The chemokine monocyte chemoattractant protein-1/CCL2 is a promoter of breast cancer metastasis

Breast cancer is the most prevalent cancer worldwide,and metastasis is the leading cause of death in cancer patients.Human monocyte chemoattractant protein-1(MCP-1/CCL2)was isolated from the culture supernatants of not only mitogen-activated peripheral blood mononuclear leukocytes but also malignant glioma cells based on its in vitro chemotactic activity toward human monocytes.MCP-1 was subsequently found to be identical to a previously described tumor cell-derived chemotactic factor thought to be responsible for the accumulation of tumor-associated macrophages(TAMs),and it became a candidate target of clinical intervention;however,the role of TAMs in cancer development was still controversial at the time of the discovery of MCP-1.The in vivo role of MCP-1 in cancer progression was first evaluated by examining human cancer tissues,including breast cancers.Positive correlations between the level of MCP-1 production in tumors and the degree of TAM infiltration and cancer progression were established.The contribution of MCP-1 to the growth of primary tumors and metastasis to the lung,bone,and brain was examined in mouse breast cancer models.The results of these studies strongly suggested that MCP-1 is a promoter of breast cancer metastasis to the lung and brain but not bone.Potential mechanisms of MCP-1 production in the breast cancer microenvironment have also been reported.In the present manuscript,we review studies in which the role of MCP-1 in breast cancer development and progression and the mechanisms of its production were examined and attempt to draw a consensus and discuss the potential use of MCP-1 as a biomarker for diagnosis.

New genetic and epigenetic insights into the chemokine system: the latest discoveries aiding progression toward precision medicine

Over the past thirty years,the importance of chemokines and their seven-transmembrane G protein-coupled receptors(GPCRs)has been increasingly recognized.Chemokine interactions with receptors trigger signaling pathway activity to form a network fundamental to diverse immune processes,including host homeostasis and responses to disease.Genetic and nongenetic regulation of both the expression and structure of chemokines and receptors conveys chemokine functional heterogeneity.Imbalances and defects in the system contribute to the pathogenesis of a variety of diseases,including cancer,immune and inflammatory diseases,and metabolic and neurological disorders,which render the system a focus of studies aiming to discover therapies and important biomarkers.The integrated view of chemokine biology underpinning divergence and plasticity has provided insights into immune dysfunction in disease states,including,among others,coronavirus disease 2019(COVID-19).In this review,by reporting the latest advances in chemokine biology and results fromanalyses of a plethora of sequencing-based datasets,we outline recent advances in the understanding of the genetic variations and nongenetic heterogeneity of chemokines and receptors and provide an updated view of their contribution to the pathophysiological network,focusing on chemokine-mediated inflammation and cancer.Clarification of the molecular basis of dynamic chemokine-receptor interactions will help advance the understanding of chemokine biology to achieve precision medicine application in the clinic.

The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally?

Macrophages are one of the most abundant leukocyte populations infiltrating tumor tissues and can exhibit both tumoricidal and tumor-promoting activities.In 1989,we reported the purification of monocyte chemoattractant protein-1(MCP-1)from culture supernatants of mitogen-activated peripheral blood mononuclear cells and tumor cells.MCP-1 is a potent monocyte-attracting chemokine,identical to the previously described lymphocyte-derived chemotactic factor or tumor-derived chemotactic factor,and greatly contributes to the recruitment of blood monocytes into sites of inflammatory responses and tumors.Because in vitro-cultured tumor cells often produce significant amounts of MCP-1,tumor cells are considered to be the main source of MCP-1.However,various nontumor cells in the tumor stroma also produce MCP-1 in response to stimuli.Studies performed in vitro and in vivo have provided evidence that MCP-1 production in tumors is a consequence of complex interactions between tumor cells and non-tumor cells and that both tumor cells and non-tumor cells contribute to the production of MCP-1.Although MCP-1 production was once considered to be a part of host defense against tumors,it is now believed to regulate the vicious cycle between tumor cells and macrophages that promotes the progression of tumors.

Chemokines in homeostasis and diseases

For the past twenty years,chemokines have emerged as a family of critical mediators of cell migration during immune surveillance,development,inflammation and cancer progression.Chemokines bind to seven transmembrane G protein-coupled receptors(GPCRs)that are expressed by a wide variety of cell types and cause conformational changes in trimeric G proteins that trigger the intracellular signaling pathways necessary for cell movement and activation.Although chemokines have evolved to benefit the host,inappropriate regulation or utilization of these small proteins may contribute to or even cause diseases.Therefore,understanding the role of chemokines and their GPCRs in the complex physiological and diseased microenvironment is important for the identification of novel therapeutic targets.This review introduces the functional array and signals of multiple chemokine GPCRs in guiding leukocyte trafficking as well as their roles in homeostasis,inflammation,immune responses and cancer.