It was developed by PDL (Incline Village, NV, USA) and subsequently licensed to Biogen-Idec, Ophthotech (New York, NY, USA) and Abbott (Abbott Park, IL, USA), but development was stopped after lack of efficacy in PH2 trials [103,104]. were disturbing. Indeed, in animal models, increased angiogenesis and vascular leakiness can enhance intratumoral delivery of conventional drugs, and improve treatment efficacy [28]. This apparently reverses the widely accepted clinical dogma, that inhibiting angiogenesis can enhance cancer therapy. The variable clinical efficacy with the efficacious anti-angiogenic drug bevacizumab highlights how context-specific anti-angiogenic cancer therapy may be [29,30]. Though VEGF can drive tumor angiogenesis in many preclinical models, in clinical practice other tumor angiogenic factors may be present, which make anti-VEGF therapy much less effective. In summary, despite initial promising pre-clinical data, targeting v3 has so far failed MGCD0103 (Mocetinostat) in the clinic, likely in part due to insufficient knowledge of its biology. Nevertheless, these data may yet enable novel strategies based on v3. Moreover, despite conflicting preclinical data, many studies still therapeutically target endothelial v3 (reviewed in [31]). In fact, so far few anti-integrin drugs designed to target epithelial or endothelial cells have significantly benefited patients, whereas several that target leukocytes or platelets have succeeded (examples are presented below, and reviewed in [2]). Whether this reflects a greater accessibility of blood-borne cells to intravenous therapies over cells of solid tissues remains to be determined. However, emerging data on integrins in the pathology of fibrosis and cancer suggests this balance may change. This is due MGCD0103 (Mocetinostat) to the unexpected and rapidly expanding picture we have about v-integrins in the localized activation of TGF- family cytokines. 1.2. TGF Activation and Integrins: An Emerging Strategy? TGFs are pleiotropic cytokines that are locally activated during tissue remodeling to conduct a concert of repair processes including trans-differentiating fibroblasts into a contractile, collagen-producing myofibroblast MGCD0103 (Mocetinostat) phenotype; promoting angiogenesis; and suppressing immune response [32,33,34]. TGF1 also suppresses normal epithelial cell proliferation during repair, and is thus considered a tumor suppressor [32,33,34]. However, excess TGF activity can result in life-threatening tissue fibrosis, and it has thus long been a GATA2 target for therapeutic intervention. Yet, some effective TGF signaling inhibitors, including ligand-traps MGCD0103 (Mocetinostat) and TGF receptor (TGFR) kinase inhibitors are toxic, and can even enhance development of skin cancer (reviewed in [34,35]). Although drugs directly targeting the TGF signaling pathways are in development [36], novel TGF- therapeutic strategies dependent on integrins are emerging. TGF is deposited by somatic and tumor cells in an inactive form, latent-TGF (LTGF). This is bound to the extracellular matrix (ECM) in a protein complex (reviewed in [37]). The initial LTGF protein complex is post-translationally processed so that TGF, bound to its protective pro-peptide, latency associated peptide (LAP), forms a homo-dimer. Several seminal papers have shown that v integrins, and particularly v6 and v8, can mechanochemically help activate LTGF1 + 3, initially through high-affinity recognition of an RGD amino-acid motif in the LAPs of TGF1 and TGF3 [38,39]. Antibody-blockade of v6 can suppress TGF-dependent bleomycin- [38] and radiation-induced lung fibrosis [40] and kidney fibrosis [41] in mouse models. This led Biogen-Idec to develop a humanized v6-inhibitory antibody, STX-100, as a treatment for Idiopathic Pulmonary Fibrosis (IPF) (ClinicalTrials.gov: “type”:”clinical-trial”,”attrs”:”text”:”NCT01371305″,”term_id”:”NCT01371305″NCT01371305). Recently, both v8-blocking antibodies [42], and v1-blocking small molecules have been shown preclinically in mice to suppress fibro-inflammatory lung [43, 44] and renal fibrosis [45], and the v1-inhibitor also inhibits carbon tetrachloride-induced liver fibrosis [43]. These studies showed that by inhibiting local- rather than systemic -activation of LTGF it was possible to combine efficacy with low off-target toxicity. Activated TGF is implicated in promoting late-stage cancer development and spread. Cancer cells MGCD0103 (Mocetinostat) often accumulate mutations or deletions in biochemical pathways that protect them from its growth inhibitory.