Tumor microenvironment plays a crucial role in coordination with cancer cells in the establishment, growth and dissemination of the tumor. Among cells of the microenvironment, mesenchymal stem cells ...(MSCs) and their ability to evolve into cancer associated fibroblasts (CAFs) have recently generated a major interest in the field. Numerous studies have described the potential pro- or anti-tumorigenic action of MSCs. The goal of this review is to synthesize recent and emerging discoveries concerning the mechanisms by which MSCs can be attracted to tumor sites, how they can generate CAFs and by which way MSCs are able to modulate the growth, response to treatments, angiogenesis, invasion and metastasis of tumors. The understanding of the role of MSCs in tumor development has potential and clinical applications in terms of cancer management.
•Tumor microenvironment appears crucial for tumor development and dissemination.•MSCs display a tropism for tumor sites.•MSCs exhibit features characteristics to the hallmarks of cancers.•MSC can favor or inhibit tumor growth and metastasis.•Soluble factors and extracellular vesicles are critical for tumor cell-MSC interaction.
This review focuses on the interaction between multipotent stromal cells (MSCs) and carcinoma and the possible use of MSCs in cell-based anticancer therapies. MSCs are present in multiple tissues and ...are defined as cells displaying the ability to differentiate in multiple lineages, including chondrocytes, osteoblasts, and adipocytes. Recent evidence also suggests that they could play a role in the progression of carcinogenesis and that MSCs could migrate toward primary tumors and metastatic sites. It is possible that MSCs could also be involved in the early stages of carcinogenesis through spontaneous transformation. In addition, it is thought that MSCs can modulate tumor growth and metastasis, although this issue remains controversial and not well understood. The immunosuppressive properties and proangiogenic properties of MSCs account, at least in part, for their effects on cancer development. On the other hand, cancer cells also have the ability to enhance MSC migration. This complex dialog between MSCs and cancer cells is certainly critical for the outcome of tumor development. Interestingly, several studies have shown that MSCs engineered to express antitumor factors could be an innovative choice as a cell-mediated gene therapy to counteract tumor growth. More evidence will be needed to understand how MSCs positively or negatively modulate carcinogenesis and to evaluate the safety of MSC use in cell-mediated gene strategies. Disclosure of potential conflicts of interest is found at the end of this article.
Schematic representation of some cytoplasmic, membrane and nuclear estrogen receptor (ERα) targets: estradiol (E2) activation of ERα signaling is indicated by blue arrows; activation/enhancement of ...targetable proteins is indicated by green arrows, and inhibition with red T symbol.
In breast cancer (BC) epithelial cells, the mitogenic action of estradiol is transduced through binding to two receptors, ERα and ERβ, which act as transcription factors. Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC. In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors. Estrogen effects are mediated not only through nuclear ERs but also through cytoplasmic/membrane ERs and G-protein-coupled ERs. These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival. The partners of nuclear ER include SRC1-3, HDACs and ERβ itself as well as newly identified proteins, such as E6-AP, LKB1, PELP1, PAX-2 and FOXA1. The partners of extra-nuclear ERα include PI3K and the tyrosine kinase Src. These various factors are all potential targets for therapeutic intervention. In addition, BC proliferation is enhanced by insulin and EGF, which stimulate signaling through the MAPK and PI3K/AKT pathways by activation of the IGF-1R and EGFR axes, respectively. These pathways are tightly interconnected with ER-activated signaling, and membrane ERα forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response. Inhibiting these pathways with specific inhibitors or activating some of the pathways by gene manipulation may be therapeutically valuable for arresting BC cell cycle progression and for inducing apoptosis to antagonize hormone-resistance. Here, we review some newly identified putatively targetable ER partners and highlight the need to develop tumor-targeting drug carrier systems affecting both the tumor cells and the tumor environment.
Neutrophils play a major role in the protection from infections but also in inflammation related to tumor microenvironment. However, cell-extrinsic and -intrinsic cues driving their function at ...steady state is still fragmentary. Using
Cxcr2
knock-out mice, we have evaluated the function of the chemokine receptor Cxcr2 in neutrophil physiology. We show here that Cxcr2 deficiency decreases the percentage of mature neutrophils in the spleen, but not in the bone marrow (BM). There is also an increase of aged CD62L
lo
CXCR4
hi
neutrophils in the spleen of KO animals. Spleen
Cxcr2
-/-
neutrophils display a reduced phagocytic ability, whereas BM neutrophils show an enhanced phagocytic ability compared to WT neutrophils. Spleen
Cxcr2
-/-
neutrophils show reduced reactive oxygen species production, F-actin and α-tubulin levels. Moreover, spleen
Cxcr2
-/-
neutrophils display an altered signaling with reduced phosphorylation of ERK1/2 and p38 MAPK, impaired PI3K-AKT, NF-κB, TGFβ and IFNγ pathways. Altogether, these results suggest that Cxcr2 is essential for neutrophil physiology.
Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to chemicals including polycyclic aromatic hydrocarbons (PAHs) and polychlorinated dibenzo-p-dioxins (PCDDs) can lead ...to severe adverse health effects and increase the risk of breast cancer. This review considers several mechanisms which link the tumor promoting effects of environmental pollutants with the AhR signaling pathway, contributing to the development and progression of breast cancer. We explore AhR's function in shaping the tumor microenvironment, modifying immune tolerance, and regulating cancer stemness, driving breast cancer chemoresistance and metastasis. The complexity of AhR, with evidence for both oncogenic and tumor suppressor roles is discussed. We propose that AhR functions as a "molecular bridge", linking disproportionate toxin exposure and policies which underlie environmental injustice with tumor cell behaviors which drive poor patient outcomes.
