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TARP WORKSHOPS

Trans-Institute Angiogenesis Research Program (TARP) Workshop, November 18–20, 2007

Inflammation and Perivascular Environment

Meeting Agenda

Summary

The second workshop of the Trans-Institute Angiogenesis Research Program (TARP) took place on November 18–20, 2007 in Bethesda, Maryland, and focused on the perivascular environment and the roles of cellular and extracellular components across diseases. The participants discussed strategies for research and translation across disciplines.

Representatives from five NIH institutes taking part in the TARP program addressed the gathering, stressing the broad importance of angiogenesis, which plays roles in (as examples) tumor growth, diabetes, brain neoblastomas, stroke, placenta development, pre-eclampsia/eclampsia, age-related eye diseases, and wound healing.

Plenary lectures set the tone. Martin Friedlander, M.D., Ph.D., of The Scripps Research Institute, recognized the retina as an opportunity to study neovasculaturization and angiogenesis. Anti-VEGF therapies have a limited benefit in controlling vascularization. Combination therapies that preserve older vessels while inhibiting new growth are showing promise in mouse studies. Also promising in the establishment of angiostasis is the use of myeloid progenitor cells taken from bone marrow.

Judah Folkman, M.D., of Children’s Hospital Boston and Harvard Medical School, focused on efforts to improve anti-angiogenesis drugs in cancer therapy. Each of the many therapies that target the vascular endothelial growth factor (VEGF) targets an individual protein, yet tumors can produce 6 or more pro-angiogenic proteins and evade the drug therapy. One area of study is the use of “direct” angiogenesis inhibitors that target the proliferating endothelium. Other anti-angiogenesis research includes elimination of the PPARa gene to stop tumor spreading, enhancement of p53 to downregulate pro-angiogenic proteins, and the search for a broad blocking mechanism as seen in persons with Down’s Syndrome.

Cell-cell interactions reveal relationships among inflammation, angiogenesis, and tumor growth. For example, inflammation leads to the circulation of some progenitor cells. In the case of gastric cancer, the cancer is a final stage in a chronic infection-based series of cell events including atrophy, metaplasia, and dysplasia.

The process of angiogenesis is complex, with many molecules other than VEGF playing roles. For example, CXCR4 plays a role in patterning during revascularization (as such it could be another therapy target). The molecule SDF-1 appears to mobilize both VEGF and CXCR4.

Studies of tight-junction complexes, involving a host of molecules in the retina, indicate processes for growth and control. For example, as vessels grow, junction proteins are turned on. The protein occludin plays a key role in permeability.

Oxygen tension plays important roles in response to injury and vasculogenesis. Decreased oxygen tension might signal the path for cell movement. CXCR4 and SDF-1 are upregulated during hypoxia. Studies in this area may shed light on the way that diabetes impairs angiogenesis.

In discussion, the workshop participants focused on difficulties in naming cell qualities (pluripotency, plasticity, trans-differentiation), measuring and marking cell types, and establishing functional definitions. Researchers do not know why bone marrow cells travel to an ischemic area.

Cell-matrix interactions are bidirectional. Studies of brain models suggest that inflammation and vascular leakage precede angiogenesis. Dexamethasone can inhibit both processes. The context of the tissue is important, however. Research in this area is needed.

In the body in general, losses in the complex endothelial layer and system occur when there is injury. Inflammation is part of a process to restore equilibrium. This involves, for example, a decreased expression of eNOS (for unknown reasons). The A20 gene appears to play an important role in restoring equilibrium. Some research suggests that defects in the A20 gene (through aging, genetics, metabolic disease) may lead to undesirable angiogenesis.

The transition of cancer from an in situ state to clinical disease requires a series of steps, including engagement of the immune system and angiogenesis. For angiogenesis to proceed, at some point activators must supersede inhibitors. One key inhibitor is endostatin. For many people, inhibitors, or defenses, are maintained, and cancer progression does not occur.

