Increased PSA expression on prostate cancer exosomes In In vitro condition and in cancer patients

Prostate specific antigen (PSA) test is the most common, clinically validated test for the diagnosis of prostate cancer (PCa). While neoplastic lesions of the prostate may cause aberrant levels of PSA in the blood, the quantitation of free or complexed PSA poorly discriminates cancer patients from those developing benign lesions, often leading to invasive and unnecessary surgical procedures. Microenvironmental acidity increases exosome release by cancer cells. In this study we evaluated whether acidity, a critical phenotype of malignancy, could influence exosome release and increase the PSA expression in nanovesicles released by PCa cells.

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Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder [Research]

The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [i.e., maternal VPA injections at embryonic day (E)12.75 decreased μ-opioid receptor–positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPA^E12.75 treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2'-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPA^E12.75 treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPA^E12.75 neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPA^E12.75 treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress–induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPA^E12.75 pups. Collectively, dysfunctional corticostriatal pathways, particularly via the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.—Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.

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Vitamin A regulates Akt signaling through the phospholipid fatty acid composition [Research]

Protein kinases, including the serine/threonine kinase Akt, mediate manifold bioactivities of vitamin A, although the mechanisms behind the sustained kinase activation are diffuse. To investigate the role of cellular lipids as targetable factors in Akt signaling, we combined mass spectrometry-based lipidomics with immunologic detection of Akt (Ser473) phosphorylation. A screening campaign revealed retinol (vitamin A alcohol) and all-trans retinoic acid (vitamin A acid) (RA) as hits that time-dependently (≥24 h) deplete phosphatidylcholine-bound polyunsaturated fatty acids (PUFA-PCs) from NIH-3T3 mouse fibroblasts while inducing Akt activation (EC₅₀ 0.1–1 µM). Other mitogenic and stress-regulated kinases were hardly affected. Organized in a coregulated phospholipid subcluster, PUFA-PCs compensated for the RA-induced loss of cellular PUFA-PCs and diminished Akt activation when supplemented. The counter-regulation of phospholipids and Akt by RA was mimicked by knockdown of lysophosphatidylcholine acyltransferase-3 or the selective retinoid X receptor (RXR) agonist bexarotene and prevented by the selective RXR antagonist Hx531. Treatment of mice with retinol decreased the tissue ratio of PUFA-PC and enhanced basal Akt activation preferentially in brain, which was attributed to astrocytes in dissociated cortical cultures. Together, our findings show that RA regulates the long-term activation of Akt by changes in the phospholipid composition.—Pein, H., Koeberle, S. C., Voelkel, M., Schneider, F., Rossi, A., Thürmer, M., Loeser, K., Sautebin, L., Morrison, H., Werz, O., Koeberle, A. Vitamin A regulates Akt signaling through the phospholipid fatty acid composition.

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Endothelial microparticles prevent lipid-induced endothelial damage via Akt/eNOS signaling and reduced oxidative stress [Research]

Endothelial microparticles (EMPs) are endothelium-derived submicron vesicles that are released in response to diverse stimuli and are elevated in cardiovascular disease, which is correlated with risk factors. This study investigates the effect of EMPs on endothelial cell function and dysfunction in a model of free fatty acid (FFA) palmitate-induced oxidative stress. EMPs were generated from TNF-α-stimulated HUVECs and quantified by using flow cytometry. HUVECs were treated with and without palmitate in the presence or absence of EMPs. EMPs were found to carry functional eNOS and to protect against oxidative stress by positively regulating eNOS/Akt signaling, which restored NO production, increased superoxide dismutase and catalase, and suppressed NADPH oxidase and reactive oxygen species (ROS) production, with the involvement of NF-erythroid 2-related factor 2 and heme oxygenase-1. Conversely, under normal conditions, EMPs reduced NO release and increased ROS and redox-sensitive marker expression. In addition, functional assays using EMP-treated mouse aortic rings that were performed under homeostatic conditions demonstrated a decline in endothelium-dependent vasodilatation, but restored the functional response under lipid-induced oxidative stress. These data indicate that EMPs harbor functional eNOS and potentially play a role in the feedback loop of damage and repair during homeostasis, but are also effective in protecting against FFA-induced oxidative stress; thus, EMP function is reflected by the microenvironment.—Mahmoud, A. M., Wilkinson, F. L., McCarthy, E. M., Moreno-Martinez, D., Langford-Smith, A., Romero, M., Duarte, J., Alexander, M. Y. Endothelial microparticles prevent lipid-induced endothelial damage via Akt/eNOS signaling and reduced oxidative stress.

