Angiogenesis refers to the generation of new blood vessels from preexisting blood vessels, a process which accompanies a wide variety of pathological states including cancer, wound healing, atherosclerosis and inflammatory disease. Angiogenesis is induced by cytokines and growth factors such as those of the VEGF family, FGF-2, PDGF-B, TGF- b, Ang-1, Ang-2, etc. However, inhibitors such as the thrombospondins are equally important in modulation of this response. Angiogenesis has now become a major field of investigation as many laboratories around the world are attempting to enhance the growth of new blood vessels (as in ischemic heart disease and intermittent claudication) and to prevent vessel growth or even to destroy preexisting vessels that have been induced by cancer.
Fc receptor mediated inflammatory processes involve allergic inflammation mediated by FcεRI, phagocytosis mediated by FcεRI and FcγRs, and inhibition of FcεRI- and surface Ig-mediated cell activation by the inhibitory FcεRIIb. Allergic inflammation plays a central role in asthma and other allergic diseases. FcεRI, a key component of allergic inflammation, is expressed at the surface of basophils and mast cells, the effector cells in the allergic reaction. Receptor aggregation induces multiple signaling pathways that control diverse effector responses, including allergic mediators and the induction of cytokine gene transcription (such as IL-4, IL-6, TNF and GM-CSF). These cytokines promote the recruitment of other inflammatory cells, such as neutrophils. FcεRI is also expressed at the surface of antigen presenting cells, such as macrophages and dendritic cells, and is capable of internalizing and delivering antigens to the appropriate compartment for presentation. FcεRs are expressed mainly on monocytes, macrophages and neutrophils. Their aggregation by multivalent antigen bound via specific IgGs induces cell activation and antigen phagocytosis. Mast cells and basophils, in addition to FcεRI, express the inhibitory receptor FcεRIIb. Co-aggregation of these two receptors results in inhibition of FcεRI signaling by FcεRIIb. A similar inhibition can be observed when FcεRIIb and the activator surface membrane Ig complex are co-aggregated on B cells. Therefore, inflammatory reactions can be modulated through the balance between activator and inhibitory Fc receptors.
Tumor Invasion and Metastasis
Tumor progression is a complex process that initially involves the ability of tumor cells to detach and to invade into surrounding tissue and survive in such surroundings. Cells that can invade and survive have a greater propensity to metastasize. The fact that both angiogenesis and inflammation facilitate tumor progression unifies the theme of this T32. Moreover, invasion, angiogenesis and inflammation are dependent on many of the same biological processes such as cell migration and extracellular matrix remodeling. To elucidate the mechanisms that underlie tumor progression, the key players (e.g., receptors, growth factors, signaling molecules) must be identified and an understanding of how they function in concert to mediate invasion and survival must be obtained.
Research Training in a Faculty Member's Laboratory
Seven general areas of concentration for the trainee's research have been identified by the faculty members. Postdoctoral trainees can select from any of these areas to develop their research training. Alternatively, they can develop a program which does not fit neatly into any of those areas (but which is relevant to the theme of the training grant) by mutual agreement with a faculty mentor and the Executive Committee. The seven major areas are:
Regulation of Angiogenesis in Cancer
Faculty members who offer training in this area include: Drs. Harold and Ann Dvorak, Benjamin, Kocher, Lawler, Senger and Sukhatme. Specific research focuses are: (1) growth factors involved in the recruitment of endothelial cells to tumors, (2) regulation of VPF/VEGF synthesis by tumor cells, (3) angiogenic growth factors in skin tumors, (4) regulation of angiogenesis in breast cancer, (5) molecular and morphological (including ultrastructural) analysis of tumor microvessels, (6) structural pathways by which circulating macromolecules and inflammatory cells exit tumor-associated and mediator-permeabilized normal microvessels, (7) molecular mechanisms for inhibition of tumor angiogenesis, (8) steps and mechanisms by which growth factors induce the formation of new blood vessels and (9) structure and molecular properties of tumor vessels.
Regulation of Angiogenesis in Inflammation and Non-Neoplastic Disorders
Angiogenesis and inflammation frequently occur in several non-neoplastic pathologic conditions, of which psoriasis and other skin disorders, diabetic retinopathy and rheumatoid arthritis are classic examples. Research training in this area specifically focuses on the angiogenic and inflammatory responses that occur in these pathological settings. Issues related to tissue-specific or environmental cues, endothelial cell specificity, and recruitment of inflammatory cells are particularly emphasized. Investigators who offer training in this area include: Drs. Harold Dvorak, Benjamin, Khosravi-Far, and Kirby.
Molecular Regulation of Inflammation
Research training under this subheading includes: (1) the effects of inflammatory mediators and cytokines on, and the production of inflammatory cytokines by, a variety of cell types including: endothelial cells, mast cells, basophils, neutrophils and monocytes/macrophages, (2) investigation of the molecular events that lead to vascular permeability in inflammatory responses, (3) immunoregulation of inflammation in ulcerative colitis and (4) biology of transplant rejection and immunosuppression. Drs. Ann Dvorak, Kinet, Strom and Terhorst offer mentorship in this area.
Angiogenic Growth Factors and Their Receptors
The cellular and molecular effects of VPF/VEGF, FGF, PDGF and PIGF will be the major research focus under this subheading. Drs. Harold Dvorak, Benjamin and Sukhatme have made significant contributions to this area of research and are the faculty members who offer mentorship for trainees in this area.
Inhibitors of Vessel Growth
Training in this area includes the investigation of known endothelial inhibitory factors (e.g. several thrombospondins, platelet factor 4, etc) and the search for novel molecules that suppress angiogenesis. Specific lines of investigation are: cellular and molecular effects of inhibitors on endothelial cells, signaling pathways of inhibitors, and targeting and delivery of inhibitors to specific vascular beds. Investigators currently working in this area include Drs. Benjamin, Khosravi-Far and Lawler.
Intracellular Signaling in Angiogenesis, Inflammation, Apoptosis and Metastasis
Much remains to be learned concerning the molecular signaling pathways that take place in endothelial cells during angiogenesis and/or inflammatory responses. Drs. Cantley, Kinet, Khosravi-Far, Neel, Strom, Terhorst and Toker have spent many years developing systems with which to examine intracellular signaling pathways in inflammatory cells and have made significant contributions to the field. Many of these approaches can be directly applied to vascular cells. Research fellows in this area will expand on current projects in each investigator's laboratory and will focus on the intracellular molecular events in vascular cells during angiogenesis and response to inflammation.
Tumor Cell Invasion and Metastasis
An understanding of the mechanisms that contribute to tumor invasion and metastasis is essential in deciphering the biology of tumor progression and for the development of rational and effective therapies. These mechanisms involve complex interactions between tumor and stromal cells and they are mediated, in part, by the concerted action of growth factor receptors, cell adhesion receptors and signaling molecules. The laboratories of Drs. Benjamin, Lawler and Toker offer training in this area.