Editors' ChoiceCancer

Restricting Bone Metastasis

Sci. Signal.  26 Nov 2013:
Vol. 6, Issue 303, pp. ec287
DOI: 10.1126/scisignal.2004941

Just as no two types of soil are the same, the “seed and soil” theory of metastasis suggests that the different microenvironments of various organs can either inhibit or promote the growth of disseminated tumor cells (DTCs), explaining why cancers seem to have preferred metastatic sites. Bragado et al. used a mouse xenograft model to show that strong signaling by transforming growth factor–β2 (TGF-β2) in the bone marrow induced the dormancy of disseminated human squamous carcinoma cells, whereas weak TGF-β2 signaling in the lungs was permissive to metastatic growth. In situ confocal microscopic analysis of the dissemination of green fluorescent protein (GFP)–tagged HEp3 cells (a human squamous carcinoma cell line from primary tumors formed in mice) revealed that secondary tumors were localized primarily to the lungs (80%) rather than the bone marrow (28%) or liver and spleen (5%). Whereas the number of DTCs in the bone marrow remained constant for at least 4 weeks after surgical removal of the primary tumor and the bone marrow DTCs showed poor proliferation when transplanted into culture, the number of DTCs in the lungs increased substantially within 2 weeks and thrived in culture. In agreement with their respective proliferative capacity, HEp3 cell cultures derived from either the lung or the primary tumor had low abundance of the cyclin-dependent kinase inhibitor p27 and a high ratio of the mitogen-activated protein kinase (MAPK) extracellular signal–regulated kinases 1 and 2 (ERK1/2) to the MAPKs p38α and p38β (p38α/β) abundance. In contrast, bone marrow–derived HEp3 cells had high p27 abundance and a low ERK:p38α/β ratio. Bone marrow–derived DTCs also had increased expression of the tumor suppressor genes p53 and DEC2, as well as of TGF-β2, but not of TGF-β1 or TGF-β3. Knockdown of MAPK14 (encoding p38α), DEC2, p53, and TGFβR1 [encoding TGF-β receptor I (TGF-βRI)] in the HEp3 initially introduced in the mice resulted in increased DTCs in the bone marrow after the primary tumors were removed. Alternatively, systemic pharmacological inhibition of TGF-βRI, TGF-βRIII, or p38α/β in the mice after removal of the primary tumor increased DTCs in the bone marrow. HEp3 cells treated with either medium conditioned by isolated lung cell cultures and supplemented with TGF-β2 or medium conditioned by isolated bone marrow cells had decreased tumorigenicity when injected into mice. Depleting TGF-β2 from the bone marrow–conditioned medium prevented activation of p38 and inhibition of HEp3 tumorigenicity in mice. In contrast, treating bone marrow–derived DTCs with TGF-β1 before injection into the mice increased their tumorigenicity. The findings suggest that TGF-β2 secreted from the bone marrow functioned as a dormancy signal for squamous carcinoma cells.

P. Bragado, Y. Estrada, F. Parikh, S. Krause, C. Capobianco, H. G. Farina, D. M. Schewe, J. A. Aguirre-Ghiso, TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling. Nat. Cell Biol. 15, 1351–1361 (2013). [PubMed]