No abstract

We demonstrated previously that a single injection of recombinant human macrophage colony-stimulating factor (rhM-CSF) is sufficient for osteoclast recruitment and survival in osteopetrotic (op/op) mice with a deficiency in osteoclasts resulting from a mutation in M-CSF gene. In this study, we show that a single injection of recombinant human vascular endothelial growth factor (rhVEGF) can similarly induce osteoclast recruitment in op/op mice. Osteoclasts predominantly expressed VEGF receptor 1 (VEGFR-1), and activity of recombinant human placenta growth factor 1 on osteoclast recruitment was comparable to that of rhVEGF, showing that the VEGF signal is mediated through VEGFR-1. The rhM-CSF–induced osteoclasts died after injections of VEGFR-1/Fc chimeric protein, and its effect was abrogated by concomitant injections of rhM-CSF. Osteoclasts supported by rhM-CSF or endogenous VEGF showed no significant difference in the bone-resorbing activity. op/op mice undergo an age-related resolution of osteopetrosis accompanied by an increase in osteoclast number. Most of the osteoclasts disappeared after injections of anti-VEGF antibody, demonstrating that endogenously produced VEGF is responsible for the appearance of osteoclasts in the mutant mice. In addition, rhVEGF replaced rhM-CSF in the support of in vitro osteoclast differentiation. These results demonstrate that M-CSF and VEGF have overlapping functions in the support of osteoclastic bone resorption.

MicroRNA (miRNA), which are stably present in serum, have been reported to be potentially useful for detecting cancer. In the present study, we examined the expression profiles of serum miRNA in several large cohorts to identify novel miRNA that can be used to detect early stage breast cancer. We comprehensively evaluated the serum miRNA expression profiles using highly sensitive microarray analysis. A total of 1280 serum samples of breast cancer patients stored in the National Cancer Center Biobank were used. In addition, 2836 serum samples were obtained from non‐cancer controls, 451 from patients with other types of cancers, and 63 from patients with non‐breast benign diseases. The samples were divided into a training cohort including non‐cancer controls, other cancers and breast cancer, and a test cohort including non‐cancer controls and breast cancer. The training cohort was used to identify a combination of miRNA that could detect breast cancer, and the test cohort was used to validate that combination. miRNA expressions were compared between patients with breast cancer and non‐breast cancer, and a combination of five miRNA (miR‐1246, miR‐1307‐3p, miR‐4634, miR‐6861‐5p and miR‐6875‐5p) was found to be able to detect breast cancer. This combination had a sensitivity of 97.3%, specificity of 82.9% and accuracy of 89.7% for breast cancer in the test cohort. In addition, this combination could detect early stage breast cancer (sensitivity of 98.0% for Tis).

A major obstacle to improving prognoses in ovarian cancer is the lack of effective screening methods for early detection. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers that could lead to clinical applications. Here, to develop an optimal detection method, we use microarrays to obtain comprehensive miRNA profiles from 4046 serum samples, including 428 patients with ovarian tumors. A diagnostic model based on expression levels of ten miRNAs is constructed in the discovery set. Validation in an independent cohort reveals that the model is very accurate (sensitivity, 0.99; specificity, 1.00), and the diagnostic accuracy is maintained even in early-stage ovarian cancers. Furthermore, we construct two additional models, each using 9–10 serum miRNAs, aimed at discriminating ovarian cancers from the other types of solid tumors or benign ovarian tumors. Our findings provide robust evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer.

Bladder cancer is the 9th leading cause of cancer death worldwide. The major problem in bladder cancer is primarily the high recurrence rate after drug treatment and resection. Although conventional screening methods, such as cystoscopy, urinary cytology and ultrasound sonography, have become widely used in clinical settings, the diagnostic performance of these modalities is unsatisfactory due to low accuracy or high invasiveness. Because circulating micro RNA (miRNA) profiles have recently been reported as an attractive tool for liquid biopsy in cancer screening, here, we performed global miRNA profiling of 392 serum samples of bladder cancer patients with 100 non‐cancer samples and 480 samples of other types of cancer as controls. We randomly classified the bladder cancer and control samples into 2 cohorts, a training set (N = 486) and a validation set (N = 486). By comparing both controls, we identified specific miRNA, such as miR‐6087, for diagnosing bladder cancer in the training and validation sets. Furthermore, we found that a combination of 7 miRNA (7‐miRNA panel: miR‐6087, miR‐6724‐5p, miR‐3960, miR‐1343‐5p, miR‐1185‐1‐3p, miR‐6831‐5p and miR‐4695‐5p) could discriminate bladder cancer from non‐cancer and other types of tumors with the highest accuracy (AUC: .97; sensitivity: 95%; specificity: 87%). The diagnostic accuracy was high, regardless of the stage and grade of bladder cancer. Our data demonstrated that the 7‐miRNA panel could be a biomarker for the specific and early detection of bladder cancer.