An integrative approach for exploring the nature of fibroepithelial neoplasms.

BACKGROUND: Malignant phyllodes tumour (MPT) is a rare breast malignancy with epithelial and mesenchymal features. Currently, there are no appropriate research models or effective targeted therapeutic approaches for MPT. METHODS: We collected fresh frozen tissues from nine patients with MPT and performed whole-exome and RNA sequencing. Additionally, we established patient-derived xenograft (PDX) models from patients with MPT and tested the efficacy of targeting dysregulated pathways in MPT using the PDX model from one MPT. RESULTS: MPT has unique molecular characteristics when compared to breast cancers of epithelial origin and can be classified into two groups. The PDX model derived from one patient with MPT showed that the mouse epithelial component increased during tumour growth. Moreover, targeted inhibition of platelet-derived growth factor receptor (PDGFR) and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) by imatinib mesylate and PKI-587 showed in vivo tumour suppression effects. CONCLUSIONS: This study revealed the molecular profiles of MPT that can lead to molecular classification and potential targeted therapy, and suggested that the MPT PDX model can be a useful tool for studying the pathogenesis of fibroepithelial neoplasms and for preclinical drug screening to find new therapeutic strategies for MPT.

Regulation of the Effect of Physical Activity Through MicroRNAs in Breast Cancer.

Physical activity and exercise can induce beneficial molecular and biological regulations that have been associated with an incidence of various diseases, including breast cancer. Recent studies demonstrated that the potential links between physical activity-induced circulating microRNAs (miRNAs) and cancer risk and progression. Here, we investigated whether altered miRNAs by exercise could influence breast cancer progression. After primary searching in PubMed and reviewing the full-text papers, candidate miRNAs altered by exercise in breast cancer were identified. Analysis of expression profiles and clinical outcomes of altered miRNAs using The Cancer Genome Atlas datasets showed altered miRNAs expressions were significantly associated with the patient's prognosis, whereas prognostic values of each miRNA varied in different stages and subtypes. In addition, altered miRNAs profiles regulated various target genes and key signaling pathways in tumorigenesis, including pathways in cancer and the PI3K-Akt signaling pathway; however, miRNAs regulated the expression of target genes differently according to tumor stages and subtypes. These results indicate that circulating miRNAs are promising noninvasive stable biomarkers for early detection, diagnosis, prognosis, and monitoring the response to clinical therapies of breast cancer. Moreover, stages and subtype-stratified approaches for breast cancer progression would be needed to evaluate the prognostic value of miRNAs for biomarkers and therapeutic targets.

NAD(P)-dependent steroid dehydrogenase-like is involved in breast cancer cell growth and metastasis.

BACKGROUND: The cholesterol biosynthesis pathway is typically upregulated in breast cancer. The role of NAD(P)-dependent steroid dehydrogenase-like (NSDHL) gene, which is involved in cholesterol biosynthesis, in breast cancer remains unknown. This study aimed to uncover the role of NSDHL in the growth and metastasis of breast cancer. METHODS: After NSDHL knockdown by transfection of short interfering RNA into human breast cancer cell lines (MCF-7, MDA-MB-231 and BT-20) and human breast epithelial cell line (MCF10A), cell proliferation assay, cell cycle analysis, three-dimensional cell culture, clonogenic assay, transwell migration and invasion assays, and wound healing assay were performed. Erlotinib was used as the target drug for epidermal growth factor receptor. Immunodeficient mice (NOD.Cg-Prkdcscid Il2rgtm1wjl /SzJ) were used as orthotropic breast tumor models by injecting them with NSDHL-knockdown MDA-MB-231 cells using lentivirus-carrying NSDHL short hairpin RNA. Clinical data from 3951 breast cancer patients in Gene Expression Omnibus databases were used to investigate the potential prognostic role of NSDHL by survival analysis. RESULTS: NSDHL knockdown in BT-20, and MDA-MB-231 resulted in a significant decrease in their viability, colony formation, migration, and invasion abilities (p < 0.05). Total cholesterol levels were observed to be significantly decreased in NSDHL-knockdown BT-20 and MDA-MB-231 (p < 0.0001). NSDHL knockdown significantly increased the rate of erlotinib-induced cell death, especially in MDA-MB-231 (p = 0.01). NSDHL knockdown led to significantly decreased tumor growth and lung metastasis in the MDA-MB-231 xenograft model (p < 0.01). Clinically, high NSDHL expression in tumors of patients with breast cancer was associated with significantly reduced recurrence-free survival (p < 0.0001). CONCLUSIONS: NSDHL might have a role in promoting breast cancer progression. The usage of NSDHL as a therapeutic target in breast cancer needs to be clarified in further studies.

