Build them up, break them down

See allHide authors and affiliations

Sci. Signal.  19 Feb 2019:
Vol. 12, Issue 569, eaax0155
DOI: 10.1126/scisignal.aax0155

Cancer and stromal cells release signals that manipulate the vasculature to promote tumor metastasis or growth.

Cancer cells and cells in the tumor microenvironment release signals that manipulate the vasculature to promote tumor metastasis or growth. Metastasizing melanoma cells must escape from blood vessels to colonize other sites, and they do so with a form of movement called amoeboid-based migration, which requires the kinase ROCK and the cytoskeletal-remodeling factor myosin II. Georgouli et al. found that human melanoma samples were enriched in rounded cancer cells, phosphorylated MLC2 (an indicator of high myosin II activity), and infiltrating macrophages, and showed increased vessel density in close proximity to macrophages. Compared with poorly metastatic, more elongated A375P melanoma cells, highly metastatic, more rounded A375M2 melanoma cells had increased myosin II activity; secreted greater amounts of proinflammatory cytokines, such as IL-1α; and had increased activity of NF-κB. Protein secretion and the increased NF-κB activity in A375M2 cells depended on myosin II and/or secreted IL-1α. Tumors formed from A375M2 cells were larger than those formed by A375P cells, and had more rounded cells, greater macrophage infiltration, and increased phosphorylation of MLC2. Melanomas frequently metastasize to the lung, and the authors found that melanoma cells with knockdown of ROCK or NF-κB did not increase lung capillary permeability and that they colonized the lung to a lesser extent than did control cells. The authors propose using ROCK inhibitors or IL-1α–blocking antibodies to limit metastatic dissemination after the primary melanoma lesion has been removed.

The hypoxia that develops in solid tumors leads to the formation of a dysfunctional vasculature that enables cancer cell survival and prevents efficient chemotherapeutic penetration. Cancer-associated fibroblasts (CAFs) in the tumor stroma release important angiogenic signals. In a paper in the Science Signaling archives, Kugeratski et al. analyzed the proteome and secretome of CAFs and found that hypoxia altered the secretome of these cells. The authors identified a previously uncharacterized protein that they renamed HIAR. HIAR was increased in abundance in hypoxic CAFs, promoted the release of the pro-angiogenic factor VEGF from CAFs, and induced VEGF-dependent signaling in endothelial cells. These results provide an overview of the CAF secretome at the protein level and a new potential target for anti-angiogenic therapy.

Highlighted Articles

View Abstract

Navigate This Article