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A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression.

ABSTRACT: Cancer progression largely depends on tumor blood vessels as well on immune cell infiltration. In various tumors, vascular cells, namely endothelial cells (ECs) and pericytes, strongly regulate leukocyte infiltration into tumors and immune cell activation, hence the immune response to cancers. Recently, a lot of compelling studies unraveled the molecular mechanisms by which tumor vascular cells regulate monocyte and tumor-associated macrophage (TAM) recruitment and phenotype, and consequently tumor progression. Reciprocally, TAMs and monocytes strongly modulate tumor blood vessel and tumor lymphatic vessel formation by exerting pro-angiogenic and lymphangiogenic effects, respectively. Finally, the interaction between monocytes/TAMs and vascular cells is also impacting several steps of the spread of cancer cells throughout the body, a process called metastasis. In this review, the impact of the bi-directional dialog between blood vascular cells and monocytes/TAMs in the regulation of tumor progression is discussed. All together, these data led to the design of combinations of anti-angiogenic and immunotherapy targeting TAMs/monocyte whose effects are briefly discussed in the last part of this review.

SUBMITTER: Delprat V

PROVIDER: S-EPMC8213675 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CSF-1R inhibition disrupts the dialog between leukaemia cells and macrophages and delays leukaemia progression.

Project description:Research in the last few years has revealed that leukaemic cells can remodel the bone marrow niche into a permissive environment favouring leukaemic stem cell expansion. Tumour-associated macrophages (TAMs) are prominent components of the tumour microenvironment and play an important role in the onset and progression of solid tumours. However, little is known about their role in the development of acute lymphoblastic leukaemia (ALL). Using a unique mouse model of T-ALL induced by injection of EL4 T-cell lymphoma cells to syngeneic C57BL/6 mice, we report herein that ALL leads to the invasion of leukaemia-associated monocyte-derived cells (LAMs) into the bone marrow and spleen of T-ALL mice. Furthermore, we found that leukaemia cells could polarize bone marrow-derived macrophages (BMDMs) into LAMs. In turn, LAMs were able to protect leukaemia cells from drug-induced apoptosis in vitro. Therapies targeted against the TAMs by inhibiting colony stimulating factor-1 receptor (CSF-1R) have emerged as a promising approach for cancer treatment. In this study, we demonstrate that CSF-1R inhibition inhibits the viability of BMDMs, blocks LAMs polarization and reduces the abundance of LAMs in T-ALL mice. In vivo, combination treatment of CSF-1R inhibitor and vincristine (VCR) dramatically increased the survival of T-ALL mice and delayed leukaemia progression compared with VCR monotherapy. Finally, these data reinforce the role of microenvironments in leukaemia and suggest that macrophages are a potential target for the development of novel therapeutic strategies in T-ALL.

| S-EPMC7701573 | biostudies-literature

An overview of gene expression dynamics during early ovarian folliculogenesis: specificity of follicular compartments and bi-directional dialog.

Project description:BACKGROUND: Successful early folliculogenesis is crucial for female reproductive function. It requires appropriate gene specific expression of the different types of ovarian cells at different developmental stages. To date, most gene expression studies on the ovary were conducted in rodents and did not distinguish the type of cell. In mono-ovulating species, few studies have addressed gene expression profiles and mainly concerned human oocytes. RESULTS: We used a laser capture microdissection method combined with RNA-seq technology to explore the transcriptome in oocytes and granulosa cells (GCs) during development of the sheep ovarian follicle. We first documented the expression profile of 15 349 genes, then focused on the 5 129 genes showing differential expression between oocytes and GCs. Enriched functional categories such as oocyte meiotic arrest and GC steroid synthesis reflect two distinct cell fates. We identified the implication of GC signal transduction pathways such as SHH, WNT and RHO GTPase. In addition, signaling pathways (VEGF, NOTCH, IGF1, etc.) and GC transzonal projections suggest the existence of complex cell-cell interactions. Finally, we highlighted several transcription regulators and specifically expressed genes that likely play an important role in early folliculogenesis. CONCLUSIONS: To our knowledge, this is the first comprehensive exploration of transcriptomes derived from in vivo oocytes and GCs at key stages in early follicular development in sheep. Collectively, our data advance our understanding of early folliculogenesis in mono-ovulating species and will be a valuable resource for unraveling human ovarian dysfunction such as premature ovarian failure (POF).

| S-EPMC3890531 | biostudies-literature

Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression.