Immunization with Escherichia coli outer membrane vesicles protects bacteria-induced lethality via Th1 and Th17 cell responses.

Outer membrane vesicles (OMVs), secreted from Gram-negative bacteria, are spherical nanometer-sized proteolipids enriched with outer membrane proteins. OMVs, also known as extracellular vesicles, have gained interests for use as nonliving complex vaccines and have been examined for immune-stimulating effects. However, the detailed mechanism on how OMVs elicit the vaccination effect has not been studied extensively. In this study, we investigated the immunological mechanism governing the protective immune response of OMV vaccines. Immunization with Escherichia coli-derived OMVs prevented bacteria-induced lethality and OMV-induced systemic inflammatory response syndrome. As verified by adoptive transfer and gene-knockout studies, the protective effect of OMV immunization was found to be primarily by the stimulation of T cell immunity rather than B cell immunity, especially by the OMV-Ag-specific production of IFN-γ and IL-17 from T cells. By testing the bacteria-killing ability of macrophages, we also demonstrated that IFN-γ and IL-17 production is the main factor promoting bacterial clearances. Our findings reveal that E. coli-derived OMV immunization effectively protects bacteria-induced lethality and OMV-induced systemic inflammatory response syndrome primarily via Th1 and Th17 cell responses. This study therefore provides a new perspective on the immunological detail regarding OMV vaccination.

Dab2 is pivotal for endothelial cell migration by mediating VEGF expression in cancer cells.

Although angiogenesis is crucial for tumor growth and metastasis, the molecular mechanisms controlling this process are not clearly understood. Here, we explore the role of Dab2 in tumor angiogenesis. We found that Dab2 is expressed in several cancer cells, including A549 lung cancer cells, but it is hardly detectable in SW480 colon cancer cells. Migration and Erk phosphorylation were enhanced in human umbilical vein endothelial cells (HUVECs) treated with the conditioned medium obtained from Dab2-overexpressing SW480 stable cells. In addition, vascular endothelial growth factor (VEGF) protein was strongly detected in conditioned medium derived from Dab2-overexpressing SW480 cells, and Erk phosphorylation enhanced by Dab2(+) CM was restored by VEGF inhibition. Moreover, Dab2 depletion in A549 cells led to a decrease in HUVEC migration and Erk phosphorylation. Furthermore, we show that Dab2 is required for the TGFß-induced gene expression of angiogenic factors such as VEGF and FGF2. Taken together, these results suggest that Dab2, which is expressed in cancer cells, is pivotal for endothelial cell migration by affecting VEGF expression.

Skin Wound Healing and Anti-Wrinkle-Promoting In Vitro Biological Activities of Caragana sinica Flower Absolute and Its Chemical Composition.

Caragana sinica (CS; family Legume) was used as a medicinal material to treat neuralgia and arthritis in folk remedies and has been shown to have antioxidant, neuroprotective, and anti-apoptotic effects. However, CS is unknown for its biological activities related to skin. The present study explored the effects of CS flower absolute (CSFAb) on skin repair responses, viz., wound healing and anti-wrinkle-related responses using keratinocytes. CSFAb was extracted using hexane, and its composition was analyzed by GC/MS. The effects of CSFAb on human keratinocytes (HaCaT cells) were evaluated using Boyden chamber, sprouting, water-soluble tetrazolium salt, 5-bromo-2'-deoxyuridine incorporation, ELISA, zymography, and immunoblotting assays. GC/MS detected 46 components in CSFAb. In addition, in HaCaT cells, CSFAb increased the proliferation, migration, and sprout outgrowth and the phosphorylation of ERK1/2, JNK, p38 MAPK, and AKT, and also increased collagen type I and IV synthesis, reduced TNF-α-increased MMP-2 and MMP-9 activities, and upregulated hyaluronic acid (HA) and HA synthase-2 levels. These effects of CSFAb on wound healing and anti-wrinkle-related responses in keratinocytes suggest its potential use for skin repair and care preparations.

