Browsing by Subject "PROMOTES"

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  • Sinha, Snehadri; Narjus-Sterba, Matilda; Tuomainen, Katja; Kaur, Sippy; Seppänen-Kaijansinkko, Riitta; Salo, Tuula; Mannerström, Bettina; Al-Samadi, Ahmed (2020)
    Mesenchymal stem cells (MSCs) are commonly isolated from bone marrow and adipose tissue. Depending on the tissue of origin, MSCs have different characteristics and physiological effects. In various cancer studies, MSCs have been found to have either tumor-promoting or tumor-inhibiting action. This study investigated the effect of adipose tissue-MSCs (AT-MSCs) and bone marrow-MSCs (BM-MSCs) on global long interspersed nuclear element-1 (LINE-1) methylation, the expression level of microenvironment remodeling genes and cell proliferation, migration and invasion of oral tongue squamous cell carcinoma (OTSCC). Additionally, we studied the effect of human tongue squamous carcinoma (HSC-3)-conditioned media on LINE-1 methylation and the expression of microenvironment remodeling genes in AT-MSCs and BM-MSCs. Conditioned media from HSC-3 or MSCs did not affect LINE-1 methylation level in either cancer cells or MSCs, respectively. In HSC-3 cells, no effect of MSCs-conditioned media was detected on the expression ofICAM1, ITGA3orMMP1. On the other hand, HSC-3-conditioned media upregulatedICAM1andMMP1expression in both types of MSCs. Co-cultures of AT-MSCs with HSC-3 did not induce proliferation, migration or invasion of the cancer cells. In conclusion, AT-MSCs, unlike BM-MSCs, seem not to participate in oral cancer progression.
  • Rademakers, Timo; van der Vorst, Emiel P. C.; Daissormont, Isabelle T. M. N.; Otten, Jeroen J. T.; Theodorou, Kosta; Theelen, Thomas L.; Gijbels, Marion; Anisimov, Andrey; Nurmi, Harri; Lindeman, Jan H. N.; Schober, Andreas; Heeneman, Sylvia; Alitalo, Kari; Biessen, Erik A. L. (2017)
    During plaque progression, inflammatory cells progressively accumulate in the adventitia, paralleled by an increased presence of leaky vasa vasorum. We here show that next to vasa vasorum, also the adventitial lymphatic capillary bed is expanding during plaque development in humans and mouse models of atherosclerosis. Furthermore, we investigated the role of lymphatics in atherosclerosis progression. Dissection of plaque draining lymph node and lymphatic vessel in atherosclerotic ApoE(-/-)mice aggravated plaque formation, which was accompanied by increased intimal and adventitial CD3(+) T cell numbers. Likewise, inhibition of VEGF-C/D dependent lymphangiogenesis by AAV aided gene transfer of hVEGFR3-Ig fusion protein resulted in CD3(+) T cell enrichment in plaque intima and adventitia. hVEGFR3-Ig gene transfer did not compromise adventitial lymphatic density, pointing to VEGF-C/D independent lymphangiogenesis. We were able to identify the CXCL12/CXCR4 axis, which has previously been shown to indirectly activate VEGFR3, as a likely pathway, in that its focal silencing attenuated lymphangiogenesis and augmented T cell presence. Taken together, our study not only shows profound, partly CXCL12/CXCR4 mediated, expansion of lymph capillaries in the adventitia of atherosclerotic plaque in humans and mice, but also is the first to attribute an important role of lymphatics in plaque T cell accumulation and development.
  • Kindler, Oliver; Pulkkinen, Otto; Cherstvy, Andrey G.; Metzler, Ralf (2019)
    Quorum-sensing bacteria in a growing colony of cells send out signalling molecules (so-called "autoinducers") and themselves sense the autoinducer concentration in their vicinity. Once-due to increased local cell density inside a "cluster" of the growing colony-the concentration of autoinducers exceeds a threshold value, cells in this clusters get "induced" into a communal, multi-cell biofilm-forming mode in a cluster-wide burst event. We analyse quantitatively the influence of spatial disorder, the local heterogeneity of the spatial distribution of cells in the colony, and additional physical parameters such as the autoinducer signal range on the induction dynamics of the cell colony. Spatial inhomogeneity with higher local cell concentrations in clusters leads to earlier but more localised induction events, while homogeneous distributions lead to comparatively delayed but more concerted induction of the cell colony, and, thus, a behaviour close to the mean-field dynamics. We quantify the induction dynamics with quantifiers such as the time series of induction events and burst sizes, the grouping into induction families, and the mean autoinducer concentration levels. Consequences for different scenarios of biofilm growth are discussed, providing possible cues for biofilm control in both health care and biotechnology.
