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Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts.

ABSTRACT: Chemokines are small soluble molecules that play critical roles in wound healing, infection, and cancer progression. In particular, overexpression of the C-C motif chemokine ligand 2 (CCL2) in multiple cancer types correlates with poor patient prognosis. Animal studies have shown that CCL2 signals to macrophages and breast cancer cells to promote tumor growth, invasion, and metastasis, indicating that CCL2 is a promising therapeutic target. However, the effectiveness of human-specific neutralizing antibodies has not been fully evaluated. Furthermore, controversies remain on the use of neutralizing antibodies to target CCL2 and could be due to mode of drug delivery. Here, we investigated the effects of continuous delivery of human CCL2-neutralizing antibodies on breast cancer progression. Nude mice bearing MCF10CA1d breast tumor xenografts were implanted with osmotic pumps containing control IgG or anti-CCL2 and analyzed for CCL2 levels and tumor progression over 4 weeks. Despite inhibiting CCL2-induced migration in vitro, CCL2-neutralizing antibodies did not significantly affect tumor growth, invasion, macrophage recruitment, or tumor angiogenesis. CCL2 antibodies did not affect murine CCL2 levels but significantly increased human CCL2 levels in circulating blood and tumor interstitial fluid. CCL2-neutralizing antibodies reduced CCL2 levels in cultured cells short term at high concentrations. Enzyme-linked immunosorbent assay analysis of CCL2 in cultured fibroblasts and breast cancer cells revealed that the neutralizing antibodies sequestered CCL2 in the media. CCL2 levels were restored once the antibodies were removed. These studies reveal limitations in CCL2-neutralizing antibodies as a therapeutic agent, with important implications for translating CCL2 targeting to the clinic.

SUBMITTER: Yao M

PROVIDER: S-EPMC5521028 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts.

Yao Min M Smart Curtis C Hu Qingting Q Cheng Nikki N

Translational oncology 20170719 5

Chemokines are small soluble molecules that play critical roles in wound healing, infection, and cancer progression. In particular, overexpression of the C-C motif chemokine ligand 2 (CCL2) in multiple cancer types correlates with poor patient prognosis. Animal studies have shown that CCL2 signals to macrophages and breast cancer cells to promote tumor growth, invasion, and metastasis, indicating that CCL2 is a promising therapeutic target. However, the effectiveness of human-specific neutralizi ...[more]

PMID: 28734227

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Project description:BACKGROUND:Circulating tumor DNA (ctDNA) and miRNA (ctmiRNA) are promising biomarkers for early tumor diagnosis, prognosis and monitoring, and to predict therapeutic response. However, a clear understanding of the fine control on their circulating levels is still lacking. METHODS:Three human colorectal carcinoma cell lines were grown in culture and as tumor xenograft models in nude mice. Chip-based and droplet digital PCR platforms were used to systematically and quantitatively assess the levels of DNAs and miRNAs released into the culture supernatants and mouse blood plasma. RESULTS:Strikingly, mutated DNAs from the same (KRAS) and different (PIK3CA and FBWX7) genomic loci were differentially detected in culture supernatants and blood, with LS174T releasing 25 to 60 times less DNA in culture, but giving rise to 7 to 8 times more DNA in blood than LoVo cells. Greater LS174T ctDNA accumulation occurred in spite of similar CD31 immunostaining (micro-vascularization) and lesser proliferation and tissue necrosis as compared to LoVo. As to the three selected miRNAs (miR-221, miR-222 and miR-141), all of them were constitutively present in the plasma of tumor-free mice. Micro-RNA miR-141 was released into HT-29 cell supernatants 10 and 6.5 times less abundantly with respect to LoVo and LS174T, respectively; on the contrary, release of miR-141 in blood of HT-29 xenografted mice was found similar to that observed in LoVo and LS174T mice. CONCLUSIONS:Taken together, our results support the existence of multiple, finely tuned (non-housekeeping) control gateways that selectively regulate the release/accumulation of distinct ctDNA and miRNA species in culture and tumor xenograft models. Different xenografts (proxies of different patients) considerably differ in gateway usage, adding several layers of complexity to the well-known idea of molecular heterogeneity. We predict that even high tissue representation of mutated DNA and miRNA may result in insufficient diagnostic analyte representation in blood. In this respect, our data show that careful modeling in mice may considerably help to alleviate complexity, for instance by pre-screening for the most abundant circulating analytes in enlarged sets of tumor xenografts.

Dataset Information

Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts.

Publications

Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts.

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