Chemical Composition of Impatiens textori Miq. Flower Absolute and Its Potential Wound Repair and Anti-Melanogenesis-Promoting Activities in Skin Cells.

Impatiens textori Miq. (ITM; family Balsaminaceae) is a traditional medicinal plant with many biological activities, which include anti-allergic, anti-inflammatory, and anti-pruritic properties. However, it remains to be determined whether ITM affects biological activities in the skin. Thus, we investigated the effects of ITM flower absolute (ITMFAb) extract on the biological activities of skin, especially those related to skin wound repair and whitening. ITMFAb was extracted with hexane, and its composition was determined through GC/MS. The biological activities of ITMFAb on HaCaT keratinocytes and B16BL6 melanoma cells were analyzed using a water-soluble tetrazolium salt, 5-bromo-2'-deoxyuridine incorporation, a Boyden chamber, an ELISA, a sprouting assay, and by immunoblotting. These analyses were performed in a range of ITMFAb concentrations that did not inhibit the viability of the cells (HaCaT, ≤400 µg/mL; B16BL6, ≤200 µg/m). Forty components were identified in ITMFAb. ITMFAb stimulated proliferation, migration, sprout outgrowth, and type I and IV collagen synthesis and upregulated the activations of ERK1/2, JNK, p38 MAPK, and AKT in HaCaT cells. In addition, ITMFAb attenuated the serum-induced proliferation of B16BL6 cells. ITMFAb inhibited melanin synthesis, tyrosinase activity, and expressions of MITF and tyrosinase in α-MSH-exposed B16BL6 cells. These findings indicate that ITMFAb has beneficial effects on wound repairing and whitening-linked responses in the skin and suggest the potential use of ITMFAb as a natural material for the development of skin wound repair and whitening agents.

Potential anticancer effect of aspirin and 2'-hydroxy-2,3,5'-trimethoxychalcone-linked polymeric micelles against cervical cancer through apoptosis.

Although early diagnosis and treatment of cancers in women are achievable through continuous diagnostic tests, cervical cancer (CVC) still has a high mortality rate. In the present study, we investigated whether certain nanoparticles (NPs), comprising aspirin conjugated 2'-hydroxy-2,3,5'-trimethoxychalcone chemicals, could induce the apoptosis of cancer cells. HeLa cells were treated with NPs and the cell viability was evaluated using WST-1 assay. Protein expression of Ki-67 was measured using immunocytochemistry. In addition, the apoptotic effect of NPs was determined using TUNEL assay. To investigate the apoptosis signaling pathways, reverse transcription quantitative PCR was performed and lipid accumulation was observed via holotomographic microscopy. The IC50 value of the NPs was 4.172 µM in HeLa cells. Furthermore, 10 µM NPs significantly inhibited the cell proliferation and stimulated the apoptosis of HeLa cells. In addition, apoptosis and mitochondrial dysfunction were induced by the NPs through lipid accumulation in HeLa cells, leading to apoptotic signaling cascades. Taken together, the results from the present study demonstrated that the NPs developed promoted apoptosis though efficient lipid accumulation in HeLa cells, suggesting that they may provide a novel way to improve the efficacy of CVC anticancer treatment.

Interplays between human microbiota and microRNAs in COVID-19 pathogenesis: a literature review.

