Editors' ChoiceCancer

Delivering a Mixed Message

Sci. Signal.  09 Jul 2013:
Vol. 6, Issue 283, pp. ec152
DOI: 10.1126/scisignal.2004488

In cancer, the focus in studying the interplay between the vasculature and the tumor has been on the tumor cell’s ability to stimulate neovascularization to provide the tumor with nutrients and oxygen. Ghajar et al. suggest that at secondary tumor sites, the vascular endothelial cells (ECs) signal to the tumor cells. Along stable microvessels, the ECs provided signals that maintain the tumor cells in a quiescent state, whereas ECs at sprouting tips of new vessels provided signals that stimulate tumor cell proliferation. Analysis of mouse models of metastasizing breast cancer showed that quiescent tumor cells (negative for Ki67) were present in contact with the microvascular endothelium of the lung and bone marrow, common sites of metastasis of breast cancer. In an engineered three-dimensional (3-D) microvascular culture system that recapitulated either bone marrow or lung stromal cells with HUVECs (human umbilical vein endothelial cells), breast cancer cells showed reduced proliferation when in contact with stable microvessels, compared with their proliferation when plated on cultures with increased sprouting vessels and microvascular tips or when in contact with the stromal cells. Proteomic analysis of decellularized extracellular matrix (ECM) derived from mature EC cultures with low numbers of microvascular tips or from cultures with a high number of sprouting tips revealed that the stable culture-derived ECM was enriched in thrombospondin-1 (TSP-1), an inhibitor of breast cancer cell metastasis, and that ECM from the sprouting cultures had higher amounts of periostin and reduced amounts of proteins that sequester transforming growth factor–β (TGF-β). Addition of TSP-1 to stromal cultures reduced breast cancer tumor cell area, and addition of an antibody to block the interaction between the cancer cells and the ECM of the ECs increased tumor cell area in the 3-D microvascular cultures. Addition of periostin and active TGF-β1 to breast cancer cells cultured on lunglike microvasculature resulted in increased tumor area. Thus, as tumor cells leave the primary site and migrate through the vasculature, their interaction with stable vessels with an ECM high in TSP-1 may trigger a quiescent state. Conditions that cause vessel sprouting trigger a change in the ECM that may lead to cancer relapse by providing growth-stimulating signals to the quiescent tumor cells in the area. Whether these events occur in vivo and whether they are associated with other types of tumors are questions posed in the commentary by Weis and Cheresh.

C. M. Ghajar, H. Peinado, H. Mori, I. R. Matei, K. J. Evason, H. Brazier, D. Almeida, A. Koller, K. A. Hajjar, D. Y. R. Stainier, E. I. Chen, D. Lyden, M. J. Bissell, The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013). [PubMed]

S. M. Weis, D. A. Cheresh, A wake-up call for hibernating tumour cells. Nat. Cell Biol. 15, 721–723 (2013). [PubMed]