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Shah S, Osuala KO, Brock EJ, Ji K, Sloane BF, Mattingly RR. Three-Dimensional Models: Biomimetic Tools That Recapitulate Breast Tissue Architecture and Microenvironment to Study Ductal Carcinoma In Situ Transition to Invasive Ductal Breast Cancer. Cells 2025; 14:220. [PMID: 39937011 PMCID: PMC11817749 DOI: 10.3390/cells14030220] [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: 12/24/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Diagnosis of ductal carcinoma in situ (DCIS) presents a challenge as we cannot yet distinguish between those lesions that remain dormant from cases that may progress to invasive ductal breast cancer (IDC) and require therapeutic intervention. Our overall interest is to develop biomimetic three-dimensional (3D) models that more accurately recapitulate the structure and characteristics of pre-invasive breast cancer in order to study the underlying mechanisms driving malignant progression. These models allow us to mimic the microenvironment to investigate many aspects of mammary cell biology, including the role of the extracellular matrix (ECM), the interaction between carcinoma-associated fibroblasts (CAFs) and epithelial cells, and the dynamics of cytoskeletal reorganization. In this review article, we outline the significance of 3D culture models as reliable pre-clinical tools that mimic the in vivo tumor microenvironment and facilitate the study of DCIS lesions as they progress to invasive breast cancer. We also discuss the role of CAFs and other stromal cells in DCIS transition as well as the clinical significance of emerging technologies like tumor-on-chip and co-culture models.
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Affiliation(s)
- Seema Shah
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
| | | | - Ethan J. Brock
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
| | - Kyungmin Ji
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Bonnie F. Sloane
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Raymond R. Mattingly
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
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Moragas N, Fernandez-Nogueira P, Recalde-Percaz L, Inman JL, López-Plana A, Bergholtz H, Noguera-Castells A, Del Burgo PJ, Chen X, Sorlie T, Gascón P, Bragado P, Bissell M, Carbó N, Fuster G. The SEMA3F-NRP1/NRP2 axis is a key factor in the acquisition of invasive traits in in situ breast ductal carcinoma. Breast Cancer Res 2024; 26:122. [PMID: 39138514 PMCID: PMC11320849 DOI: 10.1186/s13058-024-01871-0] [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: 02/15/2024] [Accepted: 07/12/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND A better understanding of ductal carcinoma in situ (DCIS) is urgently needed to identify these preinvasive lesions as distinct clinical entities. Semaphorin 3F (SEMA3F) is a soluble axonal guidance molecule, and its coreceptors Neuropilin 1 (NRP1) and NRP2 are strongly expressed in invasive epithelial BC cells. METHODS We utilized two cell line models to represent the progression from a healthy state to the mild-aggressive or ductal carcinoma in situ (DCIS) stage and, ultimately, to invasive cell lines. Additionally, we employed in vivo models and conducted analyses on patient databases to ensure the translational relevance of our results. RESULTS We revealed SEMA3F as a promoter of invasion during the DCIS-to-invasive ductal carcinoma transition in breast cancer (BC) through the action of NRP1 and NRP2. In epithelial cells, SEMA3F activates epithelialmesenchymal transition, whereas it promotes extracellular matrix degradation and basal membrane and myoepithelial cell layer breakdown. CONCLUSIONS Together with our patient database data, these proof-of-concept results reveal new SEMA3F-mediated mechanisms occurring in the most common preinvasive BC lesion, DCIS, and represent potent and direct activation of its transition to invasion. Moreover, and of clinical and therapeutic relevance, the effects of SEMA3F can be blocked directly through its coreceptors, thus preventing invasion and keeping DCIS lesions in the preinvasive state.
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MESH Headings
- Humans
- Neuropilin-1/metabolism
- Neuropilin-1/genetics
- Female
- Breast Neoplasms/pathology
- Breast Neoplasms/metabolism
- Breast Neoplasms/genetics
- Neuropilin-2/metabolism
- Neuropilin-2/genetics
- Neoplasm Invasiveness
- Carcinoma, Intraductal, Noninfiltrating/metabolism
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Cell Line, Tumor
- Nerve Tissue Proteins/metabolism
- Nerve Tissue Proteins/genetics
- Epithelial-Mesenchymal Transition/genetics
- Animals
- Membrane Proteins/metabolism
- Membrane Proteins/genetics
- Mice
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/genetics
- Gene Expression Regulation, Neoplastic
- Signal Transduction
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Affiliation(s)
- Núria Moragas
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
- Institute of Biomedicine of the Universitat de Barcelona (IBUB), Barcelona, Spain
| | - Patricia Fernandez-Nogueira
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
- Institute of Biomedicine of the Universitat de Barcelona (IBUB), Barcelona, Spain
- Department of Biomedicine, School of Medicine, Universitat de Barcelona (UB), 08036, Barcelona, Spain
| | - Leire Recalde-Percaz
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
- Institute of Biomedicine of the Universitat de Barcelona (IBUB), Barcelona, Spain
| | - Jamie L Inman
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA, 94720, USA
| | - Anna López-Plana
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
- Institute of Biomedicine of the Universitat de Barcelona (IBUB), Barcelona, Spain
| | - Helga Bergholtz
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0450, Oslo, Norway
| | - Aleix Noguera-Castells
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
- Institute of Biomedicine of the Universitat de Barcelona (IBUB), Barcelona, Spain
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Catalonia, Spain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
- Department of Biosciences, Faculty of Science, Technology and Engineering, University of Vic - Central University of Catalonia (UVic-UCC), Vic, Barcelona, Catalonia, Spain
| | - Pedro J Del Burgo
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
| | - Xieng Chen
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
| | - Therese Sorlie
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0450, Oslo, Norway
| | - Pere Gascón
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
| | - Paloma Bragado
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad Complutense de Madrid, Health Research Institute of the Hospital Clínico San Carlos, 28040, Madrid, Spain
| | - Mina Bissell
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA, 94720, USA
| | - Neus Carbó
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain
- Institute of Biomedicine of the Universitat de Barcelona (IBUB), Barcelona, Spain
| | - Gemma Fuster
- Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona (UB), 08028, Barcelona, Spain.
- Institute of Biomedicine of the Universitat de Barcelona (IBUB), Barcelona, Spain.
- Tissue Repair and Regeneration Laboratory (TR2Lab), Institute of Research and Innovation of Life Sciences and Health, Catalunya Central (IRIS-CC), UVIC-UCC, Vic, Spain.
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Roberts M, Finn J, Lass M, Oviedo-Bermudez E, Kurt RA. Efficacy of IFN-γ, sCD40L, and Poly(I:C) Treated Bone Marrow-Derived Macrophages in Murine Mammary Carcinoma. Immunol Invest 2024; 53:857-871. [PMID: 38813886 DOI: 10.1080/08820139.2024.2354264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
INTRODUCTION Here, we explored methods to generate anti-tumor bone marrow-derived macrophages (BMDM) and how delivery of the BMDM at early tumor sites could impact disease progression. METHODS BMDM treated with IFN-γ, sCD40L, poly(I:C), and a combination of the three were assessed. RESULTS Treatment with sCD40L had no significant impact on the BMDM. Treating BMDM with IFN-γ impacted IL-1β, MHC Class II, and CD80 expression. While poly(I:C) treatment had a greater impact on the BMDM than IFN-γ when assessed by the in vitro assays, the BMDM treated with poly (I:C) had mixed results in vivo where they decreased growth of the EMT6 tumor, did not impact growth of the 168 tumor, and enhanced growth of the 4T1 tumor. The combination of poly(I:C), IFN-γ, and sCD40L had the greatest impact on the BMDM in vitro and in vivo. Treatment with all three agonists resulted in increased IL-1β, TNF-α, and IL-12 expression, decreased expression of arginase and mrc, increased phagocytic activity, nitrite production, and MHC Class II and CD80 expression, and significantly impacted growth of the EMT6 and 168 murine mammary carcinoma models. DISCUSSION Collectively, these data show that treating BMDM with poly(I:C), IFN-γ, and sCD40L generates BMDM with more consistent anti-tumor activity than BMDM generated with the individual agonists.
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Affiliation(s)
- Meghan Roberts
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
| | - Joshua Finn
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
| | - Melissa Lass
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
| | | | - Robert A Kurt
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
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Borowsky A, Glencer A, Ramalingam K, Schindler N, Mori H, Ghule P, Lee K, Nachmanson D, Officer A, Harismendy O, Stein J, Stein G, Evans M, Weaver D, Yau C, Hirst G, Campbell M, Esserman L. Tumor microenvironmental determinants of high-risk DCIS progression. RESEARCH SQUARE 2024:rs.3.rs-4126092. [PMID: 38766192 PMCID: PMC11100907 DOI: 10.21203/rs.3.rs-4126092/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Ductal carcinoma in situ (DCIS) constitutes an array of morphologically recognized intraductal neoplasms in the mammary ductal tree defined by an increased risk for subsequent invasive carcinomas at or near the site of biopsy detection. However, only 15-45% of untreated DCIS cases progress to invasive cancer, so understanding mechanisms that prevent progression is key to avoid overtreatment and provides a basis for alternative therapies and prevention. This study was designed to characterize the tumor microenvironment and molecular profile of high-risk DCIS that grew to a large size but remained as DCIS. All patients had DCIS lesions >5cm in size with at least one additional high-risk feature: young age (<45 years), high nuclear grade, hormone receptor negativity, HER2 positivity, the presence of comedonecrosis, or a palpable mass. The tumor immune microenvironment was characterized using multiplex immunofluorescence to identify immune cells and their spatial relationships within the ducts and stroma. Gene copy number analysis and whole exome DNA sequencing identified the mutational burden and driver mutations, and quantitative whole-transcriptome/gene expression analyses were performed. There was no association between the percent of the DCIS genome characterized by copy number variants (CNAs) and recurrence events (DCIS or invasive). Mutations, especially missense mutations, in the breast cancer driver genes PIK3CA and TP53 were common in this high-risk DCIS cohort (47% of evaluated lesions). Tumor infiltrating lymphocyte (TIL) density was higher in DCIS lesions with TP53 mutations (p=0.0079) compared to wildtype lesions, but not in lesions with PIK3CA mutations (p=0.44). Immune infiltrates were negatively associated with hormone receptor status and positively associated with HER2 expression. High levels of CD3+CD8- T cells were associated with good outcomes with respect to any subsequent recurrence (DCIS or invasive cancer), whereas high levels of CD3+Foxp3+ Treg cells were associated with poor outcomes. Spatial proximity analyses of immune cells and tumor cells demonstrated that close proximity of T cells with tumor cells was associated with good outcomes with respect to any recurrence as well as invasive recurrences. Interestingly, we found that myoepithelial continuity (distance between myoepithelial cells surrounding the involved ducts) was significantly lower in DCIS lesions compared to normal tissue (p=0.0002) or to atypical ductal hyperplasia (p=0.011). Gene set enrichment analysis identified several immune pathways associated with low myoepithelial continuity and a low myoepithelial continuity score was associated with better outcomes, suggesting that gaps in the myoepithelial layer may allow access/interactions between immune infiltrates and tumor cells. Our study demonstrates the immune microenvironment of DCIS, in particular the spatial proximity of tumor cells and T cells, and myoepithelial continuity are important determinants for progression of disease.
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Hsiao CY, Ren Y, Chng E, Tai D, Huang KW. Potential of Using qFibrosis Analysis to Predict Recurrent and Survival Outcome of Patients with Hepatocellular Carcinoma after Hepatic Resection. Oncology 2024; 102:924-934. [PMID: 38527441 PMCID: PMC11548100 DOI: 10.1159/000538456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/27/2024] [Indexed: 03/27/2024]
Abstract
BACKGROUND There remains a lack of studies addressing the stromal background and fibrosis features and their prognostic value in liver cancer. qFibrosis can identify, quantify, and visualize the fibrosis features in biopsy samples. In this study, we aim to demonstrate the prognostic value of histological features by using qFibrosis analysis in liver cancer patients. METHODS Liver specimens from 201 patients with hepatocellular carcinoma (HCC) who underwent curative resection were imaged and assessed using qFibrosis system and generated a total of 33 and 156 collagen parameters from tumor part and non-tumor liver tissue, respectively. We used these collagen parameters on patients to build two combined indexes, RFS index and OS index, in order to differentiate patients with early recurrence and early death, respectively. The models were validated using the leave-one-out method. RESULTS Both combined indexes had significant prediction value for patients' outcome. The RFS index of 0.52 well differentiates patients with early recurrence (p < 0.001), and the OS index of 0.73 well differentiates patients with early death during follow-up (p = 0.02). CONCLUSIONS Combined index calculated with qFibrosis from a digital readout of the fibrotic status of peri-tumor liver specimen in patients with HCC has prediction values for their disease and survival outcomes. These results demonstrated the potential to transform histopathological features into quantifiable data that could be used to correlate with clinical outcome.
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Affiliation(s)
- Chih-Yang Hsiao
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan,
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan,
- Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan,
| | - Yayun Ren
- HistoIndex, Pte Ltd, Singapore, Singapore
| | | | - Dean Tai
- HistoIndex, Pte Ltd, Singapore, Singapore
| | - Kai-Wen Huang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
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Fang WB, Medrano M, Cote P, Portsche M, Rao V, Hong Y, Behbod F, Knapp JR, Bloomer C, Noel-Macdonnell J, Cheng N. Transcriptome analysis reveals differences in cell cycle, growth and migration related genes that distinguish fibroblasts derived from pre-invasive and invasive breast cancer. Front Oncol 2023; 13:1130911. [PMID: 37091166 PMCID: PMC10118028 DOI: 10.3389/fonc.2023.1130911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 03/13/2023] [Indexed: 04/09/2023] Open
Abstract
Background/Introduction As the most common form of pre-invasive breast cancer, ductal carcinoma in situ (DCIS) affects over 50,000 women in the US annually. Despite standardized treatment involving lumpectomy and radiation therapy, up to 25% of patients with DCIS experience disease recurrence often with invasive ductal carcinoma (IDC), indicating that a subset of patients may be under-treated. As most DCIS cases will not progress to invasion, many patients may experience over-treatment. By understanding the underlying processes associated with DCIS to IDC progression, we can identify new biomarkers to determine which DCIS cases may become invasive and improve treatment for patients. Accumulation of fibroblasts in IDC is associated with disease progression and reduced survival. While fibroblasts have been detected in DCIS, little is understood about their role in DCIS progression. Goals We sought to determine 1) whether DCIS fibroblasts were similar or distinct from normal and IDC fibroblasts at the transcriptome level, and 2) the contributions of DCIS fibroblasts to breast cancer progression. Methods Fibroblasts underwent transcriptome profiling and pathway analysis. Significant DCIS fibroblast-associated genes were further analyzed in existing breast cancer mRNA databases and through tissue array immunostaining. Using the sub-renal capsule graft model, fibroblasts from normal breast, DCIS and IDC tissues were co-transplanted with DCIS.com breast cancer cells. Results Through transcriptome profiling, we found that DCIS fibroblasts were characterized by unique alterations in cell cycle and motility related genes such as PKMYT1, TGF-α, SFRP1 and SFRP2, which predicted increased cell growth and invasion by Ingenuity Pathway Analysis. Immunostaining analysis revealed corresponding increases in expression of stromal derived PKMYT1, TGF-α and corresponding decreases in expression of SFRP1 and SFRP2 in DCIS and IDC tissues. Grafting studies in mice revealed that DCIS fibroblasts enhanced breast cancer growth and invasion associated with arginase-1+ cell recruitment. Conclusion DCIS fibroblasts are phenotypically distinct from normal breast and IDC fibroblasts, and play an important role in breast cancer growth, invasion, and recruitment of myeloid cells. These studies provide novel insight into the role of DCIS fibroblasts in breast cancer progression and identify some key biomarkers associated with DCIS progression to IDC, with important clinical implications.
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Affiliation(s)
- Wei Bin Fang
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| | - Marcela Medrano
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| | - Paige Cote
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| | - Mike Portsche
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| | - Vinamratha Rao
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Yan Hong
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| | - Fariba Behbod
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| | - Jennifer R. Knapp
- Center for Genes Environment and Health, National Jewish Health, Denver, CO, United States
- Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Kansas City, KS, United States
| | - Clark Bloomer
- Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Kansas City, KS, United States
| | - Janelle Noel-Macdonnell
- Biostatistics and Epidemiology Core, Health Services and Outcomes Research Children’s Mercy Hospital, Kansas City, MO, United States
- Department of Pediatrics, University of Missouri-Kansas City (UMKC) School of Medicine, Kansas City, MO, United States
| | - Nikki Cheng
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, United States
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Gibson SV, Tomas Bort E, Rodríguez-Fernández L, Allen MD, Gomm JJ, Goulding I, Auf dem Keller U, Agnoletto A, Brisken C, Peck B, Cameron AJ, Marshall JF, Jones JL, Carter EP, Grose RP. TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression. NPJ Breast Cancer 2023; 9:9. [PMID: 36864079 PMCID: PMC9981685 DOI: 10.1038/s41523-023-00513-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 02/15/2023] [Indexed: 03/04/2023] Open
Abstract
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management. To understand the role of the normally tumour suppressive myoepithelial cell in disease progression we present a 3D in vitro model incorporating both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells, mediated by the collagenase MMP13 through a non-canonical TGFβ - EP300 pathway. In vivo, MMP13 expression is associated with stromal invasion in a murine model of DCIS progression and is elevated in myoepithelial cells of clinical high-grade DCIS cases. Our data identify a key role for myoepithelial-derived MMP13 in facilitating DCIS progression and point the way towards a robust marker for risk stratification in DCIS patients.
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Affiliation(s)
- Shayin V Gibson
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Elena Tomas Bort
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Lucía Rodríguez-Fernández
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Michael D Allen
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Jennifer J Gomm
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Iain Goulding
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Ulrich Auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Andrea Agnoletto
- ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole polytechnique fédérale de Lausanne (EPFL), SV2.832 Station 19, 1015, Lausanne, Switzerland
| | - Cathrin Brisken
- ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole polytechnique fédérale de Lausanne (EPFL), SV2.832 Station 19, 1015, Lausanne, Switzerland
| | - Barrie Peck
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Angus J Cameron
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - John F Marshall
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - J Louise Jones
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Edward P Carter
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
| | - Richard P Grose
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
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Darvishian F, Wu Y, Ozerdem U, Chun J, Adams S, Guth A, Axelrod D, Shapiro R, Troxel AB, Schnabel F, Roses D. Macrophage density is an adverse prognosticator for ipsilateral recurrence in ductal carcinoma in situ. Breast 2022; 64:35-40. [PMID: 35489232 PMCID: PMC9062471 DOI: 10.1016/j.breast.2022.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/16/2022] [Accepted: 04/11/2022] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION There is evidence that supports the association of dense tumor infiltrating lymphocyte (TILs) with an increased risk of ipsilateral recurrence in ductal carcinoma in situ (DCIS). However, the association of cellular composition of DCIS immune microenvironment with the histopathologic parameters and outcome is not well understood. METHODS We queried our institutional database for patients with pure DCIS diagnosed between 2010 and 2019. Immunohistochemical studies for CD8, CD4, CD68, CD163, and FOXP3 were performed and evaluated in the DCIS microenvironment using tissue microarrays. Statistical methods included Fisher's exact test for categorical variables and the two-sample t-test or the Wilcoxon Rank-Sum test for continuous variables. RESULTS The analytic sample included 67 patients. Median age was 62 years (range = 53 to 66) and median follow up was 6.7 years (range = 5.3 to 7.8). Thirteen patients had ipsilateral recurrence. Of all the clinicopathologic variables, only the DCIS size and TIL density were significantly associated with recurrence (p = 0.023 and 0.006, respectively). After adjusting for age and TIL density, only high CD68 (>50) and high CD68/CD163 ratio (>0.46) correlated with ipsilateral recurrence (p = 0.026 and 0.013, respectively) and shorter time to recurrence [hazard ratio 4.87 (95% CI: 1.24-19, p = 0.023) and 10.32 (95% CI: 1.34-80, p = 0.025), respectively]. CONCLUSIONS In addition to DCIS size and TIL density, high CD68+ tumor-associated macrophages predict ipsilateral recurrence in DCIS. High CD68+ macrophage density and CD68/CD163 ratio also predict a shorter time to recurrence.
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Affiliation(s)
- Farbod Darvishian
- New York University Langone Health, Department of Pathology, New York, NY, 10016, USA.
| | - Yinxiang Wu
- New York University Langone Health, Department of Population Health, Division of Biostatistics, New York, NY, 10016, USA
| | - Ugur Ozerdem
- New York University Langone Health, Department of Pathology, New York, NY, 10016, USA
| | - Jennifer Chun
- New York University Langone Health, Department of Surgery, New York, NY, 10016, USA
| | - Sylvia Adams
- New York University Langone Health, Department of Medicine, New York, NY, 10016, USA
| | - Amber Guth
- New York University Langone Health, Department of Surgery, New York, NY, 10016, USA
| | - Deborah Axelrod
- New York University Langone Health, Department of Surgery, New York, NY, 10016, USA
| | - Richard Shapiro
- New York University Langone Health, Department of Surgery, New York, NY, 10016, USA
| | - Andrea B Troxel
- New York University Langone Health, Department of Population Health, Division of Biostatistics, New York, NY, 10016, USA
| | - Freya Schnabel
- New York University Langone Health, Department of Surgery, New York, NY, 10016, USA
| | - Daniel Roses
- New York University Langone Health, Department of Surgery, New York, NY, 10016, USA
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Williams MM, Hafeez SA, Christenson JL, O’Neill KI, Hammond NG, Richer JK. Reversing an Oncogenic Epithelial-to-Mesenchymal Transition Program in Breast Cancer Reveals Actionable Immune Suppressive Pathways. Pharmaceuticals (Basel) 2021; 14:ph14111122. [PMID: 34832904 PMCID: PMC8622696 DOI: 10.3390/ph14111122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/16/2022] Open
Abstract
Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates that TNBC metastases are more immune suppressed than primary tumors, suggesting that combination or additional immunotherapy strategies may be required to activate an anti-tumor immune attack at metastatic sites. To identify other immune suppressive mechanisms utilized by mTNBC, our group and others manipulated oncogenic epithelial-to-mesenchymal transition (EMT) programs in TNBC models to reveal differences between this breast cancer subtype and its more epithelial counterpart. This review will discuss how EMT modulation revealed several mechanisms, including tumor cell metabolism, cytokine milieu and secretion of additional immune modulators, by which mTNBC cells may suppress both the innate and adaptive anti-tumor immune responses. Many of these pathways/proteins are under preclinical or clinical investigation as therapeutic targets in mTNBC and other advanced cancers to enhance their response to chemotherapy and/or checkpoint inhibitors.
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10
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Mao W, Xiong G, Wu Y, Wang C, St. Clair D, Li JD, Xu R. RORα Suppresses Cancer-Associated Inflammation by Repressing Respiratory Complex I-Dependent ROS Generation. Int J Mol Sci 2021; 22:ijms221910665. [PMID: 34639006 PMCID: PMC8509002 DOI: 10.3390/ijms221910665] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/21/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022] Open
Abstract
Breast cancer development is associated with macrophage infiltration and differentiation in the tumor microenvironment. Our previous study highlights the crucial function of reactive oxygen species (ROS) in enhancing macrophage infiltration during the disruption of mammary tissue polarity. However, the regulation of ROS and ROS-associated macrophage infiltration in breast cancer has not been fully determined. Previous studies identified retinoid orphan nuclear receptor alpha (RORα) as a potential tumor suppressor in human breast cancer. In the present study, we showed that retinoid orphan nuclear receptor alpha (RORα) significantly decreased ROS levels and inhibited ROS-mediated cytokine expression in breast cancer cells. RORα expression in mammary epithelial cells inhibited macrophage infiltration by repressing ROS generation in the co-culture assay. Using gene co-expression and chromatin immunoprecipitation (ChIP) analyses, we identified complex I subunits NDUFS6 and NDUFA11 as RORα targets that mediated its function in suppressing superoxide generation in mitochondria. Notably, the expression of RORα in 4T1 cells significantly inhibited cancer metastasis, reduced macrophage accumulation, and enhanced M1-like macrophage differentiation in tumor tissue. In addition, reduced RORα expression in breast cancer tissue was associated with an increased incidence of cancer metastasis. These results provide additional insights into cancer-associated inflammation, and identify RORα as a potential target to suppress ROS-induced mammary tumor progression.
