Kaposi's sarcoma (KS) is the most common AIDS-associated malignancy and the most frequent cancer in parts of Africa where HIV is endemic. The infectious agent, Kaposi's sarcoma herpesvirus (KSHV;also HHV8) is found in spindle cells, their EC precursors and monocytes in KS lesions, as well as in circulating EC progenitors and PBMC. Several features of KS suggest that chemokines and their receptors (CR) play a role in the disease. KS tumors display profound angiogenesis and an extensive inflammatory infiltrate, both features indicative of chemokine/CR activity. Also, the multi-focal nature of KS suggests that KSHV-infected spindle cell precursors or leucocytes home to permissive sites to initiate or sustain tumor development. The SDF-1/CXCR4 axis is one of the main chemokine/CR interactions associated with tumor growth, angiogenesis and metastasis. The role of SDF-1/CXCR4 in KS however remains obscure;the limited studies performed to date reveal only that these molecules are present in KS tumors. We have shown that the recently characterized alternate receptor for SDF-1, RDC1 (also CXCR7), is strongly induced in KSHV-infected EC. While RDC1 expression is limited in non-malignant cells, it is well expressed by several cancers and tumor-associated EC. We recently found that RDC1 is highly expressed on KS tumor tissue and we, and others, have shown that SDF-1 signaling through RDC1 promotes migratory, angiogenic, growth and pro-survival activity in several cell types. These findings suggest that SDF-1, signaling through either of both of its receptors CXCR4 and RDC1, plays an important role in the seeding and subsequent development of KS tumors. We hypothesize that RDC1 and CXCR4 are pathologically induced or activated by KSHV in EC/spindle cells and that SDF-1 in the tumor microenvironment and/or co-expressed by EC/spindle cells activates downstream signaling pathways that lead to a pro-angiogenic, pro-growth, pro-survival phenotype and promote trafficking of cells to sites of lesion development. To understand the role of SDF-1/CXCR4 and SDF-1/RDC1 in KS tumor seeding, initiation and development, we propose three Specific Aims.
In Aim 1 we propose to characterize the expression patterns of SDF-1, CXCR4 and RDC1 (i) in vivo, in KS tumors and (ii) in vitro, in different types of KSHV-infected endothelial cells.
In Aim 2, we will determine the nature and function of (a) SDF-1/CXCR4 and (b) SDF-1/RDC1 signaling in KSHV-infected EC.
In Aim 3, we will use samples from a cohort of KSHV seropositive patients with and without KS and HIV to enumerate CEC numbers and determine the expression and function of SDF-1, CXCR4 and RDC1 on these cells. Functional studies will also be conducted on normal and cohort CEC following their expansion in vitro as blood outgrowth EC. CXCR4 antagonists are currently in pre-clinical and clinical development for the treatment of leukemia, lung and breast cancer. Specific RDC1 antagonists have recently been developed and have shown anti-tumor activity in animal models. Thus, defining the role of SDF-1/CXCR4 and SDF-1RDC1 axes in KS may provide an avenue for therapeutic intervention.
Chemokines, secreted proteins that regulate cell function by binding to specific chemokine receptors (CR) on responsive cells, play an essential role in the development, growth and metastasis of human tumors by stimulating new blood vessel growth (tumor angiogenesis) and directing the migration of malignant or pre-malignant cells. KS tumor cells (spindle cells) express both of the CRs (CXCR4 and RDC1/CXCR7) for one of the key chemokines (SDF-1/CXCL12) involved in tumor metastasis and angiogenesis, and our preliminary data shows that KSHV induces the expression and activity of these chemokine/CR pairs. In this application we will investigate the mechanisms and functional outcomes of KSHV-induction of SDF-1, CXCR4 and RDC1, information that will both improve our understanding of KS pathogenesis and indicate if drugs that block chemokine/CR interactions are worth exploring for KS therapy.
|Totonchy, Jennifer E; Clepper, Lisa; Phillips, Kevin G et al. (2014) CXCR7 expression disrupts endothelial cell homeostasis and causes ligand-dependent invasion. Cell Adh Migr 8:165-76|
|Totonchy, Jennifer E; Osborn, Jessica M; Botto, Sara et al. (2013) Aberrant proliferation in CXCR7+ endothelial cells via degradation of the retinoblastoma protein. PLoS One 8:e69828|
|Sugaya, Makoto; Reed, Stacy; Rose, Patrick P et al. (2011) Kaposi's sarcoma and human dermal microvascular endothelial cells infected with Kaposi's sarcoma-associated herpesvirus express CCL21. J Dermatol Sci 61:139-42|
|Douglas, Janet L; Whitford, Jill G; Moses, Ashlee V (2009) Characterization of c-Kit expression and activation in KSHV-infected endothelial cells. Virology 390:174-85|
|Mansouri, Mandana; Rose, Patrick P; Moses, Ashlee V et al. (2008) Remodeling of endothelial adherens junctions by Kaposi's sarcoma-associated herpesvirus. J Virol 82:9615-28|
|Rose, P P; Carroll, J M; Carroll, P A et al. (2007) The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma. Oncogene 26:1995-2005|
|Rose, Patrick P; Bogyo, Matthew; Moses, Ashlee V et al. (2007) Insulin-like growth factor II receptor-mediated intracellular retention of cathepsin B is essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. J Virol 81:8050-62|
|Mansouri, Mandana; Douglas, Janet; Rose, Patrick P et al. (2006) Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells. Blood 108:1932-40|
|Raggo, Camilo; Ruhl, Rebecca; McAllister, Shane et al. (2005) Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. Cancer Res 65:5084-95|