Novel mechanism for OSM-promoted extracellular matrix remodeling in breast cancer: LOXL2 upregulation and subsequent ECM alignment.
TL;DR: Invasive ductal carcinoma (IDC) is a serious problem for patients as it metastasizes, decreasing 5-year patient survival from > 95 to ~ 27% as mentioned in this paper.
Abstract: Invasive ductal carcinoma (IDC) is a serious problem for patients as it metastasizes, decreasing 5-year patient survival from > 95 to ~ 27%. The breast tumor microenvironment (TME) is often saturated with proinflammatory cytokines, such as oncostatin M (OSM), which promote epithelial-to-mesenchymal transitions (EMT) in IDC and increased metastasis. The extracellular matrix (ECM) also plays an important role in promoting invasive and metastatic potential of IDC. Specifically, the reorganization and alignment of collagen fibers in stromal ECM leads to directed tumor cell motility, which promotes metastasis. Lysyl oxidase like-2 (LOXL2) catalyzes ECM remodeling by crosslinking of collagen I in the ECM. We propose a novel mechanism whereby OSM induces LOXL2 expression, mediating stromal ECM remodeling of the breast TME. Bioinformatics was utilized to determine survival and gene correlation in patients. IDC cell lines were treated with OSM (also IL-6, LIF, and IL-1β) and analyzed for LOXL2 expression by qRT-PCR and immunolabelling techniques. Collagen I contraction assays, 3D invasion assays, and confocal microscopy were performed with and without LOXL2 inhibition to determine the impact of OSM-induced LOXL2 on the ECM. Our studies demonstrate that IDC patients with high LOXL2 and OSM co-expression had worse rates of metastasis-free survival than those with high levels of either, individually, and LOXL2 expression is positively correlated to OSM/OSM receptor (OSMR) expression in IDC patients. Furthermore, human IDC cells treated with OSM resulted in a significant increase in LOXL2 mRNA, which led to upregulated protein expression of secreted, glycosylated, and enzymatically active LOXL2. The expression of LOXL2 in IDC cells did not affect OSM-promoted EMT, and LOXL2 was localized to the cytoplasm and/or secreted. OSM-induced LOXL2 promoted an increase in ECM collagen I fiber crosslinking, which led to significant fiber alignment between cells and increased IDC cell invasion. Aligned collagen fibers in the ECM provide pathways for tumor cells to migrate more easily through the stroma to nearby vasculature and tissue. These results provide a new paradigm through which proinflammatory cytokine OSM promotes tumor progression. Understanding the nuances in IDC metastasis will lead to better potential therapeutics to combat against the possibility.
Citations
More filters
TL;DR: In this paper , the authors introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers and elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside.
Abstract: Abstract Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside.
24 citations
TL;DR: While Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival, and novel pathophysiological roles and functions for LOXL2 in PDAC are established.
Abstract: Objective The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models. Design Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2KO or KCL2KO and KPCL2KI or KCL2KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation. Results Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment. Conclusion Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.
9 citations
TL;DR: Attempts that have been made, and are still on-going, that focus on the development of efficient lysyl oxidase inhibitors for the treatment of various forms of cancer, and of diseases associated with abnormal fibrosis are described.
Abstract: The five genes of the lysyl oxidase family encode enzymes that covalently cross-link components of the extracellular matrix, such as various types of collagen and elastin, and, thus, promote the stabilization of extracellular matrixes. Several of these genes, in particular lysyl oxidase (LOX) and lysyl oxidase like-2 (LOXL2) were identified as genes that are upregulated by hypoxia, and promote tumor cells invasion and metastasis. Here, we focus on the description of the diverse molecular mechanisms by which the various lysyl oxidases affect tumor progression. We also describe attempts that have been made, and are still on-going, that focus on the development of efficient lysyl oxidase inhibitors for the treatment of various forms of cancer, and of diseases associated with abnormal fibrosis.
