Silencing of HIF-1α/CD73 axis by siRNA-loaded TAT-chitosan-spion nanoparticles robustly blocks cancer cell progression.

Induction of Hypoxia Inducible Factor (HIF) as a direct consequence of oxygen deficiency in tumor tissues is a potent stimulus of CD73 (ecto-5'-nucleotidase) expression. Hypoxic environment and CD73 overexpression are associated with altered metabolism, elevated cancer cell proliferation, and tumor vascularization. Herein, a delivery system was developed for silencing CD73 and HIF-1α gene using siRNA-loaded Superparamagnetic iron oxide (SPION) nanocarriers for cancer treatment. SPIONs were encapsulated with thiolated chitosan (TC) and trimethyl chitosan (TMC) for improving their stabilization and functionalization. The nanoparticles (NPs) were about 133 nm in size, spherical, and non-toxic, and the addition of TAT peptide (derived from HIV-1 TAT protein) to TMC-TC-SPIONs significantly increased their cellular uptake by cancer cells. The produced NPs could efficiently accumulate in the tumor site, indicating their stability and targeting ability in reaching the tumor region. TAT-conjugated TMC-TC-SPIONs containing siRNAs could significantly reduce the HIF-1α and CD73 expression levels in cancer cells. Following transfection, cancer cells showed a significant reduction in migration and proliferation. Moreover, siRNA-loaded NPs could effectively reduce tumor growth and angiogenesis, as investigated by the chick chorioallantoic membrane (CAM) assay. This study suggested that TAT-TMC-TC-SPIONs can be potential nanocarrier for gene transfection in cancer therapy. Moreover, the co-silencing of CD73 and HIF-1α can be assumed as a novel anti-cancer treatment strategy with high tumor suppression potential.

Tumor associated macrophages in the molecular pathogenesis of ovarian cancer.

The tumor microenvironment is a critical factor that enhances cancer progression, drug resistance, and failure of therapeutic approaches. Several cellular and non-cellular factors are involved in cancer promotion. Among the several cell populations in the tumor microenvironment, macrophages, as one of the most abundant innate immune cells within the tumor milieu, have attracted extensive attention among several researchers because of their critical role in innate pathophysiology of multiple disorders, as well as ovarian cancer. High plasticity and consequent high ability to adapt to environmental alternations by adjusting their cellular metabolism and immunological phenotype is the notable characteristic of macrophages. Therefore, the critical function of tumor-associated macrophages in ovarian cancer is highlighted in the growing body of recent studies. In this article, we will comprehensively focus on significant impacts of the macrophages on ovarian cancer progression, by discussing the role of macrophages as one of the fundamental immune cells present in tumor milieu, in metabolic reprogramming of transformed cells, and involvement of these cells in the ovarian cancer initiation, progression, invasion, and angiogenesis. Moreover, we will summarise recent studies evaluating the effects of targeting macrophages in ovarian cancer.

Silencing of p68 and STAT3 synergistically diminishes cancer progression.

AIMS: Since several factors are involved in the tumorigenesis process, targeting only one factor most probably cannot overwhelm cancer progression. Therefore, it seems that combination therapy through targeting more than one cancer-related factor may lead to cancer control. The expression and function of p68 (DDX5; DEAD-Box Helicase 5) are dysregulated in various cancers. P68 is also a co-activator of many oncogenic transcription factors such as the signal transducer and activator of transcription-3 (STAT3), which contributes to cancer progression. This close connection between p68 and STAT3 plays an important role in the growth and development of cancer. MATERIALS AND METHODS: We decided to suppress the p68/STAT3 axis in various cancer cells by using Polyethylene glycol-trimethyl Chitosan-Hyaluronic acid (PEG-TMC-HA) nanoparticles (NPs) loaded with siRNA molecules. We assessed the impact of this combination therapy on apoptosis, proliferation, angiogenesis, and tumor growth, both in vitro and in vivo. KEY FINDINGS: The results showed that siRNA-loaded NPs notably suppressed the expression of p68/STAT3 axis in cancer cells, which was associated with blockade of tumor growth, colony formation, angiogenesis, and cancer cell migration. In addition to apoptosis induction, this combined therapy also reduced the expression of several tumor-promoting factors including Fibroblast growth factors (FGF), vascular endothelial growth factor (VEGF), transforming growth factor-ß (TGF-ß), matrix metallopeptidases-2 (MMP-2), MMP-9, hypoxia-inducible factor-(HIF-1α), interleukin-6 (IL-6), IL-33, Bcl-x, vimentin, and snail. SIGNIFICANCE: These findings indicate the potential of this nano-based anti-cancer therapeutic strategy for efficient cancer therapy which should be further investigated in future studies.