Optimization of a Luciferase-Expressing Non-Invasive Intrapleural Model of Malignant Mesothelioma in Immunocompetent Mice

Malignant Pleural Mesothelioma (MPM) is an aggressive tumor of the pleural lining that is usually identified at advanced stages and resistant to current therapies. Appropriate pre-clinical mouse tumor models are of pivotal importance to study its biology. Usually, tumor cells have been injected intraperitoneally or subcutaneously. Using three available murine mesothelioma cell lines with different histotypes (sarcomatoid, biphasic, epithelioid), we have set up a simplified model of in vivo growth orthotopically by inoculating tumor cells directly in the thorax with a minimally invasive procedure. Mesothelioma tumors grew along the pleura and spread on the superficial areas of the lungs, but no masses were found outside the thoracic cavity. As observed in human MPM, tumors were highly infiltrated by macrophages and T cells. The luciferase-expressing cells can be visualized in vivo by bioluminescent optical imaging to precisely quantify tumor growth over time. Notably, the bioluminescence signal detected in vivo correctly matched the tumor burden quantified with classical histology. In contrast, the subcutaneous or intraperitoneal growth of these mesothelioma cells was considered either non-representative of the human disease or unreliable to precisely quantify tumor load. Our non-invasive in vivo model of mesothelioma is simple and reproducible, and it reliably recapitulates the human disease.

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Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001803 ◽

2021 ◽

Vol 9 (3) ◽

pp. e001803

Author(s):

Louise M E Müller ◽

Gemma Migneco ◽

Gina B Scott ◽

Jenny Down ◽

Sancha King ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Immune Responses ◽

Stromal Cells ◽

Tumor Burden ◽

Effector Memory ◽

In Vivo Model ◽

Bm Niche

BackgroundMultiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported.MethodsThis study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment.ResultsUsing the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8+ T cell numbers; (ii) activated NK cells and CD8+ T cells and (iii) upregulated effector-memory CD8+ T cells. Moreover, increased effector-memory CD8+ T cells correlated with decreased tumor burden. Next, we explored the potential for reovirus-induced immunotherapy using human co-culture models to mimic the myeloma-supportive BM niche. MM cells co-cultured with BM stromal cells displayed resistance to reovirus-induced oncolysis and bystander cytokine-killing but remained susceptible to killing by reovirus-activated NK cells and MM-specific cytotoxic T lymphocytes.ConclusionThese data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.

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Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection

Journal of Experimental Medicine ◽

10.1084/jem.20050240 ◽

2005 ◽

Vol 202 (11) ◽

pp. 1477-1482 ◽

Cited By ~ 53

Author(s):

John M. Routes ◽

Sharon Ryan ◽

Kristin Morris ◽

Rayna Takaki ◽

Adelheid Cerwenka ◽

...

Keyword(s):

Tumor Cells ◽

Nk Cell ◽

Tumor Rejection ◽

Mouse Tumor ◽

Mutant Form ◽

Nkg2d Ligand ◽

Adenovirus Serotype ◽

Nkg2d Ligands ◽

Serotype 5

The expression of the Adenovirus serotype 5 (Ad5) E1A oncogene sensitizes tumor cells to natural killer (NK) cell–mediated killing and tumor rejection in vivo. These effects are dependent on the ability of E1A to bind the transcriptional coadaptor protein p300. To test the hypothesis that E1A up-regulates ligands recognized by the NKG2D-activating receptor, we stably transfected the highly tumorigenic mouse fibrosarcoma cell line MCA-205 with Ad5-E1A or a mutant form of E1A that does not interact with p300 (E1A-Δp300). Ad5-E1A, but not E1A-Δp300, up-regulated the expression of the NKG2D ligand retinoic acid early inducible (RAE)-1, but not murine ULBP-like transcript 1, another NKG2D ligand, in four independently derived MCA-205 transfectants. The up-regulation of RAE-1 by E1A targeted MCA-205 tumor cells to lysis by NK cells, resulting in NKG2D-dependent tumor rejection in vivo. Moreover, the up-regulation of NKG2D ligands by E1A was not limited to mouse tumor cells, as E1A also increased the expression of NKG2D ligands on primary baby mouse kidney cells, human MB435S breast cancer cells, and human H4 fibrosarcoma cells.

