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Di Spirito A, Balkhi S, Vivona V, Mortara L. Key immune cells and their crosstalk in the tumor microenvironment of bladder cancer: insights for innovative therapies. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2025; 6:1002304. [PMID: 40177538 PMCID: PMC11964778 DOI: 10.37349/etat.2025.1002304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/27/2025] [Indexed: 04/05/2025] Open
Abstract
Bladder cancer (BC) is a heterogeneous disease associated with high mortality if not diagnosed early. BC is classified into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC), with MIBC linked to poor systemic therapy response and high recurrence rates. Current treatments include transurethral resection with Bacillus Calmette-Guérin (BCG) therapy for NMIBC and radical cystectomy with chemotherapy and/or immunotherapy for MIBC. The tumor microenvironment (TME) plays a critical role in cancer progression, metastasis, and therapeutic efficacy. A comprehensive understanding of the TME's complex interactions holds substantial translational significance for developing innovative treatments. The TME can contribute to therapeutic resistance, particularly in immune checkpoint inhibitor (ICI) therapies, where resistance arises from tumor-intrinsic changes or extrinsic TME factors. Recent advancements in immunotherapy highlight the importance of translational research to address these challenges. Strategies to overcome resistance focus on remodeling the TME to transform immunologically "cold" tumors, which lack immune cell infiltration, into "hot" tumors that respond better to immunotherapy. These strategies involve disrupting cancer-microenvironment interactions, inhibiting angiogenesis, and modulating immune components to enhance anti-tumor responses. Key mechanisms include cytokine involvement [e.g., interleukin-6 (IL-6)], phenotypic alterations in macrophages and natural killer (NK) cells, and the plasticity of cancer-associated fibroblasts (CAFs). Identifying potential therapeutic targets within the TME can improve outcomes for MIBC patients. This review emphasizes the TME's complexity and its impact on guiding novel therapeutic approaches, offering hope for better survival in MIBC.
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Affiliation(s)
- Anna Di Spirito
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Sahar Balkhi
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Veronica Vivona
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Lorenzo Mortara
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
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2
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Tauch S, Hey J, Kast B, Gengenbacher N, Weiß L, Sator‐Schmitt M, Lohr S, Brobeil A, Schirmacher P, Utikal J, Augustin HG, Plass C, Angel P. A Unique Signature for Cancer-Associated Fibroblasts in Melanoma Metastases. Pigment Cell Melanoma Res 2025; 38:e70002. [PMID: 39924882 PMCID: PMC11808227 DOI: 10.1111/pcmr.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/27/2024] [Accepted: 01/16/2025] [Indexed: 02/11/2025]
Abstract
Cancer-associated fibroblasts (CAFs) represent a central cell population of the tumor microenvironment (TME). Recently, single-cell RNA-sequencing (scRNA-seq) analyses of primary tumors of different cancer entities yielded different classifications of CAF subsets underscoring the heterogeneity of CAFs within the TME. Here, we analyzed the transcriptional signatures of approximately 8400 CAFs and normal fibroblasts by scRNA-seq and compared genetic profiles of CAFs from murine melanoma primary tumors to CAFs from corresponding melanoma lung metastases. This revealed distinct subsets for primary tumor and metastasis-specific CAF populations, respectively. Combined with the spatial characterization of metastasis CAFs at the RNA and protein level, scRNA analyses indicate tumor-dependent crosstalk between neutrophils and CAFs, mediated via SAA3 and IL1b-related signaling pathways, which can be recapitulated in vitro. Analyzing tissue sections of human patient samples, this interaction was found to be present in human melanoma metastasis. Taken together, our data highlight unique characteristics of metastasis CAFs with potential therapeutic impact for melanoma metastasis.
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Affiliation(s)
- Saskia Tauch
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
| | - Joschka Hey
- Division of Cancer EpigenomicsGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Bettina Kast
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
| | - Nicolas Gengenbacher
- Division of Vascular Oncology and MetastasisGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
- European Center for Angioscience (ECAS), Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- DKFZ‐Hector Cancer Institute, University Medical Centre MannheimMannheimGermany
| | - Lena Weiß
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
| | - Melanie Sator‐Schmitt
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
| | - Sabrina Lohr
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
| | - Alexander Brobeil
- Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Peter Schirmacher
- Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Jochen Utikal
- DKFZ‐Hector Cancer Institute, University Medical Centre MannheimMannheimGermany
- Skin Cancer UnitGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Department of Dermatology, Venereology and AllergologyUniversity Medical Center Mannheim, Ruprecht‐Karl University of HeidelbergMannheimGermany
| | - Hellmut G. Augustin
- Division of Vascular Oncology and MetastasisGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
- European Center for Angioscience (ECAS), Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- DKFZ‐Hector Cancer Institute, University Medical Centre MannheimMannheimGermany
| | - Christoph Plass
- Division of Cancer EpigenomicsGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Peter Angel
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
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Antoon R, Overdevest N, Saleh AH, Keating A. Mesenchymal stromal cells as cancer promoters. Oncogene 2024; 43:3545-3555. [PMID: 39414984 PMCID: PMC11602730 DOI: 10.1038/s41388-024-03183-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 09/12/2024] [Accepted: 09/26/2024] [Indexed: 10/18/2024]
Abstract
Mesenchymal stromal cells (MSCs) are important cellular constituents of tumor stroma that play an active role in tumor development. Complex interactions between MSCs and cancer promote tumor progression by creating a favorable milieu for tumor cell proliferation, angiogenesis, motility, invasion, and metastasis. The cellular heterogeneity, source of origin, diversity in isolation methods, culture techniques and model systems of MSCs, together with the different tumor subtypes, add to the complexity of MSC-tumor interactions. In this review, we discuss the mechanisms of MSC-mediated tumor promotion and evaluate cell-stromal interactions between cancer cells, MSCs, cells of the tumor microenvironment (TME), and the extracellular matrix (ECM). A more thorough understanding of tumor-MSC interactions is likely to lead to better cancer management.
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Affiliation(s)
| | | | - Amr H Saleh
- Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.
- Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
| | - Armand Keating
- Krembil Research Institute, Toronto, ON, Canada.
- Princess Margaret Cancer Centre, Toronto, ON, Canada.
- University Health Network, Toronto, ON, Canada.
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4
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Carlomagno S, Setti C, Ortolani F, Sivori S. Pancreatic ductal adenocarcinoma microenvironment: Soluble factors and cancer associated fibroblasts as modulators of NK cell functions. Immunol Lett 2024; 269:106898. [PMID: 39019404 DOI: 10.1016/j.imlet.2024.106898] [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: 06/03/2024] [Accepted: 07/13/2024] [Indexed: 07/19/2024]
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent pancreatic cancer and represents one of the most aggressive human neoplasms. Typically identified at advance stage disease, most PDAC tumors are unresectable and resistant to standard therapies. The immunosuppressive microenvironment in PDAC impedes tumor control but a greater understanding of the complex stromal interactions within the tumor microenvironment (TME) and the development of strategies capable of restoring antitumor effector immune responses could be crucial to fight this aggressive tumor and its spread. Natural Killer (NK) cells play a crucial role in cancer immunosurveillance and represent an attractive target for immunotherapies, both as cell therapy and as a pharmaceutical target. This review describes some crucial components of the PDAC TME (collagens, soluble factors and fibroblasts) that can influence the presence, phenotype and function of NK cells in PDAC patients tumor tissue. This focused overview highlights the therapeutic relevance of dissecting the complex stromal composition to define new strategies for NK cell-based immunotherapies to improve the treatment of PDAC.
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Affiliation(s)
- Simona Carlomagno
- Department of Medicine (DMED), University of Udine, Piazzale Kolbe 4, Udine 33100, Italy.
| | - Chiara Setti
- Department of Experimental Medicine (DIMES), University of Genoa, Via Leon Battista Alberti 2, Genoa 16132, Italy
| | - Fulvia Ortolani
- Department of Medicine (DMED), University of Udine, Piazzale Kolbe 4, Udine 33100, Italy
| | - Simona Sivori
- Department of Experimental Medicine (DIMES), University of Genoa, Via Leon Battista Alberti 2, Genoa 16132, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
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Valdivia-Silva J, Chinney-Herrera A. Chemokine receptors and their ligands in breast cancer: The key roles in progression and metastasis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:124-161. [PMID: 39260935 DOI: 10.1016/bs.ircmb.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.
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Affiliation(s)
- Julio Valdivia-Silva
- Centro de Investigación en Bioingenieria (BIO), Universidad de Ingenieria y Tecnologia-UTEC, Barranco, Lima, Peru.
| | - Alberto Chinney-Herrera
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico-UNAM, Ciudad Universitaria, Coyoacan, Ciudad de Mexico, Mexico
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6
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Chen H, Fang S, Zhu X, Liu H. Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression. Front Cell Dev Biol 2024; 12:1412337. [PMID: 39092186 PMCID: PMC11291335 DOI: 10.3389/fcell.2024.1412337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
The functional heterogeneity and ecological niche of prostate cancer stem cells (PCSCs), which are major drivers of prostate cancer development and treatment resistance, have attracted considerable research attention. Cancer-associated fibroblasts (CAFs), which are crucial components of the tumor microenvironment (TME), substantially affect PCSC stemness. Additionally, CAFs promote PCSC growth and survival by releasing signaling molecules and modifying the surrounding environment. Conversely, PCSCs may affect the characteristics and behavior of CAFs by producing various molecules. This crosstalk mechanism is potentially crucial for prostate cancer progression and the development of treatment resistance. Using organoids to model the TME enables an in-depth study of CAF-PCSC interactions, providing a valuable preclinical tool to accurately evaluate potential target genes and design novel treatment strategies for prostate cancer. The objective of this review is to discuss the current research on the multilevel and multitarget regulatory mechanisms underlying CAF-PCSC interactions and crosstalk, aiming to inform therapeutic approaches that address challenges in prostate cancer treatment.
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Affiliation(s)
| | | | | | - Hao Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Bagger MM, Sjölund J, Kim J, Kohler KT, Villadsen R, Jafari A, Kassem M, Pietras K, Rønnov-Jessen L, Petersen OW. Evidence of steady-state fibroblast subtypes in the normal human breast as cells-of-origin for perturbed-state fibroblasts in breast cancer. Breast Cancer Res 2024; 26:11. [PMID: 38229104 PMCID: PMC10790388 DOI: 10.1186/s13058-024-01763-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Human breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts representing one out of two steady-state fibroblast subtypes-the other being interlobular fibroblasts. While cancer-associated fibroblasts (CAFs) are increasingly appreciated as covering a spectrum of perturbed states, we lack a coherent understanding of their relationship-if any-with the steady-state fibroblast subtypes. To address this, we here established two autologous CAF lines representing inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs) and compared them with already established interlobular- and lobular fibroblasts with respect to their origin and impact on tumor formation. METHODS Primary breast tumor-derived CAFs were transduced to express human telomerase reverse transcriptase (hTERT) and sorted into CD105low and CD105high populations using fluorescence-activated cell sorting (FACS). The two populations were tested for differentiation similarities to iCAF and myCAF states through transcriptome-wide RNA-Sequencing (RNA-Seq) including comparison to an available iCAF-myCAF cell state atlas. Inference of origin in interlobular and lobular fibroblasts relied on RNA-Seq profiles, immunocytochemistry and growth characteristics. Osteogenic differentiation and bone formation assays in culture and in vivo were employed to gauge for origin in bone marrow-derived mesenchymal stem cells (bMSCs). Functional characteristics were assessed with respect to contractility in culture and interaction with tumor cells in mouse xenografts. The cells' gene expression signatures were tested for association with clinical outcome of breast cancer patients using survival data from The Cancer Genome Atlas database. RESULTS We demonstrate that iCAFs have properties in common with interlobular fibroblasts while myCAFs and lobular fibroblasts are related. None of the CAFs qualify as bMSCs as revealed by lack of critical performance in bone formation assays. Functionally, myCAFs and lobular fibroblasts are almost equally tumor promoting as opposed to iCAFs and interlobular fibroblasts. A myCAF gene signature is found to associate with poor breast cancer-specific survival. CONCLUSIONS We propose that iCAFs and myCAFs originate in interlobular and lobular fibroblasts, respectively, and more importantly, that the tumor-promoting properties of lobular fibroblasts render the TDLU an epicenter for breast cancer evolution.
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Affiliation(s)
- Mikkel Morsing Bagger
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Centre, Lund University, Lund, Sweden.
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - Jonas Sjölund
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Centre, Lund University, Lund, Sweden
| | - Jiyoung Kim
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | | | - René Villadsen
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Abbas Jafari
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Moustapha Kassem
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
- Laboratory of Molecular Endocrinology, KMEB, Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark
| | - Kristian Pietras
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Centre, Lund University, Lund, Sweden
| | - Lone Rønnov-Jessen
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Ole William Petersen
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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8
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Lian W, Xiang P, Ye C, Xiong J. Single-cell RNA Sequencing Analysis Reveals the Role of Cancerassociated Fibroblasts in Skin Melanoma. Curr Med Chem 2024; 31:7015-7029. [PMID: 38173195 DOI: 10.2174/0109298673282799231211113347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 01/05/2024]
Abstract
AIMS Mechanism of fibroblasts in skin melanoma (SKME) revealed by single-cell RNA sequencing data. BACKGROUND SKME is responsible for more than 80% of skin-related cancer deaths. Cancer-associated fibroblasts (CAFs) generate inflammatory factors, growth factors and extracellular matrix proteins to facilitate cancer cell growth, metastasis, drug resistance and immune exclusion. However, molecular mechanisms of CAFs in SKME are still lacking. OBJECTIVE Our goal was to reveal the role of CAFs in SKME. METHODS We downloaded the single-cell RNA sequencing (scRNA-seq) dataset from the Gene Expression Omnibus (GSE215120) database. Then, the Seurat package was applied to analyze the single-cell atlas of SKME data, and cell subsets were annotated with the CellMarker database. The molecular mechanisms of CAFs in SKME were disclosed via differential gene expression and enrichment analysis, Cellchat and SCENIC methods. RESULTS Using scRNA-seq data, three SKME cases were used and downscaled and clustered to identify 11 cell subgroups and 5 CAF subsets. The enrichment of highly expressed genes among the 5 CAF subsets suggests that cell migration-inducing hyaluronan-binding protein (CEMIP) + fibroblasts and naked cuticle homolog 1 (NKD1)+ fibroblasts were closely associated with epithelial to mesenchymal transition. Cellchat analysis revealed that CAF subpopulations promoted melanocyte proliferation through Jagged1 (JAG1)-Notch homolog 1 (NOTCH1), JAG1-NOTCH3 and migration through pleiotrophin (PTN)-syndecan-3 (SDC3) receptor-ligand pairs. The SCENIC analysis identified that most of the transcription factors in each CAF subpopulation played a certain role in the metastasis of melanoma and were highly expressed in metastatic SKME samples. Specifically, we observed that CEMIP+ fibroblasts and NKD1+ fibroblasts had potential roles in participating in immune therapy resistance. Collectively, we uncovered a single-cell atlas of SKME and revealed the molecular mechanisms of CAFs in SKME development, providing a base for immune therapy and prognosis assessment. CONCLUSION Our study reveals that 5 CAFs in SKME have a promoting effect on melanocyte proliferation and metastasis. More importantly, CEMIP+ fibroblasts and NKD1+ fibroblasts displayed close connections with immune therapy resistance. These findings help provide a good basis for future immune therapy and prognosis assessment targeting CAFs in SKME.
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Affiliation(s)
- Wenqin Lian
- Department of Oral and Maxillofacial Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510032, China
| | - Pan Xiang
- Nephrology Department, Beijing Ditan Hospital, Capital Medical University, Beijing, 100102, China
| | - Chunjiang Ye
- Department of Burns and Plastic Surgery, Zhejiang Quhua Hospital, Quzhou, 324002, China
| | - Jian Xiong
- Department of Obstetrics and Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510032, China
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9
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Zhao Z, Li T, Sun L, Yuan Y, Zhu Y. Potential mechanisms of cancer-associated fibroblasts in therapeutic resistance. Biomed Pharmacother 2023; 166:115425. [PMID: 37660643 DOI: 10.1016/j.biopha.2023.115425] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/30/2023] [Accepted: 08/30/2023] [Indexed: 09/05/2023] Open
Abstract
Despite continuous improvements in research and new cancer therapeutics, the goal of eradicating cancer remains elusive because of drug resistance. For a long time, drug resistance research has been focused on tumor cells themselves; however, recent studies have found that the tumor microenvironment also plays an important role in inducing drug resistance. Cancer-associated fibroblasts (CAFs) are a main component of the tumor microenvironment. They cross-talk with cancer cells to support their survival in the presence of anticancer drugs. This review summarizes the current knowledge of the role of CAFs in tumor drug resistance. An in-depth understanding of the mechanisms underlying the cross-talk between CAFs and cancer cells and insight into the importance of CAFs in drug resistance can guide the development of new anticancer strategies.
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Affiliation(s)
- Zehua Zhao
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Tianming Li
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Liping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
| | - Yanmei Zhu
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China.
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10
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Chang M, Chen W, Xia R, Peng Y, Niu P, Fan H. Pancreatic Stellate Cells and the Targeted Therapeutic Strategies in Chronic Pancreatitis. Molecules 2023; 28:5586. [PMID: 37513458 PMCID: PMC10383437 DOI: 10.3390/molecules28145586] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP pathogenesis is gradually revealed, accumulating evidence suggests that the activation of pancreatic stellate cells (PSCs) and the appearance of a myofibroblast-like phenotype are the key gatekeepers in the development of CP. Targeting PSCs to prevent their activation and conversion to a myofibroblast-like phenotype, as well as increasing antioxidant capacity to counteract ongoing oxidative stress, are effective strategies for preventing or treating CP. Therefore, we reviewed the crosstalk between CP and pancreatic fibrosis, summarized the activation mechanisms of PSCs, and investigated potential CP therapeutic strategies targeting PSCs, including, but not limited to, anti-fibrosis therapy, antioxidant therapy, and gene therapy. Meanwhile, the above therapeutic strategies are selected in order to update the available phytopharmaceuticals as novel complementary or alternative approaches for the prevention and treatment of CP to clarify their potential mechanisms of action and their relevant molecular targets, aiming to provide the most comprehensive therapeutic treatment direction for CP and to bring new hope to CP patients.
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Affiliation(s)
- Man Chang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Wenjuan Chen
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ruting Xia
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yangyue Peng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Pandi Niu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Hui Fan
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
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11
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Sun S, Zhang Y, Li Y, Wei L. Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs. Front Immunol 2023; 14:1161628. [PMID: 37234178 PMCID: PMC10206140 DOI: 10.3389/fimmu.2023.1161628] [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: 02/08/2023] [Accepted: 05/02/2023] [Indexed: 05/27/2023] Open
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the digestive system, and its morbidity rates are increasing worldwide. Cancer-associated fibroblasts (CAFs), as part of the tumor microenvironment (TME), are not only closely linked to normal fibroblasts, but also can secrete a variety of substances (including exosomes) to participate in the regulation of the TME. Exosomes can play a key role in intercellular communication by delivering intracellular signaling substances (e.g., proteins, nucleic acids, non-coding RNAs), and an increasing number of studies have shown that non-coding RNAs of exosomal origin from CAFs are not only closely associated with the formation of the CRC microenvironment, but also increase the ability of CRC to grow in metastasis, mediate tumor immunosuppression, and are involved in the mechanism of drug resistance in CRC patients receiving. It is also involved in the mechanism of drug resistance after radiotherapy in CRC patients. In this paper, we review the current status and progress of research on CAFs-derived exosomal non-coding RNAs in CRC.
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Affiliation(s)
| | | | | | - Linlin Wei
- Department of Radiotherapy, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
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Brichkina A, Polo P, Sharma SD, Visestamkul N, Lauth M. A Quick Guide to CAF Subtypes in Pancreatic Cancer. Cancers (Basel) 2023; 15:cancers15092614. [PMID: 37174079 PMCID: PMC10177377 DOI: 10.3390/cancers15092614] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/21/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer represents one of the most desmoplastic malignancies and is characterized by an extensive deposition of extracellular matrix. The latter is provided by activated cancer-associated fibroblasts (CAFs), which are abundant cells in the pancreatic tumor microenvironment. Many recent studies have made it clear that CAFs are not a singular cellular entity but represent a multitude of potentially dynamic subgroups that affect tumor biology at several levels. As mentioned before, CAFs significantly contribute to the fibrotic reaction and the biomechanical properties of the tumor, but they can also modulate the local immune environment and the response to targeted, chemo or radiotherapy. As the number of known and emerging CAF subgroups is steadily increasing, it is becoming increasingly difficult to keep up with these developments and to clearly discriminate the cellular subsets identified so far. This review aims to provide a helpful overview that enables readers to quickly familiarize themselves with field of CAF heterogeneity and to grasp the phenotypic, functional and therapeutic distinctions of the various stromal subpopulations.
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Affiliation(s)
- Anna Brichkina
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
| | - Pierfrancesco Polo
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
| | - Shrey Dharamvir Sharma
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
| | - Nico Visestamkul
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
| | - Matthias Lauth
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
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13
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Caramelo B, Zagorac S, Corral S, Marqués M, Real FX. Cancer-associated Fibroblasts in Bladder Cancer: Origin, Biology, and Therapeutic Opportunities. Eur Urol Oncol 2023:S2588-9311(23)00043-3. [PMID: 36890105 DOI: 10.1016/j.euo.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/28/2022] [Accepted: 02/08/2023] [Indexed: 03/08/2023]
Abstract
CONTEXT Bladder cancer (BLCA) is a highly prevalent tumour and a health problem worldwide, especially among men. Recent work has highlighted the relevance of the tumour microenvironment (TME) in cancer biology with translational implications. Cancer-associated fibroblasts (CAFs) are a prominent, heterogeneous population of cells in the TME. CAFs have been associated with tumour development, progression, and poor prognosis in several neoplasms. However, their role in BLCA has not yet been exploited deeply. OBJECTIVE To review the role of CAFs in BLCA biology and provide an understanding of CAF origin, subtypes, markers, and phenotypic and functional characteristics to improve patient management. EVIDENCE ACQUISITION A PubMed search was performed to review manuscripts published using the terms "cancer associated fibroblast" and "bladder cancer" or "urothelial cancer". All abstracts were reviewed, and the full content of all relevant manuscripts was analysed. In addition, selected manuscripts on CAFs in other tumours were considered. EVIDENCE SYNTHESIS CAFs have been studied less extensively in BLCA than in other tumours. Thanks to new techniques, such as single-cell RNA-seq and spatial transcriptomics, it is now possible to accurately map and molecularly define the phenotype of fibroblasts in normal bladder and BLCA. Bulk transcriptomic analyses have revealed the existence of subtypes among both non-muscle-invasive and muscle-invasive BLCA; these subtypes display distinct features regarding their CAF content. We provide a higher-resolution map of the phenotypic diversity of CAFs in these tumour subtypes. Preclinical studies and recent promising clinical trials leverage on this knowledge through the combined targeting of CAFs or their effectors and the immune microenvironment. CONCLUSIONS Current knowledge of BLCA CAFs and the TME is being increasingly applied to improve BLCA therapy. There is a need to acquire a deeper understanding of CAF biology in BLCA. PATIENT SUMMARY Tumour cells are surrounded by nontumoural cells that contribute to the determination of the behaviour of cancers. Among them are cancer-associated fibroblasts. The "neighbourhoods" established through these cellular interactions can now be studied with much greater resolution. Understanding these features of tumours will contribute to the designing of more effective therapies, especially in relationship to bladder cancer immunotherapy.
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Affiliation(s)
- Belén Caramelo
- Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain; Hospital Sierrallana, Torrelavega, Spain
| | - Sladjana Zagorac
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
| | - Sonia Corral
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
| | - Miriam Marqués
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain; CIBERONC, Madrid, Spain.
| | - Francisco X Real
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain; CIBERONC, Madrid, Spain; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
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14
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Chen JY, Yiu WH, Tang PMK, Tang SCW. New insights into fibrotic signaling in renal cell carcinoma. Front Cell Dev Biol 2023; 11:1056964. [PMID: 36910160 PMCID: PMC9996540 DOI: 10.3389/fcell.2023.1056964] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 01/17/2023] [Indexed: 02/23/2023] Open
Abstract
Fibrotic signaling plays a pivotal role in the development and progression of solid cancers including renal cell carcinoma (RCC). Intratumoral fibrosis (ITF) and pseudo-capsule (PC) fibrosis are significantly correlated to the disease progression of renal cell carcinoma. Targeting classic fibrotic signaling processes such as TGF-β signaling and epithelial-to-mesenchymal transition (EMT) shows promising antitumor effects both preclinically and clinically. Therefore, a better understanding of the pathogenic mechanisms of fibrotic signaling in renal cell carcinoma at molecular resolution can facilitate the development of precision therapies against solid cancers. In this review, we systematically summarized the latest updates on fibrotic signaling, from clinical correlation and molecular mechanisms to its therapeutic strategies for renal cell carcinoma. Importantly, we examined the reported fibrotic signaling on the human renal cell carcinoma dataset at the transcriptome level with single-cell resolution to assess its translational potential in the clinic.
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Affiliation(s)
- Jiao-Yi Chen
- Division of Nephrology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Wai-Han Yiu
- Division of Nephrology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Sydney Chi-Wai Tang
- Division of Nephrology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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15
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Zhao G, Wang C, Jiao J, Zhang W, Yang H. The novel subclusters based on cancer-associated fibroblast for pancreatic adenocarcinoma. Front Oncol 2022; 12:1045477. [PMID: 36544710 PMCID: PMC9762551 DOI: 10.3389/fonc.2022.1045477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/09/2022] [Indexed: 12/08/2022] Open
Abstract
Introduction Pancreatic adenocarcinoma (PAAD) is a fatal disease characterized by promoting connective tissue proliferation in the stroma. Activated cancer-associated fibroblasts (CAFs) play a key role in fibrogenesis in PAAD. CAF-based tumor typing of PAAD has not been explored. Methods We extracted single-cell sequence transcriptomic data from GSE154778 and CRA001160 datasets from Gene Expression Omnibus or Tumor Immune Single-cell Hub to collect CAFs in PAAD. On the basis of Seurat packages and new algorithms in machine learning, CAF-related subtypes and their top genes for PAAD were analyzed and visualized. We used CellChat package to perform cell-cell communication analysis. In addition, we carried out functional enrichment analysis based on clusterProfiler package. Finally, we explored the prognostic and immunotherapeutic value of these CAF-related subtypes for PAAD. Results CAFs were divided into five new subclusters (CAF-C0, CAF-C1, CAF-C2, CAF-C3, and CAF-C4) based on their marker genes. The five CAF subclusters exhibited distinct signaling patterns, immune status, metabolism features, and enrichment pathways and validated in the pan-cancer datasets. In addition, we found that both CAF-C2 and CAF-C4 subgroups were negatively correlated with prognosis. With their top genes of each subclusters, the sub-CAF2 had significantly relations to immunotherapy response in the patients with pan-cancer and immunotherapy. Discussion We explored the heterogeneity of five subclusters based on CAF in signaling patterns, immune status, metabolism features, enrichment pathways, and prognosis for PAAD.
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Affiliation(s)
- Guojie Zhao
- The Seventh Department of General Surgery, HanDan Central Hospital, Handan, Hebei, China
| | - Changjing Wang
- The Department of Gastrointestinal surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jian Jiao
- The Seventh Department of General Surgery, HanDan Central Hospital, Handan, Hebei, China
| | - Wei Zhang
- The Seventh Department of General Surgery, HanDan Central Hospital, Handan, Hebei, China
| | - Hongwei Yang
- The First Department of Oncology, HanDan Central Hospital, Handan, Hebei, China,*Correspondence: Hongwei Yang,
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Ductal keratin 15 + luminal progenitors in normal breast exhibit a basal-like breast cancer transcriptomic signature. NPJ Breast Cancer 2022; 8:81. [PMID: 35821504 PMCID: PMC9276673 DOI: 10.1038/s41523-022-00444-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 06/10/2022] [Indexed: 11/09/2022] Open
Abstract
Normal breast luminal epithelial progenitors have been implicated as cell of origin in basal-like breast cancer, but their anatomical localization remains understudied. Here, we combine collection under the microscope of organoids from reduction mammoplasties and single-cell mRNA sequencing (scRNA-seq) of FACS-sorted luminal epithelial cells with multicolor imaging to profile ducts and terminal duct lobular units (TDLUs) and compare them with breast cancer subtypes. Unsupervised clustering reveals eleven distinct clusters and a differentiation trajectory starting with keratin 15+ (K15+) progenitors enriched in ducts. Spatial mapping of luminal progenitors is confirmed at the protein level by staining with critical duct markers. Comparison of the gene expression profiles of normal luminal cells with those of breast cancer subtypes suggests a strong correlation between normal breast ductal progenitors and basal-like breast cancer. We propose that K15+ basal-like breast cancers originate in ductal progenitors, which emphasizes the importance of not only lineages but also cellular position within the ductal-lobular tree.
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17
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Baumann Z, Auf der Maur P, Bentires‐Alj M. Feed-forward loops between metastatic cancer cells and their microenvironment-the stage of escalation. EMBO Mol Med 2022; 14:e14283. [PMID: 35506376 PMCID: PMC9174884 DOI: 10.15252/emmm.202114283] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/15/2022] [Accepted: 02/16/2022] [Indexed: 12/14/2022] Open
Abstract
Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancer-related deaths. While survival of early-stage breast cancer patients has increased dramatically, the 5-year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental factors influencing the sudden outgrowth of disseminated tumor cells (DTCs). This review summarizes how the environment of the most common metastatic sites (lung, liver, bone, brain) is influenced by the primary tumor and by the varying dormancy of DTCs, with a special focus on how established metastases persist and grow in distant organs due to feed-forward loops (FFLs). We discuss in detail the importance of FFL of cancer cells with their microenvironment including the secretome, interaction with specialized tissue-specific cells, nutrients/metabolites, and that novel therapies should target not only the cancer cells but also the tumor microenvironment, which are thick as thieves.
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Affiliation(s)
- Zora Baumann
- Tumor Heterogeneity Metastasis and ResistanceDepartment of BiomedicineUniversity Hospital BaselUniversity of BaselBaselSwitzerland
| | - Priska Auf der Maur
- Tumor Heterogeneity Metastasis and ResistanceDepartment of BiomedicineUniversity Hospital BaselUniversity of BaselBaselSwitzerland
| | - Mohamed Bentires‐Alj
- Tumor Heterogeneity Metastasis and ResistanceDepartment of BiomedicineUniversity Hospital BaselUniversity of BaselBaselSwitzerland
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18
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Vokurka M, Lacina L, Brábek J, Kolář M, Ng YZ, Smetana K. Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production. Int J Mol Sci 2022; 23:964. [PMID: 35055153 PMCID: PMC8778626 DOI: 10.3390/ijms23020964] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/10/2022] [Accepted: 01/13/2022] [Indexed: 12/15/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are an essential component of the tumour microenvironment. They represent a heterogeneous group of cells that are under the control of cancer cells and can reversely influence the cancer cell population. They affect the cancer cell differentiation status, and the migration and formation of metastases. This is achieved through the production of the extracellular matrix and numerous bioactive factors. IL-6 seems to play the central role in the communication of noncancerous and cancer cells in the tumour. This review outlines the role of exosomes in cancer cells and cancer-associated fibroblasts. Available data on the exosomal cargo, which can significantly intensify interactions in the tumour, are summarised. The role of exosomes as mediators of the dialogue between cancer cells and cancer-associated fibroblasts is discussed together with their therapeutic relevance. The functional unity of the paracrine- and exosome-mediated communication of cancer cells with the tumour microenvironment represented by CAFs is worthy of attention.
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Affiliation(s)
- Martin Vokurka
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, 120 00 Prague 2, Czech Republic;
| | - Lukáš Lacina
- Institute of Anatomy, First Faculty of Medicine, Charles University, 120 00 Prague 2, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Department of Dermatovenereology, First Faculty of Medicine, Charles University and General University Hospital, 120 00 Prague, Czech Republic
| | - Jan Brábek
- Department of Cell Biology, Faculty of Science, Charles University, 120 00 Prague 2, Czech Republic;
- BIOCEV, Faculty of Science, Charles University, 252 50 Vestec, Czech Republic
| | - Michal Kolář
- Institute of Molecular Genetics, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic;
| | - Yi Zhen Ng
- A*STAR Skin Research Labs (A*SRL)—Biopolis, Skin Research Institute of Singapore, 8A Biomedical Grove #06-06 Immunos Singapore, Singapore 138665, Singapore;
| | - Karel Smetana
- Institute of Anatomy, First Faculty of Medicine, Charles University, 120 00 Prague 2, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
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19
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Fibroblasts as immune regulators in infection, inflammation and cancer. Nat Rev Immunol 2021; 21:704-717. [PMID: 33911232 DOI: 10.1038/s41577-021-00540-z] [Citation(s) in RCA: 320] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
Abstract
In chronic infection, inflammation and cancer, the tissue microenvironment controls how local immune cells behave, with tissue-resident fibroblasts emerging as a key cell type in regulating activation or suppression of an immune response. Fibroblasts are heterogeneous cells, encompassing functionally distinct populations, the phenotypes of which differ according to their tissue of origin and type of inciting disease. Their immunological properties are also diverse, ranging from the maintenance of a potent inflammatory environment in chronic inflammation to promoting immunosuppression in malignancy, and encapsulating and incarcerating infectious agents within tissues. In this Review, we compare the mechanisms by which fibroblasts control local immune responses, as well as the factors regulating their inflammatory and suppressive profiles, in different tissues and pathological settings. This cross-disease perspective highlights the importance of tissue context in determining fibroblast-immune cell interactions, as well as potential therapeutic avenues to exploit this knowledge for the benefit of patients with chronic infection, inflammation and cancer.
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20
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Jiang G, Tu J, Zhou L, Dong M, Fan J, Chang Z, Zhang L, Bian X, Liu S. Single-cell transcriptomics reveal the heterogeneity and dynamic of cancer stem-like cells during breast tumor progression. Cell Death Dis 2021; 12:979. [PMID: 34675206 PMCID: PMC8531288 DOI: 10.1038/s41419-021-04261-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 09/17/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022]
Abstract
Breast cancer stem-like cells (BCSCs) play vital roles in tumorigenesis and progression. However, the origin and dynamic changes of BCSCs are still to be elucidated. Using the breast cancer mouse model MMTV-PyMT, we constructed a single-cell atlas of 31,778 cells from four distinct stages of tumor progression (hyperplasia, adenoma/MIN, early carcinoma and late carcinoma), during which malignant transition occurs. We identified that the precise cell type of ERlow epithelial cell lineage gave rise to the tumors, and the differentiation of ERhigh epithelial cell lineage was blocked. Furthermore, we discovered a specific signature with a continuum of gene expression profiles along the tumor progression and significantly correlated with clinical outcomes, and we also found a stem-like cell cluster existed among ERlow epithelial cells. Further clustering on this stem-like cluster showed several sub-clusters indicating heterogeneity of stem-like epithelial cells. Moreover, we distinguished normal and cancer stem-like cells in this stem-like epithelial cell cluster and profiled the molecular portraits from normal stem-like cell to cancer stem-like cells during the malignant transition. Finally, we found the diverse immune cell infiltration displayed immunosuppressive characteristics along tumor progression. We also found the specific expression pattern of cytokines and their corresponding cytokine receptors in BCSCs and immune cells, suggesting the possible cross-talk between BCSCs and the immune cells. These data provide a useful resource for illuminating BCSC heterogeneity and the immune cell remodeling during breast tumor progression, and shed new light on transcriptomic dynamics during the progression at the single-cell level.
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Affiliation(s)
- Guojuan Jiang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, 200032, Shanghai, China
| | - Juchuanli Tu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, 200032, Shanghai, China
| | - Lei Zhou
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, 200032, Shanghai, China
| | - Mengxue Dong
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, 200032, Shanghai, China
| | - Jue Fan
- Singleron Biotechnologies, Yaogu Avenue 11, 210043, Nanjing, Jiangsu, China
| | - Zhaoxia Chang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, 200032, Shanghai, China
| | - Lixing Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, 200032, Shanghai, China
| | - Xiuwu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University); Key Laboratory of Tumor Immunopathology, Ministry of Education of China, 400038, Chongqing, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, 200032, Shanghai, China.
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21
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Manoukian P, Bijlsma M, van Laarhoven H. The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth. Front Cell Dev Biol 2021; 9:743907. [PMID: 34646829 PMCID: PMC8502878 DOI: 10.3389/fcell.2021.743907] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 08/30/2021] [Indexed: 12/17/2022] Open
Abstract
Pancreatic tumors are known to harbor an abundant and highly desmoplastic stroma. Among the various cell types that reside within tumor stroma, cancer-associated fibroblasts (CAFs) have gained a lot of attention in the cancer field due to their contributions to carcinogenesis and tumor architecture. These cells are not a homogeneous population, but have been shown to have different origins, phenotypes, and contributions. In pancreatic tumors, CAFs generally emerge through the activation and/or recruitment of various cell types, most notably resident fibroblasts, pancreatic stellate cells (PSCs), and tumor-infiltrating mesenchymal stem cells (MSCs). In recent years, single cell transcriptomic studies allowed the identification of distinct CAF populations in pancreatic tumors. Nonetheless, the exact sources and functions of those different CAF phenotypes remain to be fully understood. Considering the importance of stromal cells in pancreatic cancer, many novel approaches have aimed at targeting the stroma but current stroma-targeting therapies have yielded subpar results, which may be attributed to heterogeneity in the fibroblast population. Thus, fully understanding the roles of different subsets of CAFs within the stroma, and the cellular dynamics at play that contribute to heterogeneity in CAF subsets may be essential for the design of novel therapies and improving clinical outcomes. Fortunately, recent advances in technologies such as microfluidics and bio-printing have made it possible to establish more advanced ex vivo models that will likely prove useful. In this review, we will present the different roles of stromal cells in pancreatic cancer, focusing on CAF origin as a source of heterogeneity, and the role this may play in therapy failure. We will discuss preclinical models that could be of benefit to the field and that may contribute to further clinical development.
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Affiliation(s)
- Paul Manoukian
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Maarten Bijlsma
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Hanneke van Laarhoven
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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22
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Chandra Jena B, Sarkar S, Rout L, Mandal M. The transformation of cancer-associated fibroblasts: Current perspectives on the role of TGF-β in CAF mediated tumor progression and therapeutic resistance. Cancer Lett 2021; 520:222-232. [PMID: 34363903 DOI: 10.1016/j.canlet.2021.08.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/16/2021] [Accepted: 08/01/2021] [Indexed: 12/12/2022]
Abstract
Over the last few years, the Transforming growth factor- β (TGF-β) has been significantly considered as an effective and ubiquitous mediator of cell growth. The cytokine, TGF-β is being increasingly recognized as the most potent inducer of cancer cell initiation, differentiation, migration as well as progression through both the SMAD-dependent and independent pathways. There is growing evidence that supports the role of secretory cytokine TGF-β as a crucial mediator of tumor-stroma crosstalk. Contextually, the CAFs are the prominent component of tumor stroma that helps in tumor progression and onset of chemoresistance. The interplay between the CAFs and the tumor cells through the paracrine signals is facilitated by cytokine TGF-β to induce the malignant progression. Here in this review, we have dissected the most recent advancements in understanding the mechanisms of TGF-β induced CAF activation, their multiple origins, and most importantly their role in conferring chemoresistance. Considering the pivotal role of TGF-β in tumor perogression and associated stemness, it is one the proven clinical targets We have also included the clinical trials going on, targeting the TGF-β and CAFs crosstalk with the tumor cells. Ultimately, we have underscored some of the outstanding issues that must be deciphered with utmost importance to unravel the successful strategies of anti-cancer therapies.
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Affiliation(s)
- Bikash Chandra Jena
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Siddik Sarkar
- CSIR-Indian Institue of Chemical Biology, Translational Research Unit of Excellence, Kolkata, West Bengal, India
| | - Lipsa Rout
- Department of Chemistry, Institute of Technical Education and Research, Siksha'O'Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
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23
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Magesh P, Thankachan S, Venkatesh T, Suresh PS. Breast cancer fibroblasts and cross-talk. Clin Chim Acta 2021; 521:158-169. [PMID: 34270953 DOI: 10.1016/j.cca.2021.07.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/07/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023]
Abstract
The breast tumor microenvironment is one of the crucial elements supporting breast cancer tumor progression and metastasis. The fibroblasts are the chief cellular component of the stromal microenvironment and are pathologically activated and differentiated into breast cancer-associated fibroblasts (CAFs). The catabolic phenotype of breast CAFs arises due to metabolic reprogramming of these fibroblasts under pseudo-hypoxic conditions. The metabolic intermediates and ATP produced by the breast CAFs are exploited by the neighboring cancer cells for energy generation. The growth factors, cytokines, and chemokines secreted by the CAFs help fuel tumor growth, invasion, and dissemination. Moreover, the interplay between breast CAFs and cancer cells, mediated by the growth factors, ROS, metabolic intermediates, exosomes, and catabolite transporters, aids in building a favorable microenvironment that promotes cancer cell proliferation, tumor progression, and metastasis. Therefore, identifying effective means to target the reprogrammed metabolism of the breast CAFs and the cross-communication between CAFs and cancer cells serve as promising strategies to develop anti-cancer therapeutics. Henceforth, the scope of the present review ranges from discussing the underlying characteristics of breast CAFs, mechanisms of metabolic reprogramming in breast CAFs, and the nature of interactions between breast CAFs and cancer cells to studying the intricacies of reprogrammed metabolism targeted cancer therapy.
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Affiliation(s)
- Priyanila Magesh
- School of Biotechnology, National Institute of Technology, Calicut 673601, Kerala, India
| | - Sanu Thankachan
- School of Biotechnology, National Institute of Technology, Calicut 673601, Kerala, India
| | - Thejaswini Venkatesh
- Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasaragod 671316, India
| | - Padmanaban S Suresh
- School of Biotechnology, National Institute of Technology, Calicut 673601, Kerala, India.
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Zacchi P, Belmonte B, Mangogna A, Morello G, Scola L, Martorana A, Borelli V. The Ferroxidase Hephaestin in Lung Cancer: Pathological Significance and Prognostic Value. Front Oncol 2021; 11:638856. [PMID: 34094919 PMCID: PMC8170403 DOI: 10.3389/fonc.2021.638856] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 04/26/2021] [Indexed: 12/30/2022] Open
Abstract
Hephaestin (HEPH) belongs to a group of exocytoplasmic ferroxidases which contribute to cellular iron homeostasis by favouring its export. Down-regulation of HEPH expression, possibly by stimulating cell proliferation due to an increase in iron availability, has shown to correlate with poor survival in breast cancer. The lung is particularly sensitive to iron-induced oxidative stress, given the high oxygen tension present, however, HEPH distribution in lung cancer and its influence on prognosis have not been investigated yet. In this study we explored the prognostic value of HEPH and its expression pattern in the most prevalent histotypes of lung cancers, namely lung adenocarcinoma and lung squamous cell carcinoma. In silico analyses, based on UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter bioinformatics, revealed a significant correlation between higher levels of HEPH expression and favorable prognosis, in both cancer histotypes. Moreover, TIMER web platform showed a statistically significant association between HEPH expression and cell elements belonging to the tumor microenvironment identified as endothelial cells and a subpopulation of cancer-associated fibroblasts, further confirmed by double immunohistochemical labeling with cell type specific markers. Taken together, these data shed a light on the complex mechanisms of local iron handling lung cancer can exploit to support tumorigenesis.
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Affiliation(s)
- Paola Zacchi
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Beatrice Belmonte
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Gaia Morello
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy
| | - Letizia Scola
- Clinical Pathology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Anna Martorana
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy
| | - Violetta Borelli
- Department of Life Sciences, University of Trieste, Trieste, Italy
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25
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Hinow P, Pinter G, Yan W, Wang SE. Modeling the bidirectional glutamine/ammonium conversion between cancer cells and cancer-associated fibroblasts. PeerJ 2021; 9:e10648. [PMID: 33520452 PMCID: PMC7811294 DOI: 10.7717/peerj.10648] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/04/2020] [Indexed: 12/13/2022] Open
Abstract
Like in an ecosystem, cancer and other cells residing in the tumor microenvironment engage in various modes of interactions to buffer the negative effects of environmental changes. One such change is the consumption of common nutrients (such as glutamine/Gln) and the consequent accumulation of toxic metabolic byproducts (such as ammonium/NH4). Ammonium is a waste product of cellular metabolism whose accumulation causes cell stress. In tumors, it is known that it can be recycled into nutrients by cancer associated fibroblasts (CAFs). Here we present monoculture and coculture growth of cancer cells and CAFs on different substrates: glutamine and ammonium. We propose a mathematical model to aid our understanding. We find that cancer cells are able to survive on ammonium and recycle it to glutamine for limited periods of time. CAFs are able to even grow on ammonium. In coculture, the presence of CAFs results in an improved survival of cancer cells compared to their monoculture when exposed to ammonium. Interestingly, the ratio between the two cell populations is maintained under various concentrations of NH4, suggesting the ability of the mixed cell system to survive temporary metabolic stress and sustain the size and cell composition as a stable entity.
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Affiliation(s)
- Peter Hinow
- Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
| | - Gabriella Pinter
- Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
| | - Wei Yan
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - Shizhen Emily Wang
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
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26
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Liu S, Ren J, Ten Dijke P. Targeting TGFβ signal transduction for cancer therapy. Signal Transduct Target Ther 2021; 6:8. [PMID: 33414388 PMCID: PMC7791126 DOI: 10.1038/s41392-020-00436-9] [Citation(s) in RCA: 227] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/04/2020] [Accepted: 12/05/2020] [Indexed: 12/19/2022] Open
Abstract
Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.
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Affiliation(s)
- Sijia Liu
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands
| | - Jiang Ren
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands.
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27
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Aghakhani S, Zerrouk N, Niarakis A. Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches. Cancers (Basel) 2020; 13:E35. [PMID: 33374292 PMCID: PMC7795338 DOI: 10.3390/cancers13010035] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/12/2020] [Accepted: 12/17/2020] [Indexed: 12/29/2022] Open
Abstract
Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modeling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.
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Affiliation(s)
- Sahar Aghakhani
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
- Lifeware Group, Inria Saclay, 91120 Palaiseau, France
| | - Naouel Zerrouk
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
| | - Anna Niarakis
- GenHotel, University of Evry, University of Paris-Saclay, Genopole, 91000 Evry, France; (S.A.); (N.Z.)
- Lifeware Group, Inria Saclay, 91120 Palaiseau, France
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28
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Esteban-Villarrubia J, Soto-Castillo JJ, Pozas J, San Román-Gil M, Orejana-Martín I, Torres-Jiménez J, Carrato A, Alonso-Gordoa T, Molina-Cerrillo J. Tyrosine Kinase Receptors in Oncology. Int J Mol Sci 2020; 21:E8529. [PMID: 33198314 PMCID: PMC7696731 DOI: 10.3390/ijms21228529] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/07/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023] Open
Abstract
Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.
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Affiliation(s)
- Jorge Esteban-Villarrubia
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (J.J.S.-C.); (J.P.); (M.S.R.-G.); (I.O.-M.); (J.T.-J.)
| | - Juan José Soto-Castillo
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (J.J.S.-C.); (J.P.); (M.S.R.-G.); (I.O.-M.); (J.T.-J.)
| | - Javier Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (J.J.S.-C.); (J.P.); (M.S.R.-G.); (I.O.-M.); (J.T.-J.)
| | - María San Román-Gil
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (J.J.S.-C.); (J.P.); (M.S.R.-G.); (I.O.-M.); (J.T.-J.)
| | - Inmaculada Orejana-Martín
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (J.J.S.-C.); (J.P.); (M.S.R.-G.); (I.O.-M.); (J.T.-J.)
| | - Javier Torres-Jiménez
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (J.E.-V.); (J.J.S.-C.); (J.P.); (M.S.R.-G.); (I.O.-M.); (J.T.-J.)
| | - Alfredo Carrato
- Medical Oncology Department, Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, Alcalá University, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (A.C.); (J.M.-C.)
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, Alcalá University, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (A.C.); (J.M.-C.)
| | - Javier Molina-Cerrillo
- Medical Oncology Department, Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, Alcalá University, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (A.C.); (J.M.-C.)
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Mukaida N, Zhang D, Sasaki SI. Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process. Cancers (Basel) 2020; 12:2896. [PMID: 33050237 PMCID: PMC7600711 DOI: 10.3390/cancers12102896] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/02/2020] [Accepted: 10/07/2020] [Indexed: 12/12/2022] Open
Abstract
Bone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs patients' quality of life and prognosis. At the first step of bone metastasis, cancer cells adhere to the endothelium in bone marrow and survive in a dormant state by utilizing hematopoietic niches present therein. Once a dormant stage is disturbed, cancer cells grow through the interaction with various bone marrow resident cells, particularly osteoclasts and osteoblasts. Consequently, osteoclast activation is a hallmark of bone metastasis. As a consequence, the drugs targeting osteoclast activation are frequently used to treat bone metastasis but are not effective to inhibit cancer cell growth in bone marrow. Thus, additional types of resident cells are presumed to contribute to cancer cell growth in bone metastasis sites. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues and can have diverse roles in cancer progression and metastasis. Given the presence of CAFs in bone metastasis sites, CAFs are emerging as an important cellular player in bone metastasis. Hence, in this review, we will discuss the potential roles of CAFs in tumor progression, particularly bone metastasis.
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Affiliation(s)
- Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; (D.Z.); (S.S.)
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30
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Hurtado P, Martínez-Pena I, Piñeiro R. Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs). Cancers (Basel) 2020; 12:E2861. [PMID: 33027902 PMCID: PMC7599894 DOI: 10.3390/cancers12102861] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/02/2020] [Accepted: 10/02/2020] [Indexed: 02/06/2023] Open
Abstract
The crosstalk between cancer cells and the tumor microenvironment (TME) is a key determinant of cancer metastasis. Cancer-associated fibroblasts (CAFs), one of the main cellular components of TME, promote cancer cell invasion and dissemination through mechanisms including cell-cell interactions and the paracrine secretion of growth factors, cytokines and chemokines. During metastasis, circulating tumor cells (CTCs) are shed from the primary tumor to the bloodstream, where they can be detected as single cells or clusters. The current knowledge about the biology of CTC clusters positions them as key actors in metastasis formation. It also indicates that CTCs do not act alone and that they may be aided by stromal and immune cells, which seem to shape their metastatic potential. Among these cells, CAFs are found associated with CTCs in heterotypic CTC clusters, and their presence seems to increase their metastatic efficiency. In this review, we summarize the current knowledge on the role that CAFs play on metastasis and we discuss their implication on the biogenesis, metastasis-initiating capacity of CTC clusters, and clinical implications. Moreover, we speculate about possible therapeutic strategies aimed to limit the metastatic potential of CTC clusters involving the targeting of CAFs as well as their difficulties and limitations.
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Affiliation(s)
- Pablo Hurtado
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (P.H.); (I.M.-P.)
| | - Inés Martínez-Pena
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (P.H.); (I.M.-P.)
| | - Roberto Piñeiro
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (P.H.); (I.M.-P.)
- CIBERONC, Centro de Investigación Biomédica en Red Cáncer, 28029 Madrid, Spain
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31
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Valcz G, Buzás EI, Sebestyén A, Krenács T, Szállási Z, Igaz P, Molnár B. Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy. Cancers (Basel) 2020; 12:cancers12082324. [PMID: 32824649 PMCID: PMC7465064 DOI: 10.3390/cancers12082324] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/12/2020] [Accepted: 08/16/2020] [Indexed: 02/07/2023] Open
Abstract
Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual tumor masses. However, these therapy-resistant cells are unlikely to be sufficient for the fast tumor repopulation and regrowth by themselves. The dynamic and coordinated plasticity of residual tumor cells is essential both for the conversion of their regulatory network and for the stromal microenvironment to produce cancer supporting signals. In this nursing tissue "niche", cancer-associated fibroblasts are known to play crucial roles in developing therapy resistance and survival of residual stem-like cells. As paracrine messengers, extracellular vesicles carrying a wide range of signaling molecules with oncogenic potential, can support the escape of some tumor cells from their deadly fate. Here, we briefly overview how extracellular vesicle signaling between fibroblasts and cancer cells including cancer progenitor/stem cells may contribute to the progression, therapy resistance and recurrence of malignant tumors.
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Affiliation(s)
- Gábor Valcz
- 2nd Department of Internal Medicine and MTA-SE Molecular Medicine Research Group, 1051 Budapest, Hungary; (P.I.); (B.M.)
- Correspondence:
| | - Edit I. Buzás
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 1089 Budapest, Hungary;
- MTA-SE Immune-Proteogenomics Extracellular Vesicle Research Group, Hungarian Academy of Sciences, 1089 Budapest, Hungary
- Hungarian Center of Excellence Molecular Medicine-Semmelweis University Extracellular Vesicle Research Group, 1085 Budapest, Hungary
| | - Anna Sebestyén
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary; (A.S.); (T.K.)
| | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary; (A.S.); (T.K.)
| | - Zoltán Szállási
- Computational Health Informatics Program (CHIP), Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
| | - Péter Igaz
- 2nd Department of Internal Medicine and MTA-SE Molecular Medicine Research Group, 1051 Budapest, Hungary; (P.I.); (B.M.)
| | - Béla Molnár
- 2nd Department of Internal Medicine and MTA-SE Molecular Medicine Research Group, 1051 Budapest, Hungary; (P.I.); (B.M.)
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32
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Hu Y, Taylor-Harding B, Raz Y, Haro M, Recouvreux MS, Taylan E, Lester J, Millstein J, Walts AE, Karlan BY, Orsulic S. Are Epithelial Ovarian Cancers of the Mesenchymal Subtype Actually Intraperitoneal Metastases to the Ovary? Front Cell Dev Biol 2020; 8:647. [PMID: 32766252 PMCID: PMC7380132 DOI: 10.3389/fcell.2020.00647] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
Primary ovarian high-grade serous carcinoma (HGSC) has been classified into 4 molecular subtypes: Immunoreactive, Proliferative, Differentiated, and Mesenchymal (Mes), of which the Mes subtype (Mes-HGSC) is associated with the worst clinical outcomes. We propose that Mes-HGSC comprise clusters of cancer and associated stromal cells that detached from tumors in the upper abdomen/omentum and disseminated in the peritoneal cavity, including to the ovary. Using comparative analyses of multiple transcriptomic data sets, we provide the following evidence that the phenotype of Mes-HGSC matches the phenotype of tumors in the upper abdomen/omentum: (1) irrespective of the primary ovarian HGSC molecular subtype, matched upper abdominal/omental metastases were typically of the Mes subtype, (2) the Mes subtype was present at the ovarian site only in patients with concurrent upper abdominal/omental metastases and not in those with HGSC confined to the ovary, and (3) ovarian Mes-HGSC had an expression profile characteristic of stromal cells in the upper abdominal/omental metastases. We suggest that ovarian Mes-HGSC signifies advanced intraperitoneal tumor dissemination to the ovary rather than a subtype of primary ovarian HGSC. This is consistent with the presence of upper abdominal/omental disease, suboptimal debulking, and worst survival previously reported in patients with ovarian Mes-HGSC compared to other molecular subtypes.
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Affiliation(s)
- Ye Hu
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Barbie Taylor-Harding
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yael Raz
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Marcela Haro
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Maria Sol Recouvreux
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Enes Taylan
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Jenny Lester
- Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Joshua Millstein
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Ann E Walts
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Beth Y Karlan
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
| | - Sandra Orsulic
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
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33
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Ramakrishnan P, Loh WM, Gopinath SC, Bonam SR, Fareez IM, Mac Guad R, Sim MS, Wu YS. Selective phytochemicals targeting pancreatic stellate cells as new anti-fibrotic agents for chronic pancreatitis and pancreatic cancer. Acta Pharm Sin B 2020; 10:399-413. [PMID: 32140388 PMCID: PMC7049637 DOI: 10.1016/j.apsb.2019.11.008] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 09/23/2019] [Accepted: 10/29/2019] [Indexed: 12/15/2022] Open
Abstract
Activated pancreatic stellate cells (PSCs) have been widely accepted as a key precursor of excessive pancreatic fibrosis, which is a crucial hallmark of chronic pancreatitis (CP) and its formidable associated disease, pancreatic cancer (PC). Hence, anti-fibrotic therapy has been identified as a novel therapeutic strategy for treating CP and PC by targeting PSCs. Most of the anti-fibrotic agents have been limited to phase I/II clinical trials involving vitamin analogs, which are abundant in medicinal plants and have proved to be promising for clinical application. The use of phytomedicines, as new anti-fibrotic agents, has been applied to a variety of complementary and alternative approaches. The aim of this review was to present a focused update on the selective new potential anti-fibrotic agents, including curcumin, resveratrol, rhein, emodin, green tea catechin derivatives, metformin, eruberin A, and ellagic acid, in combating PSC in CP and PC models. It aimed to describe the mechanism(s) of the phytochemicals used, either alone or in combination, and the associated molecular targets. Most of them were tested in PC models with similar mechanism of actions, and curcumin was tested intensively. Future research may explore the issues of bioavailability, drug design, and nano-formulation, in order to achieve successful clinical outcomes with promising activity and tolerability.
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Affiliation(s)
- Puvanesswaray Ramakrishnan
- Ageing and Age-Associated Disorders Research Group, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Wei Mee Loh
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Subash C.B. Gopinath
- School of Bioprocess Engineering, Universiti Malaysia Perlis, Arau 02600, Malaysia
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar 01000, Malaysia
| | - Srinivasa Reddy Bonam
- UMR 7242, CNRS-University of Strasbourg, Biotechnology and Cell Signaling/Laboratory of Excellence Medalis, Illkirch 67400, France
| | - Ismail M. Fareez
- Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Selangor 42610, Malaysia
| | - Rhanye Mac Guad
- Department of Biomedical Science and Therapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia
| | - Maw Shin Sim
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, Kuala Lumpur 50603, Malaysia
- Corresponding authors. Tel./fax: +60 3 51022709 (Yuan Seng Wu); +60 3 79675749 (Maw Shin Sim).
| | - Yuan Seng Wu
- Department of Biochemistry, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor 42610, Malaysia
- Corresponding authors. Tel./fax: +60 3 51022709 (Yuan Seng Wu); +60 3 79675749 (Maw Shin Sim).
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Shakib H, Rajabi S, Dehghan MH, Mashayekhi FJ, Safari-Alighiarloo N, Hedayati M. Epithelial-to-mesenchymal transition in thyroid cancer: a comprehensive review. Endocrine 2019; 66:435-455. [PMID: 31378850 DOI: 10.1007/s12020-019-02030-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 07/19/2019] [Indexed: 12/12/2022]
Abstract
The Metastatic progression of solid tumors, such as thyroid cancer is a complex process which involves various factors. Current understanding on the role of epithelial-mesenchymal transition (EMT) in thyroid carcinomas suggests that EMT is implicated in the progression from follicular thyroid cancer (FTC) and papillary thyroid cancer (PTC) to poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid cancer (ATC). According to the literature, the initiation of the EMT program in thyroid epithelial cells elevates the number of stem cells, which contribute to recurrent and metastatic diseases. The EMT process is orchestrated by a complex network of transcription factors, growth factors, signaling cascades, epigenetic modulations, and the tumor milieu. These factors have been shown to be dysregulated in thyroid carcinomas. Therefore, molecular interferences restoring the expression of tumor suppressors, or thwarting overexpressed oncogenes is a hopeful therapeutic method to improve the treatment of progressive diseases. In this review, we summarize the recent findings on EMT in thyroid cancer focusing on the main role-players and regulators of this process in thyroid tumors.
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Affiliation(s)
- Heewa Shakib
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sadegh Rajabi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Nahid Safari-Alighiarloo
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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da Cunha BR, Domingos C, Stefanini ACB, Henrique T, Polachini GM, Castelo-Branco P, Tajara EH. Cellular Interactions in the Tumor Microenvironment: The Role of Secretome. J Cancer 2019; 10:4574-4587. [PMID: 31528221 PMCID: PMC6746126 DOI: 10.7150/jca.21780] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/25/2019] [Indexed: 02/06/2023] Open
Abstract
Over the past years, it has become evident that cancer initiation and progression depends on several components of the tumor microenvironment, including inflammatory and immune cells, fibroblasts, endothelial cells, adipocytes, and extracellular matrix. These components of the tumor microenvironment and the neoplastic cells interact with each other providing pro and antitumor signals. The tumor-stroma communication occurs directly between cells or via a variety of molecules secreted, such as growth factors, cytokines, chemokines and microRNAs. This secretome, which derives not only from tumor cells but also from cancer-associated stromal cells, is an important source of key regulators of the tumorigenic process. Their screening and characterization could provide useful biomarkers to improve cancer diagnosis, prognosis, and monitoring of treatment responses.
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Affiliation(s)
- Bianca Rodrigues da Cunha
- Department of Molecular Biology, School of Medicine of São José do Rio Preto/FAMERP, São José do Rio Preto, SP, Brazil
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, SP, Brazil
| | - Célia Domingos
- Department of Biomedical Sciences and Medicine, University of Algarve, Portugal
- Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal
| | - Ana Carolina Buzzo Stefanini
- Department of Molecular Biology, School of Medicine of São José do Rio Preto/FAMERP, São José do Rio Preto, SP, Brazil
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, SP, Brazil
| | - Tiago Henrique
- Department of Molecular Biology, School of Medicine of São José do Rio Preto/FAMERP, São José do Rio Preto, SP, Brazil
| | - Giovana Mussi Polachini
- Department of Molecular Biology, School of Medicine of São José do Rio Preto/FAMERP, São José do Rio Preto, SP, Brazil
| | - Pedro Castelo-Branco
- Department of Biomedical Sciences and Medicine, University of Algarve, Portugal
- Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal
- Algarve Biomedical Center, Gambelas, Faro, Portugal
| | - Eloiza Helena Tajara
- Department of Molecular Biology, School of Medicine of São José do Rio Preto/FAMERP, São José do Rio Preto, SP, Brazil
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, SP, Brazil
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Singh S, Chakrabarti R. Consequences of EMT-Driven Changes in the Immune Microenvironment of Breast Cancer and Therapeutic Response of Cancer Cells. J Clin Med 2019; 8:jcm8050642. [PMID: 31075939 PMCID: PMC6572359 DOI: 10.3390/jcm8050642] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 04/30/2019] [Accepted: 05/04/2019] [Indexed: 02/06/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a process through which epithelial cells lose their epithelial characteristics and cell–cell contact, thus increasing their invasive potential. In addition to its well-known roles in embryonic development, wound healing, and regeneration, EMT plays an important role in tumor progression and metastatic invasion. In breast cancer, EMT both increases the migratory capacity and invasive potential of tumor cells, and initiates protumorigenic alterations in the tumor microenvironment (TME). In particular, recent evidence has linked increased expression of EMT markers such as TWIST1 and MMPs in breast tumors with increased immune infiltration in the TME. These immune cells then provide cues that promote immune evasion by tumor cells, which is associated with enhanced tumor progression and metastasis. In the current review, we will summarize the current knowledge of the role of EMT in the biology of different subtypes of breast cancer. We will further explore the correlation between genetic switches leading to EMT and EMT-induced alterations within the TME that drive tumor growth and metastasis, as well as their possible effect on therapeutic response in breast cancer.
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Affiliation(s)
- Snahlata Singh
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Rumela Chakrabarti
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Cancer-associated fibroblasts: how do they contribute to metastasis? Clin Exp Metastasis 2019; 36:71-86. [PMID: 30847799 DOI: 10.1007/s10585-019-09959-0] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 02/25/2019] [Indexed: 02/06/2023]
Abstract
Cancer-associated fibroblasts (CAFs) are activated fibroblasts in the tumor microenvironment. They are one of the most prominent cell types in the stroma and produce large amounts of extracellular matrix molecules, chemokines, cytokines and growth factors. Importantly, CAFs promote cancer progression and metastasis by multiple pathways. This, together with their genetic stability, makes them an interesting target for cancer therapy. However, CAF heterogeneity and limited knowledge about the function of the different CAF subpopulations in vivo, are currently major obstacles for identifying specific molecular targets that are of value for cancer treatment. In this review, we discuss recent major findings on CAF development and their metastasis-promoting functions, as well as open questions to be addressed in order to establish successful cancer therapies targeting CAFs.
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Wang XL, Huang C. Difference of TGF-β/Smads signaling pathway in epithelial-mesenchymal transition of normal colonic epithelial cells induced by tumor-associated fibroblasts and colon cancer cells. Mol Biol Rep 2019; 46:2749-2759. [PMID: 30835040 DOI: 10.1007/s11033-019-04719-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 02/25/2019] [Indexed: 02/07/2023]
Abstract
Tumor microenvironment (TME) crucially functions in tumor initiation and progression. Stroma-tumor interactions and cellular transdifferentiation are the prerequisite for tumor formation. Transforming growth factor-β (TGF-β), a major cytokine secreted by tumor-associated fibroblasts (TAFs) and cancer cells, is a crucial player involving cell transdifferentiation. Therefore, we hypothesized that these TAFs and cancer cells also affect normal colon epithelium. In our study, we found for the first time that colon cancer cells HCT116 and TAF-like CCD-18Co cells induced epithelial-mesenchymal transition (EMT)-like transdifferentiation in colon epithelial cells HCoEpiCs, with enhanced migratio. Dysfunction of TGF-β/Smads signal was also observed in the EMT-transformed HCoEpiCs. We wondered whether these phenomena were regulated by TGF-β/Smads signaling pathway. A TGFβ receptor kinase I (TβRI) inhibitor LY364947 was used. We found that the EMT induced by the HCT116- and CCD-18Co-derived CM was suppressed by the LY364947. Besides, different expression profiles for the components of TGF-β/Smads pathway were found in the EMT-like HCoEpiCs, but high expression of p-Smad2/3 and Smad4 was the common feature. Our observations suggest that the mechanisms of phenotypic transition of colon epithelial cells are cellular environment-dependent, which maybe a basis of potential therapy targeting TME.
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Affiliation(s)
- Xiu-Lian Wang
- Community Health Service Center, Shenzhen Bao'an Traditional Chinese Medicine Hospital Group, Shenzhen, China
| | - Chao Huang
- Central Laboratory, Affiliated Bao'an Hospital of Shenzhen, Southern Medical University, Shenzhen, China.
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Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene 2019; 38:4887-4901. [PMID: 30816343 DOI: 10.1038/s41388-019-0765-y] [Citation(s) in RCA: 223] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/16/2019] [Accepted: 02/18/2019] [Indexed: 12/12/2022]
Abstract
Increasing lines of evidence show that the malignant behavior of cancer is not exclusively attributable to cancer cells but also radically influenced by cancerous stroma activity and controlled through various mechanisms by the microenvironment. In addition to structural components, such as the extracellular matrix, stromal cells, such as macrophages, endothelial cells, and specifically cancer-associated fibroblasts (CAFs), have attracted substantial attention over recent decades. CAFs provide routes for aggressive carcinomas and contribute to invasion and metastasis through the biochemical alteration and regulation of cancer-related pathways. However, another facet of CAFs that has been neglected by numerous studies is that CAFs might serve as a negative regulator of cancer progression under certain circumstances. The various origins of CAFs, the diverse tissues in which they reside and their interactions with different cancer cells appear to be responsible for this inconsistency. This review summarizes the latest knowledge regarding CAF heterogeneity and offers a novel perspective and a beneficial approach for obtaining an improved understanding of CAFs.
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Huang C, Tao L, Wang X, Pang Z. Berberine reversed the epithelial‐mesenchymal transition of normal colonic epithelial cells induced by SW480 cells through regulating the important components in the TGF‐β pathway. J Cell Physiol 2018; 234:11679-11691. [PMID: 30536375 DOI: 10.1002/jcp.27835] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/06/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Chao Huang
- Institute of Pharmacology, Sun Yat‐Sen Zhongshan Medical College, Sun Yat‐Sen University Guangzhou China
| | - Liang Tao
- Institute of Pharmacology, Sun Yat‐Sen Zhongshan Medical College, Sun Yat‐Sen University Guangzhou China
| | - Xiu‐lian Wang
- Department of Traditional Chinese Medicine Affiliated Bao’an Hospital of Traditional Chinese Medicine of Shenzhen, Traditional Chinese Medicine University Of Guangzhou Shenzhen China
| | - Zuoliang Pang
- Department of Oncology Affiliated Bao’an Hospital of Shenzhen, Southern Medical University Shenzhen China
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Hernández-Camarero P, Jiménez G, López-Ruiz E, Barungi S, Marchal JA, Perán M. Revisiting the dynamic cancer stem cell model: Importance of tumour edges. Crit Rev Oncol Hematol 2018; 131:35-45. [PMID: 30293704 DOI: 10.1016/j.critrevonc.2018.08.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 08/22/2018] [Indexed: 02/07/2023] Open
Abstract
The lack of an effective treatment against cancer is not only due to its huge heterogeneity, but also to the fact that we don't have an answer to the question on how cancer originates. Among the proposed models to explain the development of cancer, the hierarchical model has been widely accepted. Nevertheless, this model fails to explain several experimental observations such as the cancer stem cells (CSCs) location inside a tumour or the differences between primary and metastatic tumours. Moreover, increasing evidence shows that the CSC phenotype is not a rigid state. Here, we present a critical review on the assumed tumour development models emphasizing the relevance of the dynamic and changing nature of cancer and the CSCs population in which the tumour microenvironment plays a crucial role and we propose a new model of tumour origin that could have an impact on new therapeutic strategies.
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Affiliation(s)
| | - Gema Jiménez
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, E- 18016, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, E- 18016, Spain; Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, E-18071, Spain
| | - Elena López-Ruiz
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, E- 18016, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, E- 18016, Spain; Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, E-18071, Spain
| | - Shivan Barungi
- Department of Health Sciences, University of Jaén, Jaén E-23071, Spain
| | - Juan Antonio Marchal
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, E- 18016, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, E- 18016, Spain; Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, E-18071, Spain.
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, Jaén E-23071, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, E- 18016, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain.
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Sadlecki P, Jóźwicki J, Antosik P, Grabiec M. Expression of selected epithelial-mesenchymal transition transcription factors in serous borderline ovarian tumors and type I ovarian cancers. Tumour Biol 2018; 40:1010428318784807. [PMID: 29952249 DOI: 10.1177/1010428318784807] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Epithelial ovarian neoplasms are a heterogeneous group including tumor subsets with distinct clinicopathologic and molecular features. Recent evidence from molecular and genomic studies suggests that whereas low-grade serous carcinomas and high-grade serous carcinomas likely develop on two separate pathways, the low-grade serous carcinomas and serous borderline ovarian tumors may represent various stages of the same developmental continuum. The transformation of borderline ovarian tumors into an invasive neoplasm is associated with an array of molecular changes, inter alia controlled by p53 and PI3K/Akt pathway, as well as with a decrease in E-cadherin expression. The latter implies that epithelial-mesenchymal transition is a critical determinant of borderline ovarian tumor invasiveness. The aim of this study was to analyze the expression of transcription factors involved in epithelial-mesenchymal transition: SNAIL, SLUG, TWIST 1, TWIST 2, ZEB 1, and ZEB 2 in borderline tumors and type I ovarian cancers. The study included tissue specimens from 42 patients with histopathologically verified ovarian masses. The expressions for SLUG, TWIST 1, ZEB1, and ZEB 2 were scored based on the nuclear staining, and the expressions of SNAIL and TWIST 2 based on the cytoplasmic and/or nuclear staining. The proportions of ovarian tumors with the immunoexpression of the epithelial-mesenchymal transition transcription factors were 85.7% for SNAIL, 100% for SLUG, 9.5% for TWIST 1, 95.2% for TWIST 2, 23.8% for ZEB 1, and 0% for ZEB 2. The expression patterns of SNAIL, SLUG, TWIST, and ZEB identified in this study suggest that both serous borderline ovarian tumors and type I ovarian cancers undergo dynamic epithelial-mesenchymal interconversions. Our findings obtained in the two groups of tumors which shared some etiopathogenic pathways imply that the expression of the epithelial-mesenchymal transition transcription factors may be activated at early stages of the epithelial-mesenchymal transition, and thus these molecules may play a pivotal role in the development of both serous borderline ovarian tumors and type I ovarian cancer.
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Affiliation(s)
- Pawel Sadlecki
- 1 Department of Obstetrics and Gynecology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Jakub Jóźwicki
- 2 Department of Clinical Pathomorphology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Paulina Antosik
- 2 Department of Clinical Pathomorphology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Marek Grabiec
- 1 Department of Obstetrics and Gynecology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
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Caja L, Dituri F, Mancarella S, Caballero-Diaz D, Moustakas A, Giannelli G, Fabregat I. TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer. Int J Mol Sci 2018. [PMID: 29701666 DOI: 10.3390/ijms19051294.pmid:29701666;pmcid:pmc5983604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in the matrix as part of a large latent complex bound to the latent TGF-β binding protein (LTBP) and matrix binding of latent TGF-β complexes, which is required for an adequate TGF-β function. Once TGF-β is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer-associated fibroblast (CAF) phenotype. Furthermore, TGF-β exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-β and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF-β chemical inhibitors as a new line of defence against fibrotic disorders or cancer.
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Affiliation(s)
- Laia Caja
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Box 582, 75123 Uppsala, Sweden.
| | - Francesco Dituri
- National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, 70013 Bari, Italy.
| | - Serena Mancarella
- National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, 70013 Bari, Italy.
| | - Daniel Caballero-Diaz
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199, 08908 Barcelona, Spain.
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Aristidis Moustakas
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Box 582, 75123 Uppsala, Sweden.
| | - Gianluigi Giannelli
- National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, 70013 Bari, Italy.
| | - Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199, 08908 Barcelona, Spain.
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain.
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet, 08907 Barcelona, Spain.
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Caja L, Dituri F, Mancarella S, Caballero-Diaz D, Moustakas A, Giannelli G, Fabregat I. TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer. Int J Mol Sci 2018; 19:ijms19051294. [PMID: 29701666 PMCID: PMC5983604 DOI: 10.3390/ijms19051294] [Citation(s) in RCA: 250] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/17/2018] [Accepted: 04/24/2018] [Indexed: 12/14/2022] Open
Abstract
Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in the matrix as part of a large latent complex bound to the latent TGF-β binding protein (LTBP) and matrix binding of latent TGF-β complexes, which is required for an adequate TGF-β function. Once TGF-β is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer-associated fibroblast (CAF) phenotype. Furthermore, TGF-β exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-β and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF-β chemical inhibitors as a new line of defence against fibrotic disorders or cancer.
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Affiliation(s)
- Laia Caja
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Box 582, 75123 Uppsala, Sweden.
| | - Francesco Dituri
- National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, 70013 Bari, Italy.
| | - Serena Mancarella
- National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, 70013 Bari, Italy.
| | - Daniel Caballero-Diaz
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199, 08908 Barcelona, Spain.
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Aristidis Moustakas
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Box 582, 75123 Uppsala, Sweden.
| | - Gianluigi Giannelli
- National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, 70013 Bari, Italy.
| | - Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199, 08908 Barcelona, Spain.
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain.
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet, 08907 Barcelona, Spain.
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Vincent KM, Postovit LM. Matricellular proteins in cancer: a focus on secreted Frizzled-related proteins. J Cell Commun Signal 2018; 12:103-112. [PMID: 28589318 PMCID: PMC5842174 DOI: 10.1007/s12079-017-0398-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 06/02/2017] [Indexed: 12/31/2022] Open
Abstract
Tumours are complex entities, wherein cancer cells interact with myriad soluble, insoluble and cell associated factors. These microenvironmental mediators regulate tumour growth, progression and metastasis, and are produced by cancer cells and by stromal components such as fibroblast, adipocytes and immune cells. Through their ability to bind to extracellular matrix proteins, cell surface receptors and growth factors, matricellular proteins enable a dynamic reciprocity between cancer cells and their microenvironment. Hence, matricellular proteins play a critical role in tumour progression by regulating where and when cancer cells are exposed to key growth factors and regulatory proteins. Recent studies suggest that, in addition to altering Wingless (Wnt) signalling, certain members of the Secreted Frizzled Related Protein (sFRP) family are matricellular in nature. In this review, we outline the importance of matricellular proteins in cancer, and discuss how sFRPs may function to both inhibit and promote cancer progression in a context-dependent manner. By considering the matricellular functionality of sFRPs, we may better understand their apparently paradoxical roles in cancers.
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Affiliation(s)
- Krista Marie Vincent
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 114th St and 87th Ave, Edmonton, AB T6G 2E1 Canada
- Department of Anatomy and Cell Biology, Faculty of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St, London, ON N6A 3K7 Canada
| | - Lynne-Marie Postovit
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 114th St and 87th Ave, Edmonton, AB T6G 2E1 Canada
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Santi A, Kugeratski FG, Zanivan S. Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. Proteomics 2018; 18:e1700167. [PMID: 29280568 PMCID: PMC5900985 DOI: 10.1002/pmic.201700167] [Citation(s) in RCA: 167] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 12/15/2017] [Indexed: 12/24/2022]
Abstract
Fibroblasts have exceptional phenotypic plasticity and capability to secrete vast amount of soluble factors, extracellular matrix components and extracellular vesicles. While in physiological conditions this makes fibroblasts master regulators of tissue homeostasis and healing of injured tissues, in solid tumors cancer associated fibroblasts (CAFs) co-evolve with the disease, and alter the biochemical and physical structure of the tumor microenvironment, as well as the behavior of the surrounding stromal and cancer cells. Thus CAFs are fundamental regulators of tumor progression and influence response to therapeutic treatments. Increasing efforts are devoted to better understand the biology of CAFs to bring insights to develop complementary strategies to target this cell type in cancer. Here we highlight components of the tumor microenvironment that play key roles in cancer progression and invasion, and provide an extensive overview of past and emerging understanding of CAF biology as well as the contribution that MS-based proteomics has made to this field.
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Affiliation(s)
- Alice Santi
- Cancer Research UK Beatson InstituteGlasgowUK
| | | | - Sara Zanivan
- Cancer Research UK Beatson InstituteGlasgowUK
- Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
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47
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Choi J, Cha YJ, Koo JS. Adipocyte biology in breast cancer: From silent bystander to active facilitator. Prog Lipid Res 2018; 69:11-20. [DOI: 10.1016/j.plipres.2017.11.002] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/20/2017] [Accepted: 11/20/2017] [Indexed: 12/12/2022]
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48
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Seoane J, Gomis RR. TGF-β Family Signaling in Tumor Suppression and Cancer Progression. Cold Spring Harb Perspect Biol 2017; 9:cshperspect.a022277. [PMID: 28246180 DOI: 10.1101/cshperspect.a022277] [Citation(s) in RCA: 374] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Transforming growth factor-β (TGF-β) induces a pleiotropic pathway that is modulated by the cellular context and its integration with other signaling pathways. In cancer, the pleiotropic reaction to TGF-β leads to a diverse and varied set of gene responses that range from cytostatic and apoptotic tumor-suppressive ones in early stage tumors, to proliferative, invasive, angiogenic, and oncogenic ones in advanced cancer. Here, we review the knowledge accumulated about the molecular mechanisms involved in the dual response to TGF-β in cancer, and how tumor cells evolve to evade the tumor-suppressive responses of this signaling pathway and then hijack the signal, converting it into an oncogenic factor. Only through the detailed study of this complexity can the suitability of the TGF-β pathway as a therapeutic target against cancer be evaluated.
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Affiliation(s)
- Joan Seoane
- Translational Research Program, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Roger R Gomis
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.,Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
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49
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Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway. Oncogenesis 2017; 6:e375. [PMID: 28846080 PMCID: PMC5608922 DOI: 10.1038/oncsis.2017.74] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 06/24/2017] [Accepted: 07/07/2017] [Indexed: 12/18/2022] Open
Abstract
Stromal cell populations in the tumor microenvironment (TME) play a critical role in the oncogenesis and metastasis of renal cell carcinoma. In this study, we found that there are α-smooth muscle actin positive (α-SMA (+)) cells in the stroma of clear cell renal cell carcinoma (ccRCC) tissues, and their numbers are significantly associated with poor survival in ccRCC patients. Interleukin 6 (IL-6) is a critical diver that induces α-SMA (+) cells in ccRCC tissues via promotion of epithelial to mesenchymal transition (EMT) and stimulates migration and invasion in ccRCC. Peritumoral CD4+ T cells are the main source of IL-6 in ccRCC tissues. In addition to biochemical factors, mechanical compression within tumors affects tumor cell behavior. Tumors grown in a confined space exhibit intratumoral compressive stress and, with sufficient pressure, stress-stimulated migration of cancer cells. Moreover, a combination of IL-6 secreted by CD4+ T cells and growth-induced solid stress further contributes to the regulation of cancer cell morphogenesis, EMT and acquisition of a stemness phenotype. The effects in the combination group were driven by the Akt/GSK-3β/β-catenin signaling pathway, and deregulation of β-catenin expression was predictive of poor outcome in ccRCC patients. Notably, the expression of a cancer stem cell marker, CD44, was correlated with T stage, high Fuhrman grade and metastasis in ccRCC. These data provide evidence for new stress-reducing and IL-6 targeting strategies in cancer therapy.
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50
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Pestell TG, Jiao X, Kumar M, Peck AR, Prisco M, Deng S, Li Z, Ertel A, Casimiro MC, Ju X, Di Rocco A, Di Sante G, Katiyar S, Shupp A, Lisanti MP, Jain P, Wu K, Rui H, Hooper DC, Yu Z, Goldman AR, Speicher DW, Laury-Kleintop L, Pestell RG. Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth. Oncotarget 2017; 8:81754-81775. [PMID: 29137220 PMCID: PMC5669846 DOI: 10.18632/oncotarget.19953] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 07/09/2017] [Indexed: 12/28/2022] Open
Abstract
The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that drives cell autonomous cell cycle progression and proliferation. Herein we show cyclin D1 abundance is increased >30-fold in the stromal fibroblasts of patients with invasive breast cancer, associated with poor outcome. Cyclin D1 transformed hTERT human fibroblast to a cancer-associated fibroblast phenotype. Stromal fibroblast expression of cyclin D1 (cyclin D1Stroma) in vivo, enhanced breast epithelial cancer tumor growth, restrained apoptosis, and increased autophagy. Cyclin D1Stroma had profound effects on the breast tumor microenvironment increasing the recruitment of F4/80+ and CD11b+ macrophages and increasing angiogenesis. Cyclin D1Stroma induced secretion of factors that promoted expansion of stem cells (breast stem-like cells, embryonic stem cells and bone marrow derived stem cells). Cyclin D1Stroma resulted in increased secretion of proinflammatory cytokines (CCL2, CCL7, CCL11, CXCL1, CXCL5, CXCL9, CXCL12), CSF (CSF1, GM-CSF1) and osteopontin (OPN) (30-fold). OPN was induced by cyclin D1 in fibroblasts, breast epithelial cells and in the murine transgenic mammary gland and OPN was sufficient to induce stem cell expansion. These results demonstrate that cyclin D1Stroma drives tumor microenvironment heterocellular signaling, promoting several key hallmarks of cancer.
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Affiliation(s)
- Timothy G Pestell
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Xuanmao Jiao
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, USA
| | - Mukesh Kumar
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Amy R Peck
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Marco Prisco
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Shengqiong Deng
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA.,Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhiping Li
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Adam Ertel
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Mathew C Casimiro
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, USA
| | - Xiaoming Ju
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Agnese Di Rocco
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, USA
| | - Gabriele Di Sante
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, USA
| | - Sanjay Katiyar
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Alison Shupp
- Departments of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Michael P Lisanti
- Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre, University of Salford, Salford, Greater Manchester, England, UK
| | - Pooja Jain
- Department of Microbiology and Immunology, Institute for Molecular Medicine & Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hallgeir Rui
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Douglas C Hooper
- Department of Microbiology, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA, USA
| | - Zuoren Yu
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, USA.,Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Aaron R Goldman
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA
| | - David W Speicher
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA
| | | | - Richard G Pestell
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, USA.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
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