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Suppression of endothelial cell αVβ3 activity by TNF and IFN-γ disrupts angiogenesis and promotes the demise of malignant melanoma (pages 408–414).

Neuropilin-1 (Nrp1) on regulatory T (T_reg) cells is shown to interact with semaphorin-4a (Sema4a) to promote a program of T_reg-cell stability and survival, in part through PTEN-mediated modulation of Akt signalling; Nrp1-deficient T_reg cells can maintain immune homeostasis but fail to suppress in inflammatory sites, such as tumours, providing an attractive immunotherapeutic target for the treatment of cancers.

Carlson et al. show that DTCs within the PVN are protected from chemotherapy; targeting interactions between DTCs and the PVN enhances chemosensitivity and prevents bone metastasis.

Cheresh and colleagues delineate a pathway that regulates tumour cell stemness and resistance to therapy. They find that the unliganded integrin α_vβ₃ is able to promote cancer cell self-renewal, tumour initiation and resistance to EGFR inhibitors by binding KRAS and RalB to activate the NF-κB pathway.

The tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here the authors show that radiation induced miR-103 downregulates TREX1 in endothelial cells, decreases angiogenesis and leads to the secretion of proinflammatory mediators that reduce tumour growth.

Raf kinase activity is deregulated in cancers and is thought to promote tumor growth by inducing proliferation signaling through MEK/Erk. This report identifies a new role for c-Raf independent of MEK/Erk and relying on phosphorylation of Ser338. Phospho–C-Raf interacts with the mitotic kinases Aurora-A and Plk1, activating the latter to promote mitotic progression and increase cell division, and this pathway is a crucial mediator for the protumorigenic effect of c-Raf in vivo.

VEGF is an important angiogenic factor that has been implicated in tumourigenesis. Two papers now show that the function of VEGF is far more complex, as VEGF can negatively regulate angiogenesis and limit tumourigenesis. In the second paper, VEGF production was deleted in myeloid cells, but not other cell types. Unexpectedly, more rapid tumour development in these mice was found at the same time as attenuated tumour vascularization and the formation of morphologically and functionally normalized blood vessels. In contrast, tumours lacking VEGF altogether grew more slowly.

A previously unknown signalling pathway is shown to enhance the formation of metastases in a mouse model of prostate cancer. This pathway can be activated by RANK ligand that is expressed by inflammatory cells in the tumour and triggers activation of IKKα in the nucleus, where it directly represses the transcription of maspin, a known metastases suppressor.

Robo4 expression in emerging blood vessels can neutralize signaling through the angiogenic factor vascular endothelial growth factor (VEGF) and maintain vessel integrity. The findings could lead to new therapeutic targets for angiogenesis and vascular leakage (pages 448–453).

Wu et al. identify a mechanistic role for LPAR4 in promoting a fibronectin-rich extracellular matrix via AKT, CREB and integrins, thereby generating a niche that facilitates initiation of pancreatic cancer.

Tumors hijack cellular pathways to evade the effects of cancer therapy. Here, Advaniet al. show that DNA damage-induced phosphorylation of CRAF Serine 338 triggers DNA repair by recruiting CHK2, highlighting a role for CRAF independent from its canonical function as a kinase.

Disseminated tumour cells (DTCs) can adopt a state of long-term dormancy. However, when and why they emerge from quiescence has remained unclear. Distinct microvascular niches are now shown to regulate this process. Mature blood vessels produce signals that sustain tumour cell quiescence, whereas sprouting microvasculature provides stimuli that reactivate DTCs, leading to metastatic relapse.

The mechanism of NLRP3 activation remains incompletely characterized. Here the authors show that it is dependent on vimentin, and that NLRP3-mediated lung injury and fibrosis induced by endotoxin, asbestos or bleomycin are reduced in vimentin-deficient mice.

The integrins regulate a diverse array of cellular functions that are crucial to the initiation, progression and metastasis of solid tumours. This Review discusses the exciting developments in targeting integrins, including the recent initiation of a Phase III trial for an integrin antagonist in patients with glioblastoma.

Loss of integrin-mediated attachment to the extracellular matrix triggers apoptosis through the activation of caspases. A recent study shows that disruption of integrin function also induces mitochondrial release of Bit1, a caspase-independent effector of apoptosis.

Individuals with Chuvash polycythemia have an increased red blood cell count and are prone to developing blood clots. Although mutations affecting the VHL protein are known to be causative, the underlying molecular mechanisms have been unclear. Ryan C Russell et al. now show that VHL targets the key signaling molecule JAK2 for degradation by forming a complex with the SOCS1 protein. The authors also show that JAK2 inhibition has beneficial effects in a mouse model of this disease, pointing to a new therapeutic strategy.

Recruitment of myeloid cells can be regulated by integrin CD11b. Here the authors show that in the tumor microenvironment, CD11b is not essential for recruitment of myeloid cells but rather induces macrophage anti-tumorigenic polarization via stimulating let7a and NFκB signaling and that pharmacological activation of CD11b enhances survival in mouse models of cancer.

VEGF is an important angiogenic factor that has been implicated in tumourigenesis. Two papers now show that the function of VEGF is far more complex, as VEGF can negatively regulate angiogenesis and limit tumourigenesis. This study found that VEGF can inhibit angiogenesis by impeding the function of the PDGF receptor on pericytes, leading to a loss of pericyte coverage of blood vessels. This involves the formation of heterodimers between the receptors for VEGF and PDGF.

Sudarshan Anand et al. show that endothelial cell expression of the microRNA miR-132 targets a negative regulator of Ras pathway signaling and thereby releases a brake to new blood vessel formation. miR-132 expression is upregulated in the endothelium of human hemangioma and tumor samples, and an antagonist of miR-132, delivered specifically to tumor endothelium using an integrin-targeted nanoparticle, was able to inhibit tumor angiogenesis and growth in mice.

Human herpesvirus 8 (HHV-8), an agent associated with Kaposi's sarcoma, binds to integrin α₃β₁ through its gB envelope glycoprotein, and thus gains entry into human fibroblasts. Based on an analogy with other microbial pathogens, integrin interaction with HHV-8 may induce signalling events that promote cell entry and perhaps facilitate disease progression.