9 citations
TL;DR: The targeting of myeloid-derived suppressor cells as a therapeutic strategy to inhibit the formation of pre-metastasis niche is emphasized, which provided a research idea for curbing tumor metastasis.
Abstract: Metastasis is a complex process, which depends on the interaction between tumor cells and host organs. Driven by the primary tumor, the host organ will establish an environment suitable for the growth of tumor cells before their arrival, which is called the pre-metastasis niche. The formation of pre-metastasis niche requires the participation of a variety of cells, in which myeloid-derived suppressor cells play a very important role. They reach the host organ before the tumor cells, and promote the establishment of the pre-metastasis niche by influencing immunosuppression, vascular leakage, extracellular matrix remodeling, angiogenesis and so on. In this article, we introduced the formation of the pre-metastasis niche and discussed the important role of myeloid-derived suppressor cells. In addition, this paper also emphasized the targeting of myeloid-derived suppressor cells as a therapeutic strategy to inhibit the formation of pre-metastasis niche, which provided a research idea for curbing tumor metastasis.
6 citations
TL;DR: In this article , the role of oncostatin-M (OSM) in plaque vulnerability and extracellular matrix remodeling (ECM) is investigated, and the authors focus on critically discussing the role OSM in ECM remodeling and plaque vulnerability.
Abstract: Abstract Atherosclerosis is a multifactorial inflammatory disease characterized by the development of plaque formation leading to occlusion of the vessel and hypoxia of the tissue supplied by the vessel. Chronic inflammation and altered collagen expression render stable plaque to unstable and increase plaque vulnerability. Thinned and weakened fibrous cap results in plaque rupture and formation of thrombosis and emboli formation leading to acute ischemic events such as stroke and myocardial infarction. Inflammatory mediators including TREM-1, TLRs, MMPs, and immune cells play a critical role in plaque vulnerability. Among the other inflammatory mediators, oncostatin-M (OSM), a pro-inflammatory cytokine, play an important role in the development and progression of atherosclerosis, however, the role of OSM in plaque vulnerability and extracellular matrix remodeling (ECM) is not well understood and studied. Since ECM remodeling plays an important role in atherosclerosis and plaque vulnerability, a detailed investigation on the role of OSM in ECM remodeling and plaque vulnerability is critical. This is important because the role of OSM has been discussed in the context of proliferation of vascular smooth muscle cells and regulation of cytokine expression but the role of OSM is scarcely discussed in relation to ECM remodeling and plaque vulnerability. This review focuses on critically discussing the role of OSM in ECM remodeling and plaque vulnerability.
4 citations
References
More filters
University of Jyväskylä1, University of California, Los Angeles2, California Polytechnic State University3, Los Alamos National Laboratory4, National Research University – Higher School of Economics5, University of California, Berkeley6, University of Birmingham7, Australian Nuclear Science and Technology Organisation8, University of Washington9, University of Massachusetts Amherst10, University of West Bohemia11, Brigham Young University12, University of Texas at Austin13, Universidade Federal de Minas Gerais14, Google15
TL;DR: SciPy as discussed by the authors is an open-source scientific computing library for the Python programming language, which has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories and millions of downloads per year.
Abstract: SciPy is an open-source scientific computing library for the Python programming language. Since its initial release in 2001, SciPy has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories and millions of downloads per year. In this work, we provide an overview of the capabilities and development practices of SciPy 1.0 and highlight some recent technical developments.
6,244 citations
TL;DR: The gene-expression profile studied is a more powerful predictor of the outcome of disease in young patients with breast cancer than standard systems based on clinical and histologic criteria.
Abstract: Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...
5,902 citations
TL;DR: The paradoxical roles of the tumor microenvironment during specific stages of cancer progression and metastasis are discussed, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Abstract: Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
5,396 citations
TL;DR: It is shown, using Trastuzumab (Herceptin) monotherapy as an example, that the system can be used to identify molecular features that predict or indicate response to targeted therapies or other physiological perturbations.
3,056 citations
TL;DR: This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction, with emphasis on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins.
Abstract: The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
3,050 citations