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Tumor-Penetrating Nanosystem Strongly Suppresses Breast Tumor Growth.

ABSTRACT: Antiangiogenic and vascular disrupting compounds have shown promise in cancer therapy, but tend to be only partially effective. We previously reported a potent theranostic nanosystem that was highly effective in glioblastoma and breast cancer mouse models, retarding tumor growth and producing some cures [ Agemy , L. et al. Proc. Natl. Acad. Sci. U.S.A. 2011 , 108 , 17450 - 17455 . Agemy , L. et al. Mol. Ther. 2013 , 21 , 2195 - 2204 .]. The nanosystem consists of iron oxide NPs ("nanoworms") coated with a composite peptide with tumor-homing and pro-apoptotic domains. The homing component targets tumor vessels by binding to p32/gC1qR at the surface or tumor endothelial cells. We sought to further improve the efficacy nanosystem by searching for an optimally effective homing peptide that would also incorporate a tumor-penetrating function. To this effect, we tested a panel of candidate p32 binding peptides with a sequence motif that conveys tumor-penetrating activity (CendR motif). We identified a peptide designated as Linear TT1 (Lin TT1) (sequence: AKRGARSTA) as most effective in causing tumor homing and penetration of the nanosystem. This peptide had the lowest affinity for p32 among the peptides tested. The low affinity may have moderated the avidity effect from the multivalent presentation on nanoparticles (NPs), such that the NPs avoid getting trapped by the so-called "binding-site barrier", which can hinder tissue penetration of compounds with a high affinity for their receptors. Treatment of breast cancer mice with the LinTT1 nanosystem showed greatly improved efficacy compared to the original system. These results identify a promising treatment modality and underscore the value of tumor penetration effect in improving the efficacy tumor treatment.

SUBMITTER: Sharma S

PROVIDER: S-EPMC5819594 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Tumor-Penetrating Nanosystem Strongly Suppresses Breast Tumor Growth.

Sharma Shweta S Kotamraju Venkata Ramana VR Mölder Tarmo T Tobi Allan A Teesalu Tambet T Ruoslahti Erkki E

Nano letters 20170217 3

Antiangiogenic and vascular disrupting compounds have shown promise in cancer therapy, but tend to be only partially effective. We previously reported a potent theranostic nanosystem that was highly effective in glioblastoma and breast cancer mouse models, retarding tumor growth and producing some cures [ Agemy , L. et al. Proc. Natl. Acad. Sci. U.S.A. 2011 , 108 , 17450 - 17455 . Agemy , L. et al. Mol. Ther. 2013 , 21 , 2195 - 2204 .]. The nanosystem consists of iron oxide NPs ("nanoworms") coa ...[more]

PMID: 28178415

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Project description:Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of neoplastic cells, impacting tumorigenesis and tumor progression. Correlations between the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including breast, have been widely described. Current immunotherapies utilizing checkpoint inhibitors or co-stimulatory molecule agonists aim to activate effector immune cells. However, tumors often lack adequate effector cell numbers within the TME, resulting in suboptimal responses to these agents. Chemerin (RARRES2) is a leukocyte chemoattractant widely expressed in many tissues and is known to recruit innate leukocytes. CMKLR1 is a chemotactic cellular receptor for chemerin and is expressed on subsets of dendritic cells, NK cells, and macrophages. We have previously shown that chemerin acts as a tumor suppressive cytokine in mouse melanoma models by recruiting innate immune defenses into the TME. Chemerin/RARRES2 is down-regulated in many tumors, including breast, compared to normal tissue counterparts. Here, using a syngeneic orthotopic EMT6 breast carcinoma model, we show that forced overexpression of chemerin by tumor cells results in significant recruitment of NK cells and T cells within the TME. While chemerin secretion by EMT6 cells did not alter their phenotypic behavior in vitro, it did significantly suppress tumor growth in vivo. To define the cellular effectors required for this anti-tumor phenotype, we depleted NK cells or CD8+ T cells and found that either cell type is required for chemerin-dependent suppression of EMT6 tumor growth. Finally, we show significantly reduced levels of RARRES2 mRNA in human breast cancer samples compared to matched normal tissues. Thus, for the first time we have shown that increasing chemerin expression within the breast carcinoma TME can suppress growth by recruitment of NK and T cells, thereby supporting this approach as a promising immunotherapeutic strategy.

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Tumor-Penetrating Nanosystem Strongly Suppresses Breast Tumor Growth.

Publications

Tumor-Penetrating Nanosystem Strongly Suppresses Breast Tumor Growth.

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