In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 26 ( 2012-06-26)
Abstract:
MicroRNAs are a new class of cancer genes that have only recently been exploited for therapeutic purposes. Our mouse model allows us to toggle expression of the oncogenic miRNA, miR-155. The model described here establishes the biological basis for anti-miR-155 therapies by showing that not only can miR-155 initiate lymphoid tumors, but also its maintained expression is requisite for progression and survival of these miRNA-addicted tumors. This work also introduces a robust and versatile nanoparticle-based delivery strategy that exploits miR-155 as an effective therapeutic tool for the treatment of cancer. These studies advance our understanding of miR-155 regulation of cancer and establish wider therapeutic options for cancer patients. We evaluated the ability of these NPs to inhibit miR-155 in lymphoma cell culture and tumor models. NPs were densely loaded with anti-miR-155 molecules comprising a peptide nucleic acid backbone and coated with ANTP. This surface enhancement facilitated the uptake of ANTP-coated NPs into pre-B cells. Because of their size and surface properties, ANTP-NPs passively targeted and accumulated in hypervascularized miR-155-addicted lymphoma tumors. Attenuation of tumor growth resulted from both systemic and local treatments with anti-miR-155-loaded ANTP-NPs; we note that these doses were an order of magnitude less than what has been used in related anti-miR-based tumor therapy studies. Relative to control treatment, systemic anti-miR-155 treatment reduced growth by 50% over 5 d, while local treatment delayed growth by 80% after 1 wk. Using multiple molecular markers, we demonstrated that augmentation of programmed cell death (i.e., apoptosis) contributed to tumor growth inhibition. This inducible system presented a model to evaluate our nanoscale delivery technology that was designed to inhibit miRNAs in solid lymphoid tumors. Current strategies for inhibiting the function of miRNAs utilize viral vectors or chemically modified anti-miRNAs (anti-miRs) that are perfectly complementary nucleic acid analogs that bind to the target miRNA ( 4 ). However, these approaches can be limited in vivo by safety and target-specificity concerns. Encapsulating anti-miRs in biodegradable polymer nanoparticles (NPs) represents a unique and safe delivery approach toward inhibiting miRNA function. Furthermore, as we have previously shown, the delivery capabilities of these NPs can be enhanced by coating their surface with polyethylene glycol and the cell-penetrating peptide, penetratin (ANTP), to improve delivery and tumor cell uptake ( 5 ). Nanoscale delivery systems have a history of success for improving the delivery of therapeutic agents for the treatment of cancer. To the best of our knowledge, the present work describes a previously undescribed use of a nanoparticle technology to deliver anti-miR molecules that are targeted against oncogenic miRNA in a solid tumor. This work had two main goals: ( i ) to test the hypothesis that tumors can become addicted to and dependent on the overexpression of a single miRNA, and ( ii ) to develop a unique and effective nanoparticle technology for cancer-targeted gene therapy based on inhibition of this dysregulated oncogenic miRNA. MicroRNAs are short noncoding RNA molecules that regulate gene expression. Recently, studies have implicated miRNAs as crucial regulators of cancer pathways that can contribute to tumorigenesis when inappropriately expressed ( 1 ). Several cancer pathways are regulated by miR-155; thus, miR-155 is implicated as an oncogenic miRNA ( 2 , 3 ). To further investigate miR-155 in cancer, we developed a mouse model that allowed us to conditionally overexpress miR-155 in transgenic mice. We found that ectopic expression of miR-155, specifically in lymphoid tissue, causes pre-B cell lymphoma. These aggressive lymphocytes form solid tumors that are acutely sensitive to miR-155 inhibition; withdrawal of ectopic miR-155 results in rapid lymphoma regression, which is in part caused by programmed cell death. Further characterization of the tumor cells revealed that they were oligo- and monoclonal, migratory, and highly tumorigenic. In a process described as oncomiR addiction, genetically complex tumors can become dependent on a single oncogenic microRNA (miRNA), because one miRNA can regulate numerous genes in diverse pathways. One such miRNA, miR-155, has been implicated in numerous cancers. Here, we show that miR-155-induced lymphomas can become addicted to miR-155 expression; withdrawal of miR-155 leads to rapid tumor regression and apoptosis. We employ a novel therapeutic strategy to inhibit miRNA in vivo using rationally engineered polymer nanoparticles. Our results provide a basis and means for anti-miR-155 therapies, which may be able to exploit the addictive nature of miR-155-regulated tumors ( Fig. P1 ). Fig. P1. A schematic of the oncomiR-addiction cancer model to evaluate cell-penetrating NP as an anti-miR delivery technology. ( 1 ) Transgenic mice that express high levels of miR-155 develop disseminated lymphoma comprising neoplastic lymphocytes that are dependent on miR-155 overexpression. ( 2 ) These cells can establish aggressive subcutaneous flank tumors that are acutely sensitive to miR-155 withdrawal. ( 3 ) Coating NPs with ANTP and polyethylene glycol allows them to overcome in vivo delivery barriers. ( 4 ) Once inside target tumor cells, ANTP-NPs release encapsulated anti-miR-155 molecules that ( 5 ) bind to and inhibit miR-155 in order to attenuate the oncogenic functions of the oncomiR.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1201516109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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