PURPOSE: Recent studies have shown that COVID-19 is often associated with altered gut microbiota composition and reflects disease severity. Furthermore, various reports suggest that the interaction between COVID-19 and host-microbiota homeostasis is mediated through the modulation of microRNAs (miRNAs). Thus, in this review, we aim to summarize the association between human microbiota and miRNAs in COVID-19 pathogenesis. METHODS: We searched for the existing literature using the keywords such "COVID-19 or microbiota," "microbiota or microRNA," and "COVID-19 or probiotics" in PubMed until March 31, 2021. Subsequently, we thoroughly reviewed the articles related to microbiota and miRNAs in COVID-19 to generate a comprehensive picture depicting the association between human microbiota and microRNAs in the pathogenesis of COVID-19. RESULTS: There exists strong experimental evidence suggesting that the composition and diversity of human microbiota are altered in COVID-19 patients, implicating a bidirectional association between the respiratory and gastrointestinal tracts. In addition, SARS-CoV-2 encoded miRNAs and host cellular microRNAs modulated by human microbiota can interfere with viral replication and regulate host gene expression involved in the initiation and progression of COVID-19. These findings suggest that the manipulation of human microbiota with probiotics may play a significant role against SARS-CoV-2 infection by enhancing the host immune system and lowering the inflammatory status. CONCLUSION: The human microbiota-miRNA axis can be used as a therapeutic approach for COVID-19. Hence, further studies are needed to investigate the exact molecular mechanisms underlying the regulation of miRNA expression in human microbiota and how these miRNA profiles mediate viral infection through host-microbe interactions.

A network pharmacology approach to explore the potential role of Panax ginseng on exercise performance.

PURPOSE: As Panax ginseng C. A. Meyer (ginseng) exhibits various physiological activities and is associated with exercise, we investigated the potential active components of ginseng and related target genes through network pharmacological analysis. Additionally, we analyzed the association between ginseng-related genes, such as the G-protein-coupled receptors (GPCRs), and improved exercise capacity. METHODS: Active compounds in ginseng and the related target genes were searched in the Traditional Chinese Medicine Database and Analysis Platform (TCMSP). Gene ontology functional analysis was performed to identify biological processes related to the collected genes, and a compound-target network was visualized using Cytoscape 3.7.2. RESULTS: A total of 21 ginseng active compounds were detected, and 110 targets regulated by 17 active substances were identified. We found that the active compound protein was involved in the biological process of adrenergic receptor activity in 80%, G-protein-coupled neurotransmitter in 10%, and leucocyte adhesion to arteries in 10%. Additionally, the biological response centered on adrenergic receptor activity showed a close relationship with G protein through the beta-1 adrenergic receptor gene reactivity. CONCLUSION: According to bioavailability analysis, ginseng comprises 21 active compounds. Furthermore, we investigated the ginseng-stimulated gene activation using ontology analysis. GPCR, a gene upregulated by ginseng, is positively correlated to exercise. Therefore, if a study on this factor is conducted, it will provide useful basic data for improving exercise performance and health.

Systematic analysis of the pharmacological function of Schisandra as a potential exercise supplement.

PURPOSE: Exercise can prevent conditions such as atrophy and degenerative brain diseases. However, owing to individual differences in athletic ability, exercise supplements can be used to improve a person's exercise capacity. Schisandra chinensis (SC) is a natural product with various physiologically active effects. In this study, we analyzed SC using a pharmacological network and determined whether it could be used as an exercise supplement. METHODS: The active compounds of SC and target genes were identified using the Traditional Chinese Medicine Database and Analysis Platform (TCMSP). The active compound and target genes were selected based on pharmacokinetic (PK) conditions (oral bioavailability (OB) ≥ 30%, Caco-2 permeability (Caco-2) ≥ -0.4, and drug-likeness (DL) ≥ 0.18). Gene ontology (GO) was analyzed using the Cytoscape software. RESULTS: Eight active compounds were identified according to the PK conditions. Twenty-one target genes were identified after excluding duplicates in the eight active compounds. The top 10 GOs were analyzed using GO-biological process analysis. GO was subsequently divided into three representative categories: postsynaptic neurotransmitter receptor activity (53.85%), an intracellular steroid hormone receptor signaling pathway (36.46%), and endopeptidase activity (10%). SC is related to immune function. CONCLUSION: According to the GO analysis, SC plays a role in immunity and inflammation, promotes liver metabolism, improves fatigue, and regulates the function of steroid receptors. Therefore, we suggest SC as an exercise supplement with nutritional and anti-fatigue benefits.

