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Brambilla E, Brambilla DJF, Tregnago AC, Riva F, Pasqualotto FF, Soldera J. Exploring macrophage polarization as a prognostic indicator for colorectal cancer: Unveiling the impact of metalloproteinase mutations. World J Clin Cases 2025; 13:105011. [DOI: 10.12998/wjcc.v13.i23.105011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/24/2025] [Accepted: 05/07/2025] [Indexed: 06/04/2025] Open
Abstract
BACKGROUND Macrophages play a crucial role in the tumor microenvironment, displaying remarkable plasticity that allows them to either suppress or promote tumor progression. Their polarization into M1 or M2 phenotypes could have significant prognostic implications, and manipulating this polarization may offer a novel approach to controlling colorectal neoplasms.
AIM To evaluate the infiltration rates of M1 and M2 macrophages in colorectal neoplasia, specifically comparing cases with and without metalloproteinase mutations. Additionally, it sought to explore potential prognostic factors associated with the disease.
METHODS The study involved two cohorts of patients diagnosed with colorectal neoplasia: 33 patients with metalloproteinase mutations and 33 without. Macrophage quantity and polarization were assessed using markers indicative of M1 (iNOS) and M2 (CD163, CD206) macrophages. Prognostic factors and survival outcomes related to colorectal cancer (CRC) were also analyzed.
RESULTS Among the 61 patients, 28 (45.9%) exhibited metalloproteinase mutations, while 33 (54.1%) did not. Tumor staging revealed that 16.9% were in stage I, 34.2% in stage II, 42.4% in stage III, and 8.5% in stage IV. The study recorded 12 patient deaths (19.7%), with 21.2% from the control group and 17.9% from the mutation group. M2 macrophages, identified by CD163 and CD206 markers, had mean counts of 23 and 17, respectively, with standard deviations of 21 and 17. In contrast, M1 macrophages, identified by iNOS, had a mean count of five per site, with a standard deviation of 11.
CONCLUSION The study found no statistically significant differences in macrophage density between groups, irrespective of metalloproteinase mutation status, age, gender, tumor region, staging, TILS, tumor recurrence, or clinical outcomes. No association was observed between macrophage polarization and CRC prognosis or survival. However, patients with metalloproteinase mutations demonstrated a better survival rate, suggesting a potential protective role of this mutation in colorectal neoplasia.
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Affiliation(s)
- Eduardo Brambilla
- Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, Rio Grande do Sul, Brazil
| | | | - Aline Caldart Tregnago
- Department of Pathology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, Rio Grande do Sul, Brazil
| | - Floriano Riva
- Department of Pathology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, Rio Grande do Sul, Brazil
| | - Fabio Firmbach Pasqualotto
- Department of Urology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, Rio Grande do Sul, Brazil
| | - Jonathan Soldera
- Department of Gastroenterology and Acute Medicine, University of South Wales, Cardiff CF37 1DL, United Kingdom
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Luo Y, Jin X, Huang L, Zeng D, Zhang N, Tang S, Luo S, Syed SE, Dai R, Li Q, Liang S. RUNX1/SLAMF3 Axis Drives Immunosuppression to Contribute to Colorectal Cancer Liver Metastasis by Blocking Phagocytosis and Depleting C1QC + Tumor-Associated Macrophages. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e06641. [PMID: 40448626 DOI: 10.1002/advs.202506641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2025] [Revised: 05/15/2025] [Indexed: 06/02/2025]
Abstract
Colorectal cancer liver metastasis (CRLM) is a leading cause of death in colorectal cancer (CRC) patients and is characterized by an immunosuppressive tumor microenvironment (TME). This study employs mouse in vivo selection to isolate highly metastatic CRLM derivatives for profiling their transcriptomic, proteomic, and metabolomic alterations associated with CRLM. Notably, the expression of SLAMF3 is significantly upregulated in CRLM derivatives and its knockdown effectively suppresses CRLM in mice. RUNX1 transcriptionally upregulates SLAMF3 expression and combined targeting of the RUNX1/SLAMF3 axis synergistically suppresses liver metastasis in mice. In parallel, SLAMF3 suppresses macrophage-mediated phagocytosis of CRC cells through the SHP-1/2/mTORC1 pathway. Conversely, SLAMF3 knockdown promotes M1 polarization in liver metastases and activates the CCL signaling pathway between macrophages and CD8+ T cells. It also reduces the exhausted CD8+ T cells in liver metastases and the expression of inhibitory receptors PD-1 and TIM-3, thus alleviating the immunosuppressive TME. Clinically, activation of the RUNX1/SLAMF3 axis is closely associated with CRLM progression and correlates with a reduced proportion of clinically beneficial C1QC⁺ tumor-associated macrophages (TAMs). Collectively, these findings identify the RUNX1/SLAMF3 axis as a key driver of immunosuppressive TME remodeling and CRLM progression, highlighting its potential as a promising therapeutic target for CRLM.
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Affiliation(s)
- Yinheng Luo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Xiaoli Jin
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Lan Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Dejia Zeng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Nan Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, P. R. China
| | - Shiyu Tang
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Sichuan, P. R. China
| | - Shu Luo
- Department of Medical Oncology, Suining First People's Hospital, Suining, Sichuan, P. R. China
| | - Samina Ejaz Syed
- Department of Biochemistry and Biotechnology, Baghdad Campus, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Ruiwu Dai
- Department of General Surgery, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, P. R. China
| | - Shufang Liang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China
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Chen YS, Yang WB, Li YH, Xu JY, Wei YX, Huang SM, Jiang XF, Li JH. Identification of Novel Protein Biomarkers for Intrahepatic Cholangiocarcinoma by Integrating Human Plasma Proteome with Genome. J Gastrointest Cancer 2025; 56:100. [PMID: 40240670 DOI: 10.1007/s12029-025-01226-8] [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] [Accepted: 04/06/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND The proteome serves as a key source for the discovery of therapeutic targets. This study utilized proteome-wide Mendelian randomization (MR) to identify protein biomarkers potentially associated with intrahepatic cholangiocarcinoma (ICC). METHODS We derived protein quantitative trait loci (pQTLs) from the deCODE plasma proteome GWAS and genetic ICC associations from a European meta-analysis. Proteome-wide MR identified candidate proteins linked to ICC risk. Expression of MR-identified biomarkers in the plasma of ICC patients was detected by ELISA. ScRNA-seq analysis detected the specific cell type with enrichment expression. Prognostic and diagnostic evaluations in ICC of these proteins were performed using samples derived from TCGA and GTEx databases. RESULTS MR analysis genetically predicted 5 proteins were associated with ICC risk (STX12, A2M, CD163, CXADR and FOXJ2). The results of the MR analysis for the five identified targets were consistent with the measured plasma concentrations of these targets in ICC patients and healthy volunteers. The differential RNA-seq analysis between tumor and adjacent normal tissues showed that STX12 was expressed at higher levels in tumor tissues, while A2M, CXADR, CD163, and FOXJ2 were expressed at higher levels in adjacent normal tissues. ScRNA-seq analysis revealed that these protein-coding genes are mainly expressed in TAMs, TEC, HPC-like cells and malignant cells in ICC tumor tissue. Prognosis analysis showed higher CXADR expression correlated with longer OS in CHOL (P = 0.041). The AUC for A2M, CD163, CXADR, FOXJ2, and STX12 were 0.975, 0.705, 0.917, 0.997, and 0.956, respectively. CONCLUSION This study represents the first Proteome-MR analysis of ICC, revealing its complex genetic architecture and identifying five novel blood proteins with potential causal links to the disease. Through proteome-MR analysis, scRNA-seq analysis, and diagnostic-prognostic evaluation using TCGA and GTEx databases, these proteins were assessed as promising therapeutic and diagnostic targets. The findings provide a theoretical foundation for future ICC treatment strategies.
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Affiliation(s)
- Yu-Sen Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China
| | - Wei-Bang Yang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China
| | - Yi-Hu Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China
| | - Jin-Yang Xu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China
| | - Yu-Xuan Wei
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China
| | - Si-Min Huang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China
| | - Xiao-Feng Jiang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China.
| | - Jian-Hui Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China.
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Mathiesen H, Juul-Madsen K, Tramm T, Vorup-Jensen T, Møller HJ, Etzerodt A, Andersen MN. Prognostic value of CD163 + macrophages in solid tumor malignancies: A scoping review. Immunol Lett 2025; 272:106970. [PMID: 39778658 DOI: 10.1016/j.imlet.2025.106970] [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: 11/12/2024] [Revised: 12/19/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025]
Abstract
Tumor-associated macrophages (TAMs) play crucial roles in development and progression of malignant diseases. Notably, CD163+ TAMs likely perform specific pro-tumorigenic functions, suggesting that this subset may serve as both prognostic biomarkers and targets for future anti-cancer therapy. We conducted a scoping review to map the current knowledge on the prognostic role of CD163+ TAMs in the five most lethal cancers worldwide: Lung, colorectal, gastric, liver, and breast cancer. For all cancer types, most studies showed that high tumoral presence of CD163+ cells was associated with poor patient outcome, and this association was more frequently observed when CD163+ cells were measured at the tumor periphery compared to more central parts of the tumor. These results support that CD163+ TAMs represent a biomarker of poor patient outcome across a variety of solid tumors, and highlight the relevance of further investigations of CD163+ TAMs as targets of future immunotherapies.
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Affiliation(s)
- Henriette Mathiesen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | - Kristian Juul-Madsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
| | - Trine Tramm
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Holger Jon Møller
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Anders Etzerodt
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Morten Nørgaard Andersen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
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López-Collazo E, Hurtado-Navarro L. Cell fusion as a driver of metastasis: re-evaluating an old hypothesis in the age of cancer heterogeneity. Front Immunol 2025; 16:1524781. [PMID: 39967663 PMCID: PMC11832717 DOI: 10.3389/fimmu.2025.1524781] [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: 11/08/2024] [Accepted: 01/17/2025] [Indexed: 02/20/2025] Open
Abstract
Numerous studies have investigated the molecular mechanisms and signalling pathways underlying cancer metastasis, as there is still no effective treatment for this terminal stage of the disease. However, the exact processes that enable primary cancer cells to acquire a metastatic phenotype remain unclear. Increasing attention has been focused on the fusion of cancer cells with myeloid cells, a phenomenon that may result in hybrid cells, so-called Tumour Hybrid Cells (THCs), with enhanced migratory, angiogenic, immune evasion, colonisation, and metastatic properties. This process has been shown to potentially drive tumour progression, drug resistance, and cancer recurrence. In this review, we explore the potential mechanisms that govern cancer cell fusion, the molecular mediators involved, the metastatic characteristics acquired by fusion-derived hybrids, and their clinical significance in human cancer. Additionally, we discuss emerging pharmacological strategies aimed at targeting fusogenic molecules as a means to prevent metastatic dissemination.
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Affiliation(s)
- Eduardo López-Collazo
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
- CIBER of Respiratory Diseases (CIBERES), Madrid, Spain
- UNIE University, Madrid, Spain
| | - Laura Hurtado-Navarro
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
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Shin E, Kim HM, Koo JS. CD68 positive and/or CD163 positive tumor-associated macrophages and PD-L1 expression in breast phyllodes tumor. Breast Cancer Res Treat 2025; 209:261-273. [PMID: 39242456 DOI: 10.1007/s10549-024-07487-4] [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: 06/12/2024] [Accepted: 08/28/2024] [Indexed: 09/09/2024]
Abstract
INTRODUCTION PD-L1 expression and tumor-associated macrophage (TAM) status in phyllodes tumors (PT) have only been examined in a limited number of studies. This study aimed to investigate the expression of PD-L1 and TAM in breast PT and examine their implications. METHODS Tissue microarrays were constructed from 181 PT samples, and immunohistochemistry for PD-L1 antibodies (SP142, SP263, and 22C3) and TAM markers (CD68 and CD163) were performed. The staining results were compared and analyzed with clinicopathological parameters. RESULTS Of the 181 samples, 149 were benign, 27 were borderline, and five were malignant. The number of CD68- and/or CD163-positive TAMs increased with increasing PT grades (P < 0.001), and the number of CD68-positive TAMs was significantly positively correlated with that of CD163-positive TAMs (R = 0.704, P < 0.001). Some of the CD68- and/or CD163-positive cells exhibited positivity for actin staining, displaying hybrid characteristics that resemble both histiocytes and myofibroblasts. PD-L1 SP263 tumor cells and PD-L1 SP263 immune cells were the most expressed in malignant PTs (P < 0.001). The number of CD68- and/or CD163-positive TAMs increased when PD-L1 SP263 immune cells were expressed (P < 0.001). The number of CD68- and/or CD163-positive TAMs was positively correlated with PD-L1 22C3 immune cells (R = 0.299, P < 0.001 and R = 0.336, P < 0.001, respectively). Univariate analysis showed that PD-L1 SP263 immune cell expression (P = 0.016) was associated with shorter disease-free survival and that PD-L1 22C3 tumor cell expression (P < 0.001) was associated with shorter overall survival. CONCLUSION The number of CD68- and/or CD163-positive cells increases with increasing PT histological grade, and these cells exhibit hybrid characteristics, resembling both histiocyte and myofibroblasts.
