Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies.

Uterine fibroids (UFs) are benign tumors that arise from a single genetically altered mesenchymal stem cell under the influence of gonadal hormones. UFs are the most common benign gynecologic tumors in premenopausal women worldwide. It is estimated that nearly 70% to 80% of women will develop UFs at some point during their lifetime. UFs often present with abnormal uterine bleeding (AUB), pelvic fullness, and may have deleterious effects on fertility. The natural regression of UFs begins in menopause. This is, however, a generality as this pathology may still be present in this age group. Many clinicians are concerned about hormone therapy (HT) because of UFs regrowth; nevertheless, research of this subject remains inconclusive. If UFs are present in perimenopause or menopause, they typically manifest as AUB, which represents up to 70% of all gynecological consultations in perimenopausal and postmenopausal women. As AUB is a broad symptom and may not be specific to UFs, a thorough evaluation is required for correct diagnosis and proper treatment accordingly. Understanding the unique characteristics of the available treatment modalities is crucial in deciding the appropriate treatment approach. Decision on treatment modality should be made based on selection of the least morbidity and lowest risk for each patient. Multiple modalities are available; however, surgery remains the method of choice, with the best cure rates. Various attempts to create an inexpensive, safe, and effective drug for the treatments of UFs are still in the early stages of the clinical trials with some showing great promise. Treatment options include tibolone, aromatase inhibitors, selective estrogen receptor modulators, uterine artery embolization, and selective progesterone receptor modulators. Video Summary: http://links.lww.com/MENO/A493.

Secreted protein, acidic and rich in cysteine (SPARC), is a multifunctional matricellular glycoprotein. In vitro, SPARC has antiangiogenic properties, including the ability to inhibit the proliferation and migration of endothelial cells stimulated by bFGF and VEGF. Previously, we demonstrated that platelet‐derived SPARC also inhibits angiogenesis and impairs the growth of neuroblastoma tumors in vivo. In the present study, we produced rhSPARC in the transformed human embryonic kidney cell line 293 and show that the recombinant molecule retains its ability to inhibit angiogenesis. Although 293 cell proliferation was not affected by exogenous expression of SPARC in vitro, growth of tumors formed by SPARC‐transfected 293 cells was significantly impaired compared to tumors comprised of wild‐type cells or 293 cells transfected with a control vector. Consistent with its function as an angiogenesis inhibitor, significantly fewer blood vessels were seen in SPARC‐transfected 293 tumors compared to controls, and these tumors contained increased numbers of apoptotic cells. Light microscopy revealed small nests of tumor cells surrounded by abundant stromal tissue in xenografts with SPARC expression, whereas control tumors were comprised largely of neoplastic cells with scant stroma. Mature, covalently cross‐linked collagen was detected in SPARC‐transfected 293 xenografts but not in control tumors. Our studies suggest that SPARC may regulate tumor growth by inhibiting angiogenesis, inducing tumor cell apoptosis and mediating changes in the deposition and organization of the tumor microenvironment.

Purpose: Epigenetic aberrations have been shown to play an important role in the pathogenesis of most cancers. To investigate the clinical significance of epigenetic changes in neuroblastoma, we evaluated the relationship between clinicopathologic variables and the pattern of gene methylation in neuroblastoma cell lines and tumors. Experimental Design: Methylation-specific PCR was used to evaluate the gene methylation status of 19 genes in 14 neuroblastoma cell lines and 8 genes in 70 primary neuroblastoma tumors. Associations between gene methylation, established prognostic factors, and outcome were evaluated. Log-rank tests were used to identify the number of methylated genes that was most predictive of overall survival. Results: Epigenetic changes were detected in the neuroblastoma cell lines and primary tumors, although the pattern of methylation varied. Eight of the 19 genes analyzed were methylated in >70% of the cell lines. Epigenetic changes of four genes were detected in only small numbers of cell lines. None of the cell lines had methylation of the other seven genes analyzed. In primary neuroblastoma tumors, high-risk disease and poor outcome were associated with methylation of DCR2, CASP8, and HIN-1 individually. Although methylation of the other five individual genes was not predictive of poor outcome, a trend toward decreased survival was seen in patients with a methylation phenotype, defined as ≥4 methylated genes (P = 0.055). Conclusion: Our study indicates that clinically aggressive neuroblastoma tumors have aberrant methylation of multiple genes and provides a rationale for exploring treatment strategies that include demethylating agents.