S100A8/A9 mediate the reprograming of normal mammary epithelial cells induced by dynamic cell-cell interactions with adjacent breast cancer cells.

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Direct co-culture showed most distinct phenotype changes in MCF10A cells followed by conditioned media treatment and indirect co-culture. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.

Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways.

The lymphatic system plays pivotal roles in mediating tissue fluid homeostasis and immunity, and excessive lymphatic vessel formation is implicated in many pathological conditions, which include inflammation and tumor metastasis. However, the molecular mechanisms that regulate lymphatic vessel formation remain poorly characterized. Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that is implicated in a variety of biologic processes such as inflammatory responses and angiogenesis. Here, we first report that S1P acts as a lymphangiogenic mediator. S1P induced migration, capillary-like tube formation, and intracellular Ca(2+) mobilization, but not proliferation, in human lymphatic endothelial cells (HLECs) in vitro. Moreover, a Matrigel plug assay demonstrated that S1P promoted the outgrowth of new lymphatic vessels in vivo. HLECs expressed S1P1 and S1P3, and both RNA interference-mediated down-regulation of S1P1 and an S1P1 antagonist significantly blocked S1P-mediated lymphangiogenesis. Furthermore, pertussis toxin, U73122, and BAPTA-AM efficiently blocked S1P-induced in vitro lymphangiogenesis and intracellular Ca(2+) mobilization of HLECs, indicating that S1P promotes lymphangiogenesis by stimulating S1P1/G(i)/phospholipase C/Ca(2+) signaling pathways. Our results suggest that S1P is the first lymphangiogenic bioactive lipid to be identified, and that S1P and its receptors might serve as new therapeutic targets against inflammatory diseases and lymphatic metastasis in tumors.

A systematic review of the biological mechanisms linking physical activity and breast cancer.

PURPOSE: Epidemiological evidence has shown that leisure-time physical activity and structured exercise before and after breast cancer diagnosis contribute to reducing the risk of breast cancer recurrence and mortality. Thus, in this review, we aimed to summarize the physical activity-dependent regulation of systemic factors to understand the biological and molecular mechanisms involved in the initiation, progression, and survival of breast cancer. METHODS: We systematically reviewed the studies on 1) the relationship between physical activity and the risk of breast cancer, and 2) various systemic factors induced by physical activity and exercise that are potentially linked to breast cancer outcomes. To perform this literature review, PubMed database was searched using the terms "Physical activity OR exercise" and "breast cancer", until August 5th, 2020; then, we reviewed those articles related to biological mechanisms after examining the resulting search list. RESULTS: There is strong evidence that physical activity reduces the risk of breast cancer, and the protective effect of physical activity on breast cancer has been achieved by long-term regulation of various circulatory factors, such as sex hormones, metabolic hormones, inflammatory factors, adipokines, and myokines. In addition, physical activity substantially alters wholebody homeostasis by affecting numerous other factors, including plasma metabolites, reactive oxygen species, and microRNAs as well as exosomes and gut microbiota profile, and thereby every cell and organ in the whole body might be ultimately affected by the biological perturbation induced by physical activity and exercise. CONCLUSION: The understanding of integrative mechanisms will enhance how physical activity can ultimately influence the risk and prognosis of various cancers, including breast cancer. Furthermore, physical activity could be considered an efficacious non-pharmacological therapy, and the promotion of physical activity is probably an effective strategy in primary cancer prevention.

Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells.

BACKGROUND: Various cancer cells, including those of colorectal cancer (CRC), release microvesicles (exosomes) into surrounding tissues and peripheral circulation. These microvesicles can mediate communication between cells and affect various tumor-related processes in their target cells. RESULTS: We present potential roles of CRC cell-derived microvesicles in tumor progression via a global comparative microvesicular and cellular transcriptomic analysis of human SW480 CRC cells. We first identified 11,327 microvesicular mRNAs involved in tumorigenesis-related processes that reflect the physiology of donor CRC cells. We then found 241 mRNAs enriched in the microvesicles above donor cell levels, of which 27 were involved in cell cycle-related processes. Network analysis revealed that most of the cell cycle-related microvesicle-enriched mRNAs were associated with M-phase activities. The integration of two mRNA datasets showed that these M-phase-related mRNAs were differentially regulated across CRC patients, suggesting their potential roles in tumor progression. Finally, we experimentally verified the network-driven hypothesis by showing a significant increase in proliferation of endothelial cells treated with the microvesicles. CONCLUSION: Our study demonstrates that CRC cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells, suggesting that microvesicles of cancer cells can be involved in tumor growth and metastasis by facilitating angiogenesis-related processes. This information will help elucidate the pathophysiological functions of tumor-derived microvesicles, and aid in the development of cancer diagnostics, including colorectal cancer.