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Affiliation(s)
- Wei Mao
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; (W.M.); (G.X.); (Y.W.); (C.W.); (D.S.C.)
- Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410078, China;
| | - Gaofeng Xiong
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; (W.M.); (G.X.); (Y.W.); (C.W.); (D.S.C.)
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Yuanyuan Wu
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; (W.M.); (G.X.); (Y.W.); (C.W.); (D.S.C.)
| | - Chi Wang
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; (W.M.); (G.X.); (Y.W.); (C.W.); (D.S.C.)
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
| | - Daret St. Clair
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; (W.M.); (G.X.); (Y.W.); (C.W.); (D.S.C.)
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Jia-Da Li
- Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Disease, School of Life Sciences, Central South University, Changsha 410078, China;
| | - Ren Xu
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; (W.M.); (G.X.); (Y.W.); (C.W.); (D.S.C.)
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
- Correspondence: ; Tel.: +1-859-323-7889
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11
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Fernández-Nogueira P, Fuster G, Gutierrez-Uzquiza Á, Gascón P, Carbó N, Bragado P. Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis. Cancers (Basel) 2021; 13:3146. [PMID: 34201840 PMCID: PMC8268405 DOI: 10.3390/cancers13133146] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 12/21/2022] Open
Abstract
Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs' role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.
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Affiliation(s)
- Patricia Fernández-Nogueira
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), 08028 Barcelona, Spain; (G.F.); (P.G.); (N.C.)
- Department of Biomedicine, School of Medicine, University of Barcelona, 08028 Barcelona, Spain
| | - Gemma Fuster
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), 08028 Barcelona, Spain; (G.F.); (P.G.); (N.C.)
- Department of Biochemistry & Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
- Department of Biosciences, Faculty of Sciences and Technology, University of Vic, 08500 Vic, Spain
| | - Álvaro Gutierrez-Uzquiza
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain;
- Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, Spain
| | - Pere Gascón
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), 08028 Barcelona, Spain; (G.F.); (P.G.); (N.C.)
| | - Neus Carbó
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), 08028 Barcelona, Spain; (G.F.); (P.G.); (N.C.)
| | - Paloma Bragado
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain;
- Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, Spain
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12
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Glencer AC, Wong JM, Hylton NM, Krings G, McCune E, Rothschild HT, Loveday TA, Alvarado MD, Esserman LJ, Campbell MJ. Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection. NPJ Breast Cancer 2021; 7:59. [PMID: 34035311 PMCID: PMC8149838 DOI: 10.1038/s41523-021-00267-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/19/2021] [Indexed: 12/31/2022] Open
Abstract
Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. High-risk features include age <45 years, size >5 cm, high-grade, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrates are positively associated with these high-risk features, suggesting that manipulating the immune microenvironment in high-risk DCIS could potentially alter disease progression. Patients with high-risk DCIS were enrolled in this 3 × 3 phase 1 dose-escalation pilot study of 2, 4, and 8 mg intralesional injections of the PD-1 immune checkpoint inhibitor, pembrolizumab. Study participants received two intralesional injections, three weeks apart, prior to surgery. Tissue from pre-treatment biopsies and post-treatment surgical resections was analyzed using multiplex immunofluorescence (mIF) staining for various immune cell populations. The intralesional injections were easily administered and well-tolerated. mIF analyses demonstrated significant increases in total T cell and CD8+ T cell percentages in most patients after receiving pembrolizumab, even at the 2 mg dose. T cell expansion was confined primarily to the stroma rather than within DCIS-containing ducts. Neither cleaved caspase 3 (CC3) staining, a marker for apoptosis, nor DCIS volume (as measured by MRI) changed significantly following treatment. Intralesional injection of pembrolizumab is safe and feasible in patients with DCIS. Nearly all patients experienced robust total and CD8+ T cell responses. However, we did not observe evidence of cell death or tumor volume decrease by MRI, suggesting that additional strategies may be needed to elicit stronger anti-tumor immunity.
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Affiliation(s)
- Alexa C Glencer
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Jasmine M Wong
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Nola M Hylton
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Gregor Krings
- Department of Pathology, University of California San Francisco, San Francisco, CA, USA
| | - Emma McCune
- University of California San Francisco School of Medicine, San Francisco, CA, USA
| | - Harriet T Rothschild
- University of California San Francisco School of Medicine, San Francisco, CA, USA
| | - Tristan A Loveday
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Michael D Alvarado
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Laura J Esserman
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Michael J Campbell
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
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13
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Kennedy KM, Zilkens R, Allen WM, Foo KY, Fang Q, Chin L, Sanderson RW, Anstie J, Wijesinghe P, Curatolo A, Tan HEI, Morin N, Kunjuraman B, Yeomans C, Chin SL, DeJong H, Giles K, Dessauvagie BF, Latham B, Saunders CM, Kennedy BF. Diagnostic Accuracy of Quantitative Micro-Elastography for Margin Assessment in Breast-Conserving Surgery. Cancer Res 2020; 80:1773-1783. [PMID: 32295783 DOI: 10.1158/0008-5472.can-19-1240] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 08/09/2019] [Accepted: 02/14/2020] [Indexed: 01/16/2023]
Abstract
Inadequate margins in breast-conserving surgery (BCS) are associated with an increased likelihood of local recurrence of breast cancer. Currently, approximately 20% of BCS patients require repeat surgery due to inadequate margins at the initial operation. Implementation of an accurate, intraoperative margin assessment tool may reduce this re-excision rate. This study determined, for the first time, the diagnostic accuracy of quantitative micro-elastography (QME), an optical coherence tomography (OCT)-based elastography technique that produces images of tissue microscale elasticity, for detecting tumor within 1 mm of the margins of BCS specimens. Simultaneous OCT and QME were performed on the margins of intact, freshly excised specimens from 83 patients undergoing BCS and on dissected specimens from 7 patients undergoing mastectomy. The resulting three-dimensional images (45 × 45 × 1 mm) were coregistered with postoperative histology to determine tissue types present in each scan. Data from 12 BCS patients and the 7 mastectomy patients served to build a set of images for reader training. One hundred and fifty-four subimages (10 × 10 × 1 mm) from the remaining 71 BCS patients were included in a blinded reader study, which resulted in 69.0% sensitivity and 79.0% specificity using OCT images, versus 92.9% sensitivity and 96.4% specificity using elasticity images. The quantitative nature of QME also facilitated development of an automated reader, which resulted in 100.0% sensitivity and 97.7% specificity. These results demonstrate high accuracy of QME for detecting tumor within 1 mm of the margin and the potential for this technique to improve outcomes in BCS. SIGNIFICANCE: An optical imaging technology probes breast tissue elasticity to provide accurate assessment of tumor margin involvement in breast-conserving surgery.
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Affiliation(s)
- Kelsey M Kennedy
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia
| | - Renate Zilkens
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,School of Medicine, The University of Western Australia, Perth, Australia
| | - Wes M Allen
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
| | - Ken Y Foo
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
| | - Qi Fang
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
| | - Lixin Chin
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
| | - Rowan W Sanderson
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
| | - James Anstie
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
| | - Philip Wijesinghe
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
| | - Andrea Curatolo
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia.,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
| | - Hsern Ern I Tan
- School of Medicine, The University of Western Australia, Perth, Australia
| | | | | | - Chris Yeomans
- PathWest, Fiona Stanley Hospital, Murdoch, Australia
| | - Synn Lynn Chin
- Breast Centre, Fiona Stanley Hospital, Murdoch, Australia
| | - Helen DeJong
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia
| | | | - Benjamin F Dessauvagie
- School of Medicine, The University of Western Australia, Perth, Australia.,PathWest, Fiona Stanley Hospital, Murdoch, Australia
| | - Bruce Latham
- PathWest, Fiona Stanley Hospital, Murdoch, Australia
| | - Christobel M Saunders
- School of Medicine, The University of Western Australia, Perth, Australia.,Breast Centre, Fiona Stanley Hospital, Murdoch, Australia.,Breast Clinic, Royal Perth Hospital, Perth, Australia
| | - Brendan F Kennedy
- BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, and Centre for Medical Research, The University of Western Australia, Perth, Australia. .,Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, Australia
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14
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Clinicopathologic Characteristics of Breast Cancer According to the Infiltrating Immune Cell Subtypes. Int J Mol Sci 2020; 21:ijms21124438. [PMID: 32580398 PMCID: PMC7352832 DOI: 10.3390/ijms21124438] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 12/31/2022] Open
Abstract
The clinical significance of immune cell subtypes in breast cancer remains poorly understood. To identify tumor-infiltrating immune cell subtypes in breast cancer and investigate their implications, tissue microarrays were constructed using 334 cases of invasive ductal carcinoma (luminal A type: 162 (48.5%), luminal B type: 96 (28.7%), HER-2 type: 21 (6.3%), and triple negative breast cancer: 55 (16.5%)). Hormone receptors (ER, PR, and HER-2), Ki-67, and immune cell subtype-related proteins (STAT4, STAT6, FOXP3, CD8, CD68, and CD163) were assessed immunohistochemically. The proportion of highly expressed STAT6, FOXP3, CD8, CD68, and CD163 proteins was found to be lowest in luminal A type but highest in the HER-2 type. Additionally, high-level STAT6, FOXP3, CD68, and CD163 protein expression was associated with higher histologic grade. ER negativity was associated with high STAT6, FOXP3, and CD163 expression levels, whereas PR negativity and high Ki-67 labeling index were associated with high CD163 expression. Univariate (p = 0.003) and multivariate Cox (hazard ratio: 2.435, 95% CI: 1.110-5.344, p = 0.049) analyses showed that high CD8 expression is an independent factor associated with shorter disease-free survival. Immune cell subtype-related protein expression is dependent on breast cancer molecular subtypes, and CD8 expression is associated with patient prognosis.
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15
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Zhang C, Kurt RA. Indicators of a pro-tumor immune response are evident at early stages of breast cancer. Clin Transl Oncol 2020; 22:2153-2161. [PMID: 32410118 DOI: 10.1007/s12094-020-02368-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 04/29/2020] [Indexed: 01/13/2023]
Abstract
With advances in checkpoint inhibitor and CAR T-cell therapies, among other advances in immunotherapy, this is an exciting time to be a tumor immunologist. We are witnessing the transition of decades of work at the bench leading to substantial success in the clinic. While work continues developing new and improving existing immunotherapies, there remains a great deal of basic tumor immunology still to learn, information that can only lead to greater success in the clinic. One area in need of more attention is understanding the immune response at early stages of breast cancer. While there is no question that early diagnosis and treatment save lives, a greater understanding about the immune response during early stages of breast cancer may reveal information that could assist in monitoring individuals at risk of breast cancer, and could have implications for patients diagnosed at early stages of disease, and may provide important information about the origins of an immune-suppressive environment. Here, we review studies that have looked at the very early immune response to breast cancer focusing on patients with DCIS, before invasion in spontaneous transgenic murine mammary carcinoma models, and before transplantable or orthotopic murine mammary carcinoma models become palpable. The findings revealed that indicators of a pro-tumor immune response are already present at early stages of disease.
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Affiliation(s)
- C Zhang
- Department of Molecular and Cellular Biology, University of California Berkeley, Berkeley, CA, 94720, USA
| | - R A Kurt
- Department Biology, Rockwell Integrated Science Center, Lafayette College, Easton, PA, 18042, USA.
