The Role of CXCR2/CXCR2 Ligand Biological Axis in Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) accounts for 3% of new cancer incidence and mortality in the United States. Studies in RCC have predominantly focused on VEGF in promoting tumor-associated angiogenesis. However, other angiogenic factors may contribute to the overall angiogenic milieu of RCC. We hypothesized that the CXCR2/CXCR2 ligand biological axis represents a mechanism by which RCC cells promote angiogenesis and facilitate tumor growth and metastasis. Therefore, we first examined tumor biopsies and plasma of patients with metastatic RCC for levels of CXCR2 ligands, and RCC tumor biopsies for the expression of CXCR2. The proangiogenic CXCR2 ligands CXCL1, CXCL3, CXCL5, and CXCL8, as well as VEGF were elevated in the plasma of these patients and found to be expressed within the tumors. CXCR2 was found to be expressed on endothelial cells within the tumors. To assess the role of ELR+ CXC chemokines in RCC, we next used a model of syngeneic RCC (i.e., RENCA) in BALB/c mice. CXCR2 ligand and VEGF expression temporally increased in direct correlation with RENCA growth in CXCR2+/+ mice. However, there was a marked reduction of RENCA tumor growth in CXCR2−/− mice, which correlated with decreased angiogenesis and increased tumor necrosis. Furthermore, in the absence of CXCR2, orthotopic RENCA tumors demonstrated a reduced potential to metastasize to the lungs of CXCR2−/− mice. These data support the notion that CXCR2/CXCR2 ligand biology is an important component of RCC tumor-associated angiogenesis and tumorigenesis.

Chemokines in tumor angiogenesis and metastasis

“…Of these two high affinity receptors for CXCL8, the importance of CXCR2 in mediating chemokineinduced angiogenesis was demonstrated to be fundamental to CXCL8-induced neovascularization [73,94]. The role of CXCR2 in promoting tumor-associated angiogenesis has been confirmed in other tumor systems [95,96].…”

“…In a severe combined immunedeficient (SCID) mouse model system, depletion of CXCL5 resulted in the attenuation of both tumor growth, angiogenesis and spontaneous metastasis [98]. In renal cell cancer, elevated levels of CXCL1, CXCL3, CXCL5 and CXCL8 were found to be expressed in the tumor tissue and detected in the plasma, and CXCR2 was found to be expressed on endothelial cells within the tumor biopsies [96]. Thus, multiple studies mentioned above demonstrate the important role of ELR + CXC chemokines in tumor angiogenesis.…”

Chemokines as therapeutic targets in renal cell carcinoma

“…These interferon-inducible CXC chemokines act through CXCR3 to promote cell-mediated immunity and inhibit angiogenesis. CXCR2 and CXCR3 and their ligands have been shown to be expressed in RCC tumors [16,29,30]. Furthermore, CXCR3 expression has been associated with a favorable prognosis in RCC [31,32].…”

“…Attempts to block CXCR2 and inhibit tumor-cell angiogenesis have been successful in multiple tumor models [16][17][18]. This has been accomplished by utilizing CXCR2 small-molecule antagonists, substance P analogs, or CXCR2-knockout models.…”

Phage display and hybridoma generation of antibodies to human CXCR2 yields antibodies with distinct mechanisms and epitopes

“…[8][9][10][11][12] It is also associated with the development and progression of multiple tumor types, including melanoma, glioblastoma, non-small cell lung carcinoma, prostrate, pancreatic, hepatocellular and renal carcinomas. [13][14][15][16][17][18][19][20][21][22][23][24] Thus, targeting the CXCR2 receptor with a therapeutic antibody would have potential application in multiple diseases. A number of technical challenges exist when raising antibodies to GPCR targets.…”