Novel antiangiogenic therapy targeting biglycan using tumor endothelial cell-specific liposomal siRNA delivery system.

Tumor blood vessels play important roles in tumor progression and metastasis. Targeting tumor endothelial cells (TECs) is one of the strategies for cancer therapy. We previously reported that biglycan, a small leucine-rich proteoglycan, is highly expressed in TECs. TECs utilize biglycan in an autocrine manner for migration and angiogenesis. Furthermore, TEC-derived biglycan stimulates tumor cell migration in a paracrine manner leading to tumor cell intravasation and metastasis. In this study, we explored the therapeutic effect of biglycan inhibition in the TECs of renal cell carcinoma using an in vivo siRNA delivery system known as a multifunctional envelope-type nanodevice (MEND), which contains a unique pH-sensitive cationic lipid. To specifically deliver MEND into TECs, we incorporated cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) into MEND because αV ß3 integrin, a receptor for cRGD, is selective and highly expressed in TECs. We developed RGD-MEND-encapsulating siRNA against biglycan. First, we confirmed that MEND was delivered into OS-RC-2 tumor-derived TECs and induced in vitro RNAi-mediated gene silencing. MEND was then injected intravenously into OS-RC-2 tumor-bearing mice. Flow cytometry analysis demonstrated that MEND was specifically delivered into TECs. Quantitative RT-PCR indicated that biglycan was knocked down by biglycan siRNA-containing MEND. Finally, we analyzed the therapeutic effect of biglycan silencing by MEND in TECs. Tumor growth was inhibited by biglycan siRNA-containing MEND. Tumor microenvironmental factors such as fibrosis were also normalized using biglycan inhibition in TECs. Biglycan in TECs can be a novel target for cancer treatment.

Six-transmembrane epithelial antigen of the prostate 1 accelerates cell proliferation by targeting c-Myc in liver cancer cells.

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) has emerged as an ideal target in cancer therapeutics. However, the functions of STEAP1 in liver cancer remain unexplored. The current study aimed to characterize the biological roles of STEAP1 in liver cancer. STEAP1 expression was upregulated in tumor tissues, and high STEAP1 expression was associated with poor clinical outcomes in patients with liver cancer, according to several publicly available datasets. STEAP1 silencing using small interfering RNA inhibited cell proliferation and was accompanied by G1 arrest induced by the suppression of cyclin D1 and the promotion of p27. STEAP1 silencing suppressed c-Myc expression, which was identified as a component in STEAP1 signal transduction by mining publicly available datasets and was then confirmed by PCR array. In conclusion, the knockdown of STEAP1 in liver cancer cell lines led to inhibition of cell proliferation involving G1 arrest by suppressing c-Myc. The present study provides a preclinical concept for STEAP1 as a druggable target in liver cancer.

A role for IL-34 in osteolytic disease of multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell-derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell-derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients.

Interleukin-34, a comprehensive review.

IL-34 is a novel cytokine that was identified in 2008 in a comprehensive proteomic analysis as a tissue-specific ligand of CSF-1 receptor (CSF-1R). IL-34 exists in all vertebrates including fish, amphibians, birds, and mammals, showing high conservation among species. Structurally, IL-34 belongs to the short-chain helical hematopoietic cytokine family but shows no apparent consensus structural domains, motifs, or sequence homology with other cytokines. IL-34 is synthesized as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R and receptor-type protein-tyrosine phosphatase-zeta (PTP-ζ) in addition to the chondroitin sulfate chains of syndecan-1. These interactions result in activating several signaling pathways that regulate major cellular functions, including proliferation, differentiation, survival, metabolism, and cytokine/chemokine expression in addition to cellular adhesion and migration. In the steady state, IL-34 contributes to the development and maintenance of specific myeloid cell subsets in a tissue-specific manner: Langerhans cells in the skin and microglia in the brain. In pathological conditions, changes in IL-34 expression-increased or decreased-are involved in disease pathogenesis and correlate with progression, severity, and chronicity. One decade after its discovery, IL-34 has been introduced as a newcomer to the big family of interleukins with specific physiological functions, critical pathological roles, and promising clinical applications in disease diagnosis and treatment. In this review, we celebrate the 10th anniversary of IL-34 discovery, introducing its biological characteristics, and discussing the importance of IL-34 signaling network in health and disease.

Enhanced expression of IL-34 in an inflammatory cyst of the submandibular gland: a case report.

BACKGROUND: Cysts of the salivary glands are common lesions that occur in the context of various etiologies. Although the diagnostic importance of cysts in salivary gland diseases has been well studied, molecular mechanisms that control the related pathological process remain largely unknown. IL-34 is a novel cytokine that was discovered recently as a tissue-specific ligand of colony stimulating factor-1 receptor. Since its discovery, accumulating evidence has revealed emerging roles of IL-34 in various pathological conditions and has been suggested to correlate remarkably with inflammation. In this study, we report a medical case of an inflammatory cyst within the submandibular gland, through which evaluating the possible involvement of IL-34 in salivary gland disorders. CASE PRESENTATION: A 37-year-old male patient suffered from a sudden swelling in the right submandibular region, started initially small and had gradually increased in size to reach 3-4 cm in 1 week, accompanied by pain and local fever. Ultrasonography and MRI imaging revealed the existence of a well-defined cystic lesion with sharp borders measuring 39.8 mm × 19.7 mm within the right submandibular gland. The cyst was removed surgically, and the diagnostic decision was determined based on histopathological observations as an inflammatory cyst in the submandibular gland. Sections were generated from different regions of the surgically resected inflammatory cyst and used to examine IL-34 expression by immunohistochemistry compared to normal salivary gland tissues. Immunohistochemical staining showed enhanced expression of IL-34 in the ductal epithelial cells and endothelial cells of blood vessels, with a tendency to be accompanied with high infiltration of immune cells, which suggests a possible involvement of IL-34 in the pathogenesis of salivary gland inflammation. CONCLUSIONS: In this report, we introduce interesting findings of enhanced IL-34 expression in a case of an inflamed submandibular gland. Our findings emphasize the pathological roles of IL-34 as an inflammation amplifier and angiogenic enhancer in inflammatory conditions, such as in salivary gland disorders.