In discussion, the workshop participants wondered whether researchers should focus on elements of the micro-environment rather than on the cancer. Perhaps they also should focus more on shoring up the immune system. However, the environment is complex, and tumor defects differ. Perhaps there should be a focus on homeostatic process that are lost.

Signaling (systemic responses or local paracrine factors) can be studied in the syndrome of preeclampsia, which affects 3-to-8 percent of all pregnancies over 20 weeks. Preeclampsia is a failure in vascular remodeling, with local hypoxia. The clinical syndrome follows the placental release of excessive quantities of the anti-angiogenic proteins, sFlt-1 and soluble endoglin. These proteins appear to be upregulated by hypoxia and possibly by abnormal heme catabolism.

Some researchers are attempting to prevent retinopathy in premature newborns by, in effect, establishing the environment of the third trimester. This involves stimulation and regulation of neovascularization and hypoxia. A lack of VEGF at one point leads to a reduced retinal thickness. Polyunsaturated fats that ordinarily are transferred to the baby near the end of pregnancy are missed by premature newborns. They may play a role in normal neovascularization and retinal development.

Wound healing involves a sequence of stages and variety of growth factors, with angiogenesis being both stimulated and inhibited. Chronic wounds may feature greater inhibition. Researchers are studying binding proteins and granulation in tissues, which lead to organization and collagen deposition. They are studying proteins that stimulate a response to injury, upregulating various factors.

In discussion, the workshop participants cited many areas in need of research. We need better animal models for diabetic retinopathy. The role of the protein TNFa in angiogenesis should be studied. We have just begun to study the relationship between angiogenesis and preeclampsia—and pregnancy in general. Researchers also should consider a focus on preventive processes rather than treatment of end stages. We need more research on pericytes.

Chronic inflammation and angiogenesis are linked processes. Inflammation is a heterogeneous, time-dependent process triggered by various factors (receptors, immune system). Acute and chronic inflammation are distinct—for example, acute inflammation often involves neutrophils and monocytes, whereas chronic inflammation often involves macrophages and T-cells. At times, acute inflammation can be superimposed on chronic inflammation. Chronic inflammation involves neotissues (rheumatoid synovial pannus, atheroma) that feature neovascularization. One hypothesis is that inflammatory neotissues depend on angiogenesis, so that limiting the latter may limit the former. Angiogenesis and inflammation experience an overlap of signaling pathways and mediators. Therefore, therapeutics likely will overlap. We need to study (1) angiogenesis in chronic disease settings, (2) the effects of anti-inflammatories on angiogenesis, and (3) the roles of vascular progenitor cells.

CXC chemokines can both promote and inhibit angiogenesis. Human tumors usually are a fibroproliferative response. Interstitial pneumonia is an idiopathic pulmonary fibrosis featuring abnormal repair and vascular remodeling and can lead to anastamoses. In other words, vascular remodeling may support fibrogenesis. Pathways that involve the CXC chemokines may be master switches for inflammation. The receptor CXCR2 mediates the angiogenic activity of CXC chemokines. These pathways might be used by researchers to regulate angiogenesis. However, the processes are complex and will require a combined approach.

In discussion, it was noted that we need more information on the effects of mesenchymal tissue on fibrosis. We also need to define the roles of fibroblast cells. The meeting participants welcomed an emphasis on targets outside the tumor. A variety of targets (stroma, granulation, etc.) should be considered as the biology of the microenvironment is altered through treatment. The role of VEGF in inflammation in current cancer treatments is not understood. We need better tools and data to characterize such roles. We need a more sophisticated understanding of all the players in the complex process of tumor growth.

The workshop participants made the following general recommendations:

  • Advance research on lymphoangiogenesis, which has been studied much less than angiogenesis, yet is important in, for example, cancer spread.
  • Stimulate and support more non-hypothesis-driven research. Most well-supported research is required to be hypothesis-driven. Yet other research, such as observational studies, can lead to new knowledge and breakthroughs. We need to find more support for such studies.

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