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Regulator of G protein signaling G{beta}5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion [Research]

In pancreatic β cells, muscarinic cholinergic receptor M3 (M3R) stimulates glucose-induced secretion of insulin. Regulator of G protein signaling (RGS) proteins are critical modulators of GPCR activity, yet their role in β cells remains largely unknown. R7 subfamily RGS proteins are stabilized by the G protein subunit Gβ5, such that the knockout of the Gnb5 gene results in degradation of all R7 subunits. We found that Gnb5 knockout in mice or in the insulin-secreting MIN6 cell line almost completely eliminates insulinotropic activity of M3R. Moreover, overexpression of Gβ5-RGS7 strongly promotes M3R-stimulated insulin secretion. Examination of this noncanonical mechanism in Gnb5^–/– MIN6 cells showed that cAMP, diacylglycerol, or Ca²⁺ levels were not significantly affected. There was no reduction in the amplitude of free Ca²⁺ responses in islets from the Gnb5^–/– mice, but the frequency of Ca²⁺ oscillations induced by cholinergic agonist was lowered by more than 30%. Ablation of Gnb5 impaired M3R-stimulated phosphorylation of ERK1/2. Stimulation of the ERK pathway in Gnb5^–/– cells by epidermal growth factor restored M3R-stimulated insulin release to near normal levels. Identification of the novel role of Gβ5-R7 in insulin secretion may lead to a new therapeutic approach for improving pancreatic β-cell function.—Wang, Q., Pronin, A. N., Levay, K., Almaca, J., Fornoni, A., Caicedo, A., Slepak, V. Z. Regulator of G protein signaling Gβ5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion.

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Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain [Research]

As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mito-ribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.—Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.

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Thioredoxin reductase from Toxoplasma gondii: an essential virulence effector with antioxidant function [Research]

Thioredoxin reductase (TR) can help pathogens resist oxidative-burst injury from host immune cells by maintaining a thioredoxin-reduction state during NADPH consumption. TR is a necessary virulence factor that enables the persistent infection of some parasites. We performed bioinformatics analyses and biochemical assays to characterize the activity, subcellular localization, and genetic ablation of Toxoplasma gondii TR (TgTR), to shed light on its biologic function. We expressed the TgTR protein with an Escherichia coli expression system and analyzed its enzyme activity, reporting a K_m for the recombinant TgTR of 11.47–15.57 μM, using NADPH as a substrate, and 130.48–151.09 μM with dithio-bis-nitrobenzoic acid as a substrate. The TgTR sequence shared homology with that of TR, but lacked a selenocysteine residue in the C-terminal region and was thought to contain 2 flavin adenine dinucleotide (FAD) domains and 1 NADPH domain. In addition, immunoelectron microscopy results showed that TgTR was widely dispersed in the cytoplasm, and we observed that parasite antioxidant capacity, invasion efficiency, and proliferation were decreased in TR-knockout (TR-KO) strains in vitro, although this strain still stimulated the release of reactive oxygen species release in mouse macrophages while being more sensitive to H₂O₂ toxicity in vitro. Furthermore, our in vivo results revealed that the survival time of mice infected with the TR-KO strain was significantly prolonged relative to that of mice infected with the wild-type strain. These results suggest that TgTR plays an important role in resistance to oxidative damage and can be considered a virulence factor associated with T. gondii infection.—Xue, J., Jiang, W., Chen, Y., Gong, F., Wang, M., Zeng, P., Xia, C., Wang, Q., Huang, K. Thioredoxin reductase from Toxoplasma gondii: an essential virulence effector with antioxidant function.

