor Necrosis Impacts Prognosis of Patients Undergoing Curative-Intent Hepatocellular Carcinoma. Ann Surg Oncol 2020; 28:797-805. [PMID: 33249525 DOI: 10.1245/s10434-020-09390-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 10/05/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND The impact of tumor necrosis relative to prognosis among patients undergoing curative-intent resection for hepatocellular carcinoma (HCC) remains ill-defined. METHODS Patients who underwent curative-intent resection for HCC without any prior treatment between 2000 and 2017 were identified from an international multi-institutional database. Tumor necrosis was graded as absent, moderate (< 50% area), or extensive (≥ 50% area) on histological examination. The relationship between tumor necrosis, clinicopathologic characteristics, and long-term survival were analyzed. RESULTS Among 919 patients who underwent curative-intent resection for HCC, the median tumor size was 5.0 cm (IQR, 3.0-8.5). Tumor necrosis was present in 367 (39.9%) patients (no necrosis: n = 552, 60.1% vs < 50% necrosis: n = 256, 27.9% vs ≥ 50% necrosis: n = 111, 12.1%). Extent of tumor necrosis was also associated with more advanced tumor characteristics. HCC necrosis was associated with OS (median OS: no necrosis, 84.0 months vs < 50% necrosis, 73.6 months vs ≥ 50% necrosis: 59.3 months; p < 0.001) and RFS (median RFS: no necrosis, 49.6 months vs < 50% necrosis, 38.3 months vs ≥ 50% necrosis: 26.5 months; p < 0.05). Patients with T1 tumors with extensive ≥ 50% necrosis had an OS comparable to patients with T2 tumors (median OS, 62.9 vs 61.8 months; p = 0.645). In addition, patients with T2 disease with necrosis had long-term outcomes comparable to patients with T3 disease (median OS, 61.8 vs 62.4 months; p = 0.713). CONCLUSION Tumor necrosis was associated with worse OS and RFS, as well as T-category upstaging of patients. A modified AJCC T classification that incorporates tumor necrosis should be considered in prognostic stratification of HCC patients.
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Affiliation(s)
- Tao Wei
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Surgery, Division of Surgical Oncology, Professor of Surgery, Oncology, Health Services Management and Policy, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Fabio Bagante
- Department of Surgery, Division of Surgical Oncology, Professor of Surgery, Oncology, Health Services Management and Policy, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.,Department of Surgery, University of Verona, Verona, Italy
| | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Silvia Silva
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Olivier Soubrane
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | | | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Razvan Grigorie
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Aklile Workneh
- Department of Surgery, University of Ottawa, Ottawa, Canada
| | | | - Tom Hugh
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, Australia
| | | | - Itaru Endo
- Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, Professor of Surgery, Oncology, Health Services Management and Policy, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
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Spielmann J, Mattheis L, Jung JS, Rauße H, Glaß M, Bähr I, Quandt D, Oswald J, Kielstein H. Effects of obesity on NK cells in a mouse model of postmenopausal breast cancer. Sci Rep 2020; 10:20606. [PMID: 33244094 PMCID: PMC7692502 DOI: 10.1038/s41598-020-76906-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023] Open
Abstract
Obesity is a widely spread disease and a crucial risk factor for malign disorders, including breast cancer of women in the postmenopause. Studies demonstrated that in case of obesity crucial natural killer (NK) cell functions like combating tumor cells are affected. This study aims to analyze NK cells and NK cell receptor expression of obese mice in a model for postmenopausal breast cancer. Therefore, female BALB/c mice were fed either a high fat or a standard diet. Thereafter, ovaries were ectomized and a syngeneic and orthotopical injection of 4T1-luc2 mouse mammary tumor cells into the mammary adipose tissue pad was performed. Obese mice showed increased body weights and visceral fat mass as well as increased levels of leptin and IL-6 in plasma. Moreover, compared to the lean littermates, tumor growth was increased and the NKp46-expression on circulating NK cells was decreased. Furthermore, the activating NK cell receptor NKG2D ligand (MULT1) expression was enhanced in adipose tissue of obese tumor bearing mice. The present study gives novel insights into gene expression of NK cell receptors in obesity and aims to promote possible links of the obesity-impaired NK cell physiology and the elevated breast cancer risk in obese women.
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Affiliation(s)
- Julia Spielmann
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany.
| | - Laura Mattheis
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
- Deptartment of Internal Medicine I, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Juliane-Susanne Jung
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
| | - Henrik Rauße
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
- Clinic for Psychosomatics and Psychotherapy, Landschaftsverband Westfalen-Lippe Clinic, Lengerich, Germany
| | - Markus Glaß
- Institute of Molecular Medicine, Charles Tanford Protein Center, Medical Faculty of Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ina Bähr
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
| | - Dagmar Quandt
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - Jana Oswald
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty of Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle (Saale), Germany
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