CXCR2 chemokine receptor - a master regulator in cancer and physiology.

Recent findings have modified our understanding of the roles of chemokine receptor CXCR2 and its ligands in cancer, inflammation, and immunity. Studies in Cxcr2 tissue-specific knockout mice show that this receptor is involved in, among other things, cancer, central nervous system (CNS) function, metabolism, reproduction, COVID-19, and the response to circadian cycles. Moreover, CXCR2 involvement in neutrophil function has been revisited not only in physiology but also for its major contribution to cancers.

WHIM Syndrome-linked CXCR4 mutations drive osteoporosis.

WHIM Syndrome is a rare immunodeficiency caused by gain-of-function CXCR4 mutations. Here we report a decrease in bone mineral density in 25% of WHIM patients and bone defects leading to osteoporosis in a WHIM mouse model. Imbalanced bone tissue is observed in mutant mice combining reduced osteoprogenitor cells and increased osteoclast numbers.

Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer.

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.

CXCR2 intrinsically drives the maturation and function of neutrophils in mice.

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 knock-out mice, we have evaluated the function of the chemokine receptor Cxcr2 in neutrophil physiology.

Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies.

Knowledge about the hematopoietic niche has evolved considerably in recent years, in particular through analyzes, mouse models and the use of xenografts. Its complexity in the human bone marrow, in particular in a context of hematological malignancy, is more difficult to decipher by these strategies and could benefit from the knowledge acquired on the niches of solid tumors. Indeed, some common features can be suspected, since the bone marrow is a frequent site of solid tumor metastases.

Pivotal Role for Cxcr2 in Regulating Tumor-Associated Neutrophil in Breast Cancer.

Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis.

Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development.

Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to known human carcinogens including dioxins can lead to the promotion of breast cancer. While the repressor protein of the AhR (AhRR) blocks the canonical AhR pathway, the function of AhRR in the development of breast cancer is not well-known. In the current study we examined the impact of suppressing AhR activity using its dedicated repressor protein AhRR.

Prognostic Value of CXCR2 in Breast Cancer.

The tumor microenvironment appears essential in cancer progression and chemokines are mediators of the communication between cancer cells and stromal cells. We have previously shown that the ligands of the chemokine receptor CXCR2 were expressed at higher levels in triple-negative breast cancers (TNBC). Our hypothesis was that CXCR2 expression could also be altered in breast cancer.

The health status alters the pituitary function and reproduction of mice in a -dependent manner.

Microbiota and chronic infections can affect not only immune status, but also the overall physiology of animals. Here, we report that chronic infections dramatically modify the phenotype of KO mice, impairing in particular, their reproduction ability. We show that exposure of KO females to multiple types of chronic infections prevents their ability to cycle, reduces the development of the mammary gland and alters the morphology of the uterus due to an impairment of ovary function.

Recent discoveries concerning the tumor - mesenchymal stem cell interactions.

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.

IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production.

The aim of this work was to understand whether the nature of breast cancer cells could modify the nature of the dialog of mesenchymal stem cells (MSCs) with cancer cells. By treating MSCs with the conditioned medium of metastatic Estrogen-receptor (ER)-negative MDA-MB-231, or non-metastatic ER-positive MCF-7 breast cancer cells, we observed that a number of chemokines were produced at higher levels by MSCs treated with MDA-MB-231 conditioned medium (CM). MDA-MB-231 cells were able to induce NF-κB signaling in MSC cells.

Polycyclic aromatic hydrocarbons reciprocally regulate IL-22 and IL-17 cytokines in peripheral blood mononuclear cells from both healthy and asthmatic subjects.

Pollution, including polycyclic aromatic hydrocarbons (PAH), may contribute to increased prevalence of asthma. PAH can bind to the Aryl hydrocarbon Receptor (AhR), a transcription factor involved in Th17/Th22 type polarization. These cells produce IL17A and IL-22, which allow neutrophil recruitment, airway smooth muscle proliferation and tissue repair and remodeling.

Chromatin remodeling protein SMAR1 regulates NF-κB dependent Interleukin-8 transcription in breast cancer.

Interleukin-8 (IL-8) is a pleiotropic chemokine involved in metastasis and angiogenesis of breast tumors. The expression of IL-8 is deregulated in metastatic breast carcinomas owing to aberrant NF-κB activity, which is known to positively regulate IL-8 transcription. Earlier, we have shown that tumor suppressor SMAR1 suppresses NF-κB transcriptional activity by modulating IκBα function.

Characterization of an adaptive immune response in microsatellite-instable colorectal cancer.

Sporadic or hereditary colorectal cancer (CRC) with microsatellite instability (MSI) is frequently characterized by inflammatory lymphocytic infiltration and tends to be associated with a better outcome than microsatellite stable (MSS) CRC, probably reflecting a more effective immune response. We investigated inflammatory mechanisms in 48 MSI CRCs and 62 MSS CRCs by analyzing: (1) the expression of 48 cytokines using Bio-Plex multiplex cytokine assays, and (2) the in situ immune response by immunohistochemical analysis with antibodies against CD3 (T lymphocytes), CD8 (cytotoxic T lymphocytes), CD45RO (memory T lymphocytes), T-bet (Th1 CD4 cells), and FoxP3 (regulatory T cells). MSI CRC exhibited significantly higher expression of CCL5 (RANTES), CXCL8 (IL-8), CXCL9 (MIG), IL-1β, CXCL10 (IP-10), IL-16, CXCL1 (GROα), and IL-1ra, and lower expression of MIF, compared with MSS CRC.

Estrogen receptor signaling as a target for novel breast cancer therapeutics.

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.

Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer.

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.

[PAIR-gynaecology: multi/interdisciplinary for gynecologic cancer research. Problems needed to be resolved].

Each year, 13,000 newly gynecologic cancers are diagnosed in France. Gynecologic cancers were specifically heterogeneous (localisations, histologic subgroups, age class, etc). This work was delineated for a national call dedicated to gynecologic cancers.

Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression.

The aryl hydrocarbon receptor (AhR) has been best known for its role in mediating the toxicity of dioxin. Here we show that AhR overexpression is found among estrogen receptor (ER)α-negative human breast tumors and that its overexpression is positively correlated to that of the NF-κB subunit RelB and Interleukin (IL)-8. Increased DNA binding activity of the AhR and RelB is coupled to IL-8 overexpression in primary breast cancer tissue, which was also supported by in situ hybridization.

[Mesenchymal stem cells: weapons or dangers for cancer treatment?].

Mesenchymal stem cells (MSC) have attracted recent attention for their cell therapy potential, based in particular on their immunosuppressive properties, which have served as the basis for the treatment of autoimmune diseases. Interestingly, MSC have been used in cell therapy strategies to deliver therapeutical genes. Cell therapy approaches taking advantages of MSC have been proposed, as MSC display a potential tropsim for tumors.

Coxsackie and adenovirus receptor is a target and a mediator of estrogen action in breast cancer.

The involvement of the coxsackie and adenovirus receptor (CAR), an adhesion molecule known to be the main determinant of adenovirus transduction of the cells, in cancer is currently under investigation. Recent reports suggest that CAR levels are elevated in breast cancer, and this may have an impact on its use as means of delivery for gene therapy. In this study, we show that estradiol (E(2)) treatment of the estrogen receptor (ER)-positive breast cancer cell MCF-7 increases CAR levels and, in turn, enhances adenoviral transduction.

Chemokines and chemokine receptors: new insights into cancer-related inflammation.

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).

Emerging roles of chemokines in prostate cancer.

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.

CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance.

We show here high levels of expression and secretion of the chemokine CXC ligand 5 (CXCL5) in the macrophage fraction of white adipose tissue (WAT). Moreover, we find that CXCL5 is dramatically increased in serum of human obese compared to lean subjects. Conversely, CXCL5 concentration is decreased in obese subjects after a weight reduction program, or in obese non-insulin-resistant, compared to insulin-resistant, subjects.