An Interleukin-17-Mediated Paracrine Network Promotes Tumor Resistance to Anti-Angiogenic Therapy

“Although angiogenesis inhibitors have provided substantial clinical benefit as cancer therapeutics, their use is limited by resistance to their therapeutic effects. While ample evidence indicates that such resistance can be influenced by the tumor microenvironment, the underlying mechanisms remain incompletely understood. Here, we have uncovered a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance in multiple tumor models: lymphoma, lung and colon. Tumor-infiltrating T helper type 17 (TH17) cells and interleukin-17 (IL-17) induced the expression of granulocyte colony-stimulating factor (G-CSF) through nuclear factor κB (NF-κB) and extracellular-related kinase (ERK) signaling, leading to immature myeloid-cell mobilization and recruitment into the tumor microenvironment. The occurrence of TH17 cells and Bv8-positive granulocytes was also observed in clinical tumor specimens. Tumors resistant to treatment with antibodies to VEGF were rendered sensitive in IL-17 receptor (IL-17R)-knockout hosts deficient in TH17 effector function. Furthermore, pharmacological blockade of TH17 cell function sensitized resistant tumors to therapy with antibodies to VEGF. These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy.”


An Interleukin-17-Mediated Paracrine Network Promotes Tumor Resistance to Anti-Angiogenic Therapy

“Although angiogenesis inhibitors have provided substantial clinical benefit as cancer therapeutics, their use is limited by resistance to their therapeutic effects. While ample evidence indicates that such resistance can be influenced by the tumor microenvironment, the underlying mechanisms remain incompletely understood. Here, we have uncovered a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance in multiple tumor models: lymphoma, lung and colon. Tumor-infiltrating T helper type 17 (TH17) cells and interleukin-17 (IL-17) induced the expression of granulocyte colony-stimulating factor (G-CSF) through nuclear factor κB (NF-κB) and extracellular-related kinase (ERK) signaling, leading to immature myeloid-cell mobilization and recruitment into the tumor microenvironment. The occurrence of TH17 cells and Bv8-positive granulocytes was also observed in clinical tumor specimens. Tumors resistant to treatment with antibodies to VEGF were rendered sensitive in IL-17 receptor (IL-17R)-knockout hosts deficient in TH17 effector function. Furthermore, pharmacological blockade of TH17 cell function sensitized resistant tumors to therapy with antibodies to VEGF. These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy.”


An Interleukin-17-Mediated Paracrine Network Promotes Tumor Resistance to Anti-Angiogenic Therapy

“Although angiogenesis inhibitors have provided substantial clinical benefit as cancer therapeutics, their use is limited by resistance to their therapeutic effects. While ample evidence indicates that such resistance can be influenced by the tumor microenvironment, the underlying mechanisms remain incompletely understood. Here, we have uncovered a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance in multiple tumor models: lymphoma, lung and colon. Tumor-infiltrating T helper type 17 (TH17) cells and interleukin-17 (IL-17) induced the expression of granulocyte colony-stimulating factor (G-CSF) through nuclear factor κB (NF-κB) and extracellular-related kinase (ERK) signaling, leading to immature myeloid-cell mobilization and recruitment into the tumor microenvironment. The occurrence of TH17 cells and Bv8-positive granulocytes was also observed in clinical tumor specimens. Tumors resistant to treatment with antibodies to VEGF were rendered sensitive in IL-17 receptor (IL-17R)-knockout hosts deficient in TH17 effector function. Furthermore, pharmacological blockade of TH17 cell function sensitized resistant tumors to therapy with antibodies to VEGF. These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy.”


The Calcineurin-NFAT-Angiopoietin-2 Signaling Axis in Lung Endothelium Is Critical for the Establishment of Lung Metastases

“The premetastatic niche is a predetermined site of metastases, awaiting the influx of tumor cells. However, the regulation of the angiogenic switch at these sites has not been examined. Here, we demonstrate that the calcineurin and nuclear factor of activated T cells (NFAT) pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. Upregulation of the calcineurin pathway via deletion of its endogenous inhibitor Dscr1 leads to a significant increase in lung metastases due to increased expression of a newly identified NFAT target, Angiopoietin-2 (ANG2). Increased VEGF levels specifically in the lung, and not other organ microenvironments, trigger a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR1 or the ANG2 receptor, soluble TIE2, prevents the activation of lung endothelium, inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the premetastatic niche and offer targets for lung metastases.”


New Molecular Target May Lead to Cancer Drugs that Suffocate Tumors

Researchers have identified a compound that may cut off tumors’ oxygen supply. Because they grow so rapidly, tumors eventually outgrow the ability of the surrounding blood vessels to transport enough oxygen and nutrients to them. In response to low oxygen levels, tumors trigger the formation of new blood vessels to keep them supplied. Now, scientists have discovered a protein, HIF-1, that acts as a ‘master switch’ that turns on hundreds of other genes involved in forming these new blood vessels. They then identified a new compound called cyclo-CLLFVY that blocked HIF-1 in cultured cancer cells. Researchers now hope to develop cyclo-CLLFVY into a drug that can prevent tumors from getting the oxygen they need to survive.


New Molecular Target May Lead to Cancer Drugs that Suffocate Tumors

Researchers have identified a compound that may cut off tumors’ oxygen supply. Because they grow so rapidly, tumors eventually outgrow the ability of the surrounding blood vessels to transport enough oxygen and nutrients to them. In response to low oxygen levels, tumors trigger the formation of new blood vessels to keep them supplied. Now, scientists have discovered a protein, HIF-1, that acts as a ‘master switch’ that turns on hundreds of other genes involved in forming these new blood vessels. They then identified a new compound called cyclo-CLLFVY that blocked HIF-1 in cultured cancer cells. Researchers now hope to develop cyclo-CLLFVY into a drug that can prevent tumors from getting the oxygen they need to survive.


New Molecular Target May Lead to Cancer Drugs that Suffocate Tumors

Researchers have identified a compound that may cut off tumors’ oxygen supply. Because they grow so rapidly, tumors eventually outgrow the ability of the surrounding blood vessels to transport enough oxygen and nutrients to them. In response to low oxygen levels, tumors trigger the formation of new blood vessels to keep them supplied. Now, scientists have discovered a protein, HIF-1, that acts as a ‘master switch’ that turns on hundreds of other genes involved in forming these new blood vessels. They then identified a new compound called cyclo-CLLFVY that blocked HIF-1 in cultured cancer cells. Researchers now hope to develop cyclo-CLLFVY into a drug that can prevent tumors from getting the oxygen they need to survive.


Aflibercept: Another Targeted Drug Fails in Prostate Cancer

“The addition of the targeted angiogenesis inhibitor aflibercept (Zaltrap, Regeneron/Sanofi) to chemotherapy did not prolong overall survival in men with metastatic castration-resistant prostate cancer (CRPC),” according to the phase III VENICE trial. The results, published in the July issue of Lancet Oncology, are not that surprising. There have been at least seven large, phase III trials in which a targeted agent was added to chemotherapy with docetaxel in CRPC. All have been unsuccessful. “Despite a substantial expenditure in terms of patients’ time and financial resources, none of these trials have shown an improvement in survival beyond that achieved with docetaxel alone,” write Michael Galsky, MD, and William Oh, MD, from the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, in an accompanying comment.”


LRG1 Promotes Angiogenesis by Modulating Endothelial TGF-β Signalling

“Aberrant neovascularization contributes to diseases such as cancer, blindness and atherosclerosis, and is the consequence of inappropriate angiogenic signalling. Although many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explore the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology, and uncover an upregulated gene, leucine-rich alpha-2-glycoprotein 1 (Lrg1), of previously unknown function. We show that in the presence of transforming growth factor-β1 (TGF-β1), LRG1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 develop a mild retinal vascular phenotype but exhibit a significant reduction in pathological ocular angiogenesis. LRG1 binds directly to the TGF-β accessory receptor endoglin, which, in the presence of TGF-β1, results in promotion of the pro-angiogenic Smad1/5/8 signalling pathway. LRG1 antibody blockade inhibits this switch and attenuates angiogenesis. These studies reveal a new regulator of angiogenesis that mediates its effect by modulating TGF-β signalling.”