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Affiliation(s)
- Eunah Shin
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Min Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea.
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Pirrello A, Killingsworth M, Spring K, Rasko JE, Yeo D. Cancer-associated macrophage-like cells as a prognostic biomarker in solid tumors. THE JOURNAL OF LIQUID BIOPSY 2024; 6:100275. [PMID: 40027315 PMCID: PMC11863711 DOI: 10.1016/j.jlb.2024.100275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/30/2024] [Accepted: 11/13/2024] [Indexed: 03/05/2025]
Abstract
Cancer-associated macrophage-like cells (CAMLs) are myeloid-lineage cells associated with cancer-derived material that are detectable in the blood. In addition to circulating tumor cells, CAMLs are a promising liquid biopsy biomarker which may assist with prognostication for patient stratification and monitoring response to chemotherapy and radiotherapy in solid tumors. CAMLs have been detected in blood samples from patients with various tumors including lung, pancreas, breast, oesophageal, and colorectal cancers, and to date have not been detected in healthy individuals. However, the optimal method of detection, their origin, function in the circulation, and ultimate utility have not been fully elucidated. This review provides an overview of CAML-related studies and explores their future potential to guide clinical decision-making.
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Affiliation(s)
- Anthony Pirrello
- Li Ka Shing Cell and Gene Therapy Program, The University of Sydney, Camperdown, 2050, NSW, Australia
- Precision Oncology Laboratory, Centenary Institute, Camperdown, 2050, NSW, Australia
| | - Murray Killingsworth
- Department of Anatomical Pathology, NSW Health Pathology, Liverpool, 2170, NSW, Australia
| | - Kevin Spring
- Medical Oncology Group, Liverpool Clinical School, Western Sydney University and Ingham Institute for Applied Medical Research, Liverpool, 2170, NSW, Australia
| | - John E.J. Rasko
- Li Ka Shing Cell and Gene Therapy Program, The University of Sydney, Camperdown, 2050, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, 2050, NSW, Australia
- Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, 2050, NSW, Australia
| | - Dannel Yeo
- Li Ka Shing Cell and Gene Therapy Program, The University of Sydney, Camperdown, 2050, NSW, Australia
- Precision Oncology Laboratory, Centenary Institute, Camperdown, 2050, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, 2050, NSW, Australia
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Essa AAM, Korayem MAM, Alghamdi MA, Alzahrani RA, Malibari NM, Kandil HE. Expression of CD68 and CD163 in malignant epithelial cells of oral squamous cell carcinoma: Phenotypic shift or mere cell fusion. Pathol Res Pract 2024; 263:155639. [PMID: 39383735 DOI: 10.1016/j.prp.2024.155639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 09/15/2024] [Accepted: 10/02/2024] [Indexed: 10/11/2024]
Abstract
BACKGROUND / PURPOSE The progression of epithelial to mesenchymal tissue (EMT) is a highly intricate process that facilitates the transformation of cancer cells, allowing them to changeover their characteristic epithelial properties to mesenchymal attributes. This notable change empowers the cells with enhanced mobility and the ability to migrate to distant locations. Furthermore, it is imperative to adopt the idea of macrophage tumor cell fusion to achieve comprehensive considerate of this phenomenon. Our primary objective was to conduct a thorough investigation of macrophage-restricted antigens expression, specifically CD68 and CD163, in malignant epithelial cells of oral cavity squamous cell carcinoma (OSCC) to elucidate aforementioned perceptions. MATERIALS AND METHODS CD68 and CD163 immunohistochemical expression were assessed in oral squamous cell carcinoma (OSCC), encompassing both the neoplastic cells and the tumor-associated macrophages (TAMs). RESULTS Both CD68 and CD163 antigens were revealed in OSCC malignant epithelial cells in a granular cell pattern, localized in membrane and cytoplasm of tumor cells respectively as well as in the infiltrating TAMs. CONCLUSION The macrophage antigens were not limited to the infiltrating tumor-associated macrophages (TAMs), but were also observed in a substantial proportion of OSCC malignant epithelial cells within the tumor parenchyma. This particular expression pattern may represent a subset of tumor cells that have undergone an epithelial to a mesenchymal phenotypic transition. In addition, fusion of macrophages with tumor cells cannot be excluded; both might be associated with increased metastatic activity of OSCC.
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Affiliation(s)
- Ahmed Abdelaziz Mohamed Essa
- Oral Pathology Department, Faculty of Dentistry, Tanta University, El-Gesh Street, Tanta, 31527, Egypt; Department of Biomedical Dental Sciences, Faculty of Dentistry, Al-Baha University, Al-Baha, 65511, Saudi Arabia.
| | | | - Mohammed A Alghamdi
- Otolaryngology Division, Surgery Department, Faculty of Medicine, Al-Baha University, Al-Baha, Saudi Arabia.
| | - Rajab A Alzahrani
- Otolaryngology Division, Surgery Department, Faculty of Medicine, Al-Baha University, Al-Baha, Saudi Arabia.
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Plevriti A, Lamprou M, Mourkogianni E, Skoulas N, Giannakopoulou M, Sajib MS, Wang Z, Mattheolabakis G, Chatzigeorgiou A, Marazioti A, Mikelis CM. The Role of Soluble CD163 (sCD163) in Human Physiology and Pathophysiology. Cells 2024; 13:1679. [PMID: 39451197 PMCID: PMC11506427 DOI: 10.3390/cells13201679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/30/2024] [Accepted: 10/09/2024] [Indexed: 10/26/2024] Open
Abstract
Soluble CD163 (sCD163) is a circulating inflammatory mediator, indicative of acute and chronic, systemic and non-systemic inflammatory conditions. It is the cleavage outcome, consisting of almost the entire extracellular domain, of the CD163, a receptor expressed in monocytic lineages. Its expression is proportional to the abundance of CD163+ macrophages. Various mechanisms trigger the shedding of the CD163 receptor or the accumulation of CD163-expressing macrophages, inducing the sCD163 concentration in the circulation and bodily fluids. The activities of sCD163 range from hemoglobin (Hb) scavenging, macrophage marker, decoy receptor for cytokines, participation in immune defense mechanisms, and paracrine effects in various tissues, including the endothelium. It is an established marker of macrophage activation and thus participates in many diseases, including chronic inflammatory conditions, such as atherosclerosis, asthma, and rheumatoid arthritis; acute inflammatory conditions, such as sepsis, hepatitis, and malaria; insulin resistance; diabetes; and tumors. The sCD163 levels have been correlated with the severity, stage of the disease, and clinical outcome for many of these conditions. This review article summarizes the expression and role of sCD163 and its precursor protein, CD163, outlines the sCD163 generation mechanisms, the biological activities, and the known underlying molecular mechanisms, with an emphasis on its impact on the endothelium and its contribution in the pathophysiology of human diseases.
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Affiliation(s)
- Andriana Plevriti
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504 Patras, Greece; (A.P.); (M.L.); (E.M.); (N.S.); (M.G.)
| | - Margarita Lamprou
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504 Patras, Greece; (A.P.); (M.L.); (E.M.); (N.S.); (M.G.)
| | - Eleni Mourkogianni
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504 Patras, Greece; (A.P.); (M.L.); (E.M.); (N.S.); (M.G.)
| | - Nikolaos Skoulas
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504 Patras, Greece; (A.P.); (M.L.); (E.M.); (N.S.); (M.G.)
| | - Maria Giannakopoulou
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504 Patras, Greece; (A.P.); (M.L.); (E.M.); (N.S.); (M.G.)
| | - Md Sanaullah Sajib
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA;
| | - Zhiyong Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, China;
| | - George Mattheolabakis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Antonia Marazioti
- Basic Sciences Laboratory, Department of Physiotherapy, School of Health Sciences, University of Peloponnese, 23100 Sparta, Greece;
| | - Constantinos M. Mikelis
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504 Patras, Greece; (A.P.); (M.L.); (E.M.); (N.S.); (M.G.)
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA;
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Ji M, Chen Y, Zhang L, Ying L, Huang C, Liu L. Construction and Evaluation of an M2 Macrophage-Related Prognostic Model for Colon Cancer. Appl Biochem Biotechnol 2024; 196:4934-4953. [PMID: 37987949 DOI: 10.1007/s12010-023-04789-z] [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] [Accepted: 11/07/2023] [Indexed: 11/22/2023]
Abstract
Colon cancer (CC) is a primary human malignancy. Recently, the mechanism of the tumor microenvironment (TME) in CC has been a hot topic of research. However, there is uncertainty regarding the contribution of M2 macrophages and related genes to the prognosis for CC. M2 macrophage-related genes (M2RGs) were obtained from The Cancer Genome Atlas (TCGA) database. Immune cell infiltration in CC tissue was assessed by Cibersort. Based on the TCGA-COAD training set, a Least Absolute Shrinkage and Selection Operator (LASSO) Cox risk model was constructed and its efficiency was evaluated by analyzing risk profiles and survival profiles. Using gene set enrichment analysis (GSEA), the functional distinctions between high-risk and low-risk categories were further investigated. Finally, potential immune checkpoints, immunotherapy efficiency, and clinical treatment of high-risk patients were evaluated. A total of 1063 M2RGs were identified in TCGA-COAD, 32 of these were confirmed to be strongly related to overall survival (OS), and 14 of these were picked to construct an OS-oriented prognostic model in CC patients. The M2RG signature had a positive correlation with unfavorable prognosis according to the survival analysis. Correlation analysis revealed that the risk model was positively associated with clinicopathological characteristics, immune cell infiltration, immune checkpoint inhibitor targets, the risk of immune escape, and the efficiency of anti-cancer medications. The risk model created using M2RGs may be useful in predicting the prognosis of CC.
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Affiliation(s)
- Min Ji
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yanping Chen
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
- Department of Oncology, Zhong-Da Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Lu Zhang
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Leqian Ying
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Chunchun Huang
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Lin Liu
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.
- Department of Oncology, Zhong-Da Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.
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11
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Dawoud MM, Abd El Samie Aiad H, Kasem NS, El Khouly EAB, Al-Sharaky DR. Is overexpression of CD163 and CD47 in tumour cells of breast carcinoma implicated in the recruitment of tumour-associated macrophages (TAMs) in tumour microenvironment? immunohistochemical prognostic study. J Immunoassay Immunochem 2024; 45:342-361. [PMID: 38815282 DOI: 10.1080/15321819.2024.2358879] [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: 06/01/2024]
Abstract
BACKGROUND Now, targeted therapy and immunotherapy are promoted. tumour -Associated Macrophages (TAMs) are an essential component of immune-response in breast cancer(BC) with prognostic controversy. Additionally, their recruiting factors are still obscure. Purpose:This study aimed to evaluate the prognostic significance of CD163 and CD47 in BC of No Special Type (BC-NST) and to explore their suggested role in recruiting TAMs. MATERIAL AND METHODS This immunohistochemical study was conducted on 91 archival specimens of breast cases. Immunoreactivity scores were correlated with TAMs density, clinicopathological data, and survival. RESULTS Revealed the highest CD163 expression was detected in the pure DCIS group (p = 0.016), while the highest CD47 expression and high TAMs density were reported in the invasive group (p = 0.008, and p = 0.002 respectively) followed by the DCIS group. In IC-NSTs the CD163 and CD47 scores were associated with poor prognostic parameters like(high grade, advanced stage, distant metastasis, ER negativity,Ki67 index, post-surgical chemotherapy, poor NPI group, high mitotic count, dense infiltration of TAMs, shorter OS). Also, CD47 was associated with the dens infiltration of TAMs in DCIS (p = 0.001). There was a significant correlation between tumour cell expression of CD163 and CD47 in IC-NSTs and DCIS (p = 0.002 and p = 0.009 respectively). CONCLUSIONS High CD163 and CD47 expressions in both DCIS andIBC are intimately associated, significantly associated with poor prognosis and are important provoking factors of TAMs.
