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Diverse Functions of Macrophages in Different Tumor Microenvironments | Cancer Research
Latest TAMS review

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.
TAMs  Macrophages  macrophage_differentiation  macrophage_polarization  macrophage_recruitment 
5 days ago by Segalllab
Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis | Cancer Research
MTDH/AEG1 contributes to NFKB activation in macrophages...

Chronic inflammation is a known hallmark of cancer and is central to the onset and progression of hepatocellular carcinoma (HCC). Hepatic macrophages play a critical role in the inflammatory process leading to HCC. The oncogene Astrocyte elevated gene-1 (AEG-1) regulates NFκB activation, and germline knockout of AEG-1 in mice (AEG-1−/−) results in resistance to inflammation and experimental HCC. In this study, we developed conditional hepatocyte- and myeloid cell–specific AEG-1−/− mice (AEG-1ΔHEP and AEG-1ΔMAC, respectively) and induced HCC by treatment with N-nitrosodiethylamine (DEN) and phenobarbital (PB). AEG-1ΔHEP mice exhibited a significant reduction in disease severity compared with control littermates, while AEG-1ΔMAC mice were profoundly resistant. In vitro, AEG-1−/− hepatocytes exhibited increased sensitivity to stress and senescence. Notably, AEG-1−/− macrophages were resistant to either M1 or M2 differentiation with significant inhibition in migration, endothelial adhesion, and efferocytosis activity, indicating that AEG-1 ablation renders macrophages functionally anergic. These results unravel a central role of AEG-1 in regulating macrophage activation and indicate that AEG-1 is required in both tumor cells and tumor microenvironment to stimulate hepatocarcinogenesis.
MTDH  nfkb  Macrophages  macrophage_polarization 
5 weeks ago by Segalllab
Two to Tango: Dialog between Immunity and Stem Cells in Health and Disease - ScienceDirect
Discussion of macrophages and contributions to stemness - mention notch activation of macrophages to make wnts in mammary gland


Stem cells in mammary glands (MaSCs) also require signals from tissue macrophages for ductal morphogenesis (Gyorki et al., 2009). Chakrabarti and colleagues discovered that MaSCs express a Notch ligand Delta like 1 (DLL1), which activates resident Notch-expressing macrophages (Chakrabarti et al., 2018). This interaction stimulates macrophages to produce Wnt ligands, which in turn triggers MaSC proliferation.
stem_cells  Macrophages  Notch  delta_ligands 
5 weeks ago by Segalllab
Cadherin-11–mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-β | Science Signaling
M2 macrophages especially express CDH11 and could enhance TGFB activation of fibroblasts in wound healing - possible relevance for cancer, even TNTs?

Macrophages contribute to the activation of fibroblastic cells into myofibroblasts, which secrete collagen and contract the collagen matrix to acutely repair injured tissue. Persistent myofibroblast activation leads to the accumulation of fibrotic scar tissue that impairs organ function. We investigated the key processes that turn acute beneficial repair into destructive progressive fibrosis. We showed that homotypic cadherin-11 interactions promoted the specific binding of macrophages to and persistent activation of profibrotic myofibroblasts. Cadherin-11 was highly abundant at contacts between macrophages and myofibroblasts in mouse and human fibrotic lung tissues. In attachment assays, cadherin-11 junctions mediated specific recognition and strong adhesion between macrophages and myofibroblasts. One functional outcome of cadherin-11–mediated adhesion was locally restricted activation of latent transforming growth factor–β (TGF-β) between macrophage-myofibroblast pairs that was not observed in cocultures of macrophages and myofibroblasts that were not in contact with one another. Our data suggest that cadherin-11 junctions maintain latent TGF-β–producing macrophages and TGF-β–activating myofibroblasts in close proximity to one another. Inhibition of homotypic cadherin-11 interactions could be used to cause macrophage-myofibroblast separation, thereby destabilizing the profibrotic niche.
cdh11  Macrophages  macrophage_polarization  fibroblasts  myofibroblasts  TGFB 
5 weeks ago by Segalllab
Metalloproteinase MT1-MMP islets act as memory devices for podosome reemergence
see stable sites of MT1-MMP-pHluorin


