Editors' ChoiceCancer

It’s a FAKt: Kinase Mediates Metastasis

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Science Translational Medicine  23 Feb 2011:
Vol. 3, Issue 71, pp. 71ec23
DOI: 10.1126/scitranslmed.3002275

Just as plants need fertile soil to grow, so do tumors. During metastasis, cancer cells from the primary tumor site enter the bloodstream and deposit in remote locations, commonly the lung. It has been debated why and how these distant lung foci are chosen as planting sites for cancer cells, and many have speculated that the primary tumors themselves secrete various factors, such as proteins, to prepare the “soil” for seeding. Using mouse models and genetic approaches, Hiratsuka and colleagues provide evidence to support this long-standing hypothesis.

The authors first grew mammary or lung carcinoma tumors, with well-established metastatic potential, subcutaneously in C57BL/6 mice. After the tumors reached 6 mm in diameter, a blue dye was infused into the mice so as to mark the locations in the lung that housed leaky (hyperpermeable) blood vessels. The lungs showed discrete sites of blue-stained tissue, indicating focal hyperpermeability rather than a diffuse effect. By tracking the movement of fluorescently labeled metastatic cancer cells in the tumor-bearing mice, the authors confirmed that these cells preferentially lodged in lung regions of hyperpermeability. These results may come as no surprise, considering that leaky vasculature has larger gaps between endothelial cells, which can allow the passage of circulating tumor cells and the formation of metastases.

However, solution surrounding the primary tumors recorded higher concentrations of vascular endothelial growth factor (VEGF), a protein that instigates vascular permeability by activating the focal adhesion kinase (FAK). In the lung, Hiratsuka et al. found higher amounts of phosphorylated FAK as well as increased expression of the cell-adhesion molecule E-selectin in areas of hyperpermeability. Taken together, these findings suggest that VEGF secreted by metastatic tumor cells can activate FAK in lung endothelial cells, leading to hyperpermeability and increased cell adhesion via E-selectin. This homing process shows the interplay between the tumor cells (the “seeds”), which secrete a protein signal, and the lung endothelial cells, which respond by preparing the “soil” for tumor-cell arrival.

These mechanistic insights into cancer-cell homing should help to hone approaches for predicting or controlling metastasis to lung. Indeed, the authors preliminarily demonstrated that inhibiting the major players (VEGF, E-selectin, or FAK) reduces the formation of metastases—an encouraging step toward the future development of anti-metastatic therapeutics.

S. Hiratsuka et al., Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proc. Natl. Acad. Sci. U.S.A. 14 February 2011 (10.1073/pnas.1100446108). [Abstract]

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