Prostate cancer (PCa) represents the second leading cause of death among all cancer types in men in Europe and North America. Among the factors suspected to control PCa, incidence and progression, ...chemokines, and their receptors are now intensively studied. Chemokines are produced by tumor cells and also by the stromal microenvironment, both in the primary tumor site and in distant metastatic locations. The wide and differential distribution of chemokines and their receptors account for the pleiotropic actions of chemokines in PCa, including the modulation of growth, angiogenesis, invasion, metastasis, and hormone escape. This review will focus on the roles and the mechanisms of action and regulation of chemokines in the different steps of PCa development and will discuss the novel strategies that are currently envisioned to target chemokines in PCa.
Chemokines and their receptors are key players in breast cancer progression and outcome. Previous studies have shown that the chemokine receptor CXCR2 was expressed at higher levels by cells of the ...tumor microenvironment in triple-negative breast cancers (TNBCs). The aim of this study was to focus our attention on a retrospective cohort of 290 TNBC cases and analyze the involvement of CXCR2, CD11b (a marker of granulocytes) and CD66b (a marker of neutrophils) and their link with immune infiltration and immune checkpoint markers. We report that high densities of CXCR2-, CD11b- and CD66b-positive cells were associated with high-grade tumors. Moreover, molecular apocrine TNBCs, defined here as tumors that express both AR and FOXA1 biomarkers, exhibited low levels of CXCR2 and CD11b. High CXCR2 and CD11b levels were correlated with elevated density of tumor-infiltrating lymphocytes (TILs), CD8+ cytotoxic lymphocytes, expression of PD-L1 by tumor and stromal cells and of PD-1 by stromal cells. On the other hand, CD66b levels were associated only with CD8+, stromal PD-L1 and PD-1 expression. In univariate analysis, low levels of CXCR2 were correlated with poor OS and RFS. In multivariate analysis, low levels of CXCR2 were associated with poor OS. Finally, in TNBC treated with adjuvant chemotherapy, CXCR2 density was associated with longer RFS. Overall, our data highlight the potential beneficial association of high levels of CXCR2 with a subgroup of TNBC patients characterized by a better prognosis.
Chemokines are involved in cellular interactions and tropism in situations frequently associated with inflammation. Recently, the importance of chemokines and chemokine receptors in inflammation ...associated with carcinogenesis has been highlighted. Increasing evidence suggests that chemokines are produced by tumor cells as well as by cells of the tumor microenvironment including cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, tumor-associated macrophages (TAMs) and more recently tumor-associated neutrophils (TANs). In addition to affecting tumor cell proliferation, angiogenesis and metastasis, chemokines also seem to modulate senescence and cell survival. Here, we review recent progress on the roles of chemokines and chemokine receptors in cancer-related inflammation, and discuss the mechanisms underlying chemokine action in cancer that might facilitate the development of novel therapies in the future.
The nuclear factor-κB (NF-κB) transcription factor family has a crucial role in rapid responses to stress and pathogens. We show that the NF-κB subunit RelB is functionally associated with the aryl ...hydrocarbon receptor (AhR) and mediates transcription of chemokines such as IL-8 via activation of AhR and protein kinase A. RelB physically interacts with AhR and binds to an unrecognized RelB/AhR responsive element of the IL-8 promoter linking two signaling pathways to activate gene transcription. We found a time-dependent recruitment of AhR to the RelB/AhR responsive element site of IL-8 mediated by the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and via activation of protein kinase A. Furthermore, NF-κB-binding sites that are preferentially recognized by RelB/p52 are a target for RelB/AhR complexes without addition of any stimuli, implicating the endogenous function of the AhR. RelB/AhR complexes are also found to bind on xenobiotic responsive element, and RelB drastically increases the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced xenobiotic responsive element reporter activity. The interaction of RelB with AhR signaling, and AhR with NF-κB RelB signaling pathways represent a new mechanism of cross talk between the two transcription factors.
Ovarian cancer is the gynecological cancer exhibiting the highest morbidity and improvement of treatments is still required. Previous studies have shown that Estrogen-receptor beta (ERβ) levels ...decreased along with ovarian carcinogenesis. Here, we present evidence that reintroduction of ERβ in BG-1 epithelial ovarian cancer cells, which express ERα, leads in vitro to a decrease of basal and estradiol-promoted cell proliferation. ERβ reduced the frequency of cells in S phase and increased the one of cells in G2/M phase. At the molecular level, we found that ERβ downregulated total retinoblastoma (Rb), phosphorylated Rb and phospho-AKT cellular content as well as cyclins D1 and A2. In addition, ERβ had a direct effect on ERα, by strongly inhibiting its expression and activity, which could explain part of the anti-proliferative action of ERβ. By developing a novel preclinical model of ovarian cancer based on a luminescent orthotopic xenograft in athymic Nude mice, we further revealed that ERβ expression reduces tumor growth and the presence of tumor cells in sites of metastasis, hence resulting in improved survival of mice. Altogether, these findings unveil a potential tumor-suppressor role of ERβ in ovarian carcinogenesis, which could be of potential clinical relevance for the selection of the most appropriate treatment for patients.
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