Project description:It was hypothesized that contact between chronic lymphocytic leukaemia (CLL) B-cells and marrow stromal cells impact both cell types. To test this hypothesis, we utilized a long-term primary culture system from bone biopsies that reliably generates a mesenchymal stem cell (MSC). Co-culture of MSC with CLL B-cells protected the latter from both spontaneous apoptosis and drug-induced apoptosis. The CD38 expression in previously CD38 positive CLL B-cells was up-regulated with MSC co-culture. Upregulation of CD71, CD25, CD69 and CD70 in CLL B-cells was found in the co-culture. CD71 upregulation was more significantly associated with high-risk CLL, implicating CD71 regulation in the microenvironment predicting disease progression. In MSC, rapid ERK and AKT phosphorylation (within 30 min) were detected when CLL B-cells and MSC were separated by transwell; indicating that activation of MSC was mediated by soluble factors. These findings support a bi-directional activation between bone marrow stromal cells and CLL B-cells.

| S-EPMC2783570 | biostudies-literature

Kindlin2 enables EphB/ephrinB bi-directional signaling to support vascular development.

Project description:Direct contact between cells expressing either ephrin ligands or Eph receptor tyrosine kinase produces diverse developmental responses. Transmembrane ephrinB ligands play active roles in transducing bi-directional signals downstream of EphB/ephrinB interaction. However, it has not been well understood how ephrinB relays transcellular signals to neighboring cells and what intracellular effectors are involved. Here, we report that kindlin2 can mediate bi-directional ephrinB signaling through binding to a highly conserved NIYY motif in the ephrinB2 cytoplasmic tail. We show this interaction is important for EphB/ephrinB-mediated integrin activation in mammalian cells and for blood vessel morphogenesis during zebrafish development. A mixed two-cell population study revealed that kindlin2 (in ephrinB2-expressing cells) modulates transcellular EphB4 activation by promoting ephrinB2 clustering. This mechanism is also operative for EphB2/ephrinB1, suggesting that kindlin2-mediated regulation is conserved for EphB/ephrinB signaling pathways. Together, these findings show that kindlin2 enables EphB4/ephrinB2 bi-directional signal transmission.

| S-EPMC9795039 | biostudies-literature

Bi-directional regulation between circadian rhythm and neurodegeneration-associated FUS

Project description:Circadian rhythms are daily physiological and behavioral changes governed by an internal molecular clock, and dysfunctions in circadian rhythms have long been associated with various neurodegenerative diseases. Abnormal sleep-wake cycle often precedes the onset of cognitive and motor symptoms in patients, while the pathological changes may further exacerbate the disturbance in circadian cycle. It is unclear whether dysregulated circadian rhythm is a consequence of, or a contributing factor for, neurodegeneration. In addition, the evidence directly connecting the neurodegeneration-associated proteins to core circadian clock gene expression remains sparse. Here we show that FUS, a RNA-binding protein implicated in the pathogenesis of ALS and frontotemporal dementia, exhibits a bi-directional regulation with circadian rhythm. Our meta-analysis of RNAseq datasets and subsequent biochemical analysis revealed FUS as a gene regulated by circadian oscillation. Furthermore, NR1D1 binds the FUS promoter and regulates the amplitude of FUS oscillation. Meanwhile, FUS is recruited by transcriptional co-repressor PSF, and is found in the same complex as Bmal-Clock to repress Per2 expression. More strikingly, in cells and brain tissues from homozygous knock-in rats, the pathogenic R521C mutant FUS significantly alters the oscillation patterns of core circadian genes even at young age. Therefore, our results have revealed a novel bi-directional mechanism whereby dysregulated circadian clock and FUS expression may exacerbate neurodegeneration via mutual influence.

2017-04-12 | GSE77572 | GEO

Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages.

Project description:Genetic depletion of macrophages in Polyoma Middle T oncoprotein (PyMT)-induced mammary tumors in mice delayed the angiogenic switch and the progression to malignancy. To determine whether vascular endothelial growth factor A (VEGF-A) produced by tumor-associated macrophages regulated the onset of the angiogenic switch, a genetic approach was used to restore expression of VEGF-A into tumors at the benign stages. This stimulated formation of a high-density vessel network and in macrophage-depleted mice, was followed by accelerated tumor progression. The expression of VEGF-A led to a massive infiltration into the tumor of leukocytes that were mostly macrophages. This study suggests that macrophage-produced VEGF regulates malignant progression through stimulating tumor angiogenesis, leukocytic infiltration and tumor cell invasion.

| S-EPMC2396497 | biostudies-other

The Bi-directional Relationship between Source Characteristics and Message Content.

Project description:Much of what we believe we know, we know through the testimony of others (Coady, 1992). While there has been long-standing evidence that people are sensitive to the characteristics of the sources of testimony, for example in the context of persuasion, researchers have only recently begun to explore the wider implications of source reliability considerations for the nature of our beliefs. Likewise, much remains to be established concerning what factors influence source reliability. In this paper, we examine, both theoretically and empirically, the implications of using message content as a cue to source reliability. We present a set of experiments examining the relationship between source information and message content in people's responses to simple communications. The results show that people spontaneously revise their beliefs in the reliability of the source on the basis of the expectedness of a source's claim and, conversely, adjust message impact by perceived reliability; hence source reliability and message content have a bi-directional relationship. The implications are discussed for a variety of psychological, philosophical and political issues such as belief polarization and dual-route models of persuasion.

| S-EPMC5797680 | biostudies-literature

CCL16 is a pro-tumor chemokine that recruits monocytes and macrophages to promote hepatocellular carcinoma progression.

