Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment

Abstract

Tumorigenesis is a complex and multistep process in which sequential mutations in oncogenes and tumor-suppressor genes result in enhanced proliferation and apoptosis escape. Over the past decades, several studies have provided evidence that tumors are more than merely a mass of malignant cancer cells, with the tumor microenvironment (TME) also contributing to cancer progression. For this reason, the focus of cancer research in recent years has shifted from the malignant cancer cell itself to the TME and its interactions. Since the TME actively participates in tumor progression, therapeutic strategies targeting it have created great interest. In this context, much attention has been paid to the potential application of small interfering RNA (siRNA), a class of non-coding RNA that has the ability to downregulate the expression of target genes in a sequence-specific way. This is paving the way for a novel therapeutic approach for the treatment of several diseases, including cancer. In this review, we describe recent efforts in developing siRNA therapeutics for the treatment of breast cancer, with particular emphasis on TME regulation. We focus on studies that adapt siRNA design to reprogram/re-educate the TME and eradicate the interplay between cancer cells and TME.

The long and short non-coding RNAs modulating EZH2 signaling in cancer

“…The small interfering RNA (siRNA) is a kind of RNA interference (RNAi) consisting of double-stranded RNA and has a homologous sequence to target gene [ 237 , 238 ]. SiRNAs can down-regulate the expression of target genes (silencing), a mechanism that begins in the cytoplasm with the aid of Dicer enzymes that cleaves double-stranded RAN to produce shorter RNA molecules, known as siRNA with length of 21–25 nucleotides.…”

Nanoparticle-Based Therapies for Turning Cold Tumors Hot: How to Treat an Immunosuppressive Tumor Microenvironment

“…In principle, DNA and mRNA targeting applies to any possible cellular target mentioned in the previous sections to modulate cold TIMEs. Small interfering RNA (siRNA) and short hairpin RNA (shRNA) are also applied in the modification of the TIME from cold to hot, as shown by the administration of siRNA/shRNA/miRNA encapsulated in various NPs that successfully reduced the expression of key proteins in cancer cells, endothelial cells, TAMs, DCs, monocytes and CAFs ( Lee S. W. L. et al, 2019 ; Roscigno et al, 2020 ). For example, in different preclinical tumor models, CRISPR/Cas9 knockout or siRNA/shRNA/miRNA-mediated silencing of PD-L1 immune checkpoint, in combination with chemotherapy, hyaluronidase, or radiotherapy, promoted an increased T cells activation and tumor infiltration ( Cortez et al, 2016 ; Guan et al, 2019 ; Wu et al, 2019 ; Xue et al, 2021 ).…”

Clinical Advances of siRNA-Based Nanotherapeutics for Cancer Treatment

“…Clinical application of siRNA-based nanotherapies in treating a wide variety of tumors poses numerous advantages; (1) siRNA nanotherapeutics can selectively and preferentially target any gene within the cancerous cells, especially the undruggable targets [17,18]; (2) they are readily fabricated and modified, in addition to having good safety and efficacy profiles with minimal off-target effects and immunogenicity [19,20]; (3) various siRNA therapeutics exhibited a promising antiproliferative and tumor growth suppression effect in vitro through the stat6 pathway and PLK1 [21,22], suppression of angiogenesis through inhibition of receptors including VEGFs and VEGFR-1 [23,24], or inhibition of tumor invasion and metastasis via chemokines CXCL8 and CXCL11 [25].…”

“…Clinical application of siRNA-based nanotherapies in treating a wide variety of tumors poses numerous advantages; (1) siRNA nanotherapeutics can selectively and preferentially target any gene within the cancerous cells, especially the undruggable targets [17,18];…”