Abstract A9: Galectin-3 as a biomaker in Kaposi's sarcoma

The Galectins are a family of proteins that share an affinity for Betagalactoside containing glycoconjugates. Galectin-3 is the most studied member of this family of proteins and has been implicated in a number of biological functions including cell proliferation, cell cycle regulation, angiogenesis, cell adhesion, cell differentiation, RNA processing and tumorigenesis. Galectin-3 has been implicated in tumor progression and metastasis. In prostate, ovarian and breast cancer, down regulation of galectin-3 is associated with malignancy and tumor progression.

Kaposi's sarcoma (KS) is characterized as an angioproliferative tumor of vascular endothelial cells and produces rare B cell lymphoproliferative diseases in the form of primary effusion lymphomas (PELs) and some forms of Multicentric Castleman's Disease (MDC). Lesions are usually found associated with the skin, oral cavity, esophagus and anus, and occur more frequently in men than women. African Americans currently have the highest incidence of KS in the US as well as around the world. The lesions are usually papular in nature, but can be plaque-like as well, and in a more advanced stage they develop into nodular tumors with extensive organ involvement. Before HAART in 1996, at the height of HIV/AIDS epidemic, the incidence of Kaposi's sarcoma increased 20,000 fold among gay males in the United States and is now the predominant HIV/AIDS related malignancy in Southern Africa and hence the world. Thankfully antiretroviral therapy has significantly reduced the incidence of KS in western countries however 95% of the estimated 35 million people infected with HIV have no access to these drugs and KS remains a problem worldwide. Organ transplant patients are at risk for developing KS and classical KS seen in elderly males of Mediterranean or eastern European dissent is still a problem.

Kaposi's Sarcoma-Associated Herpesvirus also known as KSHV or Human Herpesvirus type 8 (HHV8) is the etiological agent of KS. We have observed suppression of galectin-3 expression in Kaposi's sarcoma (KS). Here we demonstrate that galectin-3 protein expression is down-regulated 20-fold in KSHV infected dermal microvascular endothelial cells (DMVEC) cells. We show loss of galectin-3 staining by dual labeled immunohistochemistry in virus latency associated nuclear antigen (LANA) positive spindle cells. We also find reduced levels of galectin-3 expression in LANA positive spindle cell regions in archival KS tissue. Tissue microarrays obtained from the AIDS Cancer Specimen Resource Consortium (ACSR) representing patch/plaque and nodular forms of KS from 87 different patients were shown to be statistically significant for downregulation of galectin-3 when compared to vLANA by dual labeled immunohistochemical staining. There is also transcriptional suppression of galectin-3 message in KSHV infected DMVEC cells compared to mock infected controls. We demonstrate that KSHV vFLIP is the viral gene that likely targets galectin-3 downregulation in HeLa cells. In pleural effusion lymphoma cell lines (PEL), we observe different levels of galectin-3 expression associated with varying levels of KSHV replication. The search for novel host cell factors that may contribute to the overall pathogenesis of KS is essential for early detection of KS and development of innovative therapies for treatment.