The lymphatic system plays a key role in tissue fluid homeostasis, immune cell trafficking, and fat absorption. We previously reported a bacterial artificial chromosome (BAC)-based lymphatic reporter mouse, where EGFP is expressed under the regulation of the Prox1 promoter. This reporter line has been widely used to conveniently visualize lymphatic vessels and other Prox1-expressing tissues such as Schlemm’s canal. However, mice have a number of experimental limitations due to small body size. By comparison, laboratory rats are larger in size and more closely model the metabolic, physiological, and surgical aspects of humans. Here, we report development of a novel lymphatic reporter rat using the mouse Prox1-EGFP BAC. Despite the species mismatch, the mouse Prox1-EGFP BAC enabled a reliable expression of EGFP in Prox1-expressing cells of the transgenic rats and allowed a convenient visualization of all lymphatic vessels, including those in the central nervous system, and Schlemm’s canal. To demonstrate the utility of this new reporter rat, we studied the contractile properties and valvular functions of mesenteric lymphatics, developed a surgical model for vascularized lymph node transplantation, and confirmed Prox1 expression in venous valves. Together, Prox1-EGFP rat model will contribute to the advancement of lymphatic research as a valuable experimental resource.
Papillary thyroid cancer (PTC) is one of the most common endocrine
malignancies associated with significant morbidity and mortality. Although
multiple studies have contributed to a better understanding of the genetic
alterations underlying this frequently arising disease, the downstream molecular
effectors that impact PTC pathogenesis remain to be further defined. Here, we
report that the regulator of cell fate specification, PROX1, becomes inactivated
in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression
studies in clinical specimens revealed that aberrantly activated NOTCH signaling
promoted PROX1 downregulation and that cytoplasmic mislocalization significantly
altered PROX1 protein stability. Importantly, restoration of PROX1 activity in
thyroid carcinoma cells revealed that PROX1 not only enhanced
Wnt/β-catenin signaling, but also regulated several genes known to be
associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and
FABP4. Furthermore, PROX1 re-expression suppressed the malignant phenotypes of
thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion,
anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies
demonstrated that restoration of PROX1 severely impeded tumor formation and
suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells.
Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation
significantly promotes the malignant behavior of thyroid carcinoma, and suggest
that PROX1 reactivation may represent a potential therapeutic strategy to
attenuate disease progression
Several lymphatic reporter mouse lines have recently been developed to significantly improve imaging of lymphatic vessels. Nonetheless, the usage of direct visualization of lymphatic vessels has not been fully explored and documented. Here, we characterized a new Prox1-tdTomato transgenic lymphatic reporter mouse line, and demonstrated how this animal tool enables the researchers to efficiently assess developmental, surgical and pathological lymphangiogenesis by direct visualization of lymphatic vessels. Moreover, we have derived embryonic stem cells from this reporter line, and successfully differentiated them into lymphatic vessels in vivo. In conclusion, these experimental tools and techniques will help advance lymphatic research.
We have developed a highly reproducible model of secondary lymphedema and have demonstrated that 9-cis RA significantly prevents postsurgical lymphedema. Treatment with 9-cis RA is associated with increased lymphatic clearance and lymphangiogenesis. Because 9-cis RA (alitretinoin) is already approved for clinical use by the US Food and Drug Administration for other conditions, it has the potential to be repurposed as a preventative agent for postsurgical lymphedema in humans.
Kaposi sarcoma is the most common cancer in human immunodeficiency virus-positive individuals and is caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is believed that a small number of latently infected Kaposi sarcoma tumor cells undergo spontaneous lytic reactivation to produce viral progeny for infection of new cells. Here, we use matched donor-derived human dermal blood and lymphatic endothelial cells (BEC and LEC, respectively) to show that KSHV-infected BECs progressively lose viral genome as they proliferate. In sharp contrast, KSHV-infected LECs predominantly entered lytic replication, underwent cell lysis, and released new virus. Continuous lytic cell lysis and de novo infection allowed LEC culture to remain infected for a prolonged time. Because of the strong propensity of LECs toward lytic replication, LECs maintained virus as a population, despite the death of individual host cells from lytic lysis.The master regulator of lymphatic development, Prox1, bound the promoter of the RTA gene to upregulate its expression and physically interacted with RTA protein to coregulate lytic genes. Thus, LECs may serve as a proficient viral reservoir that provides viral progeny for continuous de novo infection of tumor origin cells, and potentially BECs and mesenchymal stem cells, which give rise to Kaposi sarcoma tumors. Our study reveals drastically different host cell behaviors between BEC and LEC and defines the underlying mechanisms of the lymphatic cell environment supporting persistent infection in Kaposi sarcoma tumors.Significance: This study defines the mechanism by which Kaposi's sarcoma could be maintained by virus constantly produced by lymphatic cells in HIV-positive individuals.
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