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Human Cancer Cell Membrane-Coated Biomimetic Nanoparticles Reduce Fibroblast-Mediated Invasion and Metastasis and Induce T-Cells.

ABSTRACT: Biomimetic nanoparticles (NPs) combine the flexibility and reproducibility of synthetic materials with the functionality of biological materials. Here, we developed and characterized biomimetic poly(lactic- co-glycolic acid) (PLGA) NPs coated with human cancer cell membrane fractions (CCMFs) to form CCMF-coated PLGA (CCMF-PLGA) NPs. We evaluated the ability of these CCMF-PLGA NPs to disrupt cancer cell-stromal cell interactions and to induce an immune response. Western blot analysis verified the plasma membrane purity of CCMFs. Confocal fluorescence microscopy and flow cytometry confirmed the presence of intact membrane-associated proteins including CXCR4 and CD44 following membrane derivation and coating. CCMFs and CCMF-PLGA NPs were capable of inhibiting cancer cell migration toward human mammary fibroblasts. Intravenous injection of CCMF-PLGA NPs significantly reduced experimental metastasis in vivo. Following immunization of Balb/c mice, near-infrared fluorescence imaging confirmed the migration of NPs to proximal draining lymph nodes (LNs). A higher percentage of CD8+ and CD4+ cytotoxic T-lymphocyte populations was observed in spleens and LNs of CCMF-PLGA NP-immunized mice. Splenocytes isolated from CCMF-PLGA NP-immunized mice had the highest number of interferon gamma-producing T-cells as detected by the ELISpot assay. CCMF-PLGA NPs hold promise for disrupting cancer cell-stromal cell interactions and for priming the immune system in cancer immunotherapy.

SUBMITTER: Jin J

PROVIDER: S-EPMC6628902 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Human Cancer Cell Membrane-Coated Biomimetic Nanoparticles Reduce Fibroblast-Mediated Invasion and Metastasis and Induce T-Cells.

Jin Jiefu J Krishnamachary Balaji B Barnett James D JD Chatterjee Samit S Chang Di D Mironchik Yelena Y Wildes Flonne F Jaffee Elizabeth M EM Nimmagadda Sridhar S Bhujwalla Zaver M ZM

ACS applied materials & interfaces 20190214 8

Biomimetic nanoparticles (NPs) combine the flexibility and reproducibility of synthetic materials with the functionality of biological materials. Here, we developed and characterized biomimetic poly(lactic- co-glycolic acid) (PLGA) NPs coated with human cancer cell membrane fractions (CCMFs) to form CCMF-coated PLGA (CCMF-PLGA) NPs. We evaluated the ability of these CCMF-PLGA NPs to disrupt cancer cell-stromal cell interactions and to induce an immune response. Western blot analysis verified the ...[more]

PMID: 30707559

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Project description:Purpose: TIAM2 (T-cell lymphoma invasion and metastasis 2), a RAC1 guanine nucleotide exchange factor, plays crucial roles in human cancer cells. Its homolog, TIAM1, has been reported to promote the migration and invasion of cancer cells through regulating the functions of cancer associated fibroblasts (CAFs). However, the functions of TIAM2 in CAFs have not been investigated. In this study, we explored how fibroblast TIAM2 influences the migration and invasion of lung cancer cells. Methods: We cultured primary lung CAFs and adjacent normal lung fibroblasts (NFs) from 12 non-small cell lung cancer (NSCLC) patients. RT-PCR and western blot were used to compare TIAM2 levels between CAFs and NFs. Two co-culture systems were designed, in which cancer cells were directly co-cultured with fibroblasts and indirectly co-cultured with conditional medium (CM) from fibroblasts. Subsequently, the wound healing and transwell tests were conducted to assess the migration and invasion ability of fibroblasts and co-cultured cancer cells. Finally, cytokine antibody arrays were used to screen differentially secreted cytokines in the CM. Results: The expression levels of TIAM2 were significantly higher in CAFs than NFs, and TIAM2-silenced fibroblasts showed decreased migration and invasion ability. In the direct co-culture system, the migration and invasion of cancer cells were retarded when co-culturing with TIAM2-silenced fibroblasts, and the expression levels of EMT-related genes also changed in cancer cells. Decreased migration and invasion of cancer cells were also observed when culturing with the CM from TIAM2-silenced fibroblasts. In addition, the cytokine antibody arrays revealed that Osteoprotegerin (OPG) was significantly decreased in the CM of TIAM2-silenced fibroblasts. This result suggested that OPG might be one of the main cytokines contributing to the migration and invasion of cancer cells in co-culture systems. Conclusion: Our results suggest that fibroblast TIAM2 promotes the invasion and migration of lung cancer cell, and OPG might be one of the main cytokines contributing to this pro-cancer process.

Project description:BackgroundThe transforming growth factor-beta (TGF-beta) pathway, which has both tumor suppressor and pro-oncogenic activities, is often constitutively active in melanoma and is a marker of poor prognosis. Recently, we identified GLI2, a mediator of the hedgehog pathway, as a transcriptional target of TGF-beta signaling.MethodsWe used real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting to determine GLI2 expression in human melanoma cell lines and subsequently classified them as GLI2high or as GLI2low according to their relative GLI2 mRNA and protein expression levels. GLI2 expression was reduced in a GLI2high cell line with lentiviral expression of short hairpin RNA targeting GLI2. We assessed the role of GLI2 in melanoma cell invasiveness in Matrigel assays. We measured secretion of matrix metalloproteinase (MMP)-2 and MMP-9 by gelatin zymography and expression of E-cadherin by western blotting and RT-PCR. The role of GLI2 in development of bone metastases was determined following intracardiac injection of melanoma cells in immunocompromised mice (n = 5-13). Human melanoma samples (n = 79) at various stages of disease progression were analyzed for GLI2 and E-cadherin expression by immunohistochemistry, in situ hybridization, or RT-PCR. All statistical tests were two-sided.ResultsAmong melanoma cell lines, increased GLI2 expression was associated with loss of E-cadherin expression and with increased capacity to invade Matrigel and to form bone metastases in mice (mean osteolytic tumor area: GLI2high vs GLI2low, 2.81 vs 0.93 mm(2), difference = 1.88 mm(2), 95% confidence interval [CI] = 1.16 to 2.60, P < .001). Reduction of GLI2 expression in melanoma cells that had expressed high levels of GLI2 substantially inhibited both basal and TGF-beta-induced cell migration, invasion (mean number of Matrigel invading cells: shGLI2 vs shCtrl (control), 52.6 vs 100, difference = 47.4, 95% CI = 37.0 to 57.8, P = .024; for shGLI2 + TGF-beta vs shCtrl + TGF-beta, 31.0 vs 161.9, difference = -130.9, 95% CI = -96.2 to -165.5, P = .002), and MMP secretion in vitro and the development of experimental bone metastases in mice. Within human melanoma lesions, GLI2 expression was heterogeneous, associated with tumor regions in which E-cadherin was lost and increased in the most aggressive tumors.ConclusionGLI2 was directly involved in driving melanoma invasion and metastasis in this preclinical study.

Dataset Information

Human Cancer Cell Membrane-Coated Biomimetic Nanoparticles Reduce Fibroblast-Mediated Invasion and Metastasis and Induce T-Cells.

Publications

Human Cancer Cell Membrane-Coated Biomimetic Nanoparticles Reduce Fibroblast-Mediated Invasion and Metastasis and Induce T-Cells.

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