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MESH Headings
- Humans
- Antigens, Differentiation, Myelomonocytic/metabolism
- Antigens, Differentiation, Myelomonocytic/analysis
- Antigens, Differentiation, Myelomonocytic/immunology
- Breast Neoplasms/pathology
- Breast Neoplasms/immunology
- Breast Neoplasms/metabolism
- Antigens, CD/metabolism
- Female
- CD47 Antigen/metabolism
- CD47 Antigen/immunology
- Tumor Microenvironment/immunology
- Receptors, Cell Surface/metabolism
- Receptors, Cell Surface/immunology
- Receptors, Cell Surface/analysis
- Tumor-Associated Macrophages/immunology
- Tumor-Associated Macrophages/metabolism
- Middle Aged
- Prognosis
- Immunohistochemistry
- Adult
- Aged
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Affiliation(s)
- Marwa Mohammed Dawoud
- Department of Pathology, Faculty of Medicine, Menoufia University, Shibin Al koom, Egypt
| | | | - Norhan Safwat Kasem
- Department of Pathology, Faculty of Medicine, Menoufia University, Shibin Al koom, Egypt
| | - Enas Abu-Bakr El Khouly
- Department of Clinical Oncology, Faculty of Medicine, Menoufia University, Shibin Al koom, Egypt
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12
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Huang R, Kang T, Chen S. The role of tumor-associated macrophages in tumor immune evasion. J Cancer Res Clin Oncol 2024; 150:238. [PMID: 38713256 PMCID: PMC11076352 DOI: 10.1007/s00432-024-05777-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME. METHODS We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs. RESULTS TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis. Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.
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Affiliation(s)
- Ruizhe Huang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Ting Kang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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13
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Dakal TC, George N, Xu C, Suravajhala P, Kumar A. Predictive and Prognostic Relevance of Tumor-Infiltrating Immune Cells: Tailoring Personalized Treatments against Different Cancer Types. Cancers (Basel) 2024; 16:1626. [PMID: 38730579 PMCID: PMC11082991 DOI: 10.3390/cancers16091626] [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: 03/13/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 05/13/2024] Open
Abstract
TIICs are critical components of the TME and are used to estimate prognostic and treatment responses in many malignancies. TIICs in the tumor microenvironment are assessed and quantified by categorizing immune cells into three subtypes: CD66b+ tumor-associated neutrophils (TANs), FoxP3+ regulatory T cells (Tregs), and CD163+ tumor-associated macrophages (TAMs). In addition, many cancers have tumor-infiltrating M1 and M2 macrophages, neutrophils (Neu), CD4+ T cells (T-helper), CD8+ T cells (T-cytotoxic), eosinophils, and mast cells. A variety of clinical treatments have linked tumor immune cell infiltration (ICI) to immunotherapy receptivity and prognosis. To improve the therapeutic effectiveness of immune-modulating drugs in a wider cancer patient population, immune cells and their interactions in the TME must be better understood. This study examines the clinicopathological effects of TIICs in overcoming tumor-mediated immunosuppression to boost antitumor immune responses and improve cancer prognosis. We successfully analyzed the predictive and prognostic usefulness of TIICs alongside TMB and ICI scores to identify cancer's varied immune landscapes. Traditionally, immune cell infiltration was quantified using flow cytometry, immunohistochemistry, gene set enrichment analysis (GSEA), CIBERSORT, ESTIMATE, and other platforms that use integrated immune gene sets from previously published studies. We have also thoroughly examined traditional limitations and newly created unsupervised clustering and deconvolution techniques (SpatialVizScore and ProTICS). These methods predict patient outcomes and treatment responses better. These models may also identify individuals who may benefit more from adjuvant or neoadjuvant treatment. Overall, we think that the significant contribution of TIICs in cancer will greatly benefit postoperative follow-up, therapy, interventions, and informed choices on customized cancer medicines.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia University, Udaipur 313001, Rajasthan, India
| | - Nancy George
- Department of Biotechnology, Chandigarh University, Mohali 140413, Punjab, India;
| | - Caiming Xu
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of the City of Hope, Monrovia, CA 91010, USA;
| | - Prashanth Suravajhala
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Clappana P.O. 690525, Kerala, India;
| | - Abhishek Kumar
- Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, Karnataka, India
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14
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Ali AM, Raza A. scRNAseq and High-Throughput Spatial Analysis of Tumor and Normal Microenvironment in Solid Tumors Reveal a Possible Origin of Circulating Tumor Hybrid Cells. Cancers (Basel) 2024; 16:1444. [PMID: 38611120 PMCID: PMC11010995 DOI: 10.3390/cancers16071444] [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: 03/01/2024] [Revised: 03/31/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Metastatic cancer is a leading cause of death in cancer patients worldwide. While circulating hybrid cells (CHCs) are implicated in metastatic spread, studies documenting their tissue origin remain sparse, with limited candidate approaches using one-two markers. Utilizing high-throughput single-cell and spatial transcriptomics, we identified tumor hybrid cells (THCs) co-expressing epithelial and macrophage markers and expressing a distinct transcriptome. Rarely, normal tissue showed these cells (NHCs), but their transcriptome was easily distinguishable from THCs. THCs with unique transcriptomes were observed in breast and colon cancers, suggesting this to be a generalizable phenomenon across cancer types. This study establishes a framework for HC identification in large datasets, providing compelling evidence for their tissue residence and offering comprehensive transcriptomic characterization. Furthermore, it sheds light on their differential function and identifies pathways that could explain their newly acquired invasive capabilities. THCs should be considered as potential therapeutic targets.
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Affiliation(s)
- Abdullah Mahmood Ali
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY 10032, USA
- Edward P Evans MDS Center, Herbert Irving Comprehensive Cancer Center, New York, NY 10032, USA
| | - Azra Raza
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY 10032, USA
- Edward P Evans MDS Center, Herbert Irving Comprehensive Cancer Center, New York, NY 10032, USA
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15
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Peta KT, Durandt C, van Heerden MB, Joubert AM, Pepper MS, Ambele MA. Effect of 2-methoxyestradiol on mammary tumor initiation and progression. Cancer Rep (Hoboken) 2024; 7:e2068. [PMID: 38600057 PMCID: PMC11006714 DOI: 10.1002/cnr2.2068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/04/2024] [Accepted: 03/24/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND The anti-cancer agent 2-methoxyestradiol (2-ME) has been shown to have anti-proliferative and anti-angiogenic properties. Previously, the effect of 2-ME on early- and late-stage breast cancer (BC) was investigated in vivo using a transgenic mouse model (FVB/N-Tg(MMTV-PyVT)) of spontaneous mammary carcinoma. Anti-tumor effects were observed in late-stage BC with no effect on early-stage BC. Given the contrasting results obtained from the different BC stages, we have now investigated the effect of 2-ME when administered before the appearance of palpable tumors. METHODS Each mouse received 100 mg/kg 2-ME on day 30 after birth, twice per week for 28 days, while control mice received vehicle only. Animals were terminated on day 59. Lung and mammary tissue were obtained for immunohistochemical analysis of CD163 and CD3 expression, and histological examination was performed to analyze tumor necrosis. Additionally, blood samples were collected to measure plasma cytokine levels. RESULTS 2-ME increased tumor mass when compared to the untreated animals (p = .0139). The pro-tumorigenic activity of 2-ME was accompanied by lower CD3+ T-cell numbers in the tumor microenvironment (TME) and high levels of the pro-inflammatory cytokine interleukin (IL)-1β. Conversely, 2-ME-treatment resulted in fewer CD163+ cells detectable in the TME, increased levels of tumor necrosis, increased IL-10 plasma levels, and low IL-6 and IL-27 plasma levels. CONCLUSION Taken together, these findings suggest that 2-ME promotes early-stage BC development.
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Affiliation(s)
- Kimberly T. Peta
- Department of Immunology, Institute for Cellular and Molecular Medicine, South African Medical Research Council, Extramural Unit for Stem Cell Research and Therapy, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Chrisna Durandt
- Department of Immunology, Institute for Cellular and Molecular Medicine, South African Medical Research Council, Extramural Unit for Stem Cell Research and Therapy, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Marlene B. van Heerden
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Anna M. Joubert
- Department of Physiology, School of Medicine, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Michael S. Pepper
- Department of Immunology, Institute for Cellular and Molecular Medicine, South African Medical Research Council, Extramural Unit for Stem Cell Research and Therapy, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
| | - Melvin A. Ambele
- Department of Immunology, Institute for Cellular and Molecular Medicine, South African Medical Research Council, Extramural Unit for Stem Cell Research and Therapy, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
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16
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Dorjkhorloo G, Erkhem-Ochir B, Shiraishi T, Sohda M, Okami H, Yamaguchi A, Shioi I, Komine C, Nakazawa N, Ozawa N, Shibasaki Y, Okada T, Osone K, Sano A, Sakai M, Ogawa H, Yokobori T, Shirabe K, Saeki H. Prognostic value of a modified‑immune scoring system in patients with pathological T4 colorectal cancer. Oncol Lett 2024; 27:104. [PMID: 38298428 PMCID: PMC10829066 DOI: 10.3892/ol.2024.14237] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/13/2023] [Indexed: 02/02/2024] Open
Abstract
Tumor-infiltrating immune cells, such as lymphocytes and macrophages, have been associated with tumor aggressiveness, prognosis and treatment response in colorectal cancer (CRC). An immune scoring system, Immunoscore (IS), based on tumor-infiltrating T cells in stage I-III CRC, was used to predict prognosis. An alternative immune scoring signature of immune activation (SIA) reflects the balance between anti- and pro-tumoral immune components. The present study aimed to evaluate the prognostic value of modified IS (mIS) and modified SIA (mSIA) in locally advanced pathological T4 (pT4) CRC, including stage IV CRC. Immunohistochemical staining for immune cell markers, such as CD3 (pan-T cell marker), CD8 (anti-tumoral cytotoxic T cell marker) and CD163 (tumor-supportive macrophage marker), in specimens from patients with radically resected pT4 CRC at stages II-IV was performed. mIS levels in the T4 CRC cohort were not associated with prognosis. However, low mSIA levels were associated with low survival. Furthermore, low mSIA was an independent predictor of recurrence in patients with radically resected pT4 CRC. In patients with CRC who did not receive postoperative adjuvant chemotherapy, low mSIA was a major poor prognostic factor; however, this was not observed in patients receiving adjuvant chemotherapy. Evaluation of the tumor-infiltrating immune cell population could serve as a valuable marker of recurrence and poor prognosis in patients with locally advanced CRC. mSIA assessment after radical CRC resection may be promising for identifying high-risk patients with pT4 CRC who require aggressive adjuvant chemotherapy.
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Affiliation(s)
- Gendensuren Dorjkhorloo
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Bilguun Erkhem-Ochir
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Gunma 371-8511, Japan
| | - Takuya Shiraishi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Makoto Sohda
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Haruka Okami
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Arisa Yamaguchi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Ikuma Shioi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Chika Komine
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Nobuhiro Nakazawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Naoya Ozawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Yuta Shibasaki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Takuhisa Okada
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Katsuya Osone
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Akihiko Sano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Makoto Sakai
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Takehiko Yokobori
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Gunma 371-8511, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
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17
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Sieler M, Dittmar T. Cell Fusion and Syncytia Formation in Cancer. Results Probl Cell Differ 2024; 71:433-465. [PMID: 37996689 DOI: 10.1007/978-3-031-37936-9_20] [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: 11/25/2023]
Abstract
The natural phenomenon of cell-cell fusion does not only take place in physiological processes, such as placentation, myogenesis, or osteoclastogenesis, but also in pathophysiological processes, such as cancer. More than a century ago postulated, today the hypothesis that the fusion of cancer cells with normal cells leads to the formation of cancer hybrid cells with altered properties is in scientific consensus. Some studies that have investigated the mechanisms and conditions for the fusion of cancer cells with other cells, as well as studies that have characterized the resulting cancer hybrid cells, are presented in this review. Hypoxia and the cytokine TNFα, for example, have been found to promote cell fusion. In addition, it has been found that both the protein Syncytin-1, which normally plays a role in placentation, and phosphatidylserine signaling on the cell membrane are involved in the fusion of cancer cells with other cells. In human cancer, cancer hybrid cells were detected not only in the primary tumor, but also in the circulation of patients as so-called circulating hybrid cells, where they often correlated with a worse outcome. Although some data are available, the questions of how and especially why cancer cells fuse with other cells are still not fully answered.
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Affiliation(s)
- Mareike Sieler
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke, Witten, Germany.
| | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke, Witten, Germany
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18
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Cozzo AJ, Coleman MF, Hursting SD. You complete me: tumor cell-myeloid cell nuclear fusion as a facilitator of organ-specific metastasis. Front Oncol 2023; 13:1191332. [PMID: 37427108 PMCID: PMC10324515 DOI: 10.3389/fonc.2023.1191332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/25/2023] [Indexed: 07/11/2023] Open
Abstract
Every cancer genome is unique, resulting in potentially near infinite cancer cell phenotypes and an inability to predict clinical outcomes in most cases. Despite this profound genomic heterogeneity, many cancer types and subtypes display a non-random distribution of metastasis to distant organs, a phenomenon known as organotropism. Proposed factors in metastatic organotropism include hematogenous versus lymphatic dissemination, the circulation pattern of the tissue of origin, tumor-intrinsic factors, compatibility with established organ-specific niches, long-range induction of premetastatic niche formation, and so-called "prometastatic niches" that facilitate successful colonization of the secondary site following extravasation. To successfully complete the steps required for distant metastasis, cancer cells must evade immunosurveillance and survive in multiple new and hostile environments. Despite substantial advances in our understanding of the biology underlying malignancy, many of the mechanisms used by cancer cells to survive the metastatic journey remain a mystery. This review synthesizes the rapidly growing body of literature demonstrating the relevance of an unusual cell type known as "fusion hybrid" cells to many of the hallmarks of cancer, including tumor heterogeneity, metastatic conversion, survival in circulation, and metastatic organotropism. Whereas the concept of fusion between tumor cells and blood cells was initially proposed over a century ago, only recently have technological advancements allowed for detection of cells containing components of both immune and neoplastic cells within primary and metastatic lesions as well as among circulating malignant cells. Specifically, heterotypic fusion of cancer cells with monocytes and macrophages results in a highly heterogeneous population of hybrid daughter cells with enhanced malignant potential. Proposed mechanisms behind these findings include rapid, massive genome rearrangement during nuclear fusion and/or acquisition of monocyte/macrophage features such as migratory and invasive capability, immune privilege, immune cell trafficking and homing, and others. Rapid acquisition of these cellular traits may increase the likelihood of both escape from the primary tumor site and extravasation of hybrid cells at a secondary location that is amenable to colonization by that particular hybrid phenotype, providing a partial explanation for the patterns observed in some cancers with regard to sites of distant metastases.
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Affiliation(s)
- Alyssa J. Cozzo
- Duke University School of Medicine, Durham, NC, United States
- Department of Pathology, Duke University Medical Center, Durham, NC, United States
| | - Michael F. Coleman
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Stephen D. Hursting
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States
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19
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Giacomelli M, Monti M, Pezzola DC, Lonardi S, Bugatti M, Missale F, Cioncada R, Melocchi L, Giustini V, Villanacci V, Baronchelli C, Manenti S, Imberti L, Giurisato E, Vermi W. Immuno-Contexture and Immune Checkpoint Molecule Expression in Mismatch Repair Proficient Colorectal Carcinoma. Cancers (Basel) 2023; 15:3097. [PMID: 37370706 DOI: 10.3390/cancers15123097] [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: 05/05/2023] [Revised: 06/01/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
Colorectal carcinoma (CRC) represents a lethal disease with heterogeneous outcomes. Only patients with mismatch repair (MMR) deficient CRC showing microsatellite instability and hyper-mutated tumors can obtain clinical benefits from current immune checkpoint blockades; on the other hand, immune- or target-based therapeutic strategies are very limited for subjects with mismatch repair proficient CRC (CRCpMMR). Here, we report a comprehensive typing of immune infiltrating cells in CRCpMMR. We also tested the expression and interferon-γ-modulation of PD-L1/CD274. Relevant findings were subsequently validated by immunohistochemistry on fixed materials. CRCpMMR contain a significantly increased fraction of CD163+ macrophages (TAMs) expressing TREM2 and CD66+ neutrophils (TANs) together with decrease in CD4-CD8-CD3+ double negative T lymphocytes (DNTs); no differences were revealed by the analysis of conventional and plasmacytoid dendritic cell populations. A fraction of tumor-infiltrating T-cells displays an exhausted phenotype, co-expressing PD-1 and TIM-3. Remarkably, expression of PD-L1 on fresh tumor cells and TAMs was undetectable even after in vitro stimulation with interferon-γ. These findings confirm the immune suppressive microenvironment of CRCpMMR characterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion, and interferon-γ unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCpMMR.
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Affiliation(s)
- Mauro Giacomelli
- Department of Pathology, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Matilde Monti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Diego Cesare Pezzola
- Department of Surgery, Surgery Division II, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Silvia Lonardi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Mattia Bugatti
- Department of Pathology, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Francesco Missale
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
- Department of Head & Neck Oncology & Surgery Otorhinolaryngology, Antoni Van Leeuwenhoek-Nederlands Kanker Instituut, 1066 CX Amsterdam, The Netherlands
| | - Rossella Cioncada
- Department of Pathology, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Laura Melocchi
- Department of Pathology, Fondazione Poliambulanza, 25124 Brescia, Italy
| | - Viviana Giustini
- CREA Laboratory, AIL Center for Hemato-Oncologic Research, Diagnostic Department, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Vincenzo Villanacci
- Department of Pathology, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Carla Baronchelli
- Department of Pathology, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Stefania Manenti
- Department of Pathology, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Luisa Imberti
- Section of Microbiology, University of Brescia, 25123 Brescia, Italy
| | - Emanuele Giurisato
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK
| | - William Vermi
- Department of Pathology, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
- Department of Pathology and Immunology, School of Medicine, Washington University, Saint Louis, MO 63130, USA
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20
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Goesmann L, Refaian N, Bosch JJ, Heindl LM. Characterization and Quantitation of the Tumor Microenvironment of Uveal Melanoma. BIOLOGY 2023; 12:738. [PMID: 37237550 PMCID: PMC10215936 DOI: 10.3390/biology12050738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/06/2023] [Accepted: 05/14/2023] [Indexed: 05/28/2023]
Abstract
Uveal melanoma (UM) is a highly malignant tumor of the eye. Metastatic spread of UM occurs almost exclusively via blood vessels and is of tremendous interest, as half of the patients with uveal melanoma die of metastasis in the long run. The tumor microenvironment consists of all cellular and non-cellular compounds of a solid tumor, except for the tumor cells. This study aims to provide a more detailed understanding of the tumor microenvironment of UM to build the foundation for new therapeutic targets. Fluorescence immunohistochemistry was performed to examine the localization of various cell types in the tumor microenvironment in UM. Furthermore, the presence of LAG-3 and its ligands Galectine-3 and LSECtin was examined to evaluate the potential efficacy of immune checkpoint inhibitor-based therapies. The main findings are that blood vessels are mainly located in the middle of the tumor, and that immune cells are mostly found in the outer section of the tumor. LAG-3 and Galectine-3 were found to be highly represented, whereas LSECtin barely occurred in UM. Both the predominant location of tumor-associated macrophages in the outer section of the tumor and the high presence of LAG-3 and Galectine-3 in the UM serve as attainable therapeutic targets.
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Affiliation(s)
- Lara Goesmann
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (L.G.); (J.J.B.); (L.M.H.)
| | - Nasrin Refaian
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (L.G.); (J.J.B.); (L.M.H.)
| | - Jacobus J. Bosch
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (L.G.); (J.J.B.); (L.M.H.)
- Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, 50937 Cologne, Germany
- Centre for Human Drug Research, 2333 CL Leiden, The Netherlands
- Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Ludwig M. Heindl
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (L.G.); (J.J.B.); (L.M.H.)
- Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, 50937 Cologne, Germany
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21
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Matsubara E, Yano H, Pan C, Komohara Y, Fujiwara Y, Zhao S, Shinchi Y, Kurotaki D, Suzuki M. The Significance of SPP1 in Lung Cancers and Its Impact as a Marker for Protumor Tumor-Associated Macrophages. Cancers (Basel) 2023; 15:cancers15082250. [PMID: 37190178 DOI: 10.3390/cancers15082250] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/07/2023] [Accepted: 04/10/2023] [Indexed: 05/17/2023] Open
Abstract
Macrophages are a representative cell type in the tumor microenvironment. Macrophages that infiltrate the cancer microenvironment are referred to as tumor-associated macrophages (TAMs). TAMs exhibit protumor functions related to invasion, metastasis, and immunosuppression, and an increased density of TAMs is associated with a poor clinical course in many cancers. Phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional secreted phosphorylated glycoprotein. Although SPP1 is produced in a variety of organs, at the cellular level, it is expressed on only a few cell types, such as osteoblasts, fibroblasts, macrophages, dendritic cells, lymphoid cells, and mononuclear cells. SPP1 is also expressed by cancer cells, and previous studies have demonstrated correlations between levels of circulating SPP1 and/or increased SPP1 expression on tumor cells and poor prognosis in many types of cancer. We recently revealed that SPP1 expression on TAMs is correlated with poor prognosis and chemoresistance in lung adenocarcinoma. In this review, we summarize the significance of TAMs in lung cancers and discuss the importance of SPP1 as a new marker for the protumor subpopulation of monocyte-derived TAMs in lung adenocarcinoma. Several studies have shown that the SPP1/CD44 axis contribute to cancer chemoresistance in solid cancers, so the SPP1/CD44 axis may represent one of the most critical mechanisms for cell-to-cell communication between cancer cells and TAMs.
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Affiliation(s)
- Eri Matsubara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Department of Thoracic Surgery and Breast Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hiromu Yano
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Cheng Pan
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Shukang Zhao
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Department of Thoracic Surgery and Breast Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yusuke Shinchi
- Department of Thoracic Surgery and Breast Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Daisuke Kurotaki
- Laboratory of Chromatin Organization in Immune Cell Development, International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Makoto Suzuki
- Department of Thoracic Surgery and Breast Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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22
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Ma S, Zhao Y, Liu X, Sun Zhang A, Zhang H, Hu G, Sun XF. CD163 as a Potential Biomarker in Colorectal Cancer for Tumor Microenvironment and Cancer Prognosis: A Swedish Study from Tissue Microarrays to Big Data Analyses. Cancers (Basel) 2022; 14:cancers14246166. [PMID: 36551651 PMCID: PMC9776587 DOI: 10.3390/cancers14246166] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/01/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022] Open
Abstract
(1) Background: CD163, a specific macrophage receptor, affects the progression of malignant tumors. Unfortunately, the regulation and expression of CD163 are poorly understood. In this study, we determined the expressions of CD163 in TMA samples from CRC patients and combined them with patient data from several Swedish hospitals. (2) Methods: The expressions of CD163 in tissue samples from CRC patients were examined. After combining 472 CRC patients’ gene expression and 438 CRC patients’ clinical data with the TCGA database, 964 cases from the GEO database, and experimental expression data from 1247 Swedish CRC patients, we selected four genes (PCNA, LOX, BCL2, and CD163) and analyzed the tumor-infiltrating immune cells (TICs) and CRC prognosis. (3) Results: Based on histopathological TMA analysis, CD163 was strongly expressed in the stroma of both normal and cancer tissues, and the expressions in normal and cancer cells varied from negative to strong. The results from public databases show decreased expression of CD163 in cancer tissue compared to normal mucosa (|log FC| > 1 and FDR < 0.01), and it is a negative prognostic factor for CRC patients (p-value < 0.05). Through tumor microenvironment (TME) analysis, we found a potential influence of CD163 on immune cell infiltration. Furthermore, the enrichment analysis indicated the possible interaction with other proteins and biological pathways. (4) Conclusions: CD163 is expressed differently in CRC tissue and is a negative prognostic factor. Its expression is associated with the TME and tumor purity of CRC. Considering all results, CD163 has the potential to be a predictive biomarker in the investigation of CRC.