Tumor Suppressor miRNA-204-5p Regulates Growth, Metastasis, and Immune Microenvironment Remodeling in Breast Cancer.

Various miRNAs play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared with normal breast tissues, and its expression levels were associated with increased survival outcome in patients with breast cancer. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. In addition, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of patients with breast cancer showed a nonlinear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor-immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anticancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. In addition, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cell-autonomous and non-cell-autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis. SIGNIFICANCE: This study demonstrates that regulation of PI3K/Akt signaling by miR-204-5p suppresses tumor metastasis and immune cell reprogramming in breast cancer.

Polyphosphate blocks tumour metastasis via anti-angiogenic activity.

PolyP (inorganic polyphosphate) is a linear polymer of many tens or hundreds of orthophosphate residues found in a wide range of organisms, including bacteria, fungi, insects, plants and vertebrates. Despite its wide distribution in mammalian tissues and plasma, the biological functions of polyP on tumour metastasis and angiogenesis have not been previously examined. In the present study, we have shown that polyP effectively blocked in vivo pulmonary metastasis of B16BL6 cells by suppression of neovascularization, whereas it did not affect proliferation or adhesion to extracellular matrix proteins. PolyP not only inhibited bFGF (basic fibroblast growth factor)-induced proliferation and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) activation of human endothelial cells, but also blocked the binding of bFGF to its cognate cell-surface receptor. Furthermore, polyP inhibited bFGF-induced in vitro and in vivo angiogenesis, suggesting that polyP possesses an anti-angiogenic activity. Since neovascularization is essential for tumour metastasis, our present findings clearly indicate that polyP has an in vivo anti-metastatic activity via its anti-angiogenic activity. Taken together with the fact that angiogenesis occurs under various normal and pathological conditions, our observations suggest that endogenous polyP may play a critical role during embryonic development, wound healing and inflammation, as well as in the progress of pathological diseases such as rheumatoid arthritis and cancer.

Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism.

The role of adipocytes in cancer microenvironment has gained focus during the recent years. However, the characteristics of the cancer-associated adipocytes (CAA) in human breast cancer tissues and the underlying regulatory mechanism are not clearly understood. We reviewed pathology specimens of breast cancer patients to understand the morphologic characteristics of CAA, and profiled the mRNA and miRNA expression of CAA by using indirect co-culture system in vitro. The CAAs in human breast cancers showed heterogeneous topographic relationship with breast cancer cells within the breast microenvironment. The CAAs exhibited the characteristics of de-differentiation determined by their microscopic appearance and the expression levels of adipogenic markers. Additionally, the 3T3-L1 adipocytes indirectly co-cultured with breast cancer cells showed up-regulation of inflammation-related genes including Il6 and Ptx3. The up-regulation of IL6 in CAA was further observed in human breast cancer tissues. miRNA array of indirectly co-cultured 3T3-L1 cells showed increased expression of mmu-miR-5112 which may target Cpeb1. Cpeb1 is a negative regulator of Il6. The suppressive role of mmu-miR-5112 was confirmed by dual luciferase reporter assay, and mmu-miR-5112-treated adipocytes showed up-regulation of Il6. The transition of adipocytes into more inflammatory CAA resulted in proliferation-promoting effect in ER positive breast cancer cells such as MCF7 and ZR-75-1 but not in ER negative cells. In this study, we have determined the de-differentiated and inflammatory natures of CAA in breast cancer microenvironment. Additionally, we propose a miRNA-based regulatory mechanism underlying the process of acquiring inflammatory phenotypes in CAA.