Integrin β1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs
Shibue T et al. - In a study to assess whether intravenously injected, nonmetastatic cancer cells cease proliferating after extravasating into the parenchyma of the lungs, these results demonstrate the critical role of integrin β1-focal adhesion kinase (FAK) signaling axis in controlling the initial proliferation of micrometastatic cancer cells disseminated in the lungs. Methods- Development of metastases is an extended and inefficient process involving multiple steps.
- The last step involves growth of micrometastases into macroscopic tumors.
- This study tests whether intravenously injected, nonmetastatic cancer cells cease proliferating after extravasating into the parenchyma of the lungs.
Results- This response is attributable to the cells' inability to trigger adhesion-related signaling events when they are scattered sparsely within the extracellular matrix (ECM) of the parenchyma.
- This situation is recapitulated by culturing these nonmetastatic cells at low seeding density in ECM-derived gels in vitro, in which they undergo cell-cycle arrest resulting, in part, from insufficient activation of FAK.
- Metastatic cancer cells show sufficient FAK activation to enable their proliferation within ECM gels in vitro and continue cell-cycle progression within the lung parenchyma in vivo.
- Activation of FAK in these metastatic cells depends on expression of the β1 subunit of integrins, and proliferation of these cells after extravasation in the lungs is diminished by knocking down expression of either FAK or integrin β1.
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