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Affiliation(s)
- Shuwen Ma
- Institute of Environmental Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden
| | - Yuxin Zhao
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China
| | - Xingyi Liu
- Centre for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215006, China
| | - Alexander Sun Zhang
- Department of Oncology-Pathology, Karolinska Institute, SE-171 77 Stockholm, Sweden
| | - Hong Zhang
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden
| | - Guang Hu
- Centre for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215006, China
| | - Xiao-Feng Sun
- Department of Oncology, and Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83 Linköping, Sweden
- Correspondence:
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23
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Seyfried TN, Arismendi-Morillo G, Zuccoli G, Lee DC, Duraj T, Elsakka AM, Maroon JC, Mukherjee P, Ta L, Shelton L, D'Agostino D, Kiebish M, Chinopoulos C. Metabolic management of microenvironment acidity in glioblastoma. Front Oncol 2022; 12:968351. [PMID: 36059707 PMCID: PMC9428719 DOI: 10.3389/fonc.2022.968351] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/15/2022] [Indexed: 11/24/2022] Open
Abstract
Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.
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Affiliation(s)
- Thomas N. Seyfried
- Biology Department, Boston College, Chestnut Hill, MA, United States
- *Correspondence: Thomas N. Seyfried,
| | - Gabriel Arismendi-Morillo
- Instituto de Investigaciones Biológicas, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Giulio Zuccoli
- The Program for the Study of Neurodevelopment in Rare Disorders (NDRD), University of Pittsburgh, Pittsburgh, PA, United States
| | - Derek C. Lee
- Biology Department, Boston College, Chestnut Hill, MA, United States
| | - Tomas Duraj
- Faculty of Medicine, Institute for Applied Molecular Medicine (IMMA), CEU San Pablo University, Madrid, Spain
| | - Ahmed M. Elsakka
- Neuro Metabolism, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Joseph C. Maroon
- Department of Neurosurgery, University of Pittsburgh, Medical Center, Pittsburgh, PA, United States
| | - Purna Mukherjee
- Biology Department, Boston College, Chestnut Hill, MA, United States
| | - Linh Ta
- Biology Department, Boston College, Chestnut Hill, MA, United States
| | | | - Dominic D'Agostino
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, United States
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24
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Sonal S, Deshpande V, Ting DT, Cusack JC, Parikh AR, Neyaz A, Pankaj A, Taylor MS, Dinaux AM, Leijssen LGJ, Boudreau C, Locascio JJ, Kunitake H, Goldstone RN, Bordeianou LG, Cauley CE, Ricciardi R, Berger DL. Molecular Basis of Extramural Vascular Invasion (EMVI) in Colorectal Carcinoma. Ann Surg Oncol 2022; 29:7372-7382. [PMID: 35917013 DOI: 10.1245/s10434-022-12212-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.
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Affiliation(s)
- Swati Sonal
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - David T Ting
- Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA, USA
| | - James C Cusack
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Aparna R Parikh
- Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA, USA
| | - Azfar Neyaz
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.,Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Amaya Pankaj
- Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA, USA
| | - Martin S Taylor
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Anne M Dinaux
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.,Chirurgie, Albert Schweitzer Ziekenhuis, Dordrecht, The Netherlands
| | - Lieve G J Leijssen
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.,Department of Gastroenterology and Hepatology, Amsterdams University Medical Centers, Amsterdam, The Netherlands
| | - Chloe Boudreau
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Joseph J Locascio
- Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Hiroko Kunitake
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Robert N Goldstone
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Liliana G Bordeianou
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Christy E Cauley
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Rocco Ricciardi
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - David L Berger
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.
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25
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Malla R, Padmaraju V, Kundrapu DB. Tumor-associated macrophages: Potential target of natural compounds for management of breast cancer. Life Sci 2022; 301:120572. [PMID: 35489567 DOI: 10.1016/j.lfs.2022.120572] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/14/2022] [Accepted: 04/18/2022] [Indexed: 12/15/2022]
Abstract
A large body of experimental research reveals that tumor-associated macrophages (TAMs) are the major immunosuppressor cells in the breast tumor microenvironment (TME). The infiltration of macrophages is correlated with inverse outcomes like disease-free survival and overall survival of cancer patients. They are responsible for heterogeneity, metastasis, and drug resistance. Further, their density in tumor beds is correlated with stage and therapy response. The current review is aimed at summarizing mechanisms and signaling pathways that modulate immune-suppressive phenotype and expansion of TAMs. The review presents an overview of the interdependence of tumor cells and TAMs in TME to promote metastasis, drug resistance and immune suppressive phenotype. This review also presents the potential natural compounds that modulate the immune-suppressive functions of TAMs and their signaling pathways. Finally, this review provides nanotechnology approaches for the targeted delivery of natural products. This review shed light on BC management including clinical studies on the prognostic relevance of TAMs and natural compounds that sensitizes BC.
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Affiliation(s)
- RamaRao Malla
- Cancer Biology Laboratory, Dept. of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam 531001, Andhra Pradesh, India; Dept of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam 531001, Andhra Pradesh, India.
| | - Vasudevaraju Padmaraju
- Dept of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam 531001, Andhra Pradesh, India
| | - Durga Bhavani Kundrapu
- Cancer Biology Laboratory, Dept. of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam 531001, Andhra Pradesh, India; Dept of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam 531001, Andhra Pradesh, India
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26
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Generation of Cancer Stem/Initiating Cells by Cell-Cell Fusion. Int J Mol Sci 2022; 23:ijms23094514. [PMID: 35562905 PMCID: PMC9101717 DOI: 10.3390/ijms23094514] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/10/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
CS/ICs have raised great expectations in cancer research and therapy, as eradication of this key cancer cell type is expected to lead to a complete cure. Unfortunately, the biology of CS/ICs is rather complex, since no common CS/IC marker has yet been identified. Certain surface markers or ALDH1 expression can be used for detection, but some studies indicated that cancer cells exhibit a certain plasticity, so CS/ICs can also arise from non-CS/ICs. Another problem is intratumoral heterogeneity, from which it can be inferred that different CS/IC subclones must be present in the tumor. Cell–cell fusion between cancer cells and normal cells, such as macrophages and stem cells, has been associated with the generation of tumor hybrids that can exhibit novel properties, such as an enhanced metastatic capacity and even CS/IC properties. Moreover, cell–cell fusion is a complex process in which parental chromosomes are mixed and randomly distributed among daughter cells, resulting in multiple, unique tumor hybrids. These, if they have CS/IC properties, may contribute to the heterogeneity of the CS/IC pool. In this review, we will discuss whether cell–cell fusion could also lead to the origin of different CS/ICs that may expand the overall CS/IC pool in a primary tumor.
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27
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Li M, Xiao Q, Venkatachalam N, Hofheinz RD, Veldwijk MR, Herskind C, Ebert MP, Zhan T. Predicting response to neoadjuvant chemoradiotherapy in rectal cancer: from biomarkers to tumor models. Ther Adv Med Oncol 2022; 14:17588359221077972. [PMID: 35222695 PMCID: PMC8864271 DOI: 10.1177/17588359221077972] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 01/14/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a major contributor to cancer-associated morbidity worldwide and over one-third of CRC is located in the rectum. Neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection is commonly applied to treat locally advanced rectal cancer (LARC). In this review, we summarize current and novel concepts of neoadjuvant therapy for LARC such as total neoadjuvant therapy and describe how these developments impact treatment response. Moreover, as response to nCRT is highly divergent in rectal cancers, we discuss the role of potential predictive biomarkers. We review recent advances in biomarker discovery, from a clinical as well as a histopathological and molecular perspective. Furthermore, the role of emerging predictive biomarkers derived from the tumor environment such as immune cell composition and gut microbiome is presented. Finally, we describe how different tumor models such as patient-derived cancer organoids are used to identify novel predictive biomarkers for chemoradiotherapy (CRT) in rectal cancer.
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Affiliation(s)
- Moying Li
- Medical Faculty Mannheim, Heidelberg
University, Mannheim
| | - Qiyun Xiao
- Department of Medicine II, Mannheim University
Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim,
Germany
| | - Nachiyappan Venkatachalam
- Department of Medicine II, Mannheim University
Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim,
Germany
| | - Ralf-Dieter Hofheinz
- Department of Medicine III, Mannheim University
Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim,
GermanyMannheim Cancer Center, Medical Faculty Mannheim, Heidelberg
University, Mannheim, Germany
| | - Marlon R. Veldwijk
- Department of Radiation Oncology, Mannheim
University Hospital, Medical Faculty Mannheim, Heidelberg University,
Mannheim, Germany
| | - Carsten Herskind
- Department of Radiation Oncology, Mannheim
University Hospital, Medical Faculty Mannheim, Heidelberg University,
Mannheim, Germany
| | - Matthias P. Ebert
- Department of Medicine II, Mannheim University
Hospital, Medical Faculty Mannheim, Heidelberg University, Mannheim,
GermanyMannheim Cancer Center, Medical Faculty Mannheim, Heidelberg
University, Mannheim, GermanyDKFZ-Hector Cancer Institute, University
Medical Center Mannheim, Mannheim, Germany
| | - Tianzuo Zhan
- Department of Internal Medicine II, Mannheim
University Hospital, Medical Faculty Mannheim, Heidelberg University,
Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, GermanyMannheim Cancer Center,
Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Hass R, von der Ohe J, Dittmar T. Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP). Cancers (Basel) 2021; 13:4636. [PMID: 34572863 PMCID: PMC8470238 DOI: 10.3390/cancers13184636] [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: 08/17/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/17/2022] Open
Abstract
Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of cancer-cell fusion events appears questionable. However, enhanced tumor growth and/or development of certain metastases can originate from cancer-cell fusion. Formation of hybrid cells after cancer-cell fusion requires a post-hybrid selection process (PHSP) to cope with genomic instability of the parental nuclei and reorganize survival and metabolic functionality. The present review dissects mechanisms that contribute to a PHSP and resulting functional alterations of the cancer hybrids. Based upon new properties of cancer hybrid cells, the arising clinical consequences of the subsequent tumor heterogeneity after cancer-cell fusion represent a major therapeutic challenge. However, cellular partners during cancer-cell fusion such as MSC within the tumor microenvironment or MSC-derived exosomes may provide a suitable vehicle to specifically address and deliver anti-tumor cargo to cancer cells.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Thomas Dittmar
- Institute of Immunology, Center of Biomedical Education and Research (ZABF), Witten/Herdecke University, 58448 Witten, Germany
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29
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Hass R, von der Ohe J, Dittmar T. Hybrid Formation and Fusion of Cancer Cells In Vitro and In Vivo. Cancers (Basel) 2021; 13:4496. [PMID: 34503305 PMCID: PMC8431460 DOI: 10.3390/cancers13174496] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/13/2022] Open
Abstract
The generation of cancer hybrid cells by intra-tumoral cell fusion opens new avenues for tumor plasticity to develop cancer stem cells with altered properties, to escape from immune surveillance, to change metastatic behavior, and to broaden drug responsiveness/resistance. Genomic instability and chromosomal rearrangements in bi- or multinucleated aneuploid cancer hybrid cells contribute to these new functions. However, the significance of cell fusion in tumorigenesis is controversial with respect to the low frequency of cancer cell fusion events and a clonal advantage of surviving cancer hybrid cells following a post-hybrid selection process. This review highlights alternative processes of cancer hybrid cell development such as entosis, emperipolesis, cannibalism, therapy-induced polyploidization/endoreduplication, horizontal or lateral gene transfer, and focusses on the predominant mechanisms of cell fusion. Based upon new properties of cancer hybrid cells the arising clinical consequences of the subsequent tumor heterogeneity after cancer cell fusion represent a major therapeutic challenge.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Thomas Dittmar
- Institute of Immunology, Center of Biomedical Education and Research (ZABF), Witten/Herdecke University, 58448 Witten, Germany
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30
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McShane R, Arya S, Stewart AJ, Caie P, Bates M. Prognostic features of the tumour microenvironment in oesophageal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2021; 1876:188598. [PMID: 34332022 DOI: 10.1016/j.bbcan.2021.188598] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Oesophageal adenocarcinoma (OAC) is a disease with an incredibly poor survival rate and a complex makeup. The growth and spread of OAC tumours are profoundly influenced by their surrounding microenvironment and the properties of the tumour itself. Constant crosstalk between the tumour and its microenvironment is key to the survival of the tumour and ultimately the death of the patient. The tumour microenvironment (TME) is composed of a complex milieu of cell types including cancer associated fibroblasts (CAFs) which make up the tumour stroma, endothelial cells which line blood and lymphatic vessels and infiltrating immune cell populations. These various cell types and the tumour constantly communicate through environmental cues including fluctuations in pH, hypoxia and the release of mitogens such as cytokines, chemokines and growth factors, many of which help promote malignant progression. Eventually clusters of tumour cells such as tumour buds break away and spread through the lymphatic system to nearby lymph nodes or enter the circulation forming secondary metastasis. Collectively, these factors need to be considered when assessing and treating patients clinically. This review aims to summarise the ways in which these various factors are currently assessed and how they relate to patient treatment and outcome at an individual level.