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16
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Sarode P, Schaefer MB, Grimminger F, Seeger W, Savai R. Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk. Front Oncol 2020; 10:324. [PMID: 32219066 PMCID: PMC7078651 DOI: 10.3389/fonc.2020.00324] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
Regardless of the promising results of certain immune checkpoint blockers, current immunotherapeutics have met a bottleneck concerning response rate, toxicity, and resistance in lung cancer patients. Accumulating evidence forecasts that the crosstalk between tumor and immune cells takes center stage in cancer development by modulating tumor malignancy, immune cell infiltration, and immune evasion in the tumor microenvironment (TME). Cytokines and chemokines secreted by this crosstalk play a major role in cancer development, progression, and therapeutic management. An increased infiltration of Tumor-associated macrophages (TAMs) was observed in most of the human cancers, including lung cancer. In this review, we emphasize the role of cytokines and chemokines in TAM-tumor cell crosstalk in the lung TME. Given the role of cytokines and chemokines in immunomodulation, we propose that TAM-derived cytokines and chemokines govern the cancer-promoting immune responses in the TME and offer a new immunotherapeutic option for lung cancer treatment.
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Affiliation(s)
- Poonam Sarode
- Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
| | - Martina Barbara Schaefer
- Department of Internal Medicine, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany
| | - Friedrich Grimminger
- Department of Internal Medicine, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany
| | - Werner Seeger
- Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.,Department of Internal Medicine, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany
| | - Rajkumar Savai
- Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.,Department of Internal Medicine, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany.,Frankfurt Cancer Institute (FCI), Goethe University, Frankfurt am Main, Germany
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17
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The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome. Br J Cancer 2020; 122:931-942. [PMID: 31992854 PMCID: PMC7109057 DOI: 10.1038/s41416-019-0705-1] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 11/11/2019] [Accepted: 12/10/2019] [Indexed: 02/08/2023] Open
Abstract
The tumour microenvironment (TME) determines vital aspects of tumour development, such as tumour growth, metastases and response to therapy. Cancer-associated fibroblasts (CAFs) are abundant and extremely influential in this process and interact with cellular and matrix TME constituents such as endothelial and immune cells and collagens, fibronectin and elastin, respectively. However, CAFs are also the recipients of signals—both chemical and physical—that are generated by the TME, and their phenotype effectively evolves alongside the tumour mass during tumour progression. Amid a rising clinical interest in CAFs as a crucial force for disease progression, this review aims to contextualise the CAF phenotype using the chronological framework of the CAF life cycle within the evolving tumour stroma, ranging from quiescent fibroblasts to highly proliferative and secretory CAFs. The emergence, properties and clinical implications of CAF activation are discussed, as well as research strategies used to characterise CAFs and current clinical efforts to alter CAF function as a therapeutic strategy.
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18
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Shaker H, Bundred NJ, Landberg G, Pritchard SA, Albadry H, Nicholson SL, Harries LJ, Heah JYE, Castle J, Kirwan CC. Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion. Cancer Med 2020; 9:1768-1778. [PMID: 31962001 PMCID: PMC7050075 DOI: 10.1002/cam4.2748] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/13/2019] [Accepted: 11/15/2019] [Indexed: 12/25/2022] Open
Abstract
Background Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non‐healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease‐free survival (DFS), and overall survival (OS). Methods In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin‐antithrombin (TAT) and D‐dimer were correlated with clinicopathological data, and 5‐year survival. Results Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER‐ (vs ER+), and HER2+ (vs HER2‐) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D‐dimer was higher in node positive (507 (CI: 411‐625) ng/mL, n = 68) vs negative patients (428 (CI: 387‐472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16‐3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3‐fold mortality risk compared to low TAT. Conclusion This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.
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Affiliation(s)
- Hudhaifah Shaker
- Faculty of Biology, Medicine and Health, Division of Cancer Sciences, School of Medical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester, UK
| | - Nigel J Bundred
- Faculty of Biology, Medicine and Health, Division of Cancer Sciences, School of Medical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester, UK
| | - Göran Landberg
- Department of Pathology, Institute for Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
| | - Susan A Pritchard
- Department of Histopathology, Manchester University NHS Foundation Trust, Wythenshawe, Manchester, UK
| | - Harith Albadry
- Department of Histopathology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
| | - Sarah L Nicholson
- Department of Histopathology, East Lancashire Hospitals NHS Trust, Blackburn, UK
| | - Lauren J Harries
- Department of Histopathology, Manchester University NHS Foundation Trust, Wythenshawe, Manchester, UK
| | - Jing Y E Heah
- The Nightingale Centre and Prevent Breast Cancer Research Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
| | - John Castle
- Faculty of Biology, Medicine and Health, Division of Cancer Sciences, School of Medical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester, UK
| | - Cliona C Kirwan
- Faculty of Biology, Medicine and Health, Division of Cancer Sciences, School of Medical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester, UK.,The Nightingale Centre and Prevent Breast Cancer Research Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
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19
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Chen H, Bai F, Wang M, Zhang M, Zhang P, Wu K. The prognostic significance of co-existence ductal carcinoma in situ in invasive ductal breast cancer: a large population-based study and a matched case-control analysis. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:484. [PMID: 31700920 DOI: 10.21037/atm.2019.08.16] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Background To evaluate the prognostic significance of co-existence ductal carcinoma in situ (DCIS) in invasive ductal breast cancer (IDC) compared with pure IDC. Methods The Surveillance, Epidemiology, and End Results (SEER) database was searched to identify unilateral IDC cases between 2004 and 2015, which were grouped into pure IDC and IDC with DCIS component (IDC-DCIS). Comparisons of the distribution of clinical-pathological characteristics the two groups were performed using Pearson's chi-square. Breast cancer-specific survival (BCSS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared across RS groups using the log-rank statistic. Cox models were fitted to assess the factors independently associated with survival. A 1:1 matched case-control analysis was conducted with each clinical-pathological characteristic matched completely. Results A total of 98,097 pure IDC cases (39.6%) and 149,477 IDC-DCIS cases (60.4%) were enrolled. IDC-DCIS patients were presented with less aggressive characteristics such as lower proportion of histologic grade III (34.2% vs. 42.2%, P<0.001), ER negative (16.8% vs. 26.1%, P<0.001) and PR negative (26.5% vs. 35.7%, P<0.001) disease and higher proportion of T1 cases (68.7% vs. 58.2%, P<0.001) compared with pure IDC patients. Co-existence DCIS was an independent prognostic factor for BCSS and OS in the whole cohort. According to the multivariate analysis, it was an independent favorable prognostic factor among ER positive cases, but an independent negative prognostic factor among ER negative cases based on the matched cohort. Conclusions Co-existence DCIS showed quite different prognostic significance among ER positive and negative disease.
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Affiliation(s)
- Hongliang Chen
- Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Fang Bai
- Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Maoli Wang
- Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Mingdi Zhang
- Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Peng Zhang
- Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Kejin Wu
- Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
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20
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Kim H, Kim HS, Piao YJ, Moon WK. Bisphenol A Promotes the Invasive and Metastatic Potential of Ductal Carcinoma In Situ and Protumorigenic Polarization of Macrophages. Toxicol Sci 2019; 170:283-295. [DOI: 10.1093/toxsci/kfz119] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Increased cancer risk and immune disorders linked with exposure to environmental endocrine disruptors like bisphenol A (BPA) have been steadily reported. Nevertheless, the impacts of BPA on the breast ductal carcinoma in situ (DCIS) progression and macrophage polarization remain to be elucidated. Here, we analyzed the differentially expressed genes in BPA-exposed DCIS cells and explored BPA effects on DCIS progression and macrophage polarization in vitro and in vivo. Two hundred and ninety-one genes were differentially expressed in 10−8 M BPA-exposed DCIS cells, in which the gene ontology terms of biological processes associated with negative regulation of cell death, cell adhesion, and immune response was enriched. 10−8 M BPA promoted the proliferation and migration of DCIS cells and the migration of macrophages, and upregulated the expression of M1 (NOS2) or M2 markers (Arg-1 and CD206) in macrophages. In coculture system, the migratory capacity of both cells and the expression levels of NOS2, Arg-1, and CD206 in macrophages were significantly enhanced upon 10−8 M BPA. In a DCIS xenograft model, oral exposure to an environmentally human-relevant low dose of 2.5 µg/l BPA for 70 days via drinking water led to an approximately 2-fold promotion in the primary tumor growth rate and a significant enhancement of lymph node metastasis along with increased protumorigenic CD206+ M2 polarization of macrophages. These results demonstrate that BPA acts as an accelerator to promote DCIS progression to invasive breast cancer by affecting DCIS cell proliferation and migration as well macrophage polarization toward a protumorigenic phenotype.
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Affiliation(s)
- Hyelim Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Korea
| | - Hoe Suk Kim
- Department of Radiology, Seoul National University Hospital and Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Korea
| | - Yin Ji Piao
- Department of Biomedical Sciences, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Korea
| | - Woo Kyung Moon
- Department of Biomedical Sciences, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Korea
- Department of Radiology, Seoul National University Hospital and Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Korea
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21
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Gomez-Cambronero J. Lack of effective translational regulation of PLD expression and exosome biogenesis in triple-negative breast cancer cells. Cancer Metastasis Rev 2019; 37:491-507. [PMID: 30091053 DOI: 10.1007/s10555-018-9753-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is difficult to treat since cells lack the three receptors (ES, PR, or HER) that the most effective treatments target. We have used a well-established TNBC cell line (MDA-MB-231) from which we found evidence in support for a phospholipase D (PLD)-mediated tumor growth and metastasis: high levels of expression of PLD, as well as the absence of inhibitory miRs (such as miR-203) and 3'-mRNA PARN deadenylase activity in these cells. Such findings are not present in a luminal B cell line, MCF-7, and we propose a new miR•PARN•PLD node that is not uniform across breast cancer molecular subtypes and as such TNBC could be pharmacologically targeted differentially. We review the participation of PLD and phosphatidic acid (PA), its enzymatic product, as new "players" in breast cancer biology, with the aspects of regulation of the tumor microenvironment, macrophage polarization, regulation of PLD transcripts by specific miRs and deadenylases, and PLD-regulated exosome biogenesis. A new signaling miR•PARN•PLD node could serve as new biomarkers for TNBC abnormal signaling and metastatic disease staging, potentially before metastases are able to be visualized using conventional imaging.
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Affiliation(s)
- Julian Gomez-Cambronero
- Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA.
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22
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Bernard S, Myers M, Fang WB, Zinda B, Smart C, Lambert D, Zou A, Fan F, Cheng N. CXCL1 Derived from Mammary Fibroblasts Promotes Progression of Mammary Lesions to Invasive Carcinoma through CXCR2 Dependent Mechanisms. J Mammary Gland Biol Neoplasia 2018; 23:249-267. [PMID: 30094610 PMCID: PMC6582941 DOI: 10.1007/s10911-018-9407-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 07/24/2018] [Indexed: 12/21/2022] Open
Abstract
With improved screening methods, the numbers of abnormal breast lesions diagnosed in women have been increasing over time. However, it remains unclear whether these breast lesions will develop into invasive cancers. To more effectively predict the outcome of breast lesions and determine a more appropriate course of treatment, it is important to understand the underlying mechanisms that regulate progression of non-invasive lesions to invasive breast cancers. A hallmark of invasive breast cancers is the accumulation of fibroblasts. Fibroblast proliferation and activation in the mammary gland is in part regulated by the Transforming Growth Factor beta1 pathway (TGF-β). In animal models, TGF-β suppression of CCL2 and CXCL1 chemokine expression is associated with metastatic progression of mammary carcinomas. Here, we show that transgenic overexpression of the Polyoma middle T viral antigen in the mouse mammary gland of C57BL/6 mice results in slow growing non-invasive lesions that progress to invasive carcinomas in a stage dependent manner. Invasive carcinomas are associated with accumulation of fibroblasts that show decreased TGF-β expression and high levels of CXCL1, but not CCL2. Using co-transplant models, we show that decreased TGF-β signaling in fibroblasts contribute to mammary carcinoma progression through enhancement of CXCL1/CXCR2 dependent mechanisms. Using cell culture models, we show that CXCL1 mediated mammary carcinoma cell invasion through NF-κB, AKT, Stat3 and p42/44MAPK dependent mechanisms. These studies provide novel mechanistic insight into the progression of pre-invasive lesions and identify new stromal biomarkers, with important prognostic implications.