Podosomes are dynamic cell adhesions that are also sites of extracellular matrix degradation, through recruitment of matrix-lytic enzymes, particularly of matrix metalloproteinases. Using total internal reflection fluorescence microscopy, we show that the membrane-bound metalloproteinase MT1-MMP is enriched not only at podosomes but also at distinct “islets” embedded in the plasma membrane of primary human macrophages. MT1-MMP islets become apparent upon podosome dissolution and persist beyond podosome lifetime. Importantly, the majority of MT1-MMP islets are reused as sites of podosome reemergence. siRNA-mediated knockdown and recomplementation analyses show that islet formation is based on the cytoplasmic tail of MT1-MMP and its ability to bind the subcortical actin cytoskeleton. Collectively, our data reveal a previously unrecognized phase in the podosome life cycle and identify a structural function of MT1-MMP that is independent of its proteolytic activity. MT1-MMP islets thus act as cellular memory devices that enable efficient and localized reformation of podosomes, ensuring coordinated matrix degradation and invasion.
MT1-MMP-pHluorin  Macrophages  podosomes  lifeact 
6 weeks ago by Segalllab
Macrophage-Secreted TNFα and TGFβ1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways | Cancer Research
Show macrophage (raw mainly) enhanced invasion of 231 cells in microfluidic device where TNFA and TGFB stimulate MMPs and migration. Not sure why this is so different from our 3D invasion where GM6001 has no effect....


The ability of a cancer cell to migrate through the dense extracellular matrix within and surrounding the solid tumor is a critical determinant of metastasis. Macrophages enhance invasion and metastasis in the tumor microenvironment, but the basis for their effects is not fully understood. Using a microfluidic 3D cell migration assay, we found that the presence of macrophages enhanced the speed and persistence of cancer cell migration through a 3D extracellular matrix in a matrix metalloproteinases (MMP)-dependent fashion. Mechanistic investigations revealed that macrophage-released TNFα and TGFβ1 mediated the observed behaviors by two distinct pathways. These factors synergistically enhanced migration persistence through a synergistic induction of NF-κB–dependent MMP1 expression in cancer cells. In contrast, macrophage-released TGFβ1 enhanced migration speed primarily by inducing MT1-MMP expression. Taken together, our results reveal new insights into how macrophages enhance cancer cell metastasis, and they identify TNFα and TGFβ1 dual blockade as an antimetastatic strategy in solid tumors. Cancer Res; 77(2); 279–90. ©2016 AACR.
231_cells  Macrophages  raw264.7  bmdm  TGFB  tnfa  microfluidics 
11 weeks ago by Segalllab
Macrophages Promote Circulating Tumor Cell–Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients | Cancer Research
Interesting evaluation of how irradiated tissue can attract macrophages and thentumor cells - possible relationship to extravasation?


Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence after RT in patients with TNBC, we analyzed radiation effects on tumor and immune cell recruitment to tissues in an orthotopic breast cancer model. Recurrent patients exhibited a prolonged low absolute lymphocyte count when compared with nonrecurrent patients following RT. Recruitment of tumor cells to irradiated normal tissues was enhanced in the absence of CD8+ T cells. Macrophages (CD11b+F480+) preceded tumor cell infiltration and were recruited to tissues following RT. Tumor cell recruitment was mitigated by inhibiting macrophage infiltration using maraviroc, an FDA-approved CCR5 receptor antagonist. Our work poses the intriguing possibility that excessive macrophage infiltration in the absence of lymphocytes promotes local recurrence after RT. This combination thus defines a high-risk group of patients with TNBC.

Significance: This study establishes the importance of macrophages in driving tumor cell recruitment to sites of local radiation therapy and suggests that this mechanism contributes to local recurrence in women with TNBC that are also immunosuppressed.
Macrophages  extravasation  radiation 
october 2018 by Segalllab
Circuit Design Features of a Stable Two-Cell System - ScienceDirect
macrophages make pdgf and fibroblasts make csf1. Also talk about evidence for cell contact dependence - TNTs?


Macrophages and fibroblasts form a stable cell circuit resilient to perturbations


Analytical screening reveals design principles for population stability


The MP and FB circuit maintains stability through a “spring-and-ceiling” model


Cell contact provides competitive advantage because of local exchange of growth factors

Summary

Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit with specific properties that ensure homeostasis. Here, we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. We found that the macrophage-fibroblast cell circuit is stable and robust to perturbations. Analytical screening of all possible two-cell circuit topologies revealed the circuit features sufficient for stability, including environmental constraint and negative-feedback regulation. Moreover, we found that cell-cell contact is essential for the stability of the macrophage-fibroblast circuit. These findings illustrate principles of cell circuit design and provide a quantitative perspective on cell interactions.
Macrophages  fibroblasts  paracrine_loop  CSF1  pdgf  TNTs 
october 2018 by Segalllab
The role of IL-1B in breast cancer bone metastasis : Endocrine-Related Cancer
Good summary of possible roles of IL1B in bone metastasis - possible role of NRG1 induced IL1B in macrophages together with TNFA in bone metastasis?

