Corrupt policemen: inflammatory cells promote tumor angiogenesis

Zumsteg, Adrian; Christofori, Gerhard

doi:10.1097/cco.0b013e32831bed7e

Cited by 104 publications

(76 citation statements)

References 92 publications

(84 reference statements)

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“…These soluble stimuli include IL-8, IL-10, adrenomedullin (ADM), TNF-a, TGF-b, VEGFs, uPA, colony stimulating factor 1 (CSF-1), and chemokine (C-C motif) ligand 2 (CCL2). 21,22,44 In the present study, we proved that LPS facilitates pancreatic cancer cell invasion, while MCM promotes both pancreatic cancer cell growth and invasion. Both LPS and MCM repressed PP2Ac expression in pancreatic cancer cells in vitro, suggesting PP2Ac regulation could be involved in inflammation-driven pancreatic cancer progression.…”

Section: Discussionmentioning

confidence: 71%

“…Quality control of MCM was performed by evaluating secretion of the cytokines interleukin-8 (IL-8) and tumor necrosis factor-a (TNF-a) ( Figure 1C). 20,21,22 MCM promoted pancreatic cancer cell growth slightly ( Figure 1D) and stimulated invasion remarkably ( Figure 1E). These in vitro data suggest that inflammation could be a favorable factor for pancreatic cancer progression by accelerating cell growth and invasion.…”

Section: Inflammatory Stimuli Promotedpancreatic Cancer Cell Growth Amentioning

confidence: 99%

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Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

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Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Aca and PP2Acb isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-kB (NF-kB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Aca overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-kB pathway in vitro. LPS and MCM induced IKK and IkB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKa attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-kB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-kB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-kB pathway-dependent PP2Ac repression.

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Section: Discussionmentioning

confidence: 71%

Section: Inflammatory Stimuli Promotedpancreatic Cancer Cell Growth Amentioning

confidence: 99%

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

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“…t is widely accepted that tumor growth and progression are controlled by the tumor microenvironment, [1][2][3][4][5][6] which consists of cellular and noncellular components. Cellular components include tumor cells, stromal cells (fibroblasts, epithelial cells, and infiltrating immune cells), soluble factors secreted by them, extracellular matrix (ECM), and the biophysical/mechanical forces and cues generated by cell-cell and cell-ECM contacts.…”

mentioning

confidence: 99%

“…Among various 3D models, tumor aggregates, often referred to as spheroids or microtumors, are multicellular structures that have been widely used to study (1) cell-cell interactions, 7,8 (2) microenvironmental cues important for tumor growth, 5 (3) to understand complex phenomena such as angiogenesis, [9][10][11][12][13][14] and (4) to test drug penetration, tumor responses, and drug resistance. 15,16 Microtumors have been shown to recapitulate various aspects of solid tumors in vivo, including their responses to cancer drugs (e.g., development of multidrug resistance), and can serve as good models for preclinical drug testing.…”

mentioning

confidence: 99%

Production of Uniform 3D Microtumors in Hydrogel Microwell Arrays for Measurement of Viability, Morphology, and Signaling Pathway Activation

Singh

Mukundan

et al. 2015

ASSAY and Drug Development Technologies

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Despite significant investments in cancer research and drug discovery/development, the rate of new cancer drug approval is £5% and most cases of metastatic cancer remain incurable. Ninety-five percent of new cancer drugs fail in clinical development because of a lack of therapeutic efficacy and/or unacceptable toxicity. One of the major factors responsible for the low success rate of anticancer drug development is the failure of preclinical models to adequately recapitulate the complexity and heterogeneity of human cancer. For throughput and capacity reasons, high-throughput screening growth inhibition assays almost exclusively use two-dimensional (2D) monolayers of tumor cell lines cultured on tissue culture-treated plastic/glass surfaces in serum-containing medium. However, these 2D tumor cell line cultures fail to recapitulate the three-dimensional (3D) context of cells in solid tumors even though the tumor microenvironment has been shown to have a profound effect on anticancer drug responses. Tumor spheroids remain the best characterized and most widely used 3D models; however, spheroid sizes tend to be nonuniform, making them unsuitable for high-throughput drug testing. To circumvent this challenge, we have developed defined size microwell arrays using nonadhesive hydrogels that are applicable to a wide variety of cancer cell lines to fabricate sizecontrolled 3D microtumors. We demonstrate that the hydrogel microwell array platform can be applied successfully to generate hundreds of uniform microtumors within 3-6 days from many cervical and breast, as well as head and neck squamous cell carcinoma (HNSCC) cells. Moreover, controlling size of the microwells in the hydrogel array allows precise control over the size of the microtumors. Finally, we demonstrate the application of this platform technology to probe activation as well as inhibition of epidermal growth factor receptor (EGFR) signaling in 3D HNSCC microtumors in response to EGF and cetuximab treatments, respectively. We believe that the ability to generate large numbers of HNSCC microtumors of uniform size and 3D morphology using hydrogel arrays will provide more physiological in vitro 3D tumor models to investigate how tumor size influences signaling pathway activation and cancer drug efficacy.

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“…Clinical data have now accumulated indicating that human tumor samples positively correlate with infiltration of bone marrow-derived immune cells (BMDCs) such as macrophages and neutrophils. In particular, recent evidence collectively shows that bone marrow-derived macrophages and monocytes (collectively termed 'myeloid lineage cells') play crucial roles in tumor angiogenesis [76,81,82]. However, those pro-angiogenic myeloid cells are yet poorly defined, and show overlapping phenotypes [83].…”

Section: Myeloid-derived Suppressor Cells and Monocytes: An Elusive Pmentioning

confidence: 99%

Roles of Bone Marrow Cells in Skeletal Metastases: No Longer Bystanders

Park

Soki

McCauley

2011

Cancer Microenvironment

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Bone serves one of the most congenial metastatic microenvironments for multiple types of solid tumors, but its role in this process remains under-explored. Among many cell populations constituting the bone and bone marrow microenvironment, osteoblasts (originated from mesenchymal stem cells) and osteoclasts (originated from hematopoietic stem cells) have been the main research focus for pro-tumorigenic roles. Recently, increasing evidence further elucidates that hematopoietic lineage cells as well as stromal cells in the bone marrow mediate distinct but critical functions in tumor growth, metastasis, angiogenesis and apoptosis in the bone microenvironment. This review article summarizes the key evidence describing differential roles of bone marrow cells, including hematopoietic stem cells (HSCs), megakaryocytes, macrophages and myeloid-derived suppressor cells in the development of metastatic bone lesions. HSCs promote tumor growth by switching on angiogenesis, but at the same time compete with metastatic tumor cells for occupancy of osteoblastic niche. Megakaryocytes negatively regulate the extravasating tumor cells by inducing apoptosis and suppressing proliferation. Macrophages and myeloid cells have pro-tumorigenic roles in general, suggesting a similar effect in the bone marrow. Hematopoietic and stromal cell populations in the bone marrow, previously considered as simple by-standers in the context of tumor metastasis, have distinct and active roles in promoting or suppressing tumor growth and metastasis in bone. Further investigation on the extended roles of bone marrow cells will help formulate better approaches to treatment through improved understanding of the metastatic bone microenvironment.

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Corrupt policemen: inflammatory cells promote tumor angiogenesis

Cited by 104 publications

References 92 publications

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

Production of Uniform 3D Microtumors in Hydrogel Microwell Arrays for Measurement of Viability, Morphology, and Signaling Pathway Activation

Roles of Bone Marrow Cells in Skeletal Metastases: No Longer Bystanders

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