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Affiliation(s)
- Shira Bernard
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Megan Myers
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Wei Bin Fang
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Brandon Zinda
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Curtis Smart
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Diana Lambert
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - An Zou
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Fang Fan
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Nikki Cheng
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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23
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Yang M, McKay D, Pollard JW, Lewis CE. Diverse Functions of Macrophages in Different Tumor Microenvironments. Cancer Res 2018; 78:5492-5503. [PMID: 30206177 PMCID: PMC6171744 DOI: 10.1158/0008-5472.can-18-1367] [Citation(s) in RCA: 301] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/21/2018] [Accepted: 07/31/2018] [Indexed: 12/13/2022]
Abstract
Tumor-associated macrophages are a major constituent of malignant tumors and are known to stimulate key steps in tumor progression. In our review in this journal in 2006, we postulated that functionally distinct subsets of these cells exist in different areas within solid tumors. Here, we review the many experimental and clinical studies conducted since then to investigate the function(s), regulation, and clinical significance of macrophages in these sites. The latter include three sites of cancer cell invasion, tumor nests, the tumor stroma, and areas close to, or distant from, the tumor vasculature. A more complete understanding of macrophage diversity in tumors could lead to the development of more selective therapies to restore the formidable, anticancer functions of these cells. Cancer Res; 78(19); 5492-503. ©2018 AACR.
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Affiliation(s)
- Ming Yang
- Department of Oncology & Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Daniel McKay
- Department of Oncology & Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Jeffrey W Pollard
- MRC Centre for Reproductive Health, College of Medicine and Veterinary Medicine, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Claire E Lewis
- Department of Oncology & Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.
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24
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Can tumor-associated macrophages in ductal carcinoma in situ on biopsy predict invasive carcinoma on excision? Hum Pathol 2018; 82:158-162. [PMID: 30067949 DOI: 10.1016/j.humpath.2018.07.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/12/2018] [Accepted: 07/21/2018] [Indexed: 01/08/2023]
Abstract
Recent trials have explored surveillance of ductal carcinoma in situ (DCIS) without complete excision, but it is difficult to fully exclude an associated, unsampled invasive focus. Tumor microenvironment, including tumor-associated macrophages, may play a role in the transition from in situ to invasive carcinoma, and the presence of CD163-positive cells with DCIS has been associated with increased risk of progression to invasive carcinoma. We aimed to evaluate the role of DCIS-associated CD163-positive cells on biopsy in predicting associated invasion on excision. Immunohistochemistry for CD163 was performed on 57 total biopsy cases of DCIS of low (n = 13), intermediate (n = 21), and high (n = 23) nuclear grade, 27 (47%) of which showed invasion on the subsequent excision specimen. Positive intratumoral and stromal cells were quantified independently by 2 observers based on the percentage of cells staining. Intratumoral CD163 scores ranged from 0 to 2 (mean, 0.7). Stromal CD163 scores ranged from 0 to 3 (mean, 1.3). Intratumoral and stromal CD163 levels were not significantly associated with the presence of subsequent invasion when evaluated as a whole group (P = .36 and P = .47) or when subdivided into low (P = .36 and P = .17), intermediate (P = .82 and P = .82), or high (P = .09 and P = .68) nuclear grades. There was no correlation between intratumoral CD163 content and DCIS grade (P = .257). A trend for higher stromal CD163 expression was seen with higher-grade DCIS, although not statistically significant (P = .178). In conclusion, CD163 on breast core biopsy does not help select patients who may safely forgo excision of DCIS.
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25
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Tumor-infiltrating lymphocytes and ductal carcinoma in situ of the breast: friends or foes? Mod Pathol 2018; 31:1012-1025. [PMID: 29463884 DOI: 10.1038/s41379-018-0030-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/05/2018] [Accepted: 01/07/2018] [Indexed: 12/11/2022]
Abstract
In the past three decades, the detection rate of ductal carcinoma in situ of the breast has dramatically increased due to breast screening programs. As a consequence, about 20% of all breast cancer cases are detected in this early in situ stage. Some ductal carcinoma in situ cases will progress to invasive breast cancer, while other cases are likely to have an indolent biological behavior. The presence of tumor-infiltrating lymphocytes is seen as a promising prognostic and predictive marker in invasive breast cancer, mainly in HER2-positive and triple-negative subtypes. Here, we summarize the current understanding regarding immune infiltrates in invasive breast cancer and highlight recent observations regarding the presence and potential clinical significance of such immune infiltrates in patients with ductal carcinoma in situ. The presence of tumor-infiltrating lymphocytes, their numbers, composition, and potential relationship with genomic status will be discussed. Finally, we propose that a combination of genetic and immune markers may better stratify ductal carcinoma in situ subtypes with respect to tumor evolution.
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26
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Casasent AK, Schalck A, Gao R, Sei E, Long A, Pangburn W, Casasent T, Meric-Bernstam F, Edgerton ME, Navin NE. Multiclonal Invasion in Breast Tumors Identified by Topographic Single Cell Sequencing. Cell 2018; 172:205-217.e12. [PMID: 29307488 PMCID: PMC5766405 DOI: 10.1016/j.cell.2017.12.007] [Citation(s) in RCA: 306] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/15/2017] [Accepted: 12/01/2017] [Indexed: 11/17/2022]
Abstract
Ductal carcinoma in situ (DCIS) is an early-stage breast cancer that infrequently progresses to invasive ductal carcinoma (IDC). Genomic evolution has been difficult to delineate during invasion due to intratumor heterogeneity and the low number of tumor cells in the ducts. To overcome these challenges, we developed Topographic Single Cell Sequencing (TSCS) to measure genomic copy number profiles of single tumor cells while preserving their spatial context in tissue sections. We applied TSCS to 1,293 single cells from 10 synchronous patients with both DCIS and IDC regions in addition to exome sequencing. Our data reveal a direct genomic lineage between in situ and invasive tumor subpopulations and further show that most mutations and copy number aberrations evolved within the ducts prior to invasion. These results support a multiclonal invasion model, in which one or more clones escape the ducts and migrate into the adjacent tissues to establish the invasive carcinomas.
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Affiliation(s)
- Anna K Casasent
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aislyn Schalck
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ruli Gao
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Emi Sei
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Annalyssa Long
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - William Pangburn
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tod Casasent
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mary E Edgerton
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Nicholas E Navin
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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27
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Abstract
Human cancers exhibit formidable molecular heterogeneity, to a large extent accounting for the incomplete and transitory efficacy of current anti-cancer therapies. However, neoplastic cells alone do not manifest the disease, but conscript a battery of non-tumor cells to enable and sustain hallmark capabilities of cancer. Escaping immunosurveillance is one of such capabilities. Tumors evolve immunosuppressive microenvironment to subvert anti-tumor immunity. In this review, we will focus on tumor-associated myeloid cells, which constitute an essential part of the immune microenvironment and reciprocally interact with cancer cells to establish malignancy toward metastasis. The diversity and plasticity of these cells constitute another layer of heterogeneity, beyond the heterogeneity of cancer cells themselves. We envision that immune microenvironment co-evolves with the genetic heterogeneity of tumor. Addressing the question of how genetically distinct tumors shape and are shaped by unique immune microenvironment will provide an attractive rationale to develop novel immunotherapeutic modalities. Here, we discuss the complex nature of tumor microenvironment, with an emphasis on the cellular and functional heterogeneity among tumor-associated myeloid cells as well as immune environment heterogeneity in the context of a full spectrum of human breast cancers.
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28
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Gorringe KL, Fox SB. Ductal Carcinoma In Situ Biology, Biomarkers, and Diagnosis. Front Oncol 2017; 7:248. [PMID: 29109942 PMCID: PMC5660056 DOI: 10.3389/fonc.2017.00248] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022] Open
Abstract
Ductal carcinoma in situ (DCIS) is an often-diagnosed breast disease and a known, non-obligate, precursor to invasive breast carcinoma. In this review, we explore the clinical and pathological features of DCIS, fundamental elements of DCIS biology including gene expression and genetic events, the relationship of DCIS with recurrence and invasive breast cancer, and the interaction of DCIS with the microenvironment. We also survey how these various elements are being used to solve the clinical conundrum of how to optimally treat a disease that has potential to progress, and yet is also likely over-treated in a significant proportion of cases.
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Affiliation(s)
- Kylie L. Gorringe
- Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Stephen B. Fox
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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29
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Xu R. Mammary epithelial polarity and macrophage infiltration. ACTA ACUST UNITED AC 2017; 4. [PMID: 28664188 PMCID: PMC5485912 DOI: 10.14800/macrophage.1521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Loss of epithelial cell polarity and inflammation are hallmarks of breast cancer development. Although the association between the disruption of tissue polarity and inflammation has been demonstrated, we know little about how these two events are coupled. Using the 3D co-culture model of mammary epithelial cells and monocytes, a recent study reveals a link between disruption of epithelial polarity and monocytes infiltration.
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Affiliation(s)
- Ren Xu
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
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30
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Corredor G, Whitney J, Arias V, Madabhushi A, Romero E. Training a cell-level classifier for detecting basal-cell carcinoma by combining human visual attention maps with low-level handcrafted features. J Med Imaging (Bellingham) 2017; 4:021105. [PMID: 28382314 PMCID: PMC5363808 DOI: 10.1117/1.jmi.4.2.021105] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 02/22/2017] [Indexed: 12/16/2022] Open
Abstract
Computational histomorphometric approaches typically use low-level image features for building machine learning classifiers. However, these approaches usually ignore high-level expert knowledge. A computational model (M_im) combines low-, mid-, and high-level image information to predict the likelihood of cancer in whole slide images. Handcrafted low- and mid-level features are computed from area, color, and spatial nuclei distributions. High-level information is implicitly captured from the recorded navigations of pathologists while exploring whole slide images during diagnostic tasks. This model was validated by predicting the presence of cancer in a set of unseen fields of view. The available database was composed of 24 cases of basal-cell carcinoma, from which 17 served to estimate the model parameters and the remaining 7 comprised the evaluation set. A total of 274 fields of view of size [Formula: see text] were extracted from the evaluation set. Then 176 patches from this set were used to train a support vector machine classifier to predict the presence of cancer on a patch-by-patch basis while the remaining 98 image patches were used for independent testing, ensuring that the training and test sets do not comprise patches from the same patient. A baseline model (M_ex) estimated the cancer likelihood for each of the image patches. M_ex uses the same visual features as M_im, but its weights are estimated from nuclei manually labeled as cancerous or noncancerous by a pathologist. M_im achieved an accuracy of 74.49% and an [Formula: see text]-measure of 80.31%, while M_ex yielded corresponding accuracy and F-measures of 73.47% and 77.97%, respectively.