  • Gonzalez, Marta Lopez; Oosterhoff, Dinja; Lindenberg, Jelle J.; Milenova, Ioanna; Lougheed, Sinead M.; Martianez, Tania; Dekker, Henk; Quixabeira, Dafne Carolina Alves; Hangalapura, Basav; Joore, Jos; Piersma, Sander R.; Cervera-Carrascon, Victor; Santos, Joao Manuel; Scheper, Rik J.; Verheul, Henk M. W.; Jimenez, Connie R.; Van De Ven, Rieneke; Hemminki, Akseli; Van Beusechem, Victor W.; De Gruijl, Tanja D. (2019)
    In patients with cancer, the functionality of Dendritic Cells (DC) is hampered by high levels of tumor-derived suppressive cytokines, which interfere with DC development and maturation. Poor DC development can limit the efficacy of immune checkpoint blockade and in vivo vaccination approaches. Interference in intracellular signaling cascades downstream from the receptors of major tumor-associated suppressive cytokines like IL-10 and IL-6, might improve DC development and activation, and thus enhance immunotherapy efficacy. We performed exploratory functional screens on arrays consisting of >1000 human kinase peptide substrates to identify pathways involved in DC development and its inhibition by IL-10 or IL-6. The resulting alterations in phosphorylation of the kinome substrate profile pointed to glycogen-synthase kinase-3 beta (GSK3 beta) as a pivotal kinase in both DC development and suppression. GSK3 beta inhibition blocked human DC differentiation in vitro, which was accompanied by decreased levels of IL-12p70 secretion, and a reduced capacity for T cell priming. More importantly, adenoviral transduction of monocytes with a constitutively active form of GSK3 beta induced resistance to the suppressive effects of IL-10 and melanoma-derived supernatants alike, resulting in improved DC development, accompanied by up-regulation of co-stimulatory markers, an increase in CD83 expression levels in mature DC, and diminished release of IL-10. Moreover, adenovirus-mediated intratumoral manipulation of this pathway in an in vivo melanoma model resulted in DC activation and recruitment, and in improved immune surveillance and tumor control. We propose the induction of constitutive GSK3 beta activity as a novel therapeutic means to bolster DC functionality in the tumor microenvironment.
  • Martikainen, K.; Sironen, A.; Uimari, P. (2018)
    Inbreeding increases homozygosity, which in turn increases the frequency of harmful recessive alleles, resulting in inbreeding depression. Inbreeding depression on fertility reduces the profitability of dairy farming by decreasing the lifetime milk production of cows and by increasing insemination and veterinary costs. Continuous homozygous segments, called runs of homozygosity (ROH), are currently considered to provide an effective measure of genomic inbreeding. The aim of this study was to estimate the effect of increased intrachromosomal homozygosity for female fertility in the Finnish Ayrshire population using ROH and haplotype analysis. Genotypes were obtained from 13,712 females with the Illumina BovineLD v.2 BeadChip low-density panel (Illumina Inc., San Diego, CA) and imputed to 50K density. After quality control, 40,554 single nucleotide polymorphisms remained for the analysis. Phenotypic data consisted of records for nonreturn rate, intervals from first to last insemination (IFL), and intervals from calving to first insemination. The raw phenotypic values were preadjusted for systematic effects before statistical analyses. The ROH-based inbreeding coefficients (F-ROH) were used as covariats in the mixed model equation to estimate the association between inbreeding and inbreeding depression on female fertility. First, we estimated the effect of increased chromosomal F-ROH. We detected significant inbreeding depression on IFL. Based on our results, a 10% increase in F-ROH on chromosomes 2, 18, and 22 were associated with IFL of heifers lengthening by 1.6, 0.9, and 0.7 d, respectively. Similarly, a 10% increase in F-ROH on chromosome 15 was associated with IFL of second-parity cows increasing by 2.3 d. Next, we located the regions within the chromosomes showing inbreeding depression. Our analysis revealed regions near the beginning of chromosome 2 and toward the ends of chromosomes 15, 18, and 22 that were associated with inbreeding depression on IFL. Last, we performed a haplotype analysis for the detected regions. The most promising haplotypes of each region were associated with IFL of heifers increasing by 4.4, 3.2, and 4.1 d on chromosomes 2, 18, and 22, respectively. The haplotype on chromosome 15 associated with IFL of second-parity cows increasing by 7.6 d. Overall, the breeding program requires inbreeding control, as increased genomic inbreeding in our study was associated with reduced reproductive ability in Finnish Ayrshire cattle.
  • Brownlie, Demi; Scharenberg, Marlena; Mold, Jeff E.; Hard, Joanna; Kekäläinen, Eliisa; Buggert, Marcus; Nguyen, Son; Wilson, Jennifer N.; Al-Ameri, Mamdoh; Ljunggren, Hans-Gustaf; Marquardt, Nicole; Michaelsson, Jakob (2021)
    Human adaptive-like "memory" CD56(dim)CD16(+) natural killer (NK) cells in peripheral blood from cytomegalovirus-seropositive individuals have been extensively investigated in recent years and are currently explored as a treatment strategy for hematological cancers. However, treatment of solid tumors remains limited due to insufficient NK cell tumor infiltration, and it is unknown whether large expansions of adaptive-like NK cells that are equipped for tissue residency and tumor homing exist in peripheral tissues. Here, we show that human lung and blood contains adaptive-like CD56(bright)CD16(-) NK cells with hallmarks of tissue residency, including expression of CD49a. Expansions of adaptive-like lung tissue-resident NK (trNK) cells were found to be present independently of adaptive-like CD56(dim)CD16(+) NK cells and to be hyperresponsive toward target cells. Together, our data demonstrate that phenotypically, functionally, and developmentally distinct subsets of adaptive-like NK cells exist in human lung and blood. Given their tissue-related character and hyperresponsiveness, human lung adaptive-like trNK cells might represent a suitable alternative for therapies targeting solid tumors.
  • Ilmakunnas, M.; Turunen, A. J.; Lindgren, L.; Salmela, K. T.; Kyllönen, L. E.; Andersson, S.; Petäjä, J.; Pesonen, E. J. (2019)
    Background. Inflammation, coagulation, and fibrinolysis are tightly linked together. Reperfusion after transient ischemia activates both neutrophils, coagulation, and fibrinolysis. Experimental data suggest that tissue plasminogen activator (tPA) regulates renal neutrophil influx in kidney ischemia and reperfusion injury. Methods. In 30 patients undergoing kidney transplantation, we measured renal neutrophil sequestration and tPA release from blood samples drawn from the supplying artery and renal vein early after reperfusion. tPA antigen levels were measured using a commercial enzyme-linked immunosorbent assay kit. For each parameter, transrenal difference (Delta) was calculated by subtracting the value of the arterial sample (ingoing blood) from the value of the venous sample (outgoing blood). Results. Positive transrenal gradients of tPA antigen occurred at 1 minute [Delta = 14 (3-46) ng/mL, P <.01] and 5 minutes [Delta = 5 (-3 to 27) ng/mL, P <.01] after reperfusion. At 5 minutes after reperfusion, a negative transrenal gradient of neutrophils was observed [Delta = -0.17 (-1.45 to 0.24) x 10E9 cells/L, P <.001]. At 1 minute after reperfusion, neutrophil sequestration into the kidney (ie, negative transrenal neutrophil count) correlated significantly with tPA release from the kidney (ie, positive transrenal tPA concentration), (R = -0.513 and P = .006). Conclusions. The findings suggest a proinflammatory role for tPA in ischemia and reperfusion injury in human kidney transplantation.
  • Almahmoudi, Rabeia; Salem, Abdelhakim; Murshid, Sakhr; Dourado, Mauricio Rocha; Apu, Ehsanul Hoque; Salo, Tuula; Al-Samadi, Ahmed (2019)
    We recently showed that extracellular interleukin-17F (IL-17F) correlates with better disease-specific survival in oral tongue squamous cell carcinoma (OTSCC) patients. However, the underlying mechanisms of such effect remain obscure. Here, we used qRT-PCR to assess the expression of IL-17F and its receptors (IL-17RA and IL-17RC) in two OTSCC cell lines (HSC-3 and SCC-25) and in normal human oral keratinocytes (HOKs). IL-17F effects on cancer cell proliferation, migration, and invasion were studied using a live-imaging IncuCyte system, and a Caspase-3/7 reagent was used for testing apoptosis. 3D tumor spheroids were utilized to assess the impact of IL-17F on invasion with or without cancer-associated fibroblasts (CAFs). Tube-formation assays were used to examine the effects of IL-17F on angiogenesis using human umbilical vein endothelial cells (HUVEC). OTSCC cells express low levels of IL-17F, IL-17RA, and IL-17RC mRNA compared with HOKs. IL-17F inhibited cell proliferation and random migration of highly invasive HSC-3 cells. CAFs promoted OTSCC invasion in tumor spheroids, whereas IL-17F eliminated such effect. IL-17F suppressed HUVEC tube formation in a dose-dependent manner. Collectively, we suggest that IL-17F counteracts the pro-tumorigenic activity in OTSCC. Due to its downregulation in tumor cells and inhibitory activity in in vitro cancer models, targeting IL-17F or its regulatory pathways could lead to promising immunotherapeutic strategies against OTSCC.
  • Ruohtula, Terhi; de Goffau, Marcus C.; Nieminen, Janne K.; Honkanen, Jarno; Siljander, Heli; Hämäläinen, Anu-Maaria; Peet, Aleksandr; Tillmann, Vallo; Ilonen, Jorma; Niemelä, Onni; Welling, Gjalt W.; Knip, Mikael; Harmsen, Hermie J.; Vaarala, Outi (2019)
    Recent studies suggest that the cross-talk between the gut microbiota and human immune system during the first year of life is an important regulator of the later development of atopic diseases. We explored the changes in the gut microbiota, blood regulatory T cells, and atopic sensitization in a birth-cohort of Estonian and Finnish children followed from 3 to 36 months of age. We describe here an infant Treg phenotype characterized by high Treg frequency, the maturation of Treg population characterized by a decrease in their frequency accompanied with an increase in the highly activated Treg cells. These changes in Treg population associated first with the relative abundance of Bifidobacterium longum followed by increasing colonization with butyrate producing bacteria. High bifidobacterial abundance in the neonatal microbiota appeared to be protective, while colonization with Bacteroides and E. coli was associated with later risk of allergy. Estonian children with lower risk of IgE mediated allergic diseases than Finnish children showed an earlier maturation of the gut microbiota, detected as earlier switch to an increasing abundance of butyrate-producing bacteria, combined with an earlier maturation of Treg cell phenotype and total IgE production. The children with established allergic diseases by age 3 showed a decreased abundance of butyrate producing Faecalibacterium. These results suggest that as well as the maintenance of a bifidobacterial dominated gut microbiota is important during the first weeks of life, the overtake by butyrate producing bacteria seems to be a beneficial shift, which should not be postponed.
  • Normann, Lisa Svartdal; Aure, Miriam Ragle; Leivonen, Suvi-Katri; Haugen, Mads Haugland; Hongisto, Vesa; Kristensen, Vessela N.; Maelandsmo, Gunhild Mari; Sahlberg, Kristine Kleivi (2021)
    HER2-positive (HER2+) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2+breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2+cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2+breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2+breast cancer (OS: p=0.039; BCSS: p=0.012), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2+breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2+breast cancers.
