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Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

ABSTRACT: Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy.C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53(Null) orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg i.v. x1. Area under the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by IHC. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg i.v. weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed.Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin was similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P < 0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and VEGF-a, greater vascular quantity, and decreased expression of VEGF-c compared with C3-TAg (P < 0.05). PLD was more efficacious compared with NL-doxo in both models.The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small-molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes.

SUBMITTER: Song G

PROVIDER: S-EPMC4565518 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

Song Gina G Darr David B DB Santos Charlene M CM Ross Mark M Valdivia Alain A Jordan Jamie L JL Midkiff Bentley R BR Cohen Stephanie S Nikolaishvili-Feinberg Nana N Miller C Ryan CR Tarrant Teresa K TK Rogers Arlin B AB Dudley Andrew C AC Perou Charles M CM Zamboni William C WC

Clinical cancer research : an official journal of the American Association for Cancer Research 20140917 23

<h4>Purpose</h4>Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy.<h4>Experimental designs</h4>C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53(Null) orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the p ...[more]

PMID: 25231403

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Project description:Objective: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer, characterized by extensive intratumoral heterogeneity. We aimed to systematically characterize the tumor heterogeneity of TNBC. Methods: Single-cell RNA sequencing (scRNA-seq) of TNBC cells were obtained from the GSE118389 and GSE75688 datasets. After integration of the two datasets, cell clustering analysis was performed using the Seurat package. According to the marker genes of cell cycle, cell cycle of each cell cluster was determined. Then, function enrichment analysis of marker genes in each cell cluster was performed, followed by ligand-receptor signaling network analysis. CIBERSORT was used to estimate the proportion of 22 immune cells in each sample based on RNA-seq data of 58 normal adjacent tissues and 101 TNBC tissues. After that, prognostic value of immune cells was assessed. Results: In the integrated datasets, five cells types including B cells, myeloid cells, stromal cells, T cells, and tumor cells were clustered. Functional enrichment analysis revealed the functional heterogeneity of genes in each cell. Intercellular communication networks were conducted based on ligand-receptor pairs. The heterogeneity in the fractions of 22 immune cells was found in TNBC tissues. Furthermore, there was a significant difference in the fractions of these immune cells between adjacent normal tissues and TNBC tissues. Among them, M2 macrophages and neutrophils were significantly associated with clinical outcomes of TNBC. Moreover, the fractions of T cells CD4 memory resting, monocytes, neutrophils, M1 macrophages, and T cells CD4 memory activated were significantly correlated with clinical characteristics of TNBC. As shown in PCA results, these immune cells could significantly distinguish TNBC tissues into adjacent normal tissues. Conclusion: Our findings characterized the tumor heterogeneity of TNBC, which deepened the understanding of the complex interactions between tumor cells and their microenvironment, especially immune cells.

Dataset Information

Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

Publications

Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

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