" IL-1B has been identified as biomarker that can be used to predict which breast cancer patients are likely to experience relapse in bone. In vitro studies have suggested so far that IL-1B correlates with increased aggressiveness of breast cancer cell lines. Although in vivo studies are in their infancy, those that have been carried out confirm these findings. In particular, we have shown that IL-1 signalling is linked to breast cancer metastasis specifically to bone. The inhibition of IL-1R1 and reduced bone metastasis in our mouse model shows the role of this signalling axis in breast cancer metastasis to bone, but further studies are needed to elucidate whether IL-1B and/or IL-1A are primarily involved in this process.
IL1B  bone_metastasis  Macrophages  osteoclasts  tnfa 
september 2018 by Segalllab
A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation: Cell Reports
Very nice kinetic analysis of macrophage dynamics in the PyMT tumor model.


"Tumor-associated macrophages (TAMs) are critical for tumor metastasis. Two TAM subsets support cancer cell intravasation: migratory macrophages guide cancer cells toward blood vessels, where sessile perivascular macrophages assist their entry into the blood. However, little is known about the inter-relationship between these functionally distinct TAMs or their possible inter-conversion. We show that motile, streaming TAMs are newly arrived monocytes, recruited via CCR2 signaling, that then differentiate into the sessile perivascular macrophages. This unidirectional process is regulated by CXCL12 and CXCR4. Cancer cells induce TGF-β-dependent upregulation of CXCR4 in monocytes, while CXCL12 expressed by perivascular fibroblasts attracts these motile TAMs toward the blood vessels, bringing motile cancer cells with them. Once on the blood vessel, the migratory TAMs differentiate into perivascular macrophages, promoting vascular leakiness and intravasation."
Macrophages  dynamics  PyMT  perivascular_macrophages  macrophage_recruitment  macrophage_differentiation 
september 2018 by Segalllab
Oncotarget | Canonical NF-κB signaling in myeloid cells promotes lung metastasis in a mouse breast cancer model
See macrophage changes in both primary and lung but argue primary growth is not altered so effect is on lung. They look at circulating PyMT which may not be the best measure of intravasation

"In the present study, the role of canonical NF-κB signaling in myeloid cells in metastatic breast cancer was addressed by myeloid-specific deletion of Ikkβ in the MMTV polyoma middle T (PyMT) mouse model. Ikkβ deletion in myeloid cells did not affect primary mammary tumor growth but significantly reduced lung metastasis. While dissemination from the primary tumor was unaltered, myeloid-specific Ikkβ loss resulted in a strong up-regulation of pro-inflammatory genes and changes in immune cell populations in the lung, creating a tumor-suppressive microenvironment at the distant site. Thus, canonical NF-κB signaling in myeloid cells creates a permissive lung microenvironment that supports breast to lung metastasis.
PyMT-MMTV  nfkb  Macrophages  metastases  lung_colonization  macrophage_polarization  inflammation 
august 2018 by Segalllab
Lymphatic exosomes promote dendritic cell migration along guidance cues | JCB
JAG1 is increased in TNFA induced exosomes as is TNFAIP2.


"Collectively, this study introduces the novel concept of a basolateral promigratory layer of LEC-derived exosomes surrounding lymphatic vessels in inflammation and cancer. We conclude that inflammatory LEC exosomes, in a chemokinetic GPCR-signaling–dependent manner, induce the formation of dynamic exploratory cell protrusions via membrane bound CX3CL1 and thereby increase the directional movement of CX3CR1+ cells along guidance cues in complex environments. However, the contribution of additional exosome-induced migration machinery activating mechanisms cannot be ruled out. Beyond these findings the present study provides a comprehensive quantitative analysis of the composition of ss and inflammatory LEC exosomes with a large inventory of proteins whose potential relevancies in health and disease remain to be explored.
exosomes  lymphatics  inflammation  Macrophages  dendritic  cx3cr  cx3cl1 
august 2018 by Segalllab
Altered monocyte differentiation and macrophage polarization patterns in patients with breast cancer | BMC Cancer | Full Text
The percentages of circulating macrophages, which are defined as PM-2 K+ cells in the peripheral blood, were significantly higher in patients with breast cancer than in healthy controls. The percentages of M1-like macrophages were significantly lower, but those of M2-like macrophages were significantly higher in patients with breast cancer than in healthy controls. The percentage of M2c-like macrophages was significantly higher in advanced (stages II and III) breast cancer. However, the patterns of macrophage polarization were not associated with HER2 status in breast cancer.
Macrophages  circulating_macrophages  macrophage_polarization  M2_macrophages 
august 2018 by Segalllab
MKL1/2 and ELK4 co-regulate distinct serum response factor (SRF) transcription programs in macrophages
compares control and SRF siRNA in macrophages stimulated with zymosan as a way of looking at SRF regulated genes
srf  Macrophages  zymosan 
july 2018 by Segalllab
Chemotherapy Induces Breast Cancer Stemness in Association with Dysregulated Monocytosis | Clinical Cancer Research
Very nice paper showing that chemotherapy and neoadjuvant chemo can induce stemness in TNBC. Show stemness assays for 231 and BT474 cells in response to dox where macrophages (THP1) or CCL2/7/8 induce stemness including notch activation.


"Results: In human patients and mice, we detected a therapy-induced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCP). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte–macrophage differentiation and biased commitment of stimulated hematopoietic stem cells toward monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacologic inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary breast cancers following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT.

Conclusions: Our data establish a mechanism of chemotherapy-induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacologic inhibition of CCR2 as a potential cotreatment during conventional chemotherapy in neoadjuvant and adjuvant settings. Clin Cancer Res; 24(10); 2370–82. ©2018 AACR.

This article is featured in Highlights of This Issue, p. 2235
Translational Relevance

Preoperative or neoadjuvant therapy is increasingly administered to patients who are candidates for breast preservation and/or present with locally advanced or inflammatory breast cancer. However, some patients respond poorly to the treatment or relapse after neoadjuvant therapy. Our study using patient blood samples and experimental cell and mouse models shows that cytotoxic chemotherapy induces circulating monocyte-derived chemokines, which stimulate cancer stem–like cells (CSC) to potentially promote tumor relapse. Therefore, effective anticancer therapies need to block the concurrent CSC-stimulating effect to achieve better short-term and long-term outcomes. Using preclinical tumor models, we show that pharmacologic inhibition of CCR2 can serve as a potential cotreatment during conventional chemotherapy by targeting therapy-induced cancer stemness. In primary breast tumors, higher levels of CCR2 in tumor cells are associated with lack of a pathologic complete response to neoadjuvant therapy.
chemotherapy  chemoresistance  stem_cells  Notch  Macrophages  THP1  CCL2  mcps  neoadjuvant 
july 2018 by Segalllab
IL-1β enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells | PNAS
In summary, we present new evidence that IL-1β triggers CNS autoimmunity by acting on several fronts. In addition to its demonstrated role in the expansion of encephalitogenic GM-CSF–producing TH17 cells, we now report that pioneer CCR2+ monocytes must express IL-1β to be able to cross the blood–CNS barrier and initiate neuroinflammation in EAE. Furthermore, we show that IL-1β is a critical regulatory cytokine for GM-CSF production by CNS ECs, which in turn induces the differentiation of monocytes into APCs within the perivascular space of CNS blood vessels.
IL1B  transendothelial_migration  iTEM  eTEM  extravasation  CCR2  Macrophages 
june 2018 by Segalllab
Transgenic mice specifically expressing amphiregulin in white adipose tissue showed less adipose tissue mass - Yang - 2018 - Genes to Cells - Wiley Online Library
Not as useful as I hoped - male mice, epididymal fat, and obesity. No insitu or direct measurement of macrophage AREG...

"To determine adipocytokines that play a regulatory role during obesity development, we explored the genes that encode growth factors and investigated the physiological functions for adipose tissue development. Here, we isolated amphiregulin (Areg) gene whose expression was significantly up‐regulated in obese adipose tissues. Areg mRNA level was positively correlated with macrophage marker gene expression in adipose tissues in vivo. Unexpectedly, Areg transgenic mice showed less adipose tissue mass with increased mRNA expression levels of Tnf‐α and peroxisome proliferator‐activated receptor γ coactivator 1α (Pgc‐1α) and delayed white adipose tissue development during the convalescent stage in a dextran sodium sulfate‐induced colitis model. This study showed that Areg mRNA expression was significantly up‐regulated in obese adipose tissues and over‐expression of Areg in white adipose tissue caused less adipose tissue mass"
AREG  obesity  Macrophages 
may 2018 by Segalllab
Macrophages orchestrate breast cancer early dissemination and metastasis | Nature Communications
Indications of early circulating tumor cells that are dependent upon macrophages!

"Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206+/Tie2+ macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2+ early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.
Macrophages  Intravasation  CTCs  Ecadherin  CCL2  wnt1 
may 2018 by Segalllab
Twitter
love the title “Re-educating in by Dr. Joyce Johanna. Obviously they develope intrinsic e…
TME  AACR18  macrophages  from twitter_favs
april 2018 by maverickny
Circuit Design Features of a Stable Two-Cell System: Cell
Interesting idea that maybe CSF1 is on the cell surface of fibroblasts?

We also observed that the physical association between macrophages and fibroblasts depends on CSF1 (Figure 7D). Interestingly, macrophages were found in close contact with CSF1-sufficient fibroblasts, but not with CSF1-deficient cells.
CSF1  fibroblasts  Macrophages  paracrine_loop 
march 2018 by Segalllab

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