  • Long, Maeve; McWilliams, Thomas G. (2020)
    Autophagy refers to an essential mechanism that evolved to sustain eukaryotic homeostasis and metabolism during instances of nutrient deprivation. During autophagy, intracellular cargo is encapsulated and delivered to the lysosome for elimination. Loss of basal autophagy in vivo negatively impacts cellular proteostasis, metabolism and tissue integrity. Accordingly, many drug development strategies are focused on modulating autophagic capacity in various pathophysiological states, from cancer to neurodegenerative disease. The role of autophagy in cancer is particularly complicated, as either augmenting or attenuating this process can have variable outcomes on cellular survival, proliferation and transformation. This complexity is compounded by the emergence of several selective autophagy pathways, which act to eliminate damaged or superfluous cellular components in a targeted fashion. The advent of sensitive tools to monitor autophagy pathways in vivo holds promise to clarify their importance in cancer pathophysiology. In this review, we provide an overview of autophagy in cancer biology and outline how the development of tools to study autophagy in vivo could enhance our understanding of its function for translational benefit.
  • Salo, Veijo T.; Ikonen, Elina (2019)
    The formation of neutral lipid filled and phospholipid monolayer engulfed lipid droplets (LDs) from the bilayer of the endoplasmic reticulum (ER) is an active area of investigation. This process harnesses the biophysical properties of the lipids involved and necessitates cooperation of protein machineries in both organelle membranes. Increasing evidence suggests that once formed, LDs keep close contact to the mother organelle and that this may be achieved via several, morphologically distinct and potentially functionally specialized connections. These may help LDs to dynamically respond to changes in lipid metabolic status sensed by the ER. In this review, we will discuss recent progress in understanding how LDs interact with the ER.
  • Saito, Kan; Michon, Frederic; Yamada, Aya; Inuzuka, Hiroyuki; Yamaguchi, Satoko; Fukumoto, Emiko; Yoshizaki, Keigo; Nakamura, Takashi; Arakaki, Makiko; Chiba, Yuta; Ishikawa, Masaki; Okano, Hideyuki; Thesleff, Irma; Fukumoto, Satoshi (2020)
    The transcription factor Sox21 is expressed in the epithelium of developing teeth. The present study aimed to determine the role of Sox21 in tooth development. We found that disruption of Sox21 caused severe enamel hypoplasia, regional osteoporosis, and ectopic hair formation in the gingiva in Sox21 knockout incisors. Differentiation markers were lost in ameloblasts, which formed hair follicles expressing hair keratins. Molecular analysis and chromatin immunoprecipitation sequencing indicated that Sox21 regulated Anapc10, which recognizes substrates for ubiquitination-mediated degradation, and determined dental-epithelial versus hair follicle cell fate. Disruption of either Sox21 or Anapc10 induced Smad3 expression, accelerated TGF-beta 1-induced promotion of epithelial-to-mesenchymal transition (EMT), and resulted in E-cadherin degradation via Skp2. We conclude that Sox21 disruption in the dental epithelium leads to the formation of a unique microenvironment promoting hair formation and that Sox21 controls dental epithelial differentiation and enamel formation by inhibiting EMT via Anapc10.
  • Rooda, Ilmatar; Hensen, Kati; Kaselt, Birgitta; Kasvandik, Sergo; Pook, Martin; Kurg, Ants; Salumets, Andres; Velthut-Meikas, Agne (2020)
    MicroRNAs (miRNAs) are known post-transcriptional regulators of various biological processes including ovarian follicle development. We have previously identified miRNAs from human preovulatory ovarian granulosa cells that are expressed from the intronic regions of two key genes in normal follicular development: FSH receptor (FSHR) and CYP19A1, the latter encoding the aromatase enzyme. The present study aims to identify the target genes regulated by these miRNAs: hsa-miR-548ba and hsa-miR-7973, respectively. The miRNAs of interest were transfected into KGN cell line and the gene expression changes were analyzed by Affymetrix microarray. Potential miRNA-regulated genes were further filtered by bioinformatic target prediction algorithms and validated for direct miRNA:mRNA binding by luciferase reporter assay. LIFR, PTEN, NEO1 and SP110 were confirmed as targets for hsa-miR-548ba. Hsa-miR-7973 target genes ADAM19, PXDN and FMNL3 also passed all verification steps. Additionally, the expression pattern of the miRNAs was studied in human primary cumulus granulosa cell culture in relation to the expression of their host genes and FSH stimulation. Based on our findings we propose the involvement of hsa-miR-548ba in the regulation of follicle growth and activation via LIFR and PTEN. Hsa-miR-7973 may be implicated in the modulation of extracellular matrix and cell-cell interactions by regulating the expression of its identified targets.
