Biomedical subjects
Marlys H Witte
Publications and source records attributed to Marlys H Witte.
Structure function relationships in the lymphatic system and implications for cancer biology.
The lymphatic system, composed of lymphatic vessels, lymph, lymph nodes, and lymphocytes, is a distinctive vasculature (discontinuous basement membrane, open endothelial junctions, anchoring filaments, valves, and intrinsic contractility), different yet similar to the blood vasculature; an integral component of the plasma-tissue fluid-lymph circulation (the "blood-lymph loop"); and the center of the immunoregulatory network. Lymphatics are involved in diverse developmental, growth, repair, and pathologic processes both analogous to and distinct from those affecting the blood vasculature. Interference with the blood-lymph loop produces swelling [an imbalance between lymph formation (regulated by Starling's law of transcapillary fluid exchange) and lymph absorption], scarring, nutritional and immunodysregulatory disorders, as well as disturbances in lymph(hem)angiogenesis (lymphedema-angiodysplasia syndromes). The lymphatic system is also the stage on which key events during cancer development and progression are played out, and historically, also forms the basis for current evaluation, prognostication, and/or both operative and non-operative treatment of most cancers. Recent advances in molecular lymphology (e.g., discovery of lymphatic growth factors, endothelial receptors, transcription factors, genes, and highly specific immunohistochemical markers) and growing interest in lymphangiogenesis, combined with fresh insights and refined tools in clinical lymphology, including non-invasive lymphatic imaging, are opening up a window for translation to the clinical arena. Therefore, in cancer biology, attention to the multifaceted structure-function relationships within this vast, relatively unexplored system is long overdue.
Future perspectives for cancer metastasis and the lymphovascular system.
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Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity.
Multiple organs cooperate to regulate appetite, metabolism, and glucose and fatty acid homeostasis. Here, we identified and characterized lymphatic vasculature dysfunction as a cause of adult-onset obesity. We found that functional inactivation of a single allele of the homeobox gene Prox1 led to adult-onset obesity due to abnormal lymph leakage from mispatterned and ruptured lymphatic vessels. Prox1 heterozygous mice are a new model for adult-onset obesity and lymphatic vascular disease.
Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome.
The molecular events involved in lymphatic development are poorly understood. Hence, the genes responsible for hereditary lymphedema are of great interest due to the potential for providing insights into the mechanisms of lymphatic development, the diagnosis, prevention and treatment of lymphedema, and lymphangiogenesis during tumor growth. Mutations in the FOXC2 transcription factor cause a major form of hereditary lymphedema, the lymphedema-distichiasis syndrome. We have conducted a study of Foxc2 expression during mouse development using immunohistochemistry, and examined its expression in lymphatics compared to its paralog Foxc1 and to Vegfr-3, Prox1 and other lymphatic and blood vascular proteins. We have found that Foxc2 is expressed in lymphatic primordia, jugular lymph sacs, lymphatic collectors and capillaries, as well as in podocytes, developing eyelids and other tissues associated with abnormalities in lymphedema-distichiasis syndrome.
FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome.
Lymphedema-distichiasis (LD) (OMIM 153400) is a rare autosomal-dominant condition characterized by pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes arising from the meibomian glands. In some patients cardiac, skeletal and other defects coexist. We previously identified inactivating, nonsense and frameshift mutations in the forkhead transcription factor FOXC2 in affected members of LD families. To further delineate the relationship of FOXC2 deficiency to the clinical (and lymphangiodysplastic) phenotype in this syndrome, we performed dynamic lymphatic imaging and immunohistochemical examination of lymphatic tissues in mice heterozygous (+/-) for a targeted disruption of Foxc2. Adult heterozygote mice characteristically exhibited a generalized lymphatic vessel and lymph node hyper plasia and rarely exhibited hindlimb swelling. Retrograde lymph flow through apparently incompetent interlymphangion valves into the mesenteric nodes, intestinal wall and liver was also observed. In addition, Foxc2 +/- mice uniformly displayed distichiasis. We conclude that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of LD patients. Furthermore, the craniofacial, cardiovascular and skeletal abnormalities sometimes associated with LD have previously been shown to be fully penetrant in homozygous Foxc2 null mice. This Foxc2 mutant mouse thus provides an ideal model for exploring molecular mechanisms and physiologic events in mesenchymal differentiation associated with lymphatic growth and development and the clinical abnormalities seen in human LD syndrome.
Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1.
VEGF and Angiopoietin-1 requisitely collaborate during blood vessel development. While Angiopoietin-1 obligately activates its Tie2 receptor, Angiopoietin-2 can activate Tie2 on some cells, while it blocks Tie2 activation on others. Our analysis of mice lacking Angiopoietin-2 reveals that Angiopoietin-2 is dispensable for embryonic vascular development but is requisite for subsequent angiogenic remodeling. Unexpectedly, mice lacking Angiopoietin-2 also exhibit major lymphatic vessel defects. Genetic rescue with Angiopoietin-1 corrects the lymphatic, but not the angiogenesis, defects, suggesting that Angiopoietin-2 acts as a Tie2 agonist in the former setting, but as an antagonist in the latter setting. Our studies define a vascular growth factor whose primary role is in postnatal angiogenic remodeling and also demonstrate that members of the VEGF and Angiopoietin families collaborate during development of the lymphatic vasculature.