Project description:Intricate signaling cascades involving chemokines and their cognate receptors on neoplastic and immune constituents within tumor microenvironment have garnered substantial research interest. Our investigation delineates the contribution of Chemokine (C-C motif) ligand 16 (CCL16) to the clinico-pathological features and tumorigenesis of hepatocellular carcinoma (HCC). Analysis of 237 pairs of HCC specimens unraveled a significant association between CCL16 expression and vascular invasion, early-stage clinicopathological features, and diminished recurrence-free survival among HCC patients. Immunohistochemical (IHC) assays of the clinical HCC specimens indicated elevated CCL16 in tumorous versus normal hepatic tissues. Our in vivo experiments demonstrated CCL16 overexpression fostered tumor proliferation, whereas in vitro assays elucidated that CCL16-mediated chemotactic recruitment of monocytes and M2 macrophages was orchestrated via CCR1 and CCR5. In contrast to previous claims that CCL16 is physiologically irrelevant and has minimal affinity for its receptors (CCR1, CCR2, CCR5, CCR8), our findings unravel that inhibition of CCL16/CCR1 and CCL16/CCR5 interactions through receptor-specific antagonists markedly impeded CCL16-directed chemotaxis, migration, adhesion, and leukocyte recruitment. Moreover, CCL16-overexpression in HCCs significantly augmented levels of several cytokines implicated in tumor progression, namely IL-6, IL-10 and VEGFA. IHC analysis of CCL16-overexpressing xenografts elicited greatly enhanced levels of VEGFA and IL-6, while assessments of HCC specimens confirmed a positive correlation between CCL16 expression and IL-6 and VEGFA levels. Collectively, our study highlights oncogenic role of CCL16 in hepatocarcinogenesis and provides a foundational basis for novel therapeutic interventions targeting the CCL16/CCR1/CCR5 axis.

| S-EPMC11301285 | biostudies-literature

Obstructive Sleep Apnea Monocytes Exhibit High Levels of Vascular Endothelial Growth Factor Secretion, Augmenting Tumor Progression.

Project description:Obstructive sleep apnea (OSA) is a syndrome characterized by repeated pauses in breathing induced by a partial or complete collapse of the upper airways during sleep. Intermittent hypoxia (IH), a hallmark characteristic of OSA, has been proposed to be a major determinant of cancer development, and patients with OSA are at a higher risk of tumors. Both OSA and healthy monocytes have been found to show enhanced HIF1? expression under IH. Moreover, these cells under IH polarize toward a tumor-promoting phenotype in a HIF1?-dependent manner and influence tumor growth via vascular endothelial growth factor (VEGF). Monocytes from patients with OSA increased the tumor-induced microenvironment and exhibited an impaired cytotoxicity in a 3D tumor in vitro model as a result of the increased HIF1? secretion. Adequate oxygen restoration both in vivo (under continuous positive airway pressure treatment, CPAP) and in vitro leads the monocytes to revert the tumor-promoting phenotype, demonstrating the plasticity of the innate immune system and the oxygen recovery relevance in this context.

| S-EPMC5994578 | biostudies-literature

Bi-directional signaling between the intestinal epithelium and type-3 innate lymphoid cells regulates secretory dynamics and interleukin-22.

Project description:Type-3 innate lymphoid cells (ILC3) respond to localized environmental cues to regulate homeostasis and orchestrate immunity in the intestine. The intestinal epithelium is an important upstream regulator and downstream target of ILC3 signaling, however, the complexity of mucosal tissues can hinder efforts to define specific interactions between these two compartments. Here, we employ a reductionist co-culture system of murine epithelial small intestinal organoids (SIO) with ILC3 to uncover bi-directional signaling mechanisms that underlie intestinal homeostasis. We report that ILC3 induce global transcriptional changes in intestinal epithelial cells, driving the enrichment of secretory goblet cell signatures. We find that SIO enriched for goblet cells promote NKp46+ ILC3 and interleukin (IL)-22 expression, which can feedback to induce IL-22-mediated epithelial transcriptional signatures. However, we show that epithelial regulation of ILC3 in this system is contact-dependent and demonstrate a role for epithelial Delta-Like-Canonical-Notch-Ligand (Dll) in driving IL-22 production by ILC3, via subset-specific Notch1-mediated activation of T-bet+ ILC3. Finally, by interfering with Notch ligand-receptor dynamics, ILC3 appear to upregulate epithelial Atoh1 to skew secretory lineage determination in SIO-ILC3 co-cultures. This research outlines two complimentary bi-directional signaling modules between the intestinal epithelium and ILC3, which may be relevant in intestinal homeostasis and disease.

| S-EPMC7615753 | biostudies-literature

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