  • Beilmann-Lehtonen, Ines; Böckelman, Camilla; Mustonen, Harri; Koskensalo, Selja; Hagström, Jaana; Haglund, Caj (2020)
    Colorectal cancer (CRC), the second most common cancer globally, resulted in 881,000 deaths in 2018. Toll-like receptors (TLRs) are crucial to detecting pathogen invasion and inducing the host's immune response. This study aimed to explore the prognostic value of TLR2 and TLR4 tumor expressions in colorectal cancer patients. We studied the immunohistochemical expressions of TLR2 and TLR4 using tissue microarray specimens from 825 patients undergoing surgery in the Department of Surgery, Helsinki University Hospital, between 1982 and 2002. We assessed the relationships between TLR2 and TLR4 expressions and clinicopathological variables and patient survival. We generated survival curves using the Kaplan-Meier method, determining significance with the log-rank test. Among patients with lymph node-positive disease and no distant metastases (Dukes C), a strong TLR2 immunoactivity associated with a better prognosis (p <0.001). Among patients with local Dukes B disease, a strong TLR4 immunoactivity associated with a worse disease-specific survival (DSS; p = 0.017). In the multivariate survival analysis, moderate TLR4 immunoactivity compared with strong TLR4 immunoactivity (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.49-0.89, p = 0.007) served as an independent prognostic factor. In the multivariate analysis for the Dukes subgroups, moderate TLR2 immunoactivity (HR 2.63, 95% CI 1.56-4.44, p <0.001) compared with strong TLR2 immunoactivity served as an independent negative prognostic factor in the Dukes C subgroup. TLR2 and TLR4 might be new prognostic factors to indicate which CRC patients require adjuvant therapy and which could spare from an unnecessary follow-up, but further investigations are needed.
  • Kivela, Riikka; Salmela, Ida; Nguyen, Yen Hoang; Petrova, Tatiana V.; Koistinen, Heikki A.; Wiener, Zoltan; Alitalo, Kari (2016)
    The remarkable adaptive and regenerative capacity of skeletal muscle is regulated by several transcription factors and pathways. Here we show that the transcription factor Prox1 is an important regulator of myoblast differentiation and of slow muscle fibre type. In both rodent and human skeletal muscles Prox1 is specifically expressed in slow muscle fibres and in muscle stem cells called satellite cells. Prox1 activates the NFAT signalling pathway and is necessary and sufficient for the maintenance of the gene program of slow muscle fibre type. Using lineage-tracing we show that Prox1-positive satellite cells differentiate into muscle fibres. Furthermore, we provide evidence that Prox1 is a critical transcription factor for the differentiation of myoblasts via bi-directional crosstalk with Notch1. These results identify Prox1 as an essential transcription factor that regulates skeletal muscle phenotype and myoblast differentiation by interacting with the NFAT and Notch pathways.
  • Wang, Zhu; Yang, Yang; Cui, Yancheng; Wang, Chao; Lai, Zhiyong; Li, Yansen; Zhang, Wei; Mustonen, Harri; Puolakkainen, Pauli; Ye, Yingjiang; Jiang, Kewei; Shen, Zhanlong; Wang, Shan (2020)
    Objective: Recent studies have shown that tumor-associated macrophages (TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer (GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified. Methods: THP-1 monocytes were induced by PMA/interleukin (IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation (ChIP) assay were used to investigate the mechanism of transforming growth factor beta 2 (TGF beta 2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo. Results: We found that Kindlin-2 expression was upregulated at both mRNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGF beta 2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-kappa B. TAMs thus participated in the progression of GC through the TGF beta 2/NF-kappa B/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo. Conclusions: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGF beta 2/NF-kappa B/Kindlin-2 axis, providing a possibility for new treatment options and approaches.