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siRNAs Targeting Mouse-Specific lncRNA AA388235 Induce Human Tumor Cell Pyroptosis/Apoptosis

Frontiers in Oncology ◽

10.3389/fonc.2021.662444 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yan-Ru Chen ◽

Wan-Ying Feng ◽

Yuan-Xiong Cheng ◽

Hao Zhu ◽

Hong-Juan Liu ◽

...

Keyword(s):

Tumor Cell ◽

Tumor Cells ◽

Large Scale ◽

Human Tumor ◽

Mouse Tumor ◽

Human Tumor Cells ◽

Human Tumor Cell ◽

Therapeutic Drugs ◽

Species Specific

Species-specific lncRNAs significantly determine species-specific functions through various ways, such as epigenetic regulation. However, there has been no study focusing on the role of species-specific lncRNAs in other species yet. Here, we found that siRNAs targeting mouse-specific lncRNA AA388235 could significantly induce death of human tumor cells, although it has no effect on mouse tumor cells and normal human cells. The mechanism studies showed that these siRNAs could activate the response of human tumor cells to exogenous nucleic acids, induce pyroptosis and apoptosis in the presence of GSDME, but induce apoptosis in the absence of GSDME. They also significantly inhibited the growth of human tumor cells in vivo. 17 siRNAs were designed for seven more mouse-specific lncRNAs selected randomly, among which 12 siRNAs targeting five lncRNAs induced death in human tumor cell. Our study not only demonstrates that the siRNAs designed for knocking down mouse-specific lncRNA AA388235 can be potential tumor therapeutic drugs, but also suggests that non-human species-specific lncRNAs are a huge potential library that can be used to design siRNAs for tumor treatment. Large-scale screening based on this is promising.

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Dual-Function Anti-CD47mAbs Induce Tumor Cell Death and Promote Phagocytosis Resulting in Enhanced in Vivo Efficacy

Blood ◽

10.1182/blood.v124.21.991.991 ◽

2014 ◽

Vol 124 (21) ◽

pp. 991-991

Author(s):

Pamela T. Manning ◽

Benjamin J. Capoccia ◽

Michael P. Rettig ◽

Ronald R. Hiebsch ◽

Robert W. Karr ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Tumor Cells ◽

Tumor Burden ◽

Dual Function ◽

Employment Equity ◽

Hematologic Cancer ◽

Equity Ownership

Abstract Recent success in immunomodulation of cancer has targeted immune checkpoints such as CTLA-4, PD-1 and PDL-1 to enhance adaptive immunity by stimulating production of tumor-selective, cytotoxic T cells. Anti-CD47mAbs enhance innate immunity by increasing the phagocytosis of tumor cells by macrophages leading to processing and presentation of tumor antigens to prime the adaptive T cell response. Many cancers, including hematologic cancers, up-regulate the expression of CD47 presumably to avoid immune destruction. Increased CD47 expression protects cancer cells from phagocytosis by sending a “don't eat me” signal to macrophages via SIRPalpha, an inhibitory receptor that prevents phagocytosis of CD47-bearing cells. CD47mAbs that block the CD47/SIRPalpha interaction (“blocking-only” mAbs) enhance phagocytosis of cancer cells in vitro. We have identified two CD47mAbs, Vx-1000 and Vx-1004, both of which block the CD47/SIRPalpha interaction and promote phagocytosis of tumor cells by macrophages equally well. However, Vx-1004 also has the unique property of killing cancer cells, but not normal blood cells, via a direct, cell-autonomous, cytotoxic mechanism. Therefore, Vx-1004 is a dual-function antibody. Vx-1004 selectively kills a variety of hematologic cancer cells in vitro, while Vx-1000, the blocking-only mAb, does not as assessed by annexin V staining and flow cytometry (Figure 1). In dose-response studies, cell death in leukemia cells was induced in 2 hrs by <1 ug="" vx-1004="" whereas="" normal="" peripheral="" blood="" mononuclear="" cells="" are="" resistant="" to="" the="" induction="" of="" cell="" death="" by="" following="" incubation="" with="" 10="" for="" 24="" hrs="" both="" these="" cd47mabs="" bind="" many="" species="" cd47="" including="" mouse="" and="" human="" p=""> To determine if the tumor-toxic activity of Vx-1004 confers enhanced efficacy in vivo compared to Vx-1000, we compared them in two mouse hematologic cancer models: murine acute promyelocytic leukemia (APL) and B cell lymphoma (BCL). Briefly, 1x106 GFP-labeled C57BL/6 APL cells were injected IV into wild-type C57BL/6 mice that were then treated IP with 0.4 mg/kg of either Vx-1000 or Vx-1004 on the day of tumor injection and on days 3 and 6 following tumor injection, a very low dose and limited dosing regimen. On day 25, the blood of these mice was analyzed for the number of circulating APL cells. As shown in Figure 2, Vx-1000 did not significantly reduce tumor burden compared to the control group. In contrast, Vx-1004 significantly reduced tumor burden compared to controls, demonstrating greater efficacy of the dual-function CD47mAb. In addition, enhanced efficacy of Vx-1004 compared to Vx-1000 was demonstrated in BCL (Figure 3). In this model, NSG mice were injected with 1x106 murine A20 lymphoma cells subcutaneously and then treated with 0.4mg/kg/day of the CD47mAbs IP for the first five days following tumor injection. In this model, Vx-1000 also failed to inhibit tumor growth compared to controls while Vx-1004 significantly reduced tumor burden at 35 days compared to both the control and Vx-1000 groups, nearly four weeks after treatment was stopped. These data demonstrate increased anti-cancer efficacy with a dual-function CD47mAb that not only blocks the CD47/SIRPalpha interaction to increase phagocytosis of cancer cells, but also selectively kills cancer cells. These studies indicate that dual-function CD47mAbs may have better anti-tumor activity in vivo and support their use in human clinical trials. Figure 1 Figure 1. Disclosures Manning: Corvus Pharmaceutical: Employment, Equity Ownership. Capoccia:Corvus Pharmaceutical: Employment, Equity Ownership. Hiebsch:Corvus Pharmaceutical: Employment, Equity Ownership. Karr:Corvus Pharmaceutical: Employment, Equity Ownership. Frazier:Corvus Pharmaceutical: Consultancy, Equity Ownership.

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Non-invasive scoring of cellular atypia in keratinocyte cancers in 3D LC-OCT images using Deep Learning

Scientific Reports ◽

10.1038/s41598-021-04395-1 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Sébastien Fischman ◽

Javiera Pérez-Anker ◽

Linda Tognetti ◽

Angelo Di Naro ◽

Mariano Suppa ◽

...

Keyword(s):

Deep Learning ◽

Invasive Procedure ◽

Skin Lesions ◽

Small Sample ◽

Three Dimensions ◽

Line Field ◽

Biologically Relevant ◽

Non Invasive ◽

Cellular Atypia

AbstractDiagnosis based on histopathology for skin cancer detection is today’s gold standard and relies on the presence or absence of biomarkers and cellular atypia. However it suffers drawbacks: it requires a strong expertise and is time-consuming. Moreover the notion of atypia or dysplasia of the visible cells used for diagnosis is very subjective, with poor inter-rater agreement reported in the literature. Lastly, histology requires a biopsy which is an invasive procedure and only captures a small sample of the lesion, which is insufficient in the context of large fields of cancerization. Here we demonstrate that the notion of cellular atypia can be objectively defined and quantified with a non-invasive in-vivo approach in three dimensions (3D). A Deep Learning (DL) algorithm is trained to segment keratinocyte (KC) nuclei from Line-field Confocal Optical Coherence Tomography (LC-OCT) 3D images. Based on these segmentations, a series of quantitative, reproducible and biologically relevant metrics is derived to describe KC nuclei individually. We show that, using those metrics, simple and more complex definitions of atypia can be derived to discriminate between healthy and pathological skins, achieving Area Under the ROC Curve (AUC) scores superior than 0.965, largely outperforming medical experts on the same task with an AUC of 0.766. All together, our approach and findings open the door to a precise quantitative monitoring of skin lesions and treatments, offering a promising non-invasive tool for clinical studies to demonstrate the effects of a treatment and for clinicians to assess the severity of a lesion and follow the evolution of pre-cancerous lesions over time.

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The Extracellular Matrix Influences Ovarian Carcinoma Cells’ Sensitivity to Cisplatinum: A First Step towards Personalized Medicine

Cancers ◽

10.3390/cancers12051175 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1175 ◽

Cited By ~ 1

Author(s):

Andrea Balduit ◽

Chiara Agostinis ◽

Alessandro Mangogna ◽

Veronica Maggi ◽

Gabriella Zito ◽

...

Keyword(s):

Standardized Testing ◽

Ovarian Carcinoma ◽

Tumor Cells ◽

Culture Conditions ◽

Carcinoma Cells ◽

In Vitro Assays ◽

Set Up ◽

Platinum Chemotherapy

The development of personalized therapies for ovarian carcinoma patients is still hampered by several limitations, mainly the difficulty of predicting patients’ responses to chemotherapy in tumor cells isolated from peritoneal fluids. The main reason for the low predictive power of in vitro assays is related to the modification of the cancer cells’ phenotype induced by the culture conditions, which results in changes to the activation state and drug sensitivity of tumor cells compared to their in vivo properties. We have defined the optimal culture conditions to set up a prognostic test to predict high-grade serous ovarian carcinoma (HGSOC) patients’ responses to platinum chemotherapy. We evaluated the effects of hyaluronic acid (HA) and fibronectin matrices and the contribution of freezing/thawing processes to the cell response to platinum-based treatment, collecting spheroids from the ascitic fluids of 13 patients with stage II or III HGSOC. Our findings indicated that an efficient model used to generate predictive data for in vivo sensitivity to platinum is culturing fresh spheroids on HA, avoiding the use of previously frozen primary tumor cells. The establishment of this easy, reproducible and standardized testing method can significantly contribute to an improvement in therapeutic effectiveness, thus bringing the prospect of personalized therapy closer for ovarian carcinoma patients.

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Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival

Endocrine Related Cancer ◽

10.1530/erc-11-0102 ◽

2011 ◽

Vol 18 (4) ◽

pp. 491-503 ◽

Cited By ~ 85

Author(s):

Qiao Zheng ◽

Sarah M Dunlap ◽

Jinling Zhu ◽

Erinn Downs-Kelly ◽

Jeremy Rich ◽

...

Keyword(s):

Tumor Growth ◽

Tumor Cells ◽

Mammary Tumor ◽

Leptin Receptor ◽

Tumor Burden ◽

Obese Mice ◽

Leptin Deficiency ◽

Phosphorylated Akt

Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the murine mammary tumor virus-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin receptor (LepRb)-deficient (db/db) mice grow to eight times the volume of tumors transplanted into lean wild-type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared with WT or db/db mice. Furthermore, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the LepRb, compared with WT and db/db mice.In vivolimiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin deficiency were identified by fluorescence-activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheresin vitroand leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.

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Following cytotoxic nanoconjugates from injection to halting the cell cycle machinery and its therapeutic implications in oral cancer

BMC Cancer ◽

10.1186/s12885-021-07849-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hend M. Abdel Hamid ◽

Zeinab E. Darwish ◽

Sahar M. Elsheikh ◽

Ghada M. Mourad ◽

Hanaa M. Donia ◽

...

Keyword(s):

Cell Cycle ◽

Oral Cancer ◽

Tumor Cells ◽

Small Molecule ◽

Mode Of Action ◽

Small Molecule Inhibitors ◽

Phase Cell ◽

In Vivo Model ◽

Tumor Reduction

Abstract Background The concept of personalized therapy has been proven to be a promising approach. A popular technique is to utilize gold nanoparticles (AuNPs) as drug delivery vectors for cytotoxic drugs and small molecule inhibitors to target and eradicate oral cancer cells in vitro and in vivo. Both drug and nanocarrier designs play important roles in the treatment efficacy. In our study, we standardized the nanosystem regarding NPs type, size, surface ligands and coverage percentage leaving only the drugs mode of action as the confounding variable. We propose that similarly constructed nanoparticles (NPs) can selectively leverage different conjugated drugs irrelevant to their original mode of action. If proven, AuNPs may have a secondary role beyond bypassing cancer cell membrane and delivering their loaded drugs. Methods We conjugated 5- fluorouracil (5Fu), camptothecin (CPT), and a fibroblast growth factor receptor1-inhibitor (FGFR1i) to gold nanospheres (AuNSs). We followed their trajectories in Syrian hamsters with chemically induced buccal carcinomas. Results Flow cytometry and cell cycle data shows that 5Fu- and CPT- induced a similar ratio of S-phase cell cycle arrest as nanoconjugates and in their free forms. On the other hand, FGFR1i-AuNSs induced significant sub-G1 cell population compared with its free form. Despite cell cycle dynamics variability, there was no significant difference in tumor cells’ proliferation rate between CPT-, 5Fu- and FGFR1i- AuNSs treated groups. In our in vivo model, FGFR1i-AuNSs induced the highest tumor reduction rates followed by 5Fu- AuNSs. CPT-AuNSs induced significantly lower tumor reduction rates compared with the 5Fu- and FGFR1i- AuNSs despite showing similar proliferative rates in tumor cells. Conclusions Our data indicates that the cellular biological events do not predict the outcome seen in our in vivo model. Furthermore, our results suggest that AuNSs selectively enhance the therapeutic effect of small molecule inhibitors such as FGFR1i than potent anticancer drugs. Future studies are required to better understand the underlying mechanism.

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Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor Progression

10.21203/rs.3.rs-86067/v1 ◽

2020 ◽

Author(s):

Bei Li ◽

Qi Wu ◽

Qian Yang ◽

Zhiyu Li ◽

Juanjuan Li ◽

...

Keyword(s):

Western Blot ◽

Tumor Progression ◽

Tumor Cells ◽

Tumor Burden ◽

Migration Assay ◽

Novel Target ◽

Pathway Inhibition ◽

Exosomal Mirna

Abstract BackgroundAdipose tissue macrophages (ATMs) particularly contribute to the progression of obesity-related tumor. However, the mechanisms that the tumor-adipocyte crosstalk may enable the properties and plasticity of macrophages remain still unclear. MethodsSurvival probabilities for recurrence-free survival (RFS) were estimated by the Kaplan–Meier method based on immunohistochemistry and immunofluorescence images. 3T3-L1 cells were co-cultivated with 4T1 and MDA-MB-231 cells. Then the co-cultivated media were used to treat THP-1/RAW264.7 cells. The ATMs markers were detected by immunofluorescence and Western blot. Transwell migration assay, was conducted to determine the migration capability of ATMs. RT-PCR and ELISA were used to detect the expression and secretion level of chemokines, respectively. Immunofluorescence imaging and Western blot were used to investigate the role of SOCS6/STAT3 signaling pathway in the polarization of ATMs. microRNA mimic and inhibitor, and xenograft models were used to explore the role of miR-155 in the polarization of ATMs.ResultsWe demonstrate that CD163-positive macrophages aggregated to surround adipocytes in breast cancer tissues, which was associated with tumor relapse. Thereafter, the eliminated macrophages partially inhibited adipocytes-induced tumor proliferation. The expression of chemokines, CCL2 and CCL5, elevated in tumor-adipocyte microenvironment and contributed to macrophage recruit and M2-like polarization via phosphorylating STAT3. Consistently, inhibiting chemokines and their receptors or suppressing the phosphorylation of STAT3 significantly decreased tumor burden in vivo. In coculture of tumor cells and adipocytes, the level of exosomal miRNA-155 was high, then it promoted the generation and release of CCL2 and CCL5 from adipocytes through targeting SOCS6/STAT3 pathway. Inhibition of exosomal miRNA-155 in tumor cells reduced the CCL2 and CCL5 levels in tumor-adipocytes coculture, and further retarded tumor growth. Likewise, the exosomes stimulated autophagy in macrophages in TFE3-depending way. ConclusionThese results suggest a novel target of tumor-adipocyte-macrophage interconnect that could facilitate obesity-induced tumor progression.

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Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor progression

10.21203/rs.3.rs-110545/v1 ◽

2020 ◽

Author(s):

Bei Li ◽

Qi Wu ◽

Qian Yang ◽

Zhiyu Li ◽

Juanjuan Li ◽

...

Keyword(s):

Western Blot ◽

Tumor Progression ◽

Tumor Cells ◽

Tumor Burden ◽

Migration Assay ◽

Novel Target ◽

Pathway Inhibition ◽

Exosomal Mirna

Abstract Background: Macrophages particularly contribute to the progression of obesity-related tumor. However, the mechanisms that the tumor-adipocyte crosstalk may enable the properties and plasticity of macrophages remain still unclear. Methods: Survival probabilities for recurrence-free survival (RFS) were estimated by the Kaplan–Meier method based on immunohistochemistry and immunofluorescence images. 3T3-L1 cells were co-cultivated with 4T1 and MDA-MB-231 cells. Then the co-cultivated media were used to treat THP-1/RAW264.7 cells. The markers of macrophages were detected by immunofluorescence and Western blot. Transwell migration assay, was conducted to determine the migration capability of macrophages. RT-PCR and ELISA were used to detect the expression and secretion level of chemokines, respectively. Immunofluorescence imaging and Western blot were used to investigate the role of SOCS6/STAT3 signaling pathway in the polarization of macrophages. microRNA mimic and inhibitor, and xenograft models were used to explore the role of miR-155 in the polarization of macrophages.Results: We demonstrate that CD163-positive macrophages aggregated to surround adipocytes in breast cancer tissues, which was associated with tumor relapse. In tumor-adipocyte microenvironment, CD163-positive macrophages are recruited and polarized via the elevated expression of CCL2 and CCL5. Consistently, the eliminated macrophages partially inhibited adipocytes-induced tumor proliferation. Likewise, inhibiting chemokines and their receptors or suppressing the phosphorylation of STAT3 significantly decreased tumor burden in vivo. Finally, the source of CCL2 and CCL5 mainly derived from adipocytes. In coculture of tumor cells and adipocytes, the level of exosomal miRNA-155 was high, then it promoted the generation and release of CCL2 and CCL5 from adipocytes through targeting SOCS6/STAT3 pathway. Inhibition of exosomal miRNA-155 in tumor cells reduced the CCL2 and CCL5 levels in tumor-adipocytes coculture, and further retarded tumor growth. Conclusion: These results suggest a novel target of tumor-adipocyte-macrophage interconnect that could facilitate obesity-induced tumor progression.

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