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Affiliation(s)
- Germán Corredor
- Universidad Nacional de Colombia, Computer Imaging and Medical Applications Lab, Department of Medical Imaging, Bogota, Colombia
- Case Western Reserve University, Center of Computational Imaging and Personalized Diagnostics, Department of Biomedical Engineering, Cleveland, Ohio, United States
| | - Jon Whitney
- Case Western Reserve University, Center of Computational Imaging and Personalized Diagnostics, Department of Biomedical Engineering, Cleveland, Ohio, United States
| | - Viviana Arias
- Universidad Nacional de Colombia, Patología Molecular Research Group, Department of Pathology, Bogota, Colombia
| | - Anant Madabhushi
- Case Western Reserve University, Center of Computational Imaging and Personalized Diagnostics, Department of Biomedical Engineering, Cleveland, Ohio, United States
| | - Eduardo Romero
- Universidad Nacional de Colombia, Computer Imaging and Medical Applications Lab, Department of Medical Imaging, Bogota, Colombia
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31
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Wennerberg E, Lhuillier C, Vanpouille-Box C, Pilones KA, García-Martínez E, Rudqvist NP, Formenti SC, Demaria S. Barriers to Radiation-Induced In Situ Tumor Vaccination. Front Immunol 2017; 8:229. [PMID: 28348554 PMCID: PMC5346586 DOI: 10.3389/fimmu.2017.00229] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 02/17/2017] [Indexed: 12/11/2022] Open
Abstract
The immunostimulatory properties of radiation therapy (RT) have recently generated widespread interest due to preclinical and clinical evidence that tumor-localized RT can sometimes induce antitumor immune responses mediating regression of non-irradiated metastases (abscopal effect). The ability of RT to activate antitumor T cells explains the synergy of RT with immune checkpoint inhibitors, which has been well documented in mouse tumor models and is supported by observations of more frequent abscopal responses in patients refractory to immunotherapy who receive RT during immunotherapy. However, abscopal responses following RT remain relatively rare in the clinic, and antitumor immune responses are not effectively induced by RT against poorly immunogenic mouse tumors. This suggests that in order to improve the pro-immunogenic effects of RT, it is necessary to identify and overcome the barriers that pre-exist and/or are induced by RT in the tumor microenvironment. On the one hand, RT induces an immunogenic death of cancer cells associated with release of powerful danger signals that are essential to recruit and activate dendritic cells (DCs) and initiate antitumor immune responses. On the other hand, RT can promote the generation of immunosuppressive mediators that hinder DCs activation and impair the function of effector T cells. In this review, we discuss current evidence that several inhibitory pathways are induced and modulated in irradiated tumors. In particular, we will focus on factors that regulate and limit radiation-induced immunogenicity and emphasize current research on actionable targets that could increase the effectiveness of radiation-induced in situ tumor vaccination.
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Affiliation(s)
- Erik Wennerberg
- Department of Radiation Oncology, Weill Cornell Medicine , New York, NY , USA
| | - Claire Lhuillier
- Department of Radiation Oncology, Weill Cornell Medicine , New York, NY , USA
| | | | - Karsten A Pilones
- Department of Radiation Oncology, Weill Cornell Medicine , New York, NY , USA
| | - Elena García-Martínez
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA; Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain
| | | | - Silvia C Formenti
- Department of Radiation Oncology, Weill Cornell Medicine , New York, NY , USA
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medicine , New York, NY , USA
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32
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Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 2017; 30:1002-19. [PMID: 27151975 PMCID: PMC4863733 DOI: 10.1101/gad.279737.116] [Citation(s) in RCA: 556] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an important modulator and even a driver of tumorigenicity. Within the tumor stromal milieu, heterogeneous populations of fibroblast-like cells, collectively termed carcinoma-associated fibroblasts (CAFs), are key players in the multicellular, stromal-dependent alterations that contribute to malignant initiation and progression. This review focuses on novel insights into the contributions of CAFs to disease progression, emergent events leading to the generation of CAFs, identification of CAF-specific biomarkers predictive of disease outcome, and recent therapeutic approaches aimed at blunting or reverting detrimental protumorigenic phenotypes associated with CAFs.
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Affiliation(s)
- Philippe Gascard
- Department of Pathology, University of California at San Francisco, San Francisco, California 94143, USA
| | - Thea D Tlsty
- Department of Pathology, University of California at San Francisco, San Francisco, California 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA
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Groen EJ, Elshof LE, Visser LL, Rutgers EJT, Winter-Warnars HA, Lips EH, Wesseling J. Finding the balance between over- and under-treatment of ductal carcinoma in situ (DCIS). Breast 2017; 31:274-283. [DOI: 10.1016/j.breast.2016.09.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 08/19/2016] [Accepted: 09/01/2016] [Indexed: 12/21/2022] Open
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Carron EC, Homra S, Rosenberg J, Coffelt SB, Kittrell F, Zhang Y, Creighton CJ, Fuqua SA, Medina D, Machado HL. Macrophages promote the progression of premalignant mammary lesions to invasive cancer. Oncotarget 2017; 8:50731-50746. [PMID: 28881599 PMCID: PMC5584199 DOI: 10.18632/oncotarget.14913] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 12/26/2016] [Indexed: 12/17/2022] Open
Abstract
Breast cancer initiation, progression and metastasis rely on a complex interplay between tumor cells and their surrounding microenvironment. Infiltrating immune cells, including macrophages, promote mammary tumor progression and metastasis; however, less is known about the role of macrophages in early stage lesions. In this study, we utilized a transplantable p53-null model of early progression to characterize the immune cell components of early stage lesions. We show that macrophages are recruited to ductal hyperplasias with a high tumor-forming potential where they are differentiated and polarized toward a tumor-promoting phenotype. These macrophages are a unique subset of macrophages, characterized by pro-inflammatory, anti-inflammatory and immunosuppressive factors. Macrophage ablation studies showed that macrophages are required for both early stage progression and primary tumor formation. These studies suggest that therapeutic targeting of tumor-promoting macrophages may not only be an effective strategy to block tumor progression and metastasis, but may also have critical implications for breast cancer prevention.
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Affiliation(s)
- Emily C Carron
- Department of Biochemistry and Molecular Biology, Tulane School of Medicine, New Orleans, LA, USA
| | - Samuel Homra
- Department of Biochemistry and Molecular Biology, Tulane School of Medicine, New Orleans, LA, USA
| | - Jillian Rosenberg
- Department of Biochemistry and Molecular Biology, Tulane School of Medicine, New Orleans, LA, USA
| | - Seth B Coffelt
- CRUK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Frances Kittrell
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Yiqun Zhang
- Dan L. Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA
| | - Chad J Creighton
- Dan L. Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA
| | - Suzanne A Fuqua
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
| | - Daniel Medina
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Heather L Machado
- Department of Biochemistry and Molecular Biology, Tulane School of Medicine, New Orleans, LA, USA
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Myckatyn TM, Wagner IJ, Mehrara BJ, Crosby MA, Park JE, Qaqish BF, Moore DT, Busch EL, Silva AK, Kaur S, Ollila DW, Lee CN. Cancer Risk after Fat Transfer: A Multicenter Case-Cohort Study. Plast Reconstr Surg 2017; 139:11-18. [PMID: 28027219 PMCID: PMC5428547 DOI: 10.1097/prs.0000000000002838] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Fat transfer is an increasingly popular method for refining postmastectomy breast reconstructions. However, concern persists that fat transfer may promote disease recurrence. Adipocytes are derived from adipose-derived stem cells and express adipocytokines that can facilitate active breast cancer cells in laboratory models. The authors sought to evaluate the association between fat transfer to the reconstructed breast and cancer recurrence in patients diagnosed with local or regional invasive breast cancers. METHODS A multicenter, case-cohort study was performed. Eligible patients from four centers (Memorial Sloan Kettering, M. D. Anderson Cancer Center, Alvin J. Siteman Cancer Center, and the University of Chicago) were identified by each site's institutional tumor registry or cancer data warehouse. Eligibility criteria were as follows: mastectomy with immediate breast reconstruction between 2006 and 2011, age older than 21 years, female sex, and incident diagnosis of invasive ductal carcinoma (stage I, II, or III). Cases consisted of all recurrences during the study period, and controls consisted of a 30 percent random sample of the study population. Cox proportional hazards regression was used to evaluate for association between fat transfer and time to recurrence in bivariate and multivariate models. RESULTS The time to disease recurrence unadjusted hazard ratio for fat transfer was 0.99 (95 percent CI, 0.56 to 1.7). After adjustment for age, body mass index, stage, HER2/Neu receptor status, and estrogen receptor status, the hazard ratio was 0.97 (95 percent CI, 0.54 to 1.8). CONCLUSION In this population of breast cancer patients who had mastectomy with immediate reconstruction, fat transfer was not associated with a higher risk of cancer recurrence. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.
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Affiliation(s)
- Terence M Myckatyn
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - I Janelle Wagner
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Babak J Mehrara
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Melissa A Crosby
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Julie E Park
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Bahjat F Qaqish
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Dominic T Moore
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Evan L Busch
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Amanda K Silva
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Surinder Kaur
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - David W Ollila
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
| | - Clara N Lee
- St. Louis, Mo.; Chapel Hill, N.C.; New York, N.Y.; Houston, Texas; Chicago and Arlington Heights, Ill.; Boston, Mass.; and Columbus, Ohio
- From the Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in Saint Louis, and the Alvin J. Siteman Cancer Center; the Division of Plastic and Reconstructive Surgery, the Department of Biostatistics, the Department of Epidemiology, Gillings School of Global Public Health, the Lineberger Comprehensive Cancer Center, and the Division of Surgical Oncology, Department of Surgery, University of North Carolina; the Department of Surgery, Memorial Sloan Kettering Cancer Center; the Department of Plastic Surgery, M. D. Anderson Cancer Center; the Section of Plastic and Reconstructive Surgery, University of Chicago Medicine and Biological Sciences, University of Chicago; The Plastic Surgery Foundation; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Plastic and Reconstructive Surgery, Health Services Management and Policy, Ohio State University
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Campbell MJ, Baehner F, O'Meara T, Ojukwu E, Han B, Mukhtar R, Tandon V, Endicott M, Zhu Z, Wong J, Krings G, Au A, Gray JW, Esserman L. Characterizing the immune microenvironment in high-risk ductal carcinoma in situ of the breast. Breast Cancer Res Treat 2016; 161:17-28. [PMID: 27785654 DOI: 10.1007/s10549-016-4036-0] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 10/21/2016] [Indexed: 02/04/2023]
Abstract
PURPOSE The recent increase in the incidence of ductal carcinoma in situ (DCIS) has sparked debate over the classification and treatment of this disease. Although DCIS is considered a precursor lesion to invasive breast cancer, some DCIS may have more or less risk than is realized. In this study, we characterized the immune microenvironment in DCIS to determine if immune infiltrates are predictive of recurrence. METHODS Fifty-two cases of high-grade DCIS (HG-DCIS), enriched for large lesions and a history of recurrence, were age matched with 65 cases of non-high-grade DCIS (nHG-DCIS). Immune infiltrates were characterized by single- or dual-color staining of FFPE sections for the following antigens: CD4, CD8, CD20, FoxP3, CD68, CD115, Mac387, MRC1, HLA-DR, and PCNA. Nuance multispectral imaging software was used for image acquisition. Protocols for automated image analysis were developed using CellProfiler. Immune cell populations associated with risk of recurrence were identified using classification and regression tree analysis. RESULTS HG-DCIS had significantly higher percentages of FoxP3+ cells, CD68+ and CD68+PCNA+ macrophages, HLA-DR+ cells, CD4+ T cells, CD20+ B cells, and total tumor infiltrating lymphocytes compared to nHG-DCIS. A classification tree, generated from 16 immune cell populations and 8 clinical parameters, identified three immune cell populations associated with risk of recurrence: CD8+HLADR+ T cells, CD8+HLADR- T cells, and CD115+ cells. CONCLUSION These findings suggest that the tumor immune microenvironment is an important factor in identifying DCIS cases with the highest risk for recurrence and that manipulating the immune microenvironment may be an efficacious strategy to alter or prevent disease progression.
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MESH Headings
- Adult
- Aged
- Biomarkers
- Breast Neoplasms/immunology
- Breast Neoplasms/metabolism
- Breast Neoplasms/mortality
- Breast Neoplasms/therapy
- Carcinoma, Intraductal, Noninfiltrating/immunology
- Carcinoma, Intraductal, Noninfiltrating/metabolism
- Carcinoma, Intraductal, Noninfiltrating/mortality
- Carcinoma, Intraductal, Noninfiltrating/therapy
- Combined Modality Therapy
- Female
- Humans
- Lymphocyte Count
- Lymphocyte Subsets/immunology
- Lymphocyte Subsets/metabolism
- Lymphocyte Subsets/pathology
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Macrophages/immunology
- Macrophages/metabolism
- Macrophages/pathology
- Middle Aged
- Neoplasm Grading
- Neoplasm Recurrence, Local
- Neoplasm Staging
- Patient Outcome Assessment
- Prognosis
- Tumor Burden
- Tumor Microenvironment/immunology
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Affiliation(s)
- Michael J Campbell
- Department of Surgery, University of California, 2340 Sutter St, N321, San Francisco, CA, 94115, USA.
| | - Frederick Baehner
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Tess O'Meara
- Mt Zion Carol Franc Buck Breast Care Center, University of California, San Francisco, CA, USA
| | - Ekene Ojukwu
- Mt Zion Carol Franc Buck Breast Care Center, University of California, San Francisco, CA, USA
| | - Booyeon Han
- Mt Zion Carol Franc Buck Breast Care Center, University of California, San Francisco, CA, USA
| | - Rita Mukhtar
- Department of Surgery, University of California, 2340 Sutter St, N321, San Francisco, CA, 94115, USA
| | - Vickram Tandon
- Mt Zion Carol Franc Buck Breast Care Center, University of California, San Francisco, CA, USA
| | - Max Endicott
- Mt Zion Carol Franc Buck Breast Care Center, University of California, San Francisco, CA, USA
| | - Zelos Zhu
- Mt Zion Carol Franc Buck Breast Care Center, University of California, San Francisco, CA, USA
| | - Jasmine Wong
- Department of Surgery, University of California, 2340 Sutter St, N321, San Francisco, CA, 94115, USA
| | - Gregor Krings
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Alfred Au
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Joe W Gray
- Oregon Health and Science University, Portland, OR, USA
| | - Laura Esserman
- Department of Surgery, University of California, 2340 Sutter St, N321, San Francisco, CA, 94115, USA
- Mt Zion Carol Franc Buck Breast Care Center, University of California, San Francisco, CA, USA
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Liu C, Li X, Feng J, Liao F, Li D, Han D. Substrate stiffness modulates mRNA expression profiling in breast cancer cells. Clin Hemorheol Microcirc 2016; 63:399-410. [DOI: 10.3233/ch-162047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Cuiying Liu
- National Center for Nanoscience and Technology, Beijing, China
| | - Xiang Li
- National Center for Nanoscience and Technology, Beijing, China
| | - Jiantao Feng
- National Center for Nanoscience and Technology, Beijing, China
| | - Fulong Liao
- National Center for Nanoscience and Technology, Beijing, China
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dongguo Li
- Institute of Biomedical Engineering, Capital Medical University, Beijing, China
| | - Dong Han
- National Center for Nanoscience and Technology, Beijing, China
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Li L, Chen J, Xiong G, St Clair DK, Xu W, Xu R. Increased ROS production in non-polarized mammary epithelial cells induces monocyte infiltration in 3D culture. J Cell Sci 2016; 130:190-202. [PMID: 27656113 DOI: 10.1242/jcs.186031] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 08/17/2016] [Indexed: 02/01/2023] Open
Abstract
Loss of epithelial cell polarity promotes cell invasion and cancer dissemination. Therefore, identification of factors that disrupt polarized acinar formation is crucial. Reactive oxygen species (ROS) drive cancer progression and promote inflammation. Here, we show that the non-polarized breast cancer cell line T4-2 generates significantly higher ROS levels than polarized S1 and T4R cells in three-dimensional (3D) culture, accompanied by induction of the nuclear factor κB (NF-κB) pathway and cytokine expression. Minimizing ROS in T4-2 cells with antioxidants reestablished basal polarity and inhibited cell proliferation. Introducing constitutively activated RAC1 disrupted cell polarity and increased ROS levels, indicating that RAC1 is a crucial regulator that links cell polarity and ROS generation. We also linked monocyte infiltration with disruption of polarized acinar structure using a 3D co-culture system. Gain- and loss-of-function experiments demonstrated that increased ROS in non-polarized cells is necessary and sufficient to enhance monocyte recruitment. ROS also induced cytokine expression and NF-κB activity. These results suggest that increased ROS production in mammary epithelial cell leads to disruption of cell polarity and promotes monocyte infiltration.
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Affiliation(s)
- Linzhang Li
- Department of Laboratory Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130021, China.,Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
| | - Jie Chen
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
| | - Gaofeng Xiong
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
| | - Daret K St Clair
- Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA
| | - Wei Xu
- Department of Laboratory Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130021, China
| | - Ren Xu
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA .,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
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Marques O, Porto G, Rêma A, Faria F, Cruz Paula A, Gomez-Lazaro M, Silva P, Martins da Silva B, Lopes C. Local iron homeostasis in the breast ductal carcinoma microenvironment. BMC Cancer 2016; 16:187. [PMID: 26944411 PMCID: PMC4779214 DOI: 10.1186/s12885-016-2228-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 02/29/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND While the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored. METHODS Immunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization. RESULTS We confirm previous results by showing that breast cancer epithelial cells present an 'iron-utilization phenotype' with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an 'iron-donor' phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size. CONCLUSIONS The present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context.
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Affiliation(s)
- Oriana Marques
- Laboratory of Immunogenetics - Autoimmunity and Neurosciences, Unit for Multidisciplinary Biomedical Research (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228,Edif 2 Piso 4, P-4050313, Porto, Portugal. .,Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal. .,Basic and Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular (IBMC), University of Porto, Porto, Portugal. .,Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal.
| | - Graça Porto
- Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal. .,Hematology Service, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.
| | - Alexandra Rêma
- Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
| | - Fátima Faria
- Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
| | - Arnaud Cruz Paula
- Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal. .,Department of Pathology, Portuguese Oncology Institute (IPO), Porto, Portugal.
| | - Maria Gomez-Lazaro
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal. .,Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal.
| | - Paula Silva
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal. .,Faculty of Medicine of University of Porto (FMUP), Porto, Portugal. .,Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
| | - Berta Martins da Silva
- Laboratory of Immunogenetics - Autoimmunity and Neurosciences, Unit for Multidisciplinary Biomedical Research (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228,Edif 2 Piso 4, P-4050313, Porto, Portugal. .,Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
| | - Carlos Lopes
- Pathology and Molecular Immunology Department, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal. .,Department of Pathology, Portuguese Oncology Institute (IPO), Porto, Portugal.
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Mardekian SK, Bombonati A, Palazzo JP. Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions. Hum Pathol 2015; 49:114-23. [PMID: 26826418 DOI: 10.1016/j.humpath.2015.11.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 11/02/2015] [Accepted: 11/05/2015] [Indexed: 12/21/2022]
Abstract
Ductal carcinoma in situ (DCIS) of the breast is a lesion characterized by significant heterogeneity, in terms of morphology, immunohistochemical staining, molecular signatures, and clinical expression. For some patients, surgical excision provides adequate treatment, but a subset of patients will experience recurrence of DCIS or progression to invasive ductal carcinoma (IDC). Recent years have seen extensive research aimed at identifying the molecular events that characterize the transition from normal epithelium to DCIS and IDC. Tumor epithelial cells, myoepithelial cells, and stromal cells undergo alterations in gene expression, which are most important in the early stages of breast carcinogenesis. Epigenetic modifications, such as DNA methylation, together with microRNA alterations, play a major role in these genetic events. In addition, tumor proliferation and invasion is facilitated by the lesional microenvironment, which includes stromal fibroblasts and macrophages that secrete growth factors and angiogenesis-promoting substances. Characterization of DCIS on a molecular level may better account for the heterogeneity of these lesions and how this manifests as differences in patient outcome and response to therapy. Molecular assays originally developed for assessing likelihood of recurrence in IDC are recently being applied to DCIS, with promising results. In the future, the classification of DCIS will likely incorporate molecular findings along with histologic and immunohistochemical features, allowing for personalized prognostic information and therapeutic options for patients with DCIS. This review summarizes current data regarding the molecular characterization of DCIS and discusses the potential clinical relevance.
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MESH Headings
- Animals
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Biopsy
- Breast Neoplasms/chemistry
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Carcinoma/chemistry
- Carcinoma/genetics
- Carcinoma/pathology
- Carcinoma, Intraductal, Noninfiltrating/chemistry
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Carcinoma, Intraductal, Noninfiltrating/therapy
- Disease Progression
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Humans
- Immunohistochemistry
- Mastectomy
- Molecular Diagnostic Techniques
- Neoplasm Recurrence, Local
- Phenotype
- Predictive Value of Tests
- Reproducibility of Results
- Treatment Outcome
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Affiliation(s)
- Stacey K Mardekian
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107.
| | - Alessandro Bombonati
- Department of Pathology, Albert Einstein Medical Center, Philadelphia, PA 19141.
| | - Juan P Palazzo
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107.
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Afghahi A, Forgó E, Mitani AA, Desai M, Varma S, Seto T, Rigdon J, Jensen KC, Troxell ML, Gomez SL, Das AK, Beck AH, Kurian AW, West RB. Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer. Breast Cancer Res 2015; 17:108. [PMID: 26265211 PMCID: PMC4534146 DOI: 10.1186/s13058-015-0623-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 07/24/2015] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment. METHODS We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS. RESULTS We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013). CONCLUSIONS CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.
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Affiliation(s)
- Anosheh Afghahi
- Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA.
| | - Erna Forgó
- Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.
| | - Aya A Mitani
- Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA.
| | - Manisha Desai
- Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA.
| | - Sushama Varma
- Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.
| | - Tina Seto
- Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA.
| | - Joseph Rigdon
- Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA.
| | - Kristin C Jensen
- Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.
- Pathology and Laboratory Medicine, Palo Alto Veterans Affairs Health Care System, 795 Willow Road, Palo Alto, CA, 94025, USA.
| | - Megan L Troxell
- Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
| | - Scarlett Lin Gomez
- Department of Health Research and Policy, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA.
- Cancer Prevention Institute of California (CPIC), 2201 Walnut Avenue, Fremont, CA, 94538, USA.
| | - Amar K Das
- Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA.
- Department of Psychiatry and The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine, 1 Rope Ferry Road, Lebanon, NH, 03755, USA.
| | - Andrew H Beck
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
| | - Allison W Kurian
- Department of Medicine, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA.
- Department of Health Research and Policy, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA.
| | - Robert B West
- Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.
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Sousa S, Brion R, Lintunen M, Kronqvist P, Sandholm J, Mönkkönen J, Kellokumpu-Lehtinen PL, Lauttia S, Tynninen O, Joensuu H, Heymann D, Määttä JA. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res 2015; 17:101. [PMID: 26243145 PMCID: PMC4531540 DOI: 10.1186/s13058-015-0621-0] [Citation(s) in RCA: 291] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 07/21/2015] [Indexed: 01/21/2023] Open
Abstract
Introduction The immune system plays a major role in cancer progression. In solid tumors, 5-40 % of the tumor mass consists of tumor-associated macrophages (TAMs) and there is usually a correlation between the number of TAMs and poor prognosis, depending on the tumor type. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive, contribute to the matrix-remodeling, and hence favor tumor growth. The role of TAMs is not fully understood in breast cancer progression. Methods Macrophage infiltration (CD68) and activation status (HLA-DRIIα, CD163) were evaluated in a large cohort of human primary breast tumors (562 tissue microarray samples), by immunohistochemistry and scored by automated image analysis algorithms. Survival between groups was compared using the Kaplan-Meier life-table method and a Cox multivariate proportional hazards model. Macrophage education by breast cancer cells was assessed by ex vivo differentiation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of breast cancer cell conditioned media (MDA-MB231, MCF-7 or T47D cell lines) and M1 or M2 inducing cytokines (respectively IFN-γ, IL-4 and IL-10). Obtained macrophages were analyzed by flow cytometry (CD14, CD16, CD64, CD86, CD200R and CD163), ELISA (IL-6, IL-8, IL-10, monocyte colony stimulating factor M-CSF) and zymography (matrix metalloproteinase 9, MMP-9). Results Clinically, we found that high numbers of CD163+ M2-macrophages were strongly associated with fast proliferation, poor differentiation, estrogen receptor negativity and histological ductal type (p<0.001) in the studied cohort of human primary breast tumors. We demonstrated ex vivo that breast cancer cell-secreted factors modulate macrophage differentiation toward the M2 phenotype. Furthermore, the more aggressive mesenchymal-like cell line MDA-MB231, which secretes high levels of M-CSF, skews macrophages toward the more immunosuppressive M2c subtype. Conclusions This study demonstrates that human breast cancer cells influence macrophage differentiation and that TAM differentiation status correlates with recurrence free survival, thus further emphasizing that TAMs can similarly affect therapy efficacy and patient outcome. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0621-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sofia Sousa
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, FI-70211, Kuopio, Finland.