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Affiliation(s)
| | - Swati Arya
- School of Medicine, University of St Andrews, Fife, UK
| | | | - Peter Caie
- School of Medicine, University of St Andrews, Fife, UK
| | - Mark Bates
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, St James's Hospital, Dublin 8, Ireland.
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Matsubara E, Komohara Y, Shinchi Y, Mito R, Fujiwara Y, Ikeda K, Shima T, Shimoda M, Kanai Y, Sakagami T, Suzuki M. CD163-positive cancer cells are a predictor of a worse clinical course in lung adenocarcinoma. Pathol Int 2021; 71:666-673. [PMID: 34231937 DOI: 10.1111/pin.13144] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/09/2021] [Accepted: 06/12/2021] [Indexed: 11/27/2022]
Abstract
CD163 is one of the scavenger receptors expressed on macrophages. However, several immunohistochemical studies have demonstrated that CD163 is also detected on cancer cells, and is associated with a poor prognosis. In the present study, we detected CD163 staining on cancer cells in lung adenocarcinoma and squamous cell carcinoma (SCC), and investigated the relationship between CD163 on cancer cells and the clinical prognosis. CD163 staining was seen in 128 of 342 adenocarcinoma cases and 35 of 103 SCC cases. Among the lung adenocarcinoma cases, the progression-free survival and overall survival were significantly shorter in the CD163 high group than the CD163 low group. A similar trend was observed among the SCC cases, but the difference was not statistically significant. Additionally, a higher number of macrophages was detected in areas with CD163-positive cancer cells when compared to areas with CD163-negative cancer cells. In summary, we found that CD163-positive cancer cells are a predictor of a worse clinical course in lung adenocarcinoma and SCC.
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Affiliation(s)
- Eri Matsubara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan
| | - Yusuke Shinchi
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Remi Mito
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Koei Ikeda
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Toshiyuki Shima
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Masayuki Shimoda
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yae Kanai
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Takuro Sakagami
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Makoto Suzuki
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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32
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Sieler M, Weiler J, Dittmar T. Cell-Cell Fusion and the Roads to Novel Properties of Tumor Hybrid Cells. Cells 2021; 10:cells10061465. [PMID: 34207991 PMCID: PMC8230653 DOI: 10.3390/cells10061465] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 12/15/2022] Open
Abstract
The phenomenon of cancer cell–cell fusion is commonly associated with the origin of more malignant tumor cells exhibiting novel properties, such as increased drug resistance or an enhanced metastatic capacity. However, the whole process of cell–cell fusion is still not well understood and seems to be rather inefficient since only a certain number of (cancer) cells are capable of fusing and only a rather small population of fused tumor hybrids will survive at all. The low survivability of tumor hybrids is attributed to post-fusion processes, which are characterized by the random segregation of mixed parental chromosomes, the induction of aneuploidy and further random chromosomal aberrations and genetic/epigenetic alterations in daughter cells. As post-fusion processes also run in a unique manner in surviving tumor hybrids, the occurrence of novel properties could thus also be a random event, whereby it might be speculated that the tumor microenvironment and its spatial habitats could direct evolving tumor hybrids towards a specific phenotype.
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Aboushousha T, Emad M, Rizk G, Ragab K, Hammam O, Fouad R, Helal NS. IL-4, IL-17 and CD163 Immunoexpression and IL-6 Gene Polymorphism in Chronic Hepatitis C Patients and Associated Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2021; 22:1105-1113. [PMID: 33906302 PMCID: PMC8325124 DOI: 10.31557/apjcp.2021.22.4.1105] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 03/30/2021] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVE To assess the expression of IL-4, IL-17 and CD-163 as well as study of IL6-572 C/G gene polymorphism in chronic HCV and HCC on top of HCV. METHODS Sixty HCC specimens and 60 adjacent hepatic tissue with HCV of different grades of necro-inflammation and different stages of fibrosis. In addition to 55 HCV, 60 HCC and 50 healthy venous blood samples for evaluation of IL6-572 C/G gene polymorphism. RESULTS high expression of IL-4, IL-17 and CD163 in higher grades of activity, late stages of fibrosis and higher degrees of steatosis of HCV. IL-4 and CD163 showed higher expression in advanced grades of HCC, while IL-17 more expressed in lower grades. No significant difference in IL6-572 C/G gene polymorphism among studied groups regarding G/C, G/G, C/C frequencies or G and C allele's frequencies. CONCLUSION IL-4, IL-17 and CD163 were associated with HCV severity. Their expression in HCC suggests their important role in HCC development. Blocking of these proteins may be a good target to control inflammation in HCV and can hinder progression to cirrhosis then to HCC. On the other hand, IL6-572 promoter gene polymorphism is neither associated with HCV infection nor with HCC development and its progression.
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Affiliation(s)
- Tarek Aboushousha
- Department oF Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Marine Emad
- Faculty of Biotechnology, October University for Modern Sciences and Arts, Giza, Egypt.
| | - Gina Rizk
- Faculty of Biotechnology, October University for Modern Sciences and Arts, Giza, Egypt.
| | - Khaled Ragab
- Department of Hepatology and Gastroenterology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Olfat Hammam
- Department oF Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Rabab Fouad
- Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Noha Said Helal
- Department oF Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
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Ajina R, Malchiodi ZX, Fitzgerald AA, Zuo A, Wang S, Moussa M, Cooper CJ, Shen Y, Johnson QR, Parks JM, Smith JC, Catalfamo M, Fertig EJ, Jablonski SA, Weiner LM. Antitumor T-cell Immunity Contributes to Pancreatic Cancer Immune Resistance. Cancer Immunol Res 2021; 9:386-400. [PMID: 33509790 PMCID: PMC8283778 DOI: 10.1158/2326-6066.cir-20-0272] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 10/27/2020] [Accepted: 01/26/2021] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T-cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune resistance in pancreatic cancer was induced in response to antitumor T-cell immune responses and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide evidence that T-cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune resistance. Three KPC mouse models of pancreatic cancer were used: the mT3-2D (Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre) subcutaneous and orthotopic models, as well as the KP1 (p48-CRE/LSL-Kras/Trp53 flox/flox ) subcutaneous model. KPC cancer cells were grown in immunocompetent and immunodeficient C57BL/6 mice and analyzed to determine the impact of adaptive immunity on malignant epithelial cells, as well as on whole tumors. We found that induced T-cell antitumor immunity, via signal transducer and activator of transcription 1 (STAT1), stimulated malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and altered intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA-approved drug ruxolitinib overcame these tumor-protective responses and improved anti-PD-1 therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.
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Affiliation(s)
- Reham Ajina
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Zoe X Malchiodi
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Allison A Fitzgerald
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Annie Zuo
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Shangzi Wang
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Maha Moussa
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, District of Columbia
| | - Connor J Cooper
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee
| | - Yue Shen
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee
| | - Quentin R Johnson
- Department of Chemistry and Biochemistry, Berry College, Mount Berry, Georgia
| | - Jerry M Parks
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee
- Department of Chemistry and Biochemistry, Berry College, Mount Berry, Georgia
| | - Jeremy C Smith
- Department of Chemistry and Biochemistry, Berry College, Mount Berry, Georgia
- Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee
| | - Marta Catalfamo
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, District of Columbia
| | - Elana J Fertig
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, Maryland
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sandra A Jablonski
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Louis M Weiner
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia.
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ARG1 mRNA Level Is a Promising Prognostic Marker in Head and Neck Squamous Cell Carcinomas. Diagnostics (Basel) 2021; 11:diagnostics11040628. [PMID: 33807310 PMCID: PMC8065482 DOI: 10.3390/diagnostics11040628] [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: 03/05/2021] [Revised: 03/23/2021] [Accepted: 03/29/2021] [Indexed: 01/01/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCC) can be induced by smoking or alcohol consumption, but a growing part of cases relate to a persistent high-risk papillomavirus (HPV) infection. Viral etiology has a beneficial impact on the prognosis, which may be explained by a specific immune response. Tumor associated macrophages (TAMs) represent the main immune population of the tumor microenvironment with a controversial influence on the prognosis. In this study, the level, phenotype, and spatial distribution of TAMs were evaluated, and the expression of TAM-associated markers was compared in HPV positive (HPV+) and HPV negative (HPV−) tumors. Seventy-three formalin and embedded in paraffin (FFPE) tumor specimens were examined using multispectral immunohistochemistry for the detection of TAM subpopulations in the tumor parenchyma and stroma. Moreover, the mRNA expression of TAM markers was evaluated using RT-qPCR. Results were compared with respect to tumor etiology, and the prognostic significance was evaluated. In HPV− tumors, we observed more pro-tumorigenic M2 in the stroma and a non-macrophage arginase 1 (ARG1)-expressing population in both compartments. Moreover, higher mRNA expression of M2 markers—cluster of differentiation 163 (CD163), ARG1, and prostaglandin-endoperoxide synthase 2 (PTGS2)—was detected in HPV− patients, and of M1 marker nitric oxide synthase 2 (NOS2) in HPV+ group. The expression of ARG1 mRNA was revealed as a negative prognostic factor for overall survival of HNSCC patients.
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Polano M, Fabbiani E, Adreuzzi E, Cintio FD, Bedon L, Gentilini D, Mongiat M, Ius T, Arcicasa M, Skrap M, Dal Bo M, Toffoli G. A New Epigenetic Model to Stratify Glioma Patients According to Their Immunosuppressive State. Cells 2021; 10:cells10030576. [PMID: 33807997 PMCID: PMC8001235 DOI: 10.3390/cells10030576] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/27/2021] [Accepted: 02/28/2021] [Indexed: 01/02/2023] Open
Abstract
Gliomas are the most common primary neoplasm of the central nervous system. A promising frontier in the definition of glioma prognosis and treatment is represented by epigenetics. Furthermore, in this study, we developed a machine learning classification model based on epigenetic data (CpG probes) to separate patients according to their state of immunosuppression. We considered 573 cases of low-grade glioma (LGG) and glioblastoma (GBM) from The Cancer Genome Atlas (TCGA). First, from gene expression data, we derived a novel binary indicator to flag patients with a favorable immune state. Then, based on previous studies, we selected the genes related to the immune state of tumor microenvironment. After, we improved the selection with a data-driven procedure, based on Boruta. Finally, we tuned, trained, and evaluated both random forest and neural network classifiers on the resulting dataset. We found that a multi-layer perceptron network fed by the 338 probes selected by applying both expert choice and Boruta results in the best performance, achieving an out-of-sample accuracy of 82.8%, a Matthews correlation coefficient of 0.657, and an area under the ROC curve of 0.9. Based on the proposed model, we provided a method to stratify glioma patients according to their epigenomic state.
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Affiliation(s)
- Maurizio Polano
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (F.D.C.); (L.B.); (M.D.B.); (G.T.)
- Correspondence:
| | - Emanuele Fabbiani
- Department of Electrical, Computer and Biomedical Engineering, University of Pavia, 27100 Pavia, Italy;
| | - Eva Adreuzzi
- Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Division of Molecular Oncology, 33081 Aviano, Italy; (E.A.); (M.M.)
| | - Federica Di Cintio
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (F.D.C.); (L.B.); (M.D.B.); (G.T.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Luca Bedon
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (F.D.C.); (L.B.); (M.D.B.); (G.T.)
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via L. Giorgieri 1, 34127 Trieste, Italy
| | - Davide Gentilini
- Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy;
- Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy
| | - Maurizio Mongiat
- Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Division of Molecular Oncology, 33081 Aviano, Italy; (E.A.); (M.M.)
| | - Tamara Ius
- Neurosurgery Unit, Department of Neuroscience, Santa Maria della Misericordia University Hospital, 33100 Udine, Italy; (T.I.); (M.S.)
| | - Mauro Arcicasa
- Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Department of Radiotherapy, 33081 Aviano, Italy;
| | - Miran Skrap
- Neurosurgery Unit, Department of Neuroscience, Santa Maria della Misericordia University Hospital, 33100 Udine, Italy; (T.I.); (M.S.)
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (F.D.C.); (L.B.); (M.D.B.); (G.T.)
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (F.D.C.); (L.B.); (M.D.B.); (G.T.)
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Jiang CH, Liang WH, Li FP, Xie YF, Yuan X, Zhang HJ, Li M, Li JF, Zhang AZ, Yang L, Liu CX, Pang LJ, Li F, Hu JM. Distribution and prognostic impact of M1 macrophage on esophageal squamous cell carcinoma. Carcinogenesis 2020; 42:537-545. [PMID: 33269791 DOI: 10.1093/carcin/bgaa128] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/23/2020] [Accepted: 11/23/2020] [Indexed: 11/14/2022] Open
Abstract
Macrophages are a double-edged sword with potential cancer-promoting and anticancer effects. Controversy remains regarding the effect of macrophages, especially M1 macrophages, on tumor promotion and suppression. We aimed to investigate the role of M1 macrophages in the occurrence and progression of esophageal squamous cell carcinoma (ESCC). Analyzing the data in Gene Expression Omnibus database by the CIBERSORT algorithm found that M1 macrophages were one of the important components of many immune cells in ESCCs, and the increase in their number was obviously negatively correlated with tumor T staging. This result was verified by our experimental data: the density of CD68/HLA-DR double-stained M1 macrophages in ESCC tumor nest and tumor stroma was significantly higher than that in cancer-adjacent normal (CAN) tissues. The density of M1 macrophages in ESCC tumor nest was negatively correlated with the patient's lymph node metastasis and clinical stage (P < 0.05), and the negative tendency was more obvious for M1 macrophages in ESCC tumor stroma (P < 0.001). Exposure to M1 macrophage-conditioned medium inhibited ESCC cell migration and invasion ability significantly (P < 0.05). Moreover, the increased M1 macrophage density in ESCC tumor stroma correlated positively with good prognosis of ESCC. M1 macrophages were involved in inhibiting ESCC cell migration and invasion, which could serve as a good prognostic factor in patients with ESCC.
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Affiliation(s)
- Chen Hao Jiang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Wei Hua Liang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Fan Ping Li
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Yu Fang Xie
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Xin Yuan
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Hai Jun Zhang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Man Li
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Jiang Fen Li
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - An Zhi Zhang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Lan Yang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Chun Xia Liu
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Li Juan Pang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Feng Li
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China.,Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jian Ming Hu
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
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Larionova I, Tuguzbaeva G, Ponomaryova A, Stakheyeva M, Cherdyntseva N, Pavlov V, Choinzonov E, Kzhyshkowska J. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers. Front Oncol 2020; 10:566511. [PMID: 33194645 PMCID: PMC7642726 DOI: 10.3389/fonc.2020.566511] [Citation(s) in RCA: 261] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth and metastasis. The accumulated data are essential for using TAMs as biomarkers and therapeutic targets to develop cancer-specific immunotherapy and to design efficient combinations of traditional therapy and new immunomodulatory approaches.
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Affiliation(s)
- Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Gulnara Tuguzbaeva
- Department of Pathophysiology, Bashkir State Medical University, Ufa, Russia
| | - Anastasia Ponomaryova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Marina Stakheyeva
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Nadezhda Cherdyntseva
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Valentin Pavlov
- Department of Urology, Bashkir State Medical University, Ufa, Russia
| | - Evgeniy Choinzonov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg—Hessen, Mannheim, Germany
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Wen Y, Zhao S, Holmqvist A, Hahn-Stromberg V, Adell G, Holmlund B, Pathak S, Peng Z, Sun XF. Predictive Role of Biopsy Based Biomarkers for Radiotherapy Treatment in Rectal Cancer. J Pers Med 2020; 10:jpm10040168. [PMID: 33066317 PMCID: PMC7712120 DOI: 10.3390/jpm10040168] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 12/30/2022] Open
Abstract
Background and Purpose: Radiation therapy has long been contemplated as an important mode in the treatment of rectal cancer. However, there are few ideal tools available for clinicians to make a radiotherapy decision at the time of diagnosis for rectal cancer. The purpose of this study was to assess whether biomarkers expressed in the biopsy could help to choose the suitable therapy and provide predictive and/or prognostic information. Experimental Design: In total, 30 biomarkers were analyzed in 219 biopsy samples before treatment to discover the possibility of using them as an indicator for radiotherapy selection, diagnosis, survival and recurrence. Results: Twenty-two biomarkers (COX2-RT, COX2-NonRT, etc.; 36.67%) had diagnostic value. For survival, four biomarkers (NFKBP65, p130, PINCH and PPAR) were significant in regulating gene promoter activity and overall survival, while four had a trend (AEG1, LOX, SATB1 and SIRT6). Three biomarkers (COX2, PINCH and WRAP53) correlated with disease-free survival, while eight had a trend (AEG1, COX2, Ki67, LOX, NFKBP65, PPAR and SATB1). Four biomarkers (COX2-RT, NFKBP65cyto-RT, P130cyto-NonRT and PPARcyto-RT) were independent prognostic factors for recurrence. NFKBP65 and SIRT6 were significantly correlated with lymph node metastasis regardless of radiation. Patients with high AEG1, LOX, NFKBP65, PPAR and SATB1 had or showed a positive trend for better survival after radiotherapy, while those with positive PINCH and WRAP53 expression would not benefit from radiotherapy. Conclusions: AEG1, LOX, NFKBP65cyto, PPAR and SATB1 could be used as indicators for choosing radiotherapy. COX2-RT, COX2-NonRT and some other biomarkers may provide additional help for diagnosis.
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Affiliation(s)
- Yugang Wen
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China; (Y.W.); (S.Z.)
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83 Linköping, Sweden; (A.H.); (G.A.); (B.H.)
| | - Senlin Zhao
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China; (Y.W.); (S.Z.)
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83 Linköping, Sweden; (A.H.); (G.A.); (B.H.)
| | - Annica Holmqvist
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83 Linköping, Sweden; (A.H.); (G.A.); (B.H.)
| | | | - Gunnar Adell
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83 Linköping, Sweden; (A.H.); (G.A.); (B.H.)
| | - Birgitta Holmlund
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83 Linköping, Sweden; (A.H.); (G.A.); (B.H.)
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Chennai 603 103, India;
| | - Zhihai Peng
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China; (Y.W.); (S.Z.)
- Correspondence: (Z.P.); (X.-F.S.); Tel.: +86-13761010066 (Z.P.); +46-10-1032066 (X.-F.S.)
| | - Xiao-Feng Sun
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, SE-581 83 Linköping, Sweden; (A.H.); (G.A.); (B.H.)
- Correspondence: (Z.P.); (X.-F.S.); Tel.: +86-13761010066 (Z.P.); +46-10-1032066 (X.-F.S.)
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Serum biomarker CD163 predicts overall survival in patients with pancreatic ductal adenocarcinoma. JOURNAL OF PANCREATOLOGY 2020. [DOI: 10.1097/jp9.0000000000000055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Circulating Giant Tumor-Macrophage Fusion Cells Are Independent Prognosticators in Patients With NSCLC. J Thorac Oncol 2020; 15:1460-1471. [DOI: 10.1016/j.jtho.2020.04.034] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/09/2020] [Accepted: 04/28/2020] [Indexed: 12/24/2022]
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Skytthe MK, Graversen JH, Moestrup SK. Targeting of CD163 + Macrophages in Inflammatory and Malignant Diseases. Int J Mol Sci 2020; 21:E5497. [PMID: 32752088 PMCID: PMC7432735 DOI: 10.3390/ijms21155497] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/28/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this strategy is complicated by the pleiotropic phenotype of the macrophage that is highly responsive to its microenvironment. The plasticity leads to numerous types of macrophages with rather different and, to some extent, opposing functionalities, as evident by the existence of macrophages with either stimulating or down-regulating effect on inflammation and tumor growth. The phenotypes are characterized by different surface markers and the present review describes recent progress in drug-targeting of the surface marker CD163 expressed in a subpopulation of macrophages. CD163 is an abundant endocytic receptor for multiple ligands, quantitatively important being the haptoglobin-hemoglobin complex. The microenvironment of inflammation and tumorigenesis is particular rich in CD163+ macrophages. The use of antibodies for directing anti-inflammatory (e.g., glucocorticoids) or tumoricidal (e.g., doxorubicin) drugs to CD163+ macrophages in animal models of inflammation and cancer has demonstrated a high efficacy of the conjugate drugs. This macrophage-targeting approach has a low toxicity profile that may highly improve the therapeutic window of many current drugs and drug candidates.
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Affiliation(s)
- Maria K. Skytthe
- Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (M.K.S.); (S.K.M.)
| | - Jonas Heilskov Graversen
- Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (M.K.S.); (S.K.M.)
| | - Søren K. Moestrup
- Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (M.K.S.); (S.K.M.)
- Department of Biomedicine, Aarhus University, 8200 Aarhus, Denmark
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Tumor-associated macrophage infiltration and prognosis in colorectal cancer: systematic review and meta-analysis. Int J Colorectal Dis 2020; 35:1203-1210. [PMID: 32303831 DOI: 10.1007/s00384-020-03593-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are key components of colorectal cancer (CRC) microenvironment, but their role in CRC prognosis is not fully defined. OBJECTIVE This study aimed to evaluate prognostic value of different types and distribution of TAMs in CRC. METHODS Total 27 studies with 6115 patients were searched from PubMed and Embase and analyzed to determine the association between TAMs, including distinct TAM subsets and infiltration location, and CRC survival. The prognostic impact of TAMs on CRC was further stratified by tumor type and mismatch repair system (MMR) status. RESULTS A pooled analysis indicated that high density of TAMs in CRC tissue was significantly associated with favorable 5-year overall survival (OS) but not with disease-free survival (DFS). CD 68+ TAM subset correlated with better 5-year OS, while neither CD68+NOS2+ M1 subset nor CD163+ M2 subset was correlated with 5-year OS. Increased CD68+ TAM infiltration in tumor stroma but not in tumor islet predicted improved 5-year OS. Stratification by tumor type and MMR status showed that in colon cancer or MMR-proficient CRC, elevated TAM density was associated with better 5-year OS. CONCLUSIONS High infiltration of CD68+ TAMs could be a favorable prognostic marker in CRC. Future therapies stimulating CD68+ TAM infiltration may be promising in CRC treatment.
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Shabo I, Svanvik J, Lindström A, Lechertier T, Trabulo S, Hulit J, Sparey T, Pawelek J. Roles of cell fusion, hybridization and polyploid cell formation in cancer metastasis. World J Clin Oncol 2020; 11:121-135. [PMID: 32257843 PMCID: PMC7103524 DOI: 10.5306/wjco.v11.i3.121] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/02/2020] [Accepted: 03/01/2020] [Indexed: 02/06/2023] Open
Abstract
Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE 171 77, Sweden
- Patient Area of Breast Cancer, Sarcoma and Endocrine Tumours, Theme Cancer, Karolinska University Hospital, Stockholm SE 171 76, Sweden
| | - Joar Svanvik
- The Transplant Institute, Sahlgrenska University Hospital, Gothenburg SE 413 45, Sweden
- Division of Surgery, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 83, Sweden
| | - Annelie Lindström
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 85, Sweden
| | - Tanguy Lechertier
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Sara Trabulo
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - James Hulit
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Tim Sparey
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - John Pawelek
- Department of Dermatology and the Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
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Pires IS, Savla C, Palmer AF. Poly(ethylene glycol) Surface-Conjugated Apohemoglobin as a Synthetic Heme Scavenger. Biomacromolecules 2020; 21:2155-2164. [DOI: 10.1021/acs.biomac.0c00141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Ivan S. Pires
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States
| | - Chintan Savla
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States
| | - Andre F. Palmer
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States
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Manjunath Y, Porciani D, Mitchem JB, Suvilesh KN, Avella DM, Kimchi ET, Staveley-O’Carroll KF, Burke DH, Li G, Kaifi JT. Tumor-Cell-Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer. Int J Mol Sci 2020; 21:E1872. [PMID: 32182935 PMCID: PMC7084898 DOI: 10.3390/ijms21051872] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/06/2020] [Accepted: 03/07/2020] [Indexed: 02/06/2023] Open
Abstract
Although molecular mechanisms driving tumor progression have been extensively studied, the biological nature of the various populations of circulating tumor cells (CTCs) within the blood is still not well understood. Tumor cell fusion with immune cells is a longstanding hypothesis that has caught more attention in recent times. Specifically, fusion of tumor cells with macrophages might lead to the development of metastasis by acquiring features such as genetic and epigenetic heterogeneity, chemotherapeutic resistance, and immune tolerance. In addition to the traditional FDA-approved definition of a CTC (CD45-, EpCAM+, cytokeratins 8+, 18+ or 19+, with a DAPI+ nucleus), an additional circulating cell population has been identified as being potential fusions cells, characterized by distinct, large, polymorphonuclear cancer-associated cells with a dual epithelial and macrophage/myeloid phenotype. Artificial fusion of tumor cells with macrophages leads to migratory, invasive, and metastatic phenotypes. Further studies might investigate whether these have a potential impact on the immune response towards the cancer. In this review, the background, evidence, and potential relevance of tumor cell fusions with macrophages is discussed, along with the potential role of intercellular connections in their formation. Such fusion cells could be a key component in cancer metastasis, and therefore, evolve as a diagnostic and therapeutic target in cancer precision medicine.
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Affiliation(s)
- Yariswamy Manjunath
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - David Porciani
- Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65212, USA; (D.P.); (D.H.B.)
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, USA
| | - Jonathan B. Mitchem
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Kanve N. Suvilesh
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
| | - Diego M. Avella
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Eric T. Kimchi
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Donald H. Burke
- Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65212, USA; (D.P.); (D.H.B.)
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, USA
- Department of Biochemistry, University of Missouri, Columbia, MO 65212, USA
| | - Guangfu Li
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65212, USA; (D.P.); (D.H.B.)
| | - Jussuf T. Kaifi
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
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M2 macrophages predict worse long-term outcomes in human acute tubular necrosis. Sci Rep 2020; 10:2122. [PMID: 32034190 PMCID: PMC7005727 DOI: 10.1038/s41598-020-58725-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 01/15/2020] [Indexed: 11/08/2022] Open
Abstract
Although macrophages are important players in the injury/repair processes in animal models of acute kidney injury (AKI), their roles in human AKI remains uncertain owing to a paucity of human biopsy studies. We investigated the role of macrophages in 72 cases of biopsy-proven acute tubular necrosis (ATN) and six cases of healthy kidney. Macrophages were identified by CD68 and CD163 immunohistochemistry and analyzed for their effect on renal outcomes. CD163+ M2 macrophages outnumbered CD68+ cells in the healthy kidneys, suggesting that CD163+ macrophages are resident macrophages. The infiltration of both subtypes of macrophages increased significantly in ATN. The density of the CD68+ macrophages was significantly higher in advanced-stage AKI, whereas CD163+ M2 macrophages was not. Eighty percent of patients exhibited renal functional recovery during follow-up. Older age and a higher density of CD163+ macrophages predicted non-recovery, whereas the AKI stage, tubular injury score, and density of CD68+ cells did not. The density of CD163+ M2 macrophages was an independent predictor of low eGFR at 3 months in advanced-stage AKI. This is the first human study demonstrating the possible role of macrophages in the injury and repair phases of AKI.
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Wang R, Lewis MS, Lyu J, Zhau HE, Pandol SJ, Chung LWK. Cancer-stromal cell fusion as revealed by fluorescence protein tracking. Prostate 2020; 80:274-283. [PMID: 31846114 PMCID: PMC6949378 DOI: 10.1002/pros.23941] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 12/06/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE We previously determined that cancer-stromal interaction was a direct route to tumor cell heterogeneity progression, since cancer-stromal cell fusion in coculture resulted in the creation of heterogeneous clones of fusion hybrid progeny. In this report, we modified the cancer-stromal coculture system to establish optimal experimental conditions for investigating cell fusion machinery and the mechanism of heterogeneity progression. EXPERIMENTAL DESIGN Red fluorescence protein-tagged LNCaP cells were cocultured with green fluorescence protein-labeled prostate stromal cells for cancer-stromal cell fusion, which was tracked as dual fluorescent cells by fluorescence microscopy. RESULTS We identified the most efficient strategy to isolate clones of fusion hybrid progenies. From the coculture, mixed cells including fusion hybrids were subjected to low-density replating for colony formation by fusion hybrid progeny. These colonies could propagate into derivative cell populations. Compared to the parental LNCaP cells, clones of the fusion hybrid progeny displayed divergent behaviors and exhibited permanent genomic hybridization. CONCLUSIONS Cancer-stromal cell fusion leads to cancer cell heterogeneity. The cancer-stromal coculture system characterized in this study can be used as a model for molecular characterization of cancer cell fusion as the mechanism behind the progression of heterogeneity observed in clinical prostate cancers.
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Affiliation(s)
- Ruoxiang Wang
- Uro-Oncology Research, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Pathology, VA Greater Los Angeles Healthcare System, Los Angeles, CA
| | - Michael S. Lewis
- Uro-Oncology Research, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Pathology, VA Greater Los Angeles Healthcare System, Los Angeles, CA
| | - Ji Lyu
- Uro-Oncology Research, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Haiyen E. Zhau
- Uro-Oncology Research, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Stephen J. Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Pathology, VA Greater Los Angeles Healthcare System, Los Angeles, CA
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Reduzzi C, Vismara M, Gerratana L, Silvestri M, De Braud F, Raspagliesi F, Verzoni E, Di Cosimo S, Locati LD, Cristofanilli M, Daidone MG, Cappelletti V. The curious phenomenon of dual-positive circulating cells: Longtime overlooked tumor cells. Semin Cancer Biol 2019; 60:344-350. [PMID: 31626958 DOI: 10.1016/j.semcancer.2019.10.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/05/2019] [Accepted: 10/09/2019] [Indexed: 01/29/2023]
Abstract
The presence in the blood of patients with solid tumors of circulating cells expressing both epithelial and leukocyte markers (dual-positive cells, DPcells), has often been reported, though it has never been investigated in detail. A recent study suggested that DPcells are hybrid cells derived from the fusion of tumor cells with macrophages. Such fusion hybrids acquire macrophage-associated features endowing them with accelerated growth, increased motility, enhanced invasion activity and thus, a higher efficiency in metastasis formation. However, no direct evidence proving the tumor origin of circulating DPcells was provided in patients. Here we contribute a review of literature data on DPcells and on the hybrid theory with the aim of putting the current evidence both in a biological and clinical perspective and to generate new hypotheses on the mechanisms underlying tumor progression. To add further biological and clinical context to our literature review, we also report some preliminary data from our laboratory on the identification of DPcells in several solid tumors and confirmation of their malignant genotype, thus classifying them as DP-CTCs.
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Affiliation(s)
- Carolina Reduzzi
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Marta Vismara
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Lorenzo Gerratana
- Department of Medicine (DAME), University of Udine, Italy; Department of Medicine-Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Marco Silvestri
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Filippo De Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; University of Milan, Milan, Italy
| | - Francesco Raspagliesi
- Department of surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Elena Verzoni
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Serena Di Cosimo
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Laura D Locati
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Massimo Cristofanilli
- Department of Medicine-Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Maria Grazia Daidone
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Vera Cappelletti
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
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Garvin S, Vikhe Patil E, Arnesson LG, Oda H, Hedayati E, Lindström A, Shabo I. Differences in intra-tumoral macrophage infiltration and radiotherapy response among intrinsic subtypes in pT1-T2 breast cancers treated with breast-conserving surgery. Virchows Arch 2019; 475:151-162. [PMID: 30915533 PMCID: PMC6647441 DOI: 10.1007/s00428-019-02563-3] [Citation(s) in RCA: 12] [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: 01/26/2019] [Revised: 03/12/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Abstract
Breast cancer (BC) intrinsic subtype classification is based on the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation marker Ki-67. The expression of these markers depends on both the genetic background of the cancer cells and the surrounding tumor microenvironment. In this study, we explore macrophage traits in cancer cells and intra-tumoral M2-macrophage infiltration (MI) in relation to intrinsic subtypes in non-metastatic invasive BC treated with breast conserving surgery, with and without postoperative radiotherapy (RT). Immunostaining of M2-macrophage-specific antigen CD163 in cancer cells and MI were evaluated, together with ER, PR, HER2, and Ki-67-expression in cancer cells. The tumors were classified into intrinsic subtypes according to the ESMO guidelines. The immunostaining of these markers, MI, and clinical data were analyzed in relation to ipsilateral local recurrence (ILR) as well as recurrence-free (RFS) and disease-free specific (DFS) survival. BC intrinsic subtypes are associated with T-stage, Nottingham Histologic Grade (NHG), and MI. Macrophage phenotype in cancer cells is significantly associated with NHG3-tumors. Significant differences in macrophage infiltration were observed among the intrinsic subtypes of pT1-T2 stage BC. Shorter RFS was observed in luminal B HER2neg tumors after RT, suggesting that this phenotype may be more resistant to irradiation. Ki-67-expression was significantly higher in NHG3 and CD163-positive tumors, as well as those with moderate and high MI. Cancer cell ER expression is inversely related to MI and thus might affect the clinical staging and assessment of BC.
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Affiliation(s)
- Stina Garvin
- Division of Pathology, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, SE 581 85, Linköping, Sweden
| | - Eva Vikhe Patil
- Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, SE 581 85, Linköping, Sweden
| | - Lars-Gunnar Arnesson
- Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, SE 581 85, Linköping, Sweden
| | - Husam Oda
- Department of Medical Biosciences, Pathology, Umeå University, SE-901 87, Umeå, Sweden
| | - Elham Hedayati
- Department of Oncology-Pathology, Karolinska Institutet, SE 171 76, Stockholm, Sweden
- Patient Area of Breast Cancer Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, SE 171 76, Stockholm, Sweden
| | - Annelie Lindström
- Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, SE 581 85, Linköping, Sweden
| | - Ivan Shabo
- Patient Area of Breast Cancer Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, SE 171 76, Stockholm, Sweden.
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE 171 77, Stockholm, Sweden.
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