Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Published: August 2020
AI Article Synopsis
Article Abstract
Kaposi sarcoma is a tumor caused by Kaposi sarcoma herpesvirus (KSHV) infection and is thought to originate from lymphatic endothelial cells (LEC). While KSHV establishes latency in virtually all susceptible cell types, LECs support spontaneous expression of oncogenic lytic genes, high viral genome copies, and release of infectious virus. It remains unknown the contribution of spontaneous virus production to the expansion of KSHV-infected tumor cells and the cellular factors that render the lymphatic environment unique to KSHV life cycle. We show here that expansion of the infected cell population, observed in LECs, but not in blood endothelial cells, is dependent on the spontaneous virus production from infected LECs. The drivers of lymphatic endothelium development, SOX18 and PROX1, regulated different steps of the KSHV life cycle. SOX18 enhanced the number of intracellular viral genome copies and bound to the viral origins of replication. Genetic depletion or chemical inhibition of SOX18 caused a decrease of KSHV genome copy numbers. PROX1 interacted with ORF50, the viral initiator of lytic replication, and bound to the KSHV genome in the promoter region of ORF50, increasing its transactivation activity and KSHV spontaneous lytic gene expression and infectious virus release. In Kaposi sarcoma tumors, SOX18 and PROX1 expression correlated with latent and lytic KSHV protein expression. These results demonstrate the importance of two key transcriptional drivers of LEC fate in the regulation of the tumorigenic KSHV life cycle. Moreover, they introduce molecular targeting of SOX18 as a potential novel therapeutic avenue in Kaposi sarcoma. SIGNIFICANCE: SOX18 and PROX1, central regulators of lymphatic development, are key factors for KSHV genome maintenance and lytic cycle in lymphatic endothelial cells, supporting Kaposi sarcoma tumorigenesis and representing attractive therapeutic targets.
Kaposi sarcoma is a low-grade vascular neoplasm linked to the human herpesvirus 8, with the AIDS-associated epidemic variant being the most common and aggressive. Although Kaposi sarcoma more commonly affects the cutaneous tissues, lymph nodes, and visceral organs, it can also be present in ocular and ocular adnexal tissues. We report a case of a 58-year-old Indo-Caribbean woman living with AIDS who presented with a large upper eyelid mass that was clinically diagnosed as Kaposi sarcoma.
Primary Kaposi sarcoma (KS) is a rare cancer caused by human herpesvirus-8 that most often affects people with compromised immune systems. Since knowledge of the relationship between disease and sociodemographic factors contributes to the development of precision medicine, we investigated the prevalence of KS within the US population. Using SEER, we found that the Black population had the highest prevalence rate in 2018 compared to other racial groups.
Background: Kaposiform hemangioendothelioma is a rare vascular tumor primarily occurring in infants and children. The most common sites for kaposiform hemangioendothelioma are extremities, with very few cases of abdominal kaposiform hemangioendothelioma reported in neonates. Making a diagnosis of Kaposiform hemangioendothelioma can be challenging when the patient presents with generalized symptoms such as bilious vomiting and constipation that can be attributed to other more common causes of intestinal obstruction.
Purpose: To characterize factors associated with response to immune checkpoint inhibitors (ICIs) in advanced sarcoma.
Experimental Design: This is a retrospective study with a cohort of 216 patients with advanced sarcoma treated with ICIs between 2016-2023 at Stanford Health Care. Overall survival (OS), progression free survival (PFS), objective response rates per RECIST criteria (ORR), and reason for ICI discontinuation were analyzed across histologic subtypes, ICI regimens, tumor mutational burden (TMB), and PD-L1 expression.