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The use of electronic-neutral penetrating peptides cyclosporin A to deliver pro-apoptotic peptide: A possibly better choice than positively charged TAT

Publication date: 10 September 2017
Source:Journal of Controlled Release, Volume 261
Author(s): Wei Gao, Xiucong Yang, Zhiqiang Lin, Bing He, Dong Mei, Dan Wang, Haoran Zhang, Hua Zhang, Wenbing Dai, Xueqing Wang, Qiang Zhang
Cell-penetrating peptides (CPPs) are increasingly important in transporting macromolecules across cell membranes, but their use remains confined to narrow clinical applications due to the systemic toxicity induced by their positive charges. Several newly discovered electronic neutral penetrating peptides are not attracting much attention because their penetrating capacity is normally far less powerful than cationic or amphiphilic CPPs. In this study, we found the electronic neutral cyclic peptide cyclosporin A (CsA) exhibited 5.6-fold and 19.1-fold stronger penetrating capacity, respectively, than two reported electronic neutral peptides PFVYLI (PFV) and pentapeptide VPTLQ (VPT) in MCF-7 human breast cancer cells. To systematically evaluate the efficiency and toxicity of CsA, we utilized CsA to deliver a membrane-impenetrable pro-apoptotic peptide (PAD) and compared this to the well-established cationic penetrating peptide TAT (RKKRRQRRR). By conjugating CsA to PAD, the internalization of PAD increased 2.2- to 4.7-fold in four different tumor cell lines, and that of CsA-PAD conjugate was significantly higher than TAT-PAD conjugate in MCF-7 and HeLa human cervical cancer cells. Cytotoxicity studies demonstrated that CsA-PAD exhibited a large increase in cell cytotoxicity compared to PAD in four different tumor cell lines, with the effect being similar or greater than the effect of TAT-PAD, depending upon the cell type. The mechanistic studies demonstrated that modifying CsA or TAT did not change the cytotoxicity mechanism of PAD, which occurred via mitochondrial membrane damage related to apoptosis. In vivo studies showed that CsA-PAD could achieve similar anti-tumor efficacy to TAT-PAD but with much lower systemic toxicity, especially to the heart and liver. In conclusion, our study demonstrates for the first time that the electronic-neutral penetrating peptide CsA can be used as a powerful tool to deliver peptide drugs with similar efficiency and less toxicity than the positively charged TAT peptide.

Graphical abstract

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A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles

Publication date: 10 September 2017
Source:Journal of Controlled Release, Volume 261
Author(s): Emine Sekerdag, Sevda Lüle, Sibel Bozdağ Pehlivan, Naile Öztürk, Aslı Kara, Abbas Kaffashi, Imran Vural, Ilkay Işıkay, Burҫin Yavuz, Kader Karlı Oguz, Figen Söylemezoğlu, Yasemin Gürsoy-Özdemir, Melike Mut
New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brain-barrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500μM freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment.

Graphical abstract

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Google Searches Could Help Track Cancer Incidence, Mortality - UCSF News Services

UCSF News Services

Google Searches Could Help Track Cancer Incidence, Mortality UCSF News Services Linos and her team found that by state, Google search volume correlated with the incidence of five of the country's eight most common cancer types: lymphoma, melanoma, colon, lung and thyroid cancers. For four of those five – all but thyroid cancer ... and more »

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Hereditary hemorrhagic telangiectasia with severe anemia and recurrent CNS infections

Peesapati Nrushen, S Sunitha, PV Sivaram

Astrocyte 2017 3(4):228-230

Hereditary hemorrhagic telangiectasia also known as Osler–Rendu–Weber disease is a rare autosomal dominant disorder affecting small vessels of multiple systems whose main pathological change is the presence of abnormal arteriovenous communications. It usually presents as skin and mucosal telangiectasia, epistaxis, gastrointestinal bleeding, and visceral arteriovenous malformations. Although epistaxis and gastrointestinal blood loss can result in anemia, patients with hereditary hemorrhagic telangiectasia rarely present with severe anemia and central nervous system (CNS) infections. Here, we report the case of a 57-year-old man who presented with severe anemia resulting in congestive cardiac failure with a history of recurrent blood transfusions and recurrent CNS infections who was ultimately diagnosed as hereditary hemorrhagic telangiectasia with recurrent epistaxis as a cause of his severe anemia.

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Assessment of serum lipid profile and liver function parameters in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond

Muzamil M Mugloo, Rubeena Akhtar, Seema Malik

Astrocyte 2017 3(4):180-183

Objectives: The highest incidence of epilepsy in children coupled with the need of long-term antiepileptic treatment could lead to development of metabolic complications at an early age. Phenytoin and valproic acid are commonly used antiepileptic drugs in children. This study aimed to assess the serum lipid profile and liver function tests in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond. Materials and Methods: This prospective descriptive study recruited children from the pediatric outpatient department of a tertiary care GB Pant Children Hospital, Srinagar, Kashmir, India from August 2009 to September 2011. All consecutive children diagnosed with epilepsy as per International League Against Epilepsy definition aged 3–18 years on phenytoin or valproic acid monotherapy for 6 months or beyond were enrolled. After baseline clinical and anthropometric evaluation (including body mass index [BMI]), the fasting blood samples were analyzed for serum lipid profile and liver enzyme changes. Results: Total of 75 children were enrolled. There were 25 patients each in phenytoin, valproic acid, and control group. We observed statistically significant high mean total cholesterol and alkaline phosphatase levels in group receiving phenytoin when compared with valproic acid or control group. Conclusion: The lipid and liver enzyme abnormalities may be observed in children on phenytoin or valproic acid therapy, which warrants careful screening and monitoring.

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Stenting of complex coarctation of aorta with aberrant right subclavian artery

Anil K Singhi, Sunip Banerjee

Astrocyte 2017 3(4):221-223

Coarctation of aorta with aberrant right subclavian artery distal to coarctation is very rare. Detailed evaluation and planning is required for management of such case. Coarctation of the thoracic aorta (CoA) occurs at an incidence of approximately 1:1000 in the general population, ranging from 0.08 to 0.14% in large surveys. Anomalous origin of right subclavian artery (RSCA) is reported in up to 1% cases of CoA.Presence of aberrant RSCA makes treatment of such anomaly challenging. We report here successful placement of bare metal stent in a young lady with severe CoA and aberrant RSCA distal to CoA. Transcatheter stenting of CoA with aberrant RSCA is safe and effective procedure with good outcome. A detailed preprocedure evaluation and planning is the key to success.

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Exfoliative dermatitis in thai children

Wanee Wisuthsarewong, Rattanavalai Nitiyarom, Theerawat Buddawong

Astrocyte 2017 3(4):184-187

Background: Exfoliative dermatitis (ED) is an inflammatory skin disorder in which generalized skin erythema and scaling affect at least 90% of the body. Aims: To determine the etiology, clinical presentations, laboratory findings, management, and outcomes of ED. Materials and Methods: This retrospective study was conducted at the Department of Pediatrics, Siriraj Hospital. Data of pediatric patients diagnosed with ED during January 1992 and June 2014 were reviewed. Results: Forty-seven patients were identified. The median age at diagnosis was 4 years and 8 months (range 1–164 months), and 10 cases (21.3%) were infants. Presenting symptoms included itching (76.6%), fever (38.3%), painful sensation (17.0%), and diarrhea (12.8%). Physical findings were dehydration (42.6%), fever (34.0%), failure to thrive (29.8%), tachycardia (29.8%), hepatomegaly (17.0%), edema (12.8%), lymphadenaopathy (8.5%), and splenomegaly (6.4%). Common laboratory abnormalities revealed thrombocytosis (51.4%), eosinophilia (48.6%), elevated erythrocyte sedimentation rate (42.9%), and elevated liver enzymes (30.3%). Hepatosplenomegaly and lymphadenopathy were found to be statistically significantly correlated with immunodeficiency syndrome (P < 0.05). No other clinical or laboratory findings were associated with any specific etiology. Preexisting skin diseases (53.2%), including atopic dermatitis (23.4%), psoriasis (17.0%), pityriasis rubra pilaris (10.6%), and seborrheic dermatitis (2.1%), were the most common causes of ED. Other causes were primary immunodeficiency (12.8%), congenital ichthyosis (10.6%), drugs (10.6%), metabolic disorders (4.3%), and unknown etiology (8.5%). Mortality rate was 8.5%. Limitation: Some data from this retrospective study may have been missing and some investigations may not have been performed in all patients. Conclusion: The most common etiology of ED in children was preexisting skin diseases. Prognosis was poor in immunodeficiency disorders.

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Walking through the hospital corridors

Yatish Agarwal, Bipin Batra

Astrocyte 2017 3(4):177-179



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Practical significance of exercise stress test in individuals at low risk for atherosclerotic coronary artery disease

Sanjeev V Mangrulkar, Pramod Katare, Ashiwini Joshi

Astrocyte 2017 3(4):196-200

Background: Despite not finding favor with a number of apex global bodies including the American Heart Association, American College of Cardiology, United States Preventive Services Task Force, exercise stress test continues to be performed customarily among asymptomatic individuals to screen for potential presence of ischemic heart disease. Materials and Methods: This retrospective study comprises a successive total of 2042 individuals who were put through a screening stress test as a part of their health checkup package. A telephonic communication was made with all the persons who had been advised further assessment such as repeat stress test, drug therapy, stress thallium testing, or coronary angiography. The compliance of this group to the advice offered was noted along with their subjective sense of satisfaction with the overall process. Based on these inputs the practical utility of stress test was calculated as either good or poor. Results: Out of 2042 individuals who underwent stress test, 183 (9%) were reported as positive. Out of these 183 individuals only 132 with positive stress test could be contacted telephonically. After a detailed analysis of their compliance with the advice offered, it was noted that the screening had best practical utility when the test report was negative. Only one person with a positive report had followed the advice to the logical end by undergoing coronary artery bypass grafting and had a likely good practical utility. In rest of the scenarios, the practical utility was poor. Conclusion: The screening exercise stress tests are sought by most individuals as means of reassurance about health. Its practical significance in all other scenarios is poor. Therefore, unless definite indications exist, stress test should not be performed as a screening test.

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Coexistence of anaplastic astrocytoma and arteriovenous malformation

Arun Oommen, Jayasree Govindan, Muhammed Jasim Abdul Jalal

Astrocyte 2017 3(4):224-227

Coexistence of astrocytoma with cerebral vascular malformations is unusual, especially if both lesions occur separately. Preoperative angiogram will help us to identify any coexisting arteriovenous malformation (AVM). This will in turn change the treatment strategy for astrocytoma. Preoperative embolization for AVM may be done prior to the glioma excision. There is increased risk of bleeding if AVMs are not preoperatively diagnosed. AVMs coexisting with astrocytomas are rare. We report a case of anaplastic astrocytoma coexisting with an acquired AVM.

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Field-Free Isolation of Exosomes from Extracellular Vesicles by Microfluidic Viscoelastic Flows

ACS Nano

DOI: 10.1021/acsnano.7b02277

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Cancer-Associated Fibroblasts Share Characteristics and Pro-tumorigenic Activity with Mesenchymal Stromal Cells

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship to MSC is not clear. Here we have isolated from primary human neuroblastoma (NB) tumors a population of αFAP- and FSP-1-expressing CAF that share phenotypic and functional characteristics with bone marrow-derived MSC (BM-MSC). Analysis of human NB tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSC) enhanced in vitro NB cell proliferation, survival, and resistance to chemotherapy and stimulated NB tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The pro-tumorigenic activity of MSC in vitro and in xenografted mice was dependent on the co-activation of JAK2/STAT3 and MEK/ERK1/2 in NB cells. In a mouse model of orthotopically implanted NB cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type pro-tumorigenic CAF in the tumor microenvironment (TME) of NB and to STAT3 and ERK1/2 as mediators of their activity.

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Kindlin-2 regulates the growth of breast cancer tumors by activating CSF-1-mediated macrophage infiltration

Interplay between tumor cells and host cells in the tumor microenvironment dictates the development of all cancers. In breast cancer, malignant cells educate host macrophages to adopt a pro-tumorigenic phenotype. In this study, we show how the integrin regulatory protein kindlin-2 (FERMT2) promotes metastatic progression of breast cancer through the recruitment and subversion of host macrophages. Kindlin-2 expression was elevated in BC biopsy tissues where its levels correlated with reduced patient survival. Based on these observations, we used CRISPR/Cas9 technology to ablate Kindlin-2 expression in human MDA-MB-231 and murine 4T1 breast cancer cells. Kindlin-2 deficiency inhibited invasive and migratory properties in vitro without affecting proliferation rates. However, in vivo tumor outgrowth was inhibited by >80% in a manner associated with reduced macrophage infiltration and secretion of the macrophage attractant and growth factor CSF-1. The observed loss of CSF-1 appeared to be caused by a more proximal deficiency in TGF-β-dependent signaling in Kindlin-2 deficient cells. Collectively, our results illuminate a Kindlin-2/TGF-β/CSF-1 signaling axis employed by breast cancer cells to capture host macrophage functions that drive tumor progression.

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