Dataset Information

Inferring alterations in cell-to-cell communication in HER2+ breast cancer using secretome profiling of three cell models.

ABSTRACT: Challenges in demonstrating durable clinical responses to molecular-targeted therapies have sparked a re-emergence in viewing cancer as an evolutionary process. In somatic evolution, cellular variants are introduced through a random process of somatic mutation and are selected for improved fitness through a competition for survival. In contrast to Darwinian evolution, cellular variants that are retained may directly alter the fitness competition. If cell-to-cell communication is important for selection, the biochemical cues secreted by malignant cells that emerge should be altered to bias this fitness competition. To test this hypothesis, we compared the proteins secreted in vitro by two human HER2+ breast cancer cell lines (BT474 and SKBR3) relative to a normal human mammary epithelial cell line (184A1) using a proteomics workflow that leveraged two-dimensional gel electrophoresis (2DE) and MALDI-TOF mass spectrometry. Supported by the 2DE secretome maps and identified proteins, the two breast cancer cell lines exhibited secretome profiles that were similar to each other and, yet, were distinct from the 184A1 secretome. Using protein-protein interaction and pathway inference tools for functional annotation, the results suggest that all three cell lines secrete exosomes, as confirmed by scanning electron microscopy. Interestingly, the HER2+ breast cancer cell line exosomes are enriched in proteins involved in antigen-processing and presentation and glycolytic metabolism. These pathways are associated with two of the emerging hallmarks of cancer: evasion of tumor immunosurveillance and deregulating cellular energetics.

SUBMITTER: Klinke DJ

PROVIDER: S-EPMC4423606 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inferring alterations in cell-to-cell communication in HER2+ breast cancer using secretome profiling of three cell models.

Klinke David J DJ Kulkarni Yogesh M YM Wu Yueting Y Byrne-Hoffman Christina C

Biotechnology and bioengineering 20140418 9

Challenges in demonstrating durable clinical responses to molecular-targeted therapies have sparked a re-emergence in viewing cancer as an evolutionary process. In somatic evolution, cellular variants are introduced through a random process of somatic mutation and are selected for improved fitness through a competition for survival. In contrast to Darwinian evolution, cellular variants that are retained may directly alter the fitness competition. If cell-to-cell communication is important for se ...[more]

PMID: 24752654

Similar Datasets

Project description:BACKGROUND:Therapy targeted to the human epidermal growth factor receptor type 2 (HER2) is used in combination with cytotoxic therapy in treatment of HER2+ breast cancer. Trastuzumab, a monoclonal antibody that targets HER2, has been shown pre-clinically to induce vascular changes that can increase delivery of chemotherapy. To quantify the role of immune modulation in treatment-induced vascular changes, this study identifies temporal changes in myeloid cell infiltration with corresponding vascular alterations in a preclinical model of HER2+ breast cancer following trastuzumab treatment. METHODS:HER2+ tumor-bearing mice (N?=?46) were treated with trastuzumab or saline. After extraction, half of each tumor was analyzed by immunophenotyping using flow cytometry. The other half was quantified by immunohistochemistry to characterize macrophage infiltration (F4/80), vascularity (CD31 and ?-SMA), proliferation (Ki67) and cellularity (H&E). Additional mice (N?=?10) were used to quantify differences in tumor cytokines between control and treated groups. RESULTS:Immunophenotyping showed an increase in macrophage infiltration 24?h after trastuzumab treatment (P???0.05). With continued trastuzumab treatment, the M1 macrophage population increased (P?=?0.02). Increases in vessel maturation index (i.e., the ratio of ?-SMA to CD31) positively correlated with increases in tumor infiltrating M1 macrophages (R?=?0.33, P?=?0.04). Decreases in VEGF-A and increases in inflammatory cytokines (TNF-?, IL-1?, CCL21, CCL7, and CXCL10) were observed with continued trastuzumab treatment (P???0.05). CONCLUSIONS:Preliminary results from this study in a murine model of HER2+ breast cancer show correlations between immune modulation and vascular changes, and reveals the potential for anti-HER2 therapy to reprogram immunosuppressive components of the tumor microenvironment. The quantification of immune modulation in HER2+ breast cancer, as well as the mechanistic insight of vascular alterations after anti-HER2 treatment, represent novel contributions and warrant further assessment for potential clinical translation.

Dataset Information

Inferring alterations in cell-to-cell communication in HER2+ breast cancer using secretome profiling of three cell models.

Publications

Inferring alterations in cell-to-cell communication in HER2+ breast cancer using secretome profiling of three cell models.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets