Spotlight

Abstract

Jiang et al., pp. 505–512 Each year, about 30,000 Americans are diagnosed with oral squamous cell carcinoma. In roughly 40%, the disease starts on the floor of the mouth or on the lateral and ventral surfaces of the tongue. This subtype is significantly more aggressive than tumors at other intraoral locations; tongue cancer spreads rapidly, is highly invasive and often recurs after treatment. Jiang and colleagues recently identified microRNA-138 (miR-138) as a novel regulator of metastatic growth in tongue cancer cells. Significantly lower levels of miR-138 were observed in the highly invasive UM1 cell line than in the less invasive sister cell line UM2 established from the same patient. In this study, the authors pinpoint the molecular targets of miR-138. They uncovered a total of 86 potential cellular targets of miR-138 using bioinformatics prediction programs. Three of the candidates were associated with the family of Rho GTPases, well-known regulators of cell shape, polarity and locomotion. From the 3 hits, RhoC, one of three human Rho-GTPases, and ROCK2, a Rho-associated kinase, were confirmed as bona fide miR-138 targets using standard reporter assays and microRNA inhibitors. Consistent with a role of miR-138 in intracellular actin dynamics, different patterns of stress fiber formation were observed in the UM1 versus UM2 cell lines when expression levels of miR-138 were modified. These findings support a model in which miR-138 functions as a novel multifunctional regulator of cancer cell invasion and as a potential new target for therapeutic intervention in tongue cancer patients. Hombach-Klonisch et al., pp. 521–531 Insulin-like peptide 3 (INSL3) is produced mainly in gonadal tissues and is known for its role in intraabdominal testicular descent in boys. Ectopic expression of INSL3 was found in several tumors but the functional relevance of this expression is largely unknown. Hombach-Klonisch and colleagues reported recently that INSL3 is expressed in hyperplastic thyroid adenoma and thyroid cancer cells but that it is strikingly absent in the normal thyroid gland. In this issue of IJC, the authors identify the molecular program associated with INSL3 action in thyroid cancer cells, a program leading to enhanced tumor invasion and neovascularization. Transcripts for RXFP2, the receptor of INSL3, were detected in tissue samples from thyroid cancer patients, supporting the model that the INSL3/RXFP2 axis is functional in these tissues. Interestingly, RXFP2 gene expression was also detected in normal thyroid tissue, mainly in follicular epithelial cells, where INSL3 is absent. Thyroid cancer cells expressing INSL3 produced increased amounts of the multifactorial Ca2+-binding protein S100A4 known to increase motility and metastasis of cancer cells. Recombinant S100A4 in nanomolar concentrations promoted the formation of microvessel tubes by human umbilical vein endothelial cells similar to vascular endothelial growth factor (VEGF). The authors conclude that in the cancerous thyroid gland, INSL3 adopts the role of an autocrine/paracrine growth factor with potent tissue remodeling and angiogenic properties. Saarinen et al., pp. 737–745 Soy protein, known for its high level of dietary phytoestrogens, may not be the best choice for women who are worried about breast cancer. A new study by Saarinen and colleagues reports that the main phytoestrogenic ingredient in soy protein, genistein, lacks protective properties against breast cancer. Because of structural similarities with 17-β-estradiol, phytoestrogens can either mildly mimic or antagonize the hormone's effects on breast cancer development. In contrast to genistein, the authors find that enterolactone, the main metabolite of plant lignans and the main source of phytoestradiol in the Western diet has beneficial effects and inhibits estrogen-induced growth and angiogenesis in a murine model of human breast cancer. The main sources of dietary enterolactone include flaxseeds, cereals, vegetables and berries. Because of molecular similarities with 17- β-estradiol, phytoestrogens can either mildly mimic or antagonize the hormone's effects on breast cancer development. In estrogen-exposed mice transplanted with the estrogen receptor-positive MCF-7 breast cancer cell line, enterolactone ingestion decreased the release of VEGF derived from the human cancer cells and the murine stroma, resulting in reduced microvessel density of the tumors. In addition, estradiol-induced endothelial cell infiltration was inhibited in mice fed enterolactone but not in those on a genistein-based diet. The combination of enterolactone and genistein had the same beneficial effects as enterlactone alone added to the food.