| | - Régis Brion
- INSERM, UMR957, Equipe LIGUE 2012, Nantes, F-44035, France. .,Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, F-44035, France. .,CHU de Nantes, Nantes, F-44035, France.
| | - Minnamaija Lintunen
- Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
| | - Pauliina Kronqvist
- Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
| | - Jouko Sandholm
- Cell Imaging Core, Turku Centre for Biotechnology, University of Turku, and Åbo Akademi University, Turku, Finland.
| | - Jukka Mönkkönen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, FI-70211, Kuopio, Finland.
| | | | - Susanna Lauttia
- Laboratory of Molecular Oncology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
| | - Olli Tynninen
- Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland.
| | - Heikki Joensuu
- Laboratory of Molecular Oncology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. .,Comprehensive Cancer Center, Helsinki University Hospital, and Department of Oncology, University of Helsinki, Helsinki, Finland.
| | - Dominique Heymann
- INSERM, UMR957, Equipe LIGUE 2012, Nantes, F-44035, France. .,Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, F-44035, France. .,CHU de Nantes, Nantes, F-44035, France.
| | - Jorma A Määttä
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, FI-70211, Kuopio, Finland. .,Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
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Giussani M, De Maria C, Michele V, Montemurro F, Triulzi T, Tagliabue E, Gelfi C, Vozzig G. Biomimicking of the Breast Tumor Microenvironment. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/s40610-015-0014-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Valta M, Fagerlund K, Suominen M, Halleen J, Tuomela J. Importance of microenvironment in preclinical models of breast and prostate cancer. World J Pharmacol 2015; 4:47-57. [DOI: 10.5497/wjp.v4.i1.47] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 11/18/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
The majority of cancer drugs entering clinical trials fail to reach the market due to poor efficacy. Preclinical efficacy has been traditionally tested using subcutaneous xenograft models that are cheap, fast and easy to perform. However, these models lack the correct tumor microenvironment, leading to poor clinical predictivity. Selecting compounds for clinical trials based on efficacy results obtained from subcutaneous xenograft models may therefore be one important reason for the high failure rates. In this review we concentrate in describing the role and importance of the tumor microenvironment in progression of breast and prostate cancer, and describe some breast and prostate cancer cell lines that are widely used in preclinical studies. We go through different preclinical efficacy models that incorporate the tissue microenvironment and should therefore be clinically more predictive than subcutaneous xenografts. These include three-dimensional cell culture models, orthotopic and metastasis models, humanized and transgenic mouse models, and patient-derived xenografts. Different endpoint measurements and applicable imaging techniques are also discussed. We conclude that models that incorporate the tissue microenvironment should be increasingly used in preclinical efficacy studies to reduce the current high attrition rates of cancer drugs in clinical trials.
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Shiao SL, Ruffell B, DeNardo DG, Faddegon BA, Park CC, Coussens LM. TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy. Cancer Immunol Res 2015; 3:518-25. [PMID: 25716473 DOI: 10.1158/2326-6066.cir-14-0232] [Citation(s) in RCA: 203] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 01/29/2015] [Indexed: 11/16/2022]
Abstract
Radiotherapy and chemotherapy following surgery are mainstays of treatment for breast cancer. Although multiple studies have recently revealed the significance of immune cells as mediators of chemotherapy response in breast cancer, less is known regarding roles for leukocytes as mediating outcomes following radiotherapy. To address this question, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to radiotherapy could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor-bearing mice with either a neutralizing mAb to colony-stimulating factor-1 (CSF-1) or a small-molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following radiotherapy. Delayed tumor growth in this setting was associated with increased presence of CD8(+) T cells and reduced presence of CD4(+) T cells, the main source of the TH2 cytokine IL4 in mammary tumors. Selective depletion of CD4(+) T cells or neutralization of IL4 in combination with radiotherapy phenocopied results following macrophage depletion, whereas depletion of CD8(+) T cells abrogated improved response to radiotherapy following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the chemotherapy paclitaxel, resulted in slowed primary mammary tumor growth by CD8(+) T-cell-dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant TH2-based programs driving protumorigenic and immune-suppressive pathways in mammary (breast) tumors to improve outcomes.
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Affiliation(s)
- Stephen L Shiao
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Brian Ruffell
- Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
| | - David G DeNardo
- Department of Medicine, Department of Pathology and Immunology, and Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
| | - Bruce A Faddegon
- Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
| | - Catherine C Park
- Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
| | - Lisa M Coussens
- Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
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Assefnia S, Dakshanamurthy S, Guidry Auvil JM, Hampel C, Anastasiadis PZ, Kallakury B, Uren A, Foley DW, Brown ML, Shapiro L, Brenner M, Haigh D, Byers SW. Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies. Oncotarget 2015; 5:1458-74. [PMID: 24681547 PMCID: PMC4039224 DOI: 10.18632/oncotarget.1538] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cadherin-11 (CDH11), associated with epithelial to mesenchymal transformation in development, poor prognosis malignancies and cancer stem cells, is also a major therapeutic target in rheumatoid arthritis (RA). CDH11 expressing basal-like breast carcinomas and other CDH11 expressing malignancies exhibit poor prognosis. We show that CDH11 is increased early in breast cancer and ductal carcinoma in-situ. CDH11 knockdown and antibodies effective in RA slowed the growth of basal-like breast tumors and decreased proliferation and colony formation of breast, glioblastoma and prostate cancer cells. The repurposed arthritis drug celecoxib, which binds to CDH11, and other small molecules designed to bind CDH11 without inhibiting COX-2 preferentially affect the growth of CDH11 positive cancer cells in vitro and in animals. These data suggest that CDH11 is important for malignant progression, and is a therapeutic target in arthritis and cancer with the potential for rapid clinical translation
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Affiliation(s)
- Shahin Assefnia
- The Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
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Allen MD, Marshall JF, Jones JL. αvβ6 Expression in Myoepithelial Cells: A Novel Marker for Predicting DCIS Progression with Therapeutic Potential. Cancer Res 2014; 74:5942-7. [DOI: 10.1158/0008-5472.can-14-1841] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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48
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Laoui D, Van Overmeire E, De Baetselier P, Van Ginderachter JA, Raes G. Functional Relationship between Tumor-Associated Macrophages and Macrophage Colony-Stimulating Factor as Contributors to Cancer Progression. Front Immunol 2014; 5:489. [PMID: 25339957 PMCID: PMC4188035 DOI: 10.3389/fimmu.2014.00489] [Citation(s) in RCA: 155] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 09/22/2014] [Indexed: 12/14/2022] Open
Abstract
The current review article describes the functional relationship between tumor-associated macrophages (TAM) as key cellular contributors to cancer malignancy on the one hand and macrophage-colony-stimulating factor (M-CSF or CSF-1) as an important molecular contributor on the other. We recapitulate the available data on expression of M-CSF and the M-CSF receptor (M-CSFR) in human tumor tissue as constituents of a stromal macrophage signature and on the limits of the predictive and prognostic value of plasma M-CSF levels. After providing an update on current insights into the nature of TAM heterogeneity at the level of M1/M2 phenotype and TAM subsets, we give an overview of experimental evidence, based on genetic, antibody-mediated, and pharmacological disruption of M-CSF/M-CSFR signaling, for the extent to which M-CSFR signaling can not only determine the TAM quantity, but can also contribute to shaping the phenotype and heterogeneity of TAM and other related tumor-infiltrating myeloid cells (TIM). Finally, we review the accumulating information on the – sometimes conflicting – effects blocking M-CSFR signaling may have on various aspects of cancer progression such as tumor growth, invasion, angiogenesis, metastasis, and resistance to therapy and we thereby discuss in how far these different effects actually reflect a contribution of TAM.
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Affiliation(s)
- Damya Laoui
- Myeloid Cell Immunology Laboratory, VIB , Brussels , Belgium ; Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel , Brussels , Belgium
| | - Eva Van Overmeire
- Myeloid Cell Immunology Laboratory, VIB , Brussels , Belgium ; Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel , Brussels , Belgium
| | - Patrick De Baetselier
- Myeloid Cell Immunology Laboratory, VIB , Brussels , Belgium ; Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel , Brussels , Belgium
| | - Jo A Van Ginderachter
- Myeloid Cell Immunology Laboratory, VIB , Brussels , Belgium ; Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel , Brussels , Belgium
| | - Geert Raes
- Myeloid Cell Immunology Laboratory, VIB , Brussels , Belgium ; Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel , Brussels , Belgium
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DeFilippis RA, Fordyce C, Patten K, Chang H, Zhao J, Fontenay GV, Kerlikowske K, Parvin B, Tlsty TD. Stress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density. Cancer Res 2014; 74:5032-5044. [PMID: 25172842 DOI: 10.1158/0008-5472.can-13-3390] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Telomere malfunction and other types of DNA damage induce an activin A-dependent stress response in mortal nontumorigenic human mammary epithelial cells that subsequently induces desmoplastic-like phenotypes in neighboring fibroblasts. Some characteristics of this fibroblast/stromal response, such as reduced adipocytes and increased extracellular matrix content, are observed not only in tumor tissues but also in disease-free breast tissues at high risk for developing cancer, especially high mammographic density tissues. We found that these phenotypes are induced by repression of the fatty acid translocase CD36, which is seen in desmoplastic and disease-free high mammographic density tissues. In this study, we show that epithelial cells from high mammographic density tissues have more DNA damage signaling, shorter telomeres, increased activin A secretion and an altered DNA damage response compared with epithelial cells from low mammographic density tissues. Strikingly, both telomere malfunction and activin A expression in epithelial cells can repress CD36 expression in adjacent fibroblasts. These results provide new insights into how high mammographic density arises and why it is associated with breast cancer risk, with implications for the definition of novel invention targets (e.g., activin A and CD36) to prevent breast cancer.
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Affiliation(s)
- Rosa Anna DeFilippis
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.,Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Colleen Fordyce
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.,Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Kelley Patten
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.,Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Hang Chang
- Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
| | - Jianxin Zhao
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.,Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | | | - Karla Kerlikowske
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.,Departments of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Bahram Parvin
- Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
| | - Thea D Tlsty
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.,Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
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50
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Sullivan AR, Pixley FJ. CSF-1R signaling in health and disease: a focus on the mammary gland. J Mammary Gland Biol Neoplasia 2014; 19:149-59. [PMID: 24912655 DOI: 10.1007/s10911-014-9320-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 06/02/2014] [Indexed: 12/21/2022] Open
Abstract
Colony-stimulating factor-1 (CSF-1), also known as macrophage-colony stimulating factor (M-CSF), is the primary growth factor regulating survival, proliferation and differentiation of macrophages. It is also a potent chemokine for macrophages and monocytes. Signaling via the CSF-1 receptor (CSF-1R) is necessary for the production of almost all tissue resident macrophage populations and these macrophages participate, via trophic mechanisms, in the normal development and homeostasis of tissues and organs in which they reside, including the mammary gland. The drawback of this close interaction between macrophages and parenchymal cells is that dysregulation of macrophage trophic functions assists in the development and progression of many cancers, including breast cancer. Furthermore, tumour cells secrete CSF-1 to attract more macrophages to the tumour microenvironment where CSF-1R signaling frequently drives the behaviour of these tumour-associated macrophages (TAMs) to promote tumour progression and metastasis. Evidence is mounting that treated tumours secrete more CSF-1 and the increased recruitment of TAMs limits treatment efficacy. Thus, therapeutic targeting of the CSF-1R to inhibit TAM function is likely to enhance tumour response and improve patient outcomes in the treatment of cancer, including breast cancer.
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Affiliation(s)
